PHARMACEUTICAL
I
DUSTRY
Hazardous Waste Generation,
Treatment, and Disposal


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This report has been reviewed by the U.S. Environmental Protection Agency
and approved for publication.  Approval does not signify that the contents
necessarily reflect the views and policies of the U.S. Environmental
Protection Agency, nor does mention of commercial products constitute
endorsement by the U.S. Government.

An environmental protection publication (SW-508) in the solid waste
management series,

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              PHARMACEUTICAL INDUSTRY

Hazardous Waste Generation, Treatment, and Disposal
This final report (SW-508) describes work performed
   for the Federal solid waste management program
           under contract no. 68-01-^2684
 and is reproduced as received from the contractor
       U.S. ENVIRONMENTAL PROTECTION AGENCY

                        1976

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                         TABLE OF CONTENTS

                                                                 Page

List of Tables                                                        vii

List of Figures                                                       xi

1.0    EXECUTIVE SUMMARY                                          1

      1.1    INTRODUCTION                                          1
      1.2    PURPOSE OF THE STUDY                                   1
      1.3    STUDY APPROACH                                        2
      1.4    CHARACTERIZATION OF THE PHARMACEUTICAL INDUSTRY     2
      1.5    WASTE CHARACTERIZATION                               3
      1.6    TREATMENT AND DISPOSAL TECHNOLOGY                   5
      1.7    TREATMENT AND DISPOSAL COSTS                          5

2.0    CHARACTERIZATION OF THE U.S. PHARMACEUTICAL INDUSTRY      11

      2.1    CHARACTERIZATION OF THE INDUSTRY BY FUNCTION        11
      2.2    BREAKDOWN OF THE PHARMACEUTICAL INDUSTRY BY
            SIC CODES                                              12
      2.3    DOMESTIC SALES OF THE U.S. PHARMACEUTICAL INDUSTRY    13
      2.4    HISTORICAL GROWTH OF THE U.S. PHARMACEUTICAL
            INDUSTRY                                              16
      2.5    ROLE OF RESEARCH AND DEVELOPMENT IN GROWTH OF
            THE U.S. PHARMACEUTICAL INDUSTRY                      19
      2.6    PHARMACEUTICAL CONSUMPTION-RECENT TRENDS         22
      2.7    PHARMACEUTICAL INDUSTRY OUTLOOK FOR 1975-1980        23
      2.8    NUMBER OF PHARMACEUTICAL PLANTS AND EMPLOYMENT
            IN THE INDUSTRY                                        25

3.0   WASTE CHARACTERIZATION IN THE PHARMACEUTICAL INDUSTRY    31

     3.1    SELECTION AND APPLICATION OF HAZARDOUS WASTE
            CRITERIA                                              31

            3.1.1    Background  Information for the Selection of
                   Hazardous Wastes                                  31
            3.1.2    Selection of Criteria for Classification of Potentially
                   Hazardous Substances from the Pharmaceutical Industry      32
            3.1.3    Application of the Classification Scheme to Categorize
                   Wastes from  the Pharmaceutical Industry as Priority
                   I or Priority  II Potentially Hazardous Wastes               36

                                 iii

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                       TABLE OF CONTENTS (Continued)

                                                                        Page

3.0   WASTE CHARACTERIZATION IN THE PHARMACEUTICAL INDUSTRY
      (Continued)

      3.2    WASTE GENERATION DATA DEVELOPMENT                    38

             3.2.1     Approach to the Problem of Obtaining Valid Industry
                     Hazardous Waste Data                                  38

                     3.2.1.1  Wastes from Research and Development
                             Installations                                   42

                     3.2.1.2  Wastes from the Production of Active
                             Ingredients                                   43

                             3.2.1.2.1  Synthetic Organic Medicinal Chemicals   44
                             3.2.1.2.2  Inorganic Medicinal Chemicals          48
                             3.2.1.2.3  Fermentation Products (Antibiotics)     49
                             3.2.1.2.4  Botanicals                           53
                             3.2.1.2.5  Medicinals from Animal Glands         58
                             3.2.1.2.6  Biologicals                          60

                     3.2.1.3  Pharmaceutical Preparations                     63

                     3.2.1.4  U.S. Pharmaceutical Industry Process Wastes and
                             Projections to 1977 and 1983                    66

                             3.2.1.4.1  Annual Waste of Pharmaceutical
                                      Industry                            66
                             3.2.1.4.2  Typical Types of Pharmaceutical
                                      Hazardous Wastes and Their
                                      Properties                           74
                             3.2.1.4.3  Projections of Pharmaceutical Proc.ess
                                      Wastes to 1977 and 1983              74

                     DATA SOURCES FOR SECTION 3.1                     80
                     DATA SOURCES FOR SECTION 3.2                    85

4.0   TREATMENT AND DISPOSAL TECHNOLOGIES                         87

      4.1    BACKGROUND                                              87
      4.2    DESCRIPTION OF PRESENT TREATMENT AND DISPOSAL
             TECHNOLOGIES                                             87
                                      IV

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                      TABLE OF CONTENTS (Continued)

                                                                       Page

4.0    TREATMENT AND DISPOSAL TECHNOLOGIES (Continued)

            4.2.1     Present Treatment/Disposal Technologies for General
                     Process Wastes (Hazardous and Non-hazardous)            87
            4.2.2     Present Treatment/Disposal Technologies for Waste
                     Solvents                                            96
            4.2.3     Present Treatment/Disposal Technologies for Organic
                     Chemical Residues                                   101
            4.2.4     Present Treatment/Disposal Technologies for Potentially
                     Hazardous High Inert Content Wastes (Such as Filter Cakes)  103
            4.2.5     Present Treatment/Disposal Technologies for Heavy
                     Metal Wastes                                        104
            4.2.6     Present Treatment/Disposal Technologies for Returned
                     Goods and Reject Material from Formulation              104
            4.2.7     General Description of Treatment and Disposal Tech-
                     nologies                                            106

      4.3   ANALYSIS OF ON-SITE/OFF-SITE DISPOSAL METHODS          114
      4.4   SAFEGUARDS USED IN DISPOSAL                            115
      4.5   TREATMENT AND DISPOSAL TECHNOLOGY LEVELS AS
            APPLIED TO LAND-DESTINED HAZARDOUS WASTE STREAMS
            FROM THE PHARMACEUTICAL INDUSTRY                    115

            4.5.1     Treatment and Disposal Levels for Halogenated and
                     Non-Halogenated Waste Solvents                        118
            4.5.2     Treatment and Disposal Levels for Organic Chemical
                     Residues                                            120
            4.5.3     Treatment and Disposal Levels for Potentially Hazardous
                     High Inert Content Wastes, Such as Filter Cakes            122
            4.5.4     Treatment and Disposal Levels for Heavy Metal Wastes      126
            4.5.5     Treatment and Disposal Levels for Returned Goods and
                     Reject Materials from Formulation                       127

                     GENERAL BIBLIOGRAPHY - SECTION 4.0             130

5.0    COST ANALYSIS                                                  133

      5.1    BACKGROUND                                             133
      5.2   SUMMARY OF COSTS FOR CONTROLLED TREATMENT
            AND DISPOSAL OF LAND-DESTINED HAZARDOUS WASTES      133
      5.3   RATIONALE AND REFERENCES USED IN COST ESTIMATING     133
      5.4   COSTS FOR TREATMENT AND DISPOSAL OF HAZARDOUS
            WASTES                                                   138

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                     TABLE OF CONTENTS (Continued)

                                                                  Page

5.0    COST ANALYSIS (Continued)

            5.4.1     Research and Development                          138
            5.4.2     Production of Active Ingredients (SIC 2831 and 2833)      138
            5.4.3     Formulation and Packaging (SIC 2834)                 142

APPENDIX A - DESCRIPTION OF HAZARD GRADES                       155

APPENDIX B - PROPERTIES OF HAZARDOUS CONSTITUENTS -
             EXPLANATION OF SPECIAL TERMS                        161

GLOSSARY OF TERMS                                               175
                                  VI

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                                 LIST OF TABLES

Table No.                                                                     Page

  1.5           Estimates of Pharmaceutical Industry Generated Wastes for
                1973, 1977 and 1983                                             6
  1.6           Technology Levels for Disposal and Treatment of Pharmaceutical
                Industry Process Wastes                                           8
  1.7A         Perspectives on the Pharmaceutical Industry: Hazardous Waste
                Treatment and Disposal Costs                                      9
  1.7B         Perspectives on the Pharmaceutical Industry: Cost Impact of
                Hazardous Waste Treatment and Disposal                           10
  2.3A         Shipments of Ethical and Proprietary Products                      13
  2.3B         Estimated Domestic Sales of Ethical Pharmaceutical Products         15
  2.3C         Facilities by Sales and Geographic Location                        17
  2.5           Ranking of Research Categories by Number of Compounds
                Under Study                                                    22
  2.6           Number of Prescriptions Filled at Retail Pharmacies                 24
  2.8A         Estimated Number of Pharmaceutical Plants (SIC 2831, 2833,
                and 2834) Total Number of Plants and Those with More
                Than 100  Employees                                            26
  2.8B         Number of Employees                                           27
  3.1.2A        Summary of Hazard Evaluation Criteria                            34
  3.1.2B        Biological Functions and Toxicities of Selected Elements             35
  3.1.3A        Priority I Hazardous Wastes                                      37
  3.1.3B        Characterization of Typical Waste Solvents or Still Bottoms
                Containing the Listed Chemicals                                   37
  3.1.3C        Typical Toxicities of Pharmaceutical Active Ingredients
                as Measured by Oral LDggOn Mice and Rats                        39
  3.2.1.2.1      Estimated Average of Chemical Wastes Generated in Organic
                Medicinal Chemical Production                                   46
  3.2.1.2.3      Typical Antibiotic Production Plant  (Procaine Penicillin G)           50
  3.2.1.2.4.1    Typical Plant for Producing Botanical Medicinals (Plant
                Alkaloids)                                                       55
  3.2.1.2.4.2    Typical Plant for Producing Botanical Medicinals
                (Stigmasterol for Hormone Synthesis)                              56
  3.2.1.2.5      Typical Plant for Producing Medicinals from Animal Glands
                (Insulin)                                                        60
  3.2.1.4.1A    Pharmaceutical Industry Waste Generation Estimate for 1973         68
  3.2.1.4.1B    Distribution of Pharmaceutical Industry Waste Generation (1973)     70
  3.2.1.4.1C    Estimated Distribution of Waste Generated by the Pharmaceutical
                Industry in 1973                                                73
  3.2.1.4.2      Summary of Typical Types of Pharmaceutical Hazardous Waste
                Materials                                                       75
                                        VII

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                           LIST OF TABLES (Continued)

Table No.                                                                     Page

  3.2.1.4.3A    Estimates of Pharmaceutical Industry Generated Wastes for 1973,
                1977 and 1983                                                  76
  3.2.1.4.3B    Projected Distribution by State of Wastes Generated by the
                Pharmaceutical Industry in 1977                                  78
  3.2.1.4.3C    Projected Distribution by State of Wastes Generated by the
                Pharmaceutical Industry in 1983                                  79
  4.2.2         Waste Solvent Disposal Methods                                   98
  4.2.3         Organic Chemical Residue Disposal Methods                       101
  4.2.4         High Inert Content Wastes Disposal Methods                       103
  4.2.5         Heavy Metal Waste Disposal Methods                             104
  4.2.6         Disposal Methods for Returned Goods and Reject Material          105
  4.2.7A       Functions and Waste Types of Currently Used Hazardous
                Waste Treatment and Disposal Processes                          107
  4.2.7B        Waste Treatment Processes Used to Separate a Waste Destined
                for Land Disposal                                               108
  4.3           Analysis of On-Site/Off-Site Disposal Methods                     116
  4.4           Use of Safeguards  in Disposal Operations                          117
  4.5.1A       Treatment and Disposal Technology Levels for Non-Halogenated
                Waste Solvents                                                 119
  4.5.1B        Treatment and Disposal Technology Levels for Halogentated
                Waste Solvents                                                 121
  4.5.2         Treatment and Disposal Technology Levels for Organic
                Chemical Residues                                             123
  4.5.3A       Treatment and Disposal Technology Levels for Potentially
                Hazardous High Inert Content Wastes                             124
  4.5.3B       Treatment and Disposal Technology Levels for Potentially
                Hazardous High Inert Content Wastes                             125
  4.5.4         Treatment and Disposal Technology Levels for Heavy Metal
                Wastes                                                        128
  4.5.5         Treatment and Disposal Technology Levels for Potentially
                Hazardous Returned Goods and Reject Material from Formulation   129
  5.2A         Perspective on the Pharmaceutical Industry:  Treatment and
                Disposal Costs Per Unit of Hazardous Waste                        134
  5.2B         Perspective on the Pharmaceutical Industry: Hazardous
                Waste Treatment and Disposal Costs                              135
  5.2C         Perspectives on the Pharmaceutical Industry:  Cost Impact
                of Hazardous Waste Treatment and Disposal                       136
  5.3A         Cost of Transporting Wastes                                     137
  5.3B         Contract Disposal  Charges for Hazardous Wastes                   137
  5.3C         Capital Investment for Industrial Solid Waste Incineration           140
                                        Vlll

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                           LIST OF TABLES (Continued)

Table No.                                                                     Page

  5.4.2.1A      Treatment and Disposal Costs:  Active Ingredient Production;
                Organic Medicinal Chemicals Waste Stream — Non-Halogenated
                Waste Solvent                                                  143
  5.4.2.1B      Treatment and Disposal Costs:  Active Ingredient Production;
                Organic Medicinal Chemicals Waste Stream — Halogenated Waste
                Solvent                                                       144
  5.4.2.1C      Treatment and Disposal Costs: Active Ingredient Production;
                Organic Medicinal Chemicals Waste Stream: Potentially Hazardous
                High Inert Content Wastes                                      145
  5.4.2.1D      Treatment and Disposal Costs:  Active Ingredient Production;
                Organic Medicinal Chemicals Waste Stream — Organic Chemical
                Residues                                                      146
  5.4.2.3A      Active Ingredient Production; Fermentation Products; Penicillin
                Waste Stream - Waste Solvent Concentrate (50% Solids)            147
  5.4.2.3B      Treatment and Disposal Costs:  Active Ingredient Production;
                Fermentation Products; Penicillin Waste Stream — Waste
                Solvent Concentrate (50% Solids)                                148
  5.4.2.4A      Treatment and Disposal Costs: Active Ingredient Production;
                Botanicals; Alkaloids Waste Stream — Aqueous Solvent with
                Solids (30% Solvent, 20% Water, 50% Solids)                      149
  5.4.2.4B      Treatment and Disposal Costs — Active Ingredient Production;
                Botanicals; Alkaloids Waste Tream — Halogenated Waste
                Solvent                                                       150
  5.4.2.4C      Treatment and Disposal Costs:  Active Ingredient Production;
                Botanicals; Alkaloids Waste Stream — Non-Halogenated Waste
                Solvent                                                       151
  5.4.2.5       Treatment and Disposal Costs: Active Ingredient Production;
                Drugs from Animal Sources; Insulin Waste Stream — Aqueous
                Alcohol with Organic Solids (25% Alcohol, 25% Solids, 50%
                Water)                                                        152
  5.4.2.6       Treatment and Disposal Costs: Active Ingredient Production;
                Biological Products; Plasma Protein  Fractions
                Waste Stream — Aqueous Solvent                                153
  5.4.3         Treatment and Disposal Costs: Formulation and Packaging
                (Finished Pharmaceutical Preparations) Waste Stream  —
                Returned Goods and Reject Material                             154
                                         IX

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                                 LIST OF FIGURES

Figure No.                                                                      Page

  2.3A          Estimated Domestic Sales at Manufacturers' Level of Ethical
                Products                                                        14
  2.3B          Industry Concentration of Domestic Ethical Sales                   18
  2.5           Research and Development Expenditures for Ethical Products        20
  2.8A          Number of Plants                                                28
  2.8B          Number of Plants (> 100 Employees)                              29
  2.8C          Pharmaceutical Employment Trends by SIC Codes                  30
  3.2.1.2.1      Typical Synthetic Organic Medicinal Chemical Process               45
  3.2.1.2.3      Representative Process for Antibiotic Production (Procaine
                Penicillin G)                                                     51
  3.2.1.2.4.1    Representative Process for Botanical Medicinals (Plant
                Alkaloids)                                                       54
  3.2.1.2.4.2    Representative Process for Botanical Medicinals (Stigmasterol
                for Hormone Synthesis)                                          57
  3.2.1.2.5      Representative Process for Medicinals from Animal Glands
                (Insulin)                                                        59
  3.2.1.2.6      Diagrammatic Representation of Method 6 Blood  Fractionation       62
  3.2.1.3A      Pharmaceutical Tablet Production                                 64
  3.2.1.3B      Pharmaceutical Capsule Production                                65
  3.2.1.3C      Pharmaceutical Ointment Production                              67
  4.2.1.5        Solid Waste Disposal Facilities in Puerto Rico                       95
  5.3A          In-Plant Storage and Landfill Charges                             139
  5.3B          General Industrial Solid Waste Incineration — Capacity Ranges
                and Investment Costs                                           139
  5.3C          General Industrial Solid Waste Incineration Operating Costs          139
                                         XI

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1.0 EXECUTIVE SUMMARY

1.1 INTRODUCTION

    This report is the result of a study commissioned by the U.S. Environmental Protection
Agency (EPA)  to assess "Hazardous Waste Generation, Treatment  and Disposal in  the
Pharmaceutical  Industry." This  industry study is one of a series sponsored by the Office of
Solid  Waste Management Programs, Hazardous  Waste Management Division. The studies
were  conducted for information  purposes only and  not in response to a Congressional
regulatory mandate. As such, the studies serve to provide EPA with: (1) an initial data base
concerning current and  projected types and quantities of industrial wastes and applicable
disposal methods and costs; (2) a data base for technical assistance activities; and (3) a
background for guidelines  development work pursuant to  Sec. 209, Solid Waste Disposal
Act, as amended.

    The definition of "potentially hazardous waste"  in this study was developed based
upon  contractor investigations  and  professional judgment. This definition does not neces-
sarily  reflect EPA thinking since such a definition, especially in  a regulatory context, must
be broadly applicable to widely differing types of waste streams. Obviously, the presence of
a toxic substance should not  be the major determinant of hazardousness if there were
mechanisms to represent or illustrate actual effects of wastes in specified  environments.
Thus, the reader is cautioned that  the data presented in this report constitute only  the
contractor's assessment of the hazardous waste management problem in this industry. EPA
reserves its judgments pending a specific legislative mandate.

1.2 PURPOSE  OF THE STUDY

    The study had four basic objectives:

     1.   to determine the nature and quantities of hazardous wastes originating from
         the pharmaceutical industry (1973) and to project these wastes to 1977 and
          1983;

    2.   to determine the current treatment and disposal practices within the indus-
         try;

    3.   to examine improved control technologies which could be applied to reduce
         hazards presented by the wastes; and

    4.   to calculate the cost of implementing three levels of control technology in a
         typical hypothetical or existing plant. The three levels of technology are:

         Level I - Technology currently applied by  typical facilities;

         Level II — Best technology currently employed; and

         Level III — Technology necessary to provide adequate health and environ-
         mental protection.

                                          1

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1.3 STUDY APPROACH

     Our study consisted of four interrelated tasks:

     1.   Industry characterization (Section 2.0);

     2.   Waste characterization (Section 3.0);

     3.   Treatment and Disposal Technology (Section 4.0); and

     4.   Cost Analysis (Section 5.0).

Since no Federal law (except the Federal Insecticide, Fungicide and Rodenticide Act, Public
Law 92-516)  has yet been passed requiring industry to obtain and report data on non-radio-
active hazardous wastes destined for land disposal, we had to obtain the voluntary coopera-
tion of  companies that  represented a significant portion of the pharmaceutical industry.
Fortunately,  the Pharmaceutical Manufacturers Association (PMA) supported the planned
attempt to obtain useful information on which EPA's Office of Solid Waste Management
Programs could  base part of its future planning' and programs. The PMA Environmental
Control Committee  lent us its support and assisted  in obtaining the cooperation of several
major pharmaceutical producers.

     Because  the industry had never had to report  detailed composition of waste streams,
we realized that mailing of questionnaires would not produce usable information. We there-
fore chose to conduct in-depth interviews and plant inspections at the plants of the cooper-
ating companies. We visited  the principal production facilities of companies which repre-
sented an estimated 27 percent of the total U.S. sales of ethical Pharmaceuticals and an even
higher percentage of active ingredient production of the industry. All 14 facilities we visited
had multiple  plants and multiple operations, so that in all we surveyed more than 35 com-
ponent plants. Good representative information was obtained on research and development
(R&D),  fermentation, biological products, organic  synthesis, extraction  of animal  glands,
and formulation and packaging operations in the United States, including Puerto Rico. We
checked the information we  received in the interviews and by letter and  confirmed it with
the companies. We then extrapolated the collected data to obtain information applicable to
the entire industry.

     During the course of the study we also visited eight landfills and four contractors that
were treating wastes, principally by incineration. We also interviewed 11 contractors by tele-
phone to confirm information obtained fr6m plant visits.

1.4  CHARACTERIZATION OF THE PHARMACEUTICAL INDUSTRY

     For this report we found it advantageous to characterize the industry by function as well
as by SIC codes. The main function of the pharmaceutical industry is to provide delivery of
active  therapeutic  substances in  stable,  useful dosage forms,  such as tablets, injectables,
capsules, and the like. However, the overall pharmaceutical industry can be considered to have
four functional sections:
                                          2

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     1.   Research and Development (R&D) — The function of R&D is to discover new
         drugs and to develop and improve formulations of these and older drugs.

     2.   Production of Active Ingredients — This stage involves the production of the
         basic active drugs in bulk form.

     3.   Formulation and Packaging — Bulk drugs are formulated into dosage forms,
         such as tablets, ointments, syrups, injectable solutions, and the like, that can be
         taken or used by patients easily and in accurate amounts.

     4.   Marketing and Distribution — To get Pharmaceuticals to doctors, hospitals,
         pharmacies, and ultimately to the  patient or consumer, Pharmaceuticals are
         promoted by  pharmaceutical companies and distributed either directly or
         through wholesalers. Pharmaceuticals promoted by advertising directly to the
         consumer are called "proprietary Pharmaceuticals" and those advertised to the
         medical, dental and veterinary professions are called 'ethical Pharmaceuticals."

     The U.S. Department of Commerce has divided the pharmaceutical industry into three
SIC codes:  2831, 2833, and 2834. SIC 2834 (Pharmaceutical Preparations) is essentially the
same as the Formulation and Packaging  function described above. SIC 2833 covers the major
portion of bulk active ingredient manufacture. SIC 2831 covers a group of products which
were formerly regulated by the Division of Biologies Standards in the National Institute of
Health and not by the Food and Drug Administration. Because the manufacturing and isola-
tion  procedures are similar to those in  SIC 2833 (Medicinals and Botanicals), the SIC 2831
(Biological Products) operations are combined with SIC 2833 for the purposes of this study.

     While the Department of Commerce indicated a 1972 total of 1058 plants in the United
States  manufactured pharmaceutical products,  only 416  of those plants had 20  or more
employees. These 416 plants were distributed as follows: SIC 2834 - 302 plants, SIC 2831 -
60 plants, and SIC 2833 — 54 plants. Employment in these three SIC categories in 1972*
totaled approximately 130,000. Estimated U.S. domestic sales of ethical Pharmaceuticals in
1973*  were approximately $5.5 billion and sales of proprietary Pharmaceuticals were about
$1.9 billion.

1.5 WASTE CHARACTERIZATION

     The largest tonnage of process wastes currently being landfilled comes from the produc-
tion of antibiotics by fermentation. In the fermentation industry the antibiotics are produced
* Employment figures are based on Census of Manufactures data which are published every five years (the last
 being 1972), whereas sales figures have been estimated by ADL utilizing U.S. Department of Commerce data
 for 1973 and other sources.

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as by-products of the growth of microorganisms (molds and bacteria). During operations to
recover the antibiotics, the microorganisms are filtered off, usually with the addition of an
inorganic filter aid, such as diatomaceous  earth. This discarded product is usually called
"mycelium."

     Because mycelium wastes  consist  only  of  cells  of organisms, filter aid and residual
nutrients, the product is not considered hazardous. However, due to the large quantities pro-
duced  by a typical fermentation plant and  the tendency of the mycelium to emit odors on
decomposition, the waste can be a nuisance if not properly handled. The fermentation industry
likewise  produces a high BOD  effluent stream, similar to that produced  in the brewing
industry, that must be treated in  an activated sludge system. Neither the mycelium waste nor
the biological sludge from treatment of the effluent streams contains significant quantities of
hazardous materials.

     Hazardous wastes are  produced during the recovery of antibiotics in the form of waste
solvents  and still bottoms.  These solvents are usually nonhalogenated  and are relatively non-
toxic,  but they are hazardous due to their flammability.

     The production of organic medicinal ingredients  represent the major source of hazard-
ous wastes and a significant source  of nonhazardous wastes. Of the roughly 90,700 metric
tons of organic medicinals (excluding  antibiotics) produced in the United  States in  1973,
only about  34,000 metric tons  were produced by  the pharmaceutical industry itself. The
remainder was produced by closely allied suppliers to the industry. Production of organic
medicinals resulted in wastes consisting of  filter  cakes, carbon, filter  paper, sewage process
sludge, unrecoverable halogenated and nonhalogenated solvents, and still bottoms.

     Wastes produced by the packaging and  shipping sections of the industry are mostly glass,
paper, wood, rubber, aluminum, and the like, that are discarded. We estimate only a small
fraction  of  1  percent of this  material  to be active pharmaceutical ingredient.  We further
estimate that 75,000 metric tons of this rubbish is disposed of in regular municipal landfills,
along with cafeteria wastes, office wastes, and the like.

     Goods  returned  to the pharmaceutical producer are received by the formulation  and
packaging section of the industry. We estimate that the approximately 10,000 metric tons of
returned goods consist of approximately 85% glass, paper, water, and the like. Of the remaining
15% solids, the active ingredient may range from 100% down to approximately 1%. Because of
the low concentration of active ingredient in many products and the low toxicity of the active
ingredients,  the resulting mix of materials disposed  of on land is considered nonhazardous.
However, a small number of compounds, such as mercurials, controlled drugs, and  the like, are
segregated and treated by environmentally acceptable methods.

     The only hazardous waste of major concern produced in sufficient quantity from R&D
installations is waste solvents (1500 metric tons). Because of the generally flammable nature
and the wide variety of solvents in  the mixed solvents disposed of, all of these materials are
considered hazardous. Many of the R&D personnel are scattered in small groups  throughout
the industry, but some companies may employ from 200 to over 2000 researchers at a single
location.                                   4

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     We  classified  waste  streams from  the various  industry  segments as hazardous or
nonhazardous according to criteria explained in Section 3.1.2. Estimates of waste quantities
are summarized in Table 1.5.

     We expect quantities of both nonhazardous and hazardous wastes to increase in propor-
tion to production in the future with no significant effect of air and water guidelines for 1977
and 1983. We estimate production will increase only at a 3% compounded annual rate from
1973  to  1977 due  to the present energy shortages and economic recession. We anticipate
economic recovery and the passage of national health insurance will take place in 1976. There-
fore, we expect production and concomitant wastes to increase at an annual compounded rate
of 7% from 1977 to 1983. Waste projections for 1977 and 1983 are also included in Table 1.5.

     Approximately 244,000 metric tons of land-destined process wastes (on a dry basis)
were produced by the pharmaceutical industry in 1973. The amount of hazardous wastes is
about  25 percent of the total waste, or 61,000 metric tons in  1973. The total wastes are
expected to grow to nearly 400,000 metric tons per year and hazardous wastes to 100,000
metric tons per year by 1983.
1.6 TREATMENT AND DISPOSAL TECHNOLOGY

     Approximately 85 percent of total wastes and 60 percent of hazardous  wastes are esti-
mated to be treated and disposed of by contractors. Of the total wastes, ADL estimates that 60
percent,  or 150,000 metric tons,  are finally  disposed of on land. About 9 percent, or 5,600
metric tons of the hazardous wastes, are finally  disposed of on land. These percentages reflect
the extensive use of incineration, both on-site  and by contractors off-site, by the pharma-
ceutical industry. Where possible, materials are recovered for reuse. Also secure chemical land-
fills and encapsulation are being used now — and will most probably be used in the future — for
the disposal of heavy metal wastes and the like, which are too dilute or contaminated for re-
covery, and general process wastes of a nonhazardous nature.

     In the disposal of a major portion of hazardous wastes generated in the pharmaceutical
industry, Level I technology will be adequate for Level II and Level III also. This is true for
those wastes such as solvents and organic chemical residues that, are presently disposed of
by incineration.  Some other pharmaceutical wastes that  are presently  landfilled, such  as
returned  goods and rejected product and high inert content wastes, such as filter cakes, may
require incineration  to meet Level II and III criteria.

     The heavy metal wastes or high inert content wastes, such as filter cakes, that contain
heavy metals and are presently landfilled, may require further treatment to meet Level II and
Level III criteria.

     Table 1.6 presents a summary of the treatment and disposal technology levels for pharma-
ceutical industry process wastes determined to be hazardous.

1.7 TREATMENT AND DISPOSAL COSTS

     We  have calculated costs  for "end-of-pipe" treatment and disposal of each hazardous
pharmaceutical waste. These costs do not include charges for in-process changes made to
                                          5

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                                                                                         TABLE 1.5

                                  ESTIMATES OF PHARMACEUTICAL  INDUSTRY GENERATED WASTES FOR  1973, 1977 AND 1983*
                                                                           (All Figures in Metric Tons Per Year)
Industry Segment


R&D
   Solvent
                Total R&D
 SIC Code 2833: Production of Active Ingredients
    Organic Medicinal Chemicals (34,000 Metric Tons/Yr)
       Biological Sludge (from wastewater treatment)
       High Inert Content (filter aid, carbon)
       Contaminated High Inert Content (i.e., filter aid and solvent)
-^     Organic Chemical Residues (tars, mud, still bottoms)
       Halogenated Solvent
       Non-Halogenated Solvent
       Heavy Metal Wastes
         Zinc Compounds
         Arsenic Compounds
         Chromium Compounds
         Copper Compounds
         Mercury Compounds

                  Total for Organic Medicinal Chemicals
                  Rounded to:

    Inorganic Medicinal
       Heavy Metals (i.e., selenium waste)

    Antibiotics (by Fermentation, 10,000 Metric Tons/Yr)
       Mycelium (plus filter aid and sawdust)
       Biological Sludge
       Waste Solvent Concentrate

                  Total for Antibiotics
                  Rounded to:

    Botanicals (Plant Alkaloids, 2,000 Metric Tons/Yr Plant Material)
       Wet Plant Material
       Aqueous Solvent Concentrate
       Halogenated Solvent
       Non-Halogenated Solvent

                 Total for Plant Alkaloids

   Botanicals (Plant Steroids. ISO Metric Tons/Yr Stigmasterol)
      Fused Plant Steroid Ingots
1973
Non-Hazardous
Dry Basis Wet Basist

-
47,600 476,000
3,400 6,800
-
51,000 482,800
51,000 480,000
-
75,000 300,000
35,000 350,000
1 1 0,000 650,000
1 1 0,000 650,000
2,000 4,000
Hazardous
Dry Basis
1,500
1,500
1,700
13,600
3,400
23,800
2,200
450
20
4
1
45,175
45,000
200
12,000
12,000
12,000
720
60
120
Wet Basis1
1,500
1,500
3,400
1 3,600
3,400
23,800
2,200
450
20
4
1
46,875
47,000
200
12,000
12,000
12,000
850
60
120
                                                          2,000
                                                                      4,000
                                                                       750
                                                                                     900
                                                                                               1,030
                                                                                                                              1977
Non-Hazardous
Dry Basis

-
53,600
3,800
-
57,400
57,000
-
84,400
39,400
123,800
124,000
2,250
Wet Basis*

-
536,000
7,600
_
543,600
540,000
-
338,000
394,000
732,000
730,000
4,500
Hazardous
Dry Basis
1,900
1,900
1,900
15,300
3,800
26,800
2,500
500
22
4
1
50,827
51,000
225
13,500
13,500
14,000
810
70
140
Wet Basis*
1,900
1,900
3,800
15,300
3,800
26,800
2,500
500
22
4
1
52,727
53,000
225
13,500
13,500
14,000
960
70
140
                                                                                                             2,250
                                                                                                              840
                                                                                                                        4,500
                                                                                                                         840
                                                                                                                                      1,020
                                                                                                                                                 1,170
                                                                                                                                                                                 1983
Non-Hazardous
Dry Basis

-
80,400
5,700
-
86,100 -
86,000
-
127,000
60,000
187,000
190,000
3,400
Wet Basis*

-
804,000
1 1 ,400
—
815,400
815,000
-
508,000
600,000
1,108,000
1,100,000
6,800
Hazardous
Dry Basis
2,700
2,700
2,900
23,000
5,700
40,000
3,700
750
35
6
1
76,092
76,000
350
20,000
20.000
20,000
1,200
100
200
Wet Basis*
2,700
2,700
5,800
23,000
5,700
40,000
3,700
750
35
6
1
78,992
79,000
350
20,000
20,000
20,000
1,400
100
200
                                                                                                                                                               3,400
                                                                                                                                                               1,000
                                                                                                                                                                          6,800
                                                                                                                                                                          1,000
                                                                                                                                                                                        1,400
                                                                                                                                                                                                   1,700

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                                                                                       TABLE  1.5 (Continued)
                                                                                                                                                                                                  1983
Industry Segment


   MedicinaIs from Animal Glands (8,000 Metric Tons Glands/Yr)
      Extracted Animal Tissue
      Fats or Oils
      Filter Cake (Containing protein)
      Aqueous Solvent Concentrate

                  Total Medicinals from Animal Glands

       Total for Production of Active Ingredients (SIC Code 2833)

SIC Code 2831: Biological Products
      Aqueous Ethanol Waste from Blood Fractionation
      Antiviral Vaccine
      Other Biologicals

                  Total for Biological Products

SIC Code 2834: Pharmaceutical Preparations
      Returned Goods
      Contaminated or Decomposed Active Ingredient
                  Totals for All Industry Segments
                  Rounded to:
Non-Hazardous
Dry Basis
7,500
350
250
8,100
172,000
-
-
10,000
10,000
181,850
182,000
Wet Basis*
7,500
350
500
8,350
1,143,000
-
-
1 0,000
1 0,000
1,153,000
1,153,000
Hazardous
Dry Basis
800
800
59,000
250
3OO
200
750
500
500
61,650
62,000
Wet Basis*
1,600
1,600
62,000
600
300
200
1,100
500
500
65,100
65,000
Non-Hazardous
Dry Basis
8,400
400
280
9,080
193,000
-
-
11,300
11,300
204,300
204,000
Wet Basis*
8,400
400
560
9,360
1,285,000
-
-
11,300
11,300
1,836,300
1,836,000
Hazardous
Dry Basis
900
900
67,000
280
350
225
855
600
600
70,445
70,000
Wet Basis*
1.8OO
1,800
70.0OO
680
350
225
1,255
600
600
73,755
74,000
Non-Hazardous
Dry Basis
12,500
600
420
13,520
294,000
-
-
17,000
17,000
311,000
310,000
Wet Basis*
12,500
6OO
840
13,940
1 ,937,000
-
-
17,000
17,000
1,954,000
1 ,954,000
Hazardous
Dry Basis
1,350
1,350
99,000
400
500
350
1,250
900
900
103,850
104,000
Wet Basis*
2,700
2,700
103,000
1,000
500
350
1,850
900
900
108,450
108,000
* Source: Arthur D. Little, Inc., estimates.

 Wet weight estimates are given for all wastes.  The two wastes that typically have the highest moisture content are biological sludge and
 mycelium from fermentations. Where the wet waste estimates are the same as on the dry basis, the waste is usually disposed of with only
 a minor amount of moisture.  However, disposal practices vary from plant to plant, depending on the form in which the waste is produced.

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                                                                         TABLE 1.6

                 TECHNOLOGY LEVELS FOR DISPOSAL AND TREATMENT OF PHARMACEUTICAL INDUSTRY PROCESS WASTES*

                                                                                   Treatment and Disposal Technology
          Industry Segment                                        Level I                     Level II                        Level III
             R&D
               Solvent                                          Incineration     	
               Animals                                         Incineration     	
               Heavy metals                                     Recovery       	
             Active  Ingredient Production
             — Organic Medicinal Chemicals
                  Non-halogenated waste solvent                  Incineration     	
                  Halogenated waste solvent                       Incineration     	
                  High inert content wastes
                  —  containing flammables only             Landfill or incineration           Incineration
                  —  containing heavy metals or corrosives          Landfill               Secure chemical landfill*  	ป
                  Heavy metal wastes                       Secure chemical landfill**    Level  I and recovery         Recovery and engineered storage
                  Organic chemical residues                       Incineration     	*
               Inorganic Medicinal Chemicals
                  Heavy metal wastes                       Chemical landfill***         Secure chemical landfill***   	*
               Fermentation Products
oo
                  Waste solvent concentrate                       Incineration     	
            — Botanicals
                  Aqueous solvent                                Incineration     	
                  Halogenated waste solvent                       Incineration     	
                  Non-halogenated waste solvent                   Incineration     	
            — Drugs from Animal Sources
                  Aqueous alcohol                                Incineration	
            — Biologicals
                  Aqueous alcohol                                Incineration     	
                  Antiviral vaccines                               Incineration     	
                  Other biologicals (toxoids, serum)                Incineration     	
         • Pharmaceutical Preparations
               Returned goods and reject material                  Landfill                    Incineration
            *Neutralize waste or precipitate heavy metal prior to placing in landfill.
           **Convert heavy metal to most insoluble form and place in drum prior to placing in landfill.
         ***Waste is dilute; therefore, Level II technology will involve a more secure landfill rather than a recovery operation.

          Source: Arthur D. Little, Inc.

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minimize or to change the hazardous nature of the wastes. More detailed analyses are given
in Section 5.0. Table 1.7A and 1.7B summarize generalized costs of treatment and disposal
systems either currently in use or recommended for future use in pharmaceutical production
facilities.  Because typical plants were used to develop an estimate of the total industry cost
of treatment and disposal of hazardous wastes, the total industry costs should be taken only
as an indication  of the order of magnitude of such costs rather than as the outcome of a
detailed industry survey of the costs. Issues such as site specific costs, different products or
product mixes, local disposal rates, and available disposal methods were not included in this
estimate.

                                       TABLE 1.7A

                   PERSPECTIVES ON THE PHARMACEUTICAL INDUSTRY:
                 HAZARDOUS WASTE TREATMENT AND DISPOSAL COSTS*

                                                      Total Annual Costs, $000**
                                                 1973          1977           1983
     Product Category

     • Bulk Active Ingredient

          Organic Medicinal Chemicals                3,800          4,295          6,140
          Inorganic Medicinal Chemicals*               —             —             —
          Fermentation Products                     1,440          1,620          2,300
          Botanicals                                165           180            260
          Drugs from Animal Sources                  115           130            180
          Biologicals                                 50             60             85

     • Pharmaceutical Preparations                     15             40             50
       Partial Total"1"                               5585          6325           9015

      *0ne hazardous waste cost is included in organic medicinal chemicals.
     **December 1973 dollars.
      + Excludes R&D costs.

      Source: Arthur D. Little, Inc.

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                                    TABLE 1.7B

               PERSPECTIVES ON THE PHARMACEUTICAL INDUSTRY:
      COST IMPACT OF HAZARDOUS WASTE TREATMENT AND DISPOSAL*

                                                    Estimated Hazardous Waste
                                                 Control Cost as Percent of Price*
Product Category
•  Bulk Active Ingredient
Price
Level

$/kg
                                                Level I
Level II
Level III
     Organic Medicinal Chemicals        22
     Inorganic Medicinal Chemicals**/    —
     Fermentation Products            44
     Botanicals                       ***
     Drugs from Animal Sources        ***
     Biologicals                      ***
            0.2%      0.22%       as Level 11

            0.34%    as Level I     as Level I

         < 0.1       as Level I     as Level I
  * Manufacturers selling price in the case of pharmaceutical preparations; value of sales,
    that  is, the net selling value FOB plant or warehouse, or delivered value, whichever
    represents the normal practice for bulk activity ingredient.
 ** Representative data  not available because most inorganic medicinal ingredients that
    might produce a hazardous waste are purchased from the chemical industry.
*** Data not available; the selling price of many of these products is stated in terms of
    biological activity.

 Source:  Arthur D. Little, Inc.
                                        10

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2.0 CHARACTERIZATION OF THE U.S. PHARMACEUTICAL INDUSTRY

2.1 CHARACTERIZATION OF THE INDUSTRY BY FUNCTION

     The pharmaceutical industry can be described or characterized in several ways, depend-
ing on  the needs of  the  particular  study.  For  purposes  of this report, we  found it
advantageous to break down the industry along functional lines in addition to classifying it
by SIC codes.

     The main function of the pharmaceutical industry is  to provide delivery  of active
therapeutic substances in stable, useful dosage forms. Thus it may be distinguished from the
chemical industry, the function of which is to synthesize various chemicals which may be
useful in a  variety of applications. It is true that the pharmaceutical industry may integrate
vertically and become involved in the synthesis of active ingredients, but its major function
is  to prepare the tablets, injectables, ointments, capsules, and the like, to provide what is
needed, where it is needed, and when it is needed.

     The production and sale of Pharmaceuticals may be outlined in a four-step series:

     1.   Research and Development:  New drugs are discovered  and developed by
         research laboratories (principally those of the pharmaceutical industry itself,
         but  also those of government and educational institutions). After clinical
         trials and government  approval, the  drugs are  ready for general production
         and sale.

     2.   Production of Active Ingredients: At this stage, the basic active drugs used in
         medicine are produced in bulk. These drugs can be categorized according to
         their principal ingredients as follows:

         a.    organic medicinal chemicals (such as aspirin), inorganic medicinal chem-
               icals (such as magnesium sulfate), fermentation products (such as peni-
               cillin  and tetracycline), botanicals (such  as quinine), and  drugs from
               animal sources (such as insulin); and

         b.    biological products,  including  vaccines  (such  as  smallpox  vaccine),
               toxoids (such as tetanus toxoid), serums (such as tetanus antitoxin),
               and products from human blood (such as plasma).

     3.   Formulation and Packaging:  The  basic  drugs, which are manufactured in
         bulk, are formulated into various  dosage forms such as tablets, ointments,
         syrups, lotions, injectable solutions, and the  like, that can  be  taken by
         patients easily and in accurate amounts. The formulated products are pack-
         aged in appropriate containers.
                                         11

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    4.   Pharmaceutical Marketing and Distribution: To get the Pharmaceuticals to
         doctors, hospitals, pharmacies, and ultimately to the patient or consumer,
         they are promoted by the pharmaceutical companies and distributed either
         directly by the companies or through wholesalers. Pharmaceuticals promoted
         by advertising directly to  the consumer are called "proprietary  pharmaceu-
         ticals" and those advertised to the medical, dental,  and  veterinary profes-
         sions are called "ethical Pharmaceuticals."

    The larger, established pharmaceutical  companies engage in all four functions - re-
search, production,  formulation, and marketing -  although these may be carried out by
separate divisions, often located many miles apart.  Other companies, however, specialize in
only one phase, such as producing medicinal chemicals in bulk or in formulating pharmaceu-
tical products from purchased raw materials.

2.2 BREAKDOWN  OF THE PHARMACEUTICAL INDUSTRY BY SIC CODES

     The drug industry as defined by the U.S. Department of Commerce actually consists of
three  industries, consisting of producers of  biological products, medicinal  chemicals and
botanical products,  and pharmaceutical preparations. Under the 1972 SIC system, the three
industry codes are assigned as follows:

     •   SIC 2831—Biological Products: Establishments  primarily  engaged in the
              production of bacterial and virus vaccines, toxoids and analogous prod-
              ucts  (such  as allergenic extracts), serums,  plasmas,  and other blood
              derivatives for human and veterinary use.

     •   SIC 2833—Medicinals and Botanicals:  Establishments primarily engaged in
              (1) manufacturing bulk organic and inorganic medicinal chemicals and
              their derivatives; and  (2) processing (grading, grinding, and milling) bulk
              botanical drugs and herbs. Also included in the industry are establish-
              ments primarily engaged in manufacturing agar-agar and similar prod-
              ucts  of natural  origin, endocrine  products,  manufacturing or isolating
              basic vitamins,  and isolating active  medicinal principals, such as alka-
              loids, from botanical  drugs and herbs.

     •   SIC 2834-Pharmaceutical Preparations: Establishments primarily engaged in
              manufacturing,  fabricating, or processing drugs in pharmaceutical prep-
              arations for human  and veterinary use. Most of the products of these
              establishments are finished in the form intended for final consumption,
              such as ampuls, tablets, capsules, vials, ointments, medicinal powders,
              solutions, and  suspensions. Products of  this industry  consist of two
              important lines, namely (1) pharmaceutical preparations promoted pri-
              marily to the dental, medical, or veterinary professions; and (2) phar-
              maceutical preparations promoted primarily to the public.
                                        12

-------
     While there  is no SIC code for Research and  Development, the other SIC codes —
2831, 2833, and 2834 — can be fitted into the functional classification of the industry.

     SIC 2834 (Pharmaceutical Preparations) is essentially the same as the Formulation and
Packaging function described in Section 2.1.

     SIC  2831 (Biological Products) has many  manufacturing and isolation procedures
similar to those in  SIC 2833  (Medicinals and Botanicals). Therefore, for purposes of this
study, we combined  plant  operations of both SIC  2831 and  2833 under Production of
Active Ingredients.

2.3  DOMESTIC SALES OF THE U.S. PHARMACEUTICAL INDUSTRY

     Total dollar  volume of shipments for ethical products and proprietary products by the
three sectors, according to Census Bureau figures, rose nearly 8% per year between 1954 and
1972, increasing from $2.05 to $7.54 billion, as shown in Table 2.3A.

                                     TABLE 2.3A

                 SHIPMENTS OF ETHICAL AND PROPRIETARY PRODUCTS*
                                      ($ Millions)

                                  1954        1958     1963        1967       1972

Biological Products (SIC 2831)            66.6        63.8     167.3       220.6        481.1
Medicinals and Botanicals (SIC 2833)      281.0        322.3     434.0       593.8        782.6
Pharmaceutical Preparations (SIC 2834)  1,700.5      2,591.8   3,000.2     4,139.7      6,276.0
       Total                      2,048.1      2,977.9   3,601.5     4,954.1      7,539.7

* Source:  U.S. Department of Commerce
     During the comparable period, U.S. domestic sales for ethical products grew at a 9%
annual rate to $5.45 billion in 1973 from $1.00 billion in  1953, as shown in Figure 2.3A.
Proprietary  pharmaceutical sales  are  estimated  at  $1.9  billion  for  1973 compared to
approximately $0.4 billion in 1953. Prior to World War II, proprietaries outsold ethicals but
the tremendous increase  in new  active ingredients  has  led to a remarkably accelerated
growth of Pharmaceuticals under prescription and other Pharmaceuticals only promoted as
ethicals.  We expect ethical Pharmaceuticals to continue  to be the dominant factor in the
expanded markets of the future.

     Table 2.3B shows the estimated domestic sales of ethical pharmaceutical products and
their growth rates by major therapeutic classes for selected years during the past decade.
Within these major categories, the growth rates have  varied substantially — from a slight
decline in sulfonamides to a  19% growth for anti-arthritics. The  most important factors
stimulating demand during the period were:

                                         13

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   6,000
   5,000 -
    4,000  -
c
o
to
CO
    3,000  -
    2,000  -
    1,000
             1955
1960
   1965

Year
1970
           Source:  Arthur D. Little, Inc., estimates.
          FIGURE 2.3A   ESTIMATED DOMESTIC SALES AT MANUFACTURERS'

                        LEVEL OF ETHICAL PRODUCTS1"
                                      14

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                                                 TABLE 2.3B

                 ESTIMATED DOMESTIC SALES* OF ETHICAL PHARMACEUTICAL PRODUCTS1"
                                                  ($ millions)
Therapeutic Group

Analgesics
Antacids
Antiarthritics
Antibiotics
Antihistamines
Antiobesity Products
Antispasmodics
Ataraxics
Cardiovasculars
Cough and. Cold Preparations
Diabetic Therapy
Diuretics
Hematinics
Hormones
Muscle Relaxants
Psychostimulants
Sedatives
Sulfonamides
Vitamins and Nutrients
Others
Total

 *At manufacturers' selling price.
**Preliminary estimates.

 Source: Arthur D. Little, Inc., estimates.


1963
90
50
20
363
33
65
53
185
110
80
72
65
36
175
27
25
65
50
200
619


1967
160
65
63
458
35
82
70
315
200
125
99
96
36
300
35
48
66
48
225
840


1972
270
109
101
697
50
67
89
530
348
198
127
174
42
455
55
75
90
43
300
1,230


1973
292
113
110
730
50
71
92
575
387
223
130
200
41
490
60
79
86
47
325
1,349


1974**
310
118
125
760
52
80
97
615
425
250
140
225
43
525
67
85
90
52
340
1,411
Annual Growth
Rate (%) From
1963 to 1973
12
9
19
7
4
1
6
12
13
11
6
12
1
11
8
12
3
0
5
8
2,383
3,366
5,050
5,450
5,810

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    •   The  introduction  of  several important  new  drugs  (e.g.,  Indocin  [anti-
         arthritic] ,  Lasix  [diuretic],  oral  contraceptives, Valium  and  Librium
         [ataraxics]);

    •   Routine consumption of more drug products to control chronic illnesses and
         geriatric deterioration;

    •   New medical techniques and other health care products; and

    •   Continued growth in private and public health insurance.

    At the present time, more  than  1000 companies  are  considered as pharmaceutical
firms  because they sell drug products. Many are relatively small  with annual  sales less than
$1 million and they frequently service a limited geographic area. Many do not manufacture
their  own products, but sell products to  various drug outlets on a contract basis. They
represent a small part of total drug sales. The distribution of pharmaceutical facilities by
sales volume and geographical location is shown in Table 2.3C. Although sales data are not
available for some firms (those in columns headed "G"), these firms usually  are small and
the numbers of facilities listed in columns headed  "F" can be taken as indicative of the
numbers of facilities with more than $10 million worth of annual sales. An inspection of the
table  indicates that only approximately 5 percent of the facilities in SIC codes 2831  and
2833  have sales greater than $10 million per year and only about 10 percent of the facilities
in SIC code 2834 are of that size.

    The Pharmaceutical Manufacturers Association  (PMA) estimates that perhaps 600 to
700 U.S. firms actually produce  ethical products. Many  of these firms are quite small. In
fact, the 110 members of the Pharmaceutical Manufacturers Association account for 95% of
industry sales  of ethical Pharmaceuticals  in this  country. As shown in Figure 2.3B,  this
figure can be broken down with  the top 15 companies accounting for greater than 50% of
ethical  sales and the top 40 companies accounting for 80% of domestic  ethical sales.
Moreover, since many drug companies function as  a division of a larger corporation, the top
40 companies actually represent 33 corporations.

     The evolving environment for  Pharmaceuticals suggests further concentration, with
balanced resources  in manufacturing,  marketing, and research/development essential for
successful participation  in the expected growth. The industry leaders today possess the
balanced resources necessary for success in the future. Because the barriers are substantial,
probably few new pharmaceutical firms will be established.

2.4 HISTORICAL GROWTH OF THE U.S. PHARMACEUTICAL INDUSTRY

     Historically, drug  companies started as drugstores established to provide drugs to the
public,  but  gradually  they became more involved in  preparing formulations for  local
physicians. The  druggist ran a one-man show and acted as purchasing agent, production

                                        16

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                                                    TABLE 2.3C



                               FACILITIES BY SALES AND GEOGRAPHIC LOCATION*

IV Alabama
X Alaska
IX Arizona
VI Arkansas
IX California
VIII Colorado
1 Connecticut
III Delaware
III District of Columbia
IV Florida
IV Georgia
IX Hawaii
X Idaho
V Illinois
V Indiana
VII Iowa
VII Kansas
IV Kentucky
VI Louisiana
1 Maine
III Maryland
1 Massachusetts
V Michigan
V Minnesota
IV Mississippi
VII Missouri
VIII Montana
VII Nebraska
IX Nevada
1 New Hampshire
II New Jersey
VI New Mexico
II New York
IV North Carolina
VIII North Dakota
V Ohio
VI Oklahoma
X Oregon
III Pennsylvania
II Puerto Rico
1 Rhode Island
IV South Carolina
VIII South Dakota
IV Tennessee
VI Texas
VIII Utah
1 Vermont
III Virginia
X Washington
III West Virginia
V Wisconsin
VIM Wyoming
National Totals
Region Totals
1
II
III
IV
V
VI
VII
VIM
IX
X






A
2

1

3

1



1


2


1



1
1




1
1




1


1
1

1





5



1


25

2
1
2
3
3
6
2
1
4
1

Key:




B


2

5
1



3
4


2


3
1


2

1
1
1


1


3

5
1



1
1


1


4


1

2

46

0
8
4
11
6
4
4
1
7
1

A
B
C

SIC 2831
Biologicalt
C D E F




1 411
1 1



1 1
3


1

1 1 1
1



1 2
1
1
1

1

2 1


2 2 1

1 5
1

1

1
3

1

1
1
2



1


14 24 9 5

0110
3710
3 120
4021
0211
0 200
1 412
1 200
1411
1 100
($1,000)
$ 0 - $ 99.9
$100- $499.9
$500 - $999.9

SIC 2833
Medicinali and Botanicals
G
3

2
1
12
4

2

3
2


10
4
1
5

1
1
3
1
2

1
2

1


1

6
1


1

4




3
8



2
4

91

2
7
9
13
20
11
9
4
14
2
A



1
9
1
1


3



4
1
1
1

1

1
1
2
1

2



1
2

4


4


1





5
2



3

52

3
6
2
3
15
7
4
3
9
0
B C


1

11 7
1
4 1


3 1
1


7
1

1


2
1 1
1
4
2
2
1 2




9 4

7 6
2

1
3

6





7 1


1

4

80 26

7 1
16 10
7 2
7 2
19 0
10 1
2 2
0 1
12 7
0 0
D E




4 2

3 1



1


4 1







1
1




1


2 1

5 2




3











2 1

27 8

4 1
7 3
0 0
1 0
7 2
0 0
1 0
0 0
4 2
3 0
F G




1 24
1
2 4
1

1
4


26
5
1


2
I 1
1
1
1 4
1

2 11




2 22

1 23
3

3
1
1
11

3
3

1
1 6
1

2

3

11 171

3 9
3 45
0 15
0 12
1 42
1 9
2 12
0 2
1 24
0 1
A
5


2
18

5

2
11
7


15
5
3
1
1
1

3
14
11
5
2
9

1

1
7

37
4

13
1
1
14


1
1
2
11
2

6
5
4

231

20
44
25
33
53
15
14
3
18
6
SIC 2834
Pharmaceutical Preparations
B
2

1

23
1
6


12
5


20
4
2

3
3

6
8
6
6
3
10

2


13

42
4

5
2
2
14

2
1
1
1
10
1
2
4
3
2

232

18
55
24
31
43
15
14
3
24
5
C


1

17
3




1


8
1
1

1


2
3
3
1

4

1


8

12
1

3

2
6

1



5


1
1
1

B8

4
20
9
3
17
5
6
3
18
3
D


1
1
18
1
4
2
1
9
3


17
4
3
4

2

2
2
3
2

5

2


25

29
2

1
1
1
10

1


3
7




4

170

7
54
15
17
31
11
14
1
19
1
E




2




1
1


2



1
1

1
1
3
1






8

3


1


5





1






32

1
11
6
3
7
2
0
0
2
0
F


1

a

2
2





7
3





1
2
4


3




15

16
1

2


7




2
1


3



80

4
31
13
3
16
1
3
0
9
0
G
2

4
3
57
6
5
3

6
7


34
9
7
4
3
4

3
8
10
5
7
24

6
1

68

71
10

14
2
2
24

1
4

15
20
1

6
3
2
8

469

14
139
38
54
80
29
41
7
62
5
A
7

1
3
30
1
7

2
14
8


21
6
4
3
1
2

5
16
13
6
2
11
1
2

2
9

42
4

18
2
1
16


1
1
2
21
4

6
6
7

308

26
51
29
39
71
28
20
7
31
7
B
2

4

39
2
10


18
9


29
5
2
4
4
3
2
9
9
11
9
6
11

3


25

54
7

6
5
3
21

2
2
1
1
21
1
2
5
3
8

358

26
79
35
49
68
29
20
4
43
6
State Total
C


1

25
5
1


2
5


8
1
2

1


3
3
3
1

6

1


14

19
1

3

3
9

1



6


2
1
1

128

5
33
14
9
17
6
9
5
26
4
D


1
1
26
2
7
2
1
9
4


21
4
4
5

2

3
4
4
3

5

5


29

39
2

2
1
4
10

1

1
3
9



1
6

221

12
68
16
18
40
13
19
3
27
5
E




5

1


1
1


4

1

1
1

3
1
3
1






10

5
1

1


5

1


1
1




1

49

3
15
8
5
10
2
1
0
5
0
F


1

10

4
2

1



7
3




1
1
2
6


6

1


17

17
1

2


7




2
2


3



96

7
34
13
4
18
2
7
0
11
0
G
5

6
4
93
11
9
6

10
13


70
18
9
9
3
7
2
7
10
16
6
8
37

7
1

91

100
14

17
4
3
39

4
7

19
34
2

8
5
2
15

731

25
191
62
79
142
49
62
13
100
8
($1,000,000)




D
E
F
G
$ 1 -
$ 5 -
$10 r-
$4.9
$9.9
over













































Not Available
f Source: Arthur D. Little, Inc., estimates based on data from Dun & Bradstreet.
                                                         17

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                            Number of Firms/
                               Percent Sales
                             1200 Firms Total
Cumulative Percent of
Domestic Ethical Sales
                  V>OOO< 1090 Firms-  5%XXX>O
                  ซซ
                  ซซ
                    :••::••::••::••::•• 15 Firms - 52% ::••::••::••::••::••
       100%
        95%
                                                          80%
                                                         52%
       Source: Arthur D. Little, Inc., estimates.
FIGURE 2.3B   INDUSTRY CONCENTRATION OF DOMESTIC ETHICAL SALES*
                                  18

-------
superintendent,  salesman,  and treasurer.  Traditionally, the drug  operation was a family
business, with the children taking an active role in the growing company. Because of this
structure of  strong family ties,  most drug manufacturers were quite secretive about their
businesses, and a strong relationship developed between the various companies. Several of
the families developed significant businesses and began to  employ professional managers to
run their businesses profitably.

     The drug industry was relatively small prior to World War II. Two distinct categories of
drugs were available in 1939 — proprietary and ethical products, with proprietary outselling
ethicals. Proprietaries were sold directly to the  consumer, while ethicals were specified or
prescribed by doctors. Most products were designated by a house label; for example, Lilly
aspirin  or Parke-Davis throat discs, and not by brand or trade names. The company name
was an  important part of the product description. Most products were relatively unsophisti-
cated compared to  those of today. Most of today's drugs were unknown, with rather simple
preparations  used to treat conditions now treated with a variety of complex, highly selective
agents.

     The principal  activities of  the larger  drug companies did not vary considerably  from
those of the  one-man shop, with the essential duties being sales and  manufacturing. The size
of the  operation  increased as  the firms began  selling  nationally, and  quality control
laboratories were installed primarily to ensure standardized production and  a high-quality
image "house name" for the physician. The  drug industry, as we now  know it, came into
existence after World War II.

2.5  ROLE OF RESEARCH AND DEVELOPMENT  IN GROWTH OF THE
     U.S. PHARMACEUTICAL INDUSTRY

     Much of the growth in ethical sales has resulted from new  classes of compounds. The
ethical pharmaceutical field is characterized by  a heavy commitment to the research and
development  of significant new agents.  Before  1950, traditional  products  like vitamins,
barbiturates, and laxatives accounted for most of the industry's growth. After  1950, the
heavy research investment  begun during the war and continuing afterwards resulted in the
new product  explosion of antibiotics, steroids, and tranquilizers. The industry's emphasis on
development  of new products since  then has produced an impressive array of effective
products.

     Figure 2.5 shows that the research and development (R&D) budget  for the ethical drug
industry has  grown from  $50 million in  1951 to $850 million in 1974. Traditionally, the
ethical drug industry spends about 9-10% of its worldwide  sales dollars on research effort —
a higher percentage than in most other industries. Moreover, the R&D  budget for specific
companies may be substantially higher. For example, Lilly had  worldwide pharmaceutical
sales of $633.6 million in 1974,  while its R&D spending was $93.3 million - nearly 15% of
sales. Industry sources indicate the following partial analysis of expenditures:
                                         19

-------
 900
    1951
1955
1960
1965
1970
                                                      1974
     Source: Pharmaceutical Manufacturers Association.
FIGURE 2.5  RESEARCH AND DEVELOPMENT EXPENDITURES FOR ETHICAL PRODUCTS"1"
     'Government contract funds are not included nor is R&D funding for veterinary ethical
      products.
                                    20

-------
            Modifying and/or improving existing products     29%
            Biological screening and testing                  18
            Clinical testing                                 17
            Synthesis and extraction                        16
            Process development, manufacturing work-up,
             and quality control                            10
            Toxicology and safety evaluation                 _9_
                                                           99%

In general, we believe that about one-sixth of the  current industry-wide  R&D budget is
devoted to basic research and close to one-third to help existing products meet the FDA's
more stringent requirements on bioavailability, efficacy, safety, and so forth. Thus, slightly
more than one-half of the stated budget is devoted to new products.

     In the past 30 years, almost 900 new active medicinal ingredients have been introduced
to the U.S.  market,  two-thirds originating in the United States.  (These active medicinal
ingredients are unique compounds in terms of molecular structure. However, they may be
used  as an active  ingredient  in varying concentrations or in conjunction with other active
ingredients in a number of different pharmaceutical products.) For the past decade, the
number of new entities introduced annually into the U.S. market has tended to decline. In
part,  this decrease may be  due to a trend in research to seek  major breakthroughs for
treatment of the more intractable diseases. However, the increased time needed for testing
and meeting  the FDA's regulatory requirements is an important factor. We estimate that the
time  factor can run five to eight years and cost from $9 to $18 million. Only the leading
pharmaceutical companies have the  money and research capacity needed to meet these
demands.

     Table 2.5 ranks  published research activities on compounds by  therapeutic categories
to determine which research areas are currently of greatest interest.  As future commercial
production will depend in part on the areas now being researched, these data should give
some indication of the future importance of various therapeutic classes. The 19 categories
listed represent nearly 75% of all the compounds currently being investigated. The types of
compounds under study suggest that there will be no drastic shift in the general types of
active medicinal ingredients  in the next  10  years, nor in the general processes (such as
organic syntheses and fermentations) required to produce them.

     R&D will be  valued even more highly  in the future, but it will also be more difficult to
develop  significant new  agents. Much  of the work which  could  lead quickly to  drug
discoveries has already been  completed, and  now investigators are concentrating on more
difficult  subjects,  such as developing a basic  understanding of heart disease, cancer, con-
genital disease, and stroke — all difficult  areas in which to achieve quick developments.
However, new breakthroughs in pharmacology will be forthcoming, involving not only new
classes of therapeutic drugs but also advances  brought about by molecular  biology, that is,
supplying missing  or substitute chemicals in minute doses or in elaborate delivery systems in
order to correct aberrant metabolism.

                                         21

-------
                                      TABLE 2.5

                 RANKING OF RESEARCH CATEGORIES BY NUMBER OF
                             COMPOUNDS UNDER STUDYt

                                                   Percent of Total Number of
                   Category                          Compounds Under Study

              Cardiovasculars                                   14
              Psychotropic Drugs                                9
              Cancer Chemotherapy Agents                       6
              Antibiotics                                      6
              Hormones                                       4
              Antivirals                                       3
              Analgesics                                       3
              Antagonists/Antidotes                             3
              Muscle Relaxants                                 3
              Anti-inflammatory Agents                          3
              Fungicides                                      3
              Cholesterol Reducers                              2
              Enzyme Inhibitors                                2
              Diuretics                                        2
              Bronchodilators                                  2
              Antibacterials                                    2
              Immunosuppressants                              2
              Anticoagulants                                   2
              Antispasmodics                                  2
              Others, each comprising less than
               2% of the total compounds                        27

               Sources: Paul de Haen, Inc., and Arthur D. Little, Inc., estimates.
2.6 PHARMACEUTICAL CONSUMPTION - RECENT TRENDS

     There is no simple unit of measure, such as millions of tablets or tons of chemicals,
which shows overall unit consumption of Pharmaceuticals. However, the trend of unit
consumption can be inferred from the number of prescriptions filled at retail pharmacies.*
* Retail pharmacies account for approximately 75% of all prescriptions, with hospitals and other institu-
 tions accounting for the balance.
                                          22

-------
Table 2.6 presents data on the number of prescriptions filled at retail pharmacies and shows
that from 1968 to 1973, the number of prescriptions filled at retail pharmacies rose at a 6%
compound annual rate to a total of 1.5 billion. New prescriptions rose at a somewhat higher
rate of 6.4% and refill prescriptions grew at a 5.6% rate. The higher rate of growth in new
prescriptions is primarily due to government restrictions on prescription refills for drugs that
are subject to abuse, and  above average growth in prescriptions for antibiotics. These  data
give a general indication of unit growth in drug consumption, but not a complete picture,
because various  drugs  are taken with different frequencies  and in different  quantities. If
anything, however, the growth rate is probably understated, since studies indicate that there
has been an increase in the  size of the average prescription in terms of numbers of tablets,
capsules, and the  like, per prescription.

2.7  PHARMACEUTICAL INDUSTRY OUTLOOK FOR 1975-1980

     We  expect the pharmaceutical industry to maintain a domestic dollar growth rate on
the order of 7-9% over the next five years, and that international growth will probably be
stronger  in the near future.  However, we believe that  the production requirements of the
industry  will become more important as  unit consumption increases. The following factors
will be affecting the drug industry during this period:

     •    Enactment of an expanded program of National Health Insurance will be of
          prime  importance during this period. We expect National Health Insurance
          to increase pharmaceutical sales and to boost  drug consumption, particularly
          over the long-term, when coverage is extended to outpatient drugs. However,
          we do  not anticipate legislation  to be passed before  1976, with additional
          time required before the  program can be implemented smoothly.

     •    Price pressures are being, and  will continue  to be, exerted by the Govern-
          ment. For example, HEW is currently assessing the maximum allowable cost
          regulations which would have an adverse impact on the profitability of the
          industry, particularly since the regulatory environment will encourage the
          use of price-competitive,  multi-source drugs.

     •    Several Congressional hearings are being held which are investigating various
          practices of the pharmaceutical industry.  For example, the Kennedy Health
          Subcommittee investigated many of the established marketing techniques of
          the industry, and  we  expect enforcement of  related changes, particularly in
          the use of sampling and in the regulation of the activities  of the medical
          representatives (detailmen). Such proposed curbs on promotional practices
          of drug companies could have a slightly adverse effect for a limited period of
          time.

     •    The -availability of new drugs has slowed significantly from  the flood of
          products introduced in the late 1950's and 1960's and is encouraging use of
          older, established drugs.

                                         23

-------
                                                     TABLE 2.6
                             NUMBER OF PRESCRIPTIONS FILLED AT RETAIL PHARMACIES1
                  Total Prescriptions
1968-1973
1973
1972
1971
1970
1969
1968
1967
to 1966
1965
1964
Millions
—
1532
1450
1351
1280
1197
1145
1069.
1055
967
857
Growth Rate %
6.0
5.7
7.3
5.5
6.9
4.5
7.1
1.3
9.1
12.8
—
New Prescriptions
Refill Prescriptions
Prescriptions
—
48
48
48
47
47
47
46
45
45
44
Millions
_
729
696
646
603
562
534
492
476
432
382
Growth Rate %
6.4
4.7
7.7
7.1
7.3
5.2
8.5
3.4
10.2
13.1
—
Millions
—
803
754
706
676
635
612
577
579
535
475
Growth Rate %
5.6
6.5
6.8
4.4
6.5
3.8
6.1
(0.4)
8.2
12.6
—
Source:  National Prescription Audit

-------
2.8 NUMBER OF PHARMACEUTICAL PLANTS AND EMPLOYMENT
    IN THE INDUSTRY

    The latest available Census of Manufactures lists a total of 1058 establishments in 1972
for the SIC codes under evaluation. In addition, there were 42 plants in operation in Puerto
Rico in 1974. Overall, a total of approximately 1100 plants are currently producing drug
products in the United States and its territories. Most of these plants are small. Of the 1058
plants  listed  in the  1972 Census  of Manufactures, in fact, only 416 had 20 or  more
employees each. For this study it is noteworthy that in the important function of producing
organic chemical-active ingredients  (SIC  2833), only 54 plants in the United States had 20
or more employees. Only 60 plants in the production of biologicals (SIC 2831) were in the
comparable category and 302 were of this size in the formulation and packaging sector (SIC
2834).

    Because Government data on a state-by-state basis were not complete at the time of
this study, we have  estimated the number of pharmaceutical plants in some of the  States
and Puerto  Rico  as shown  in Table 2.8A. Totals of  plants by EPA regions and for the
individual states are presented on the map in Figure 2.8A. The corresponding map for plants
with more than 100 employees  is presented in Figure 2.8B. As may be observed in these
tables and figures, drug industry production is  concentrated primarily  in the northeastern
and north central regions, with relatively heavy involvement also in California. As designated
by EPA  regions,  these include  Regions II (282 plants- 26% of total), Region V (215
plants -  20% of total), and Region IX (143 plants - 13% of total). It should be noted that
the new Puerto  Rican facilities are incorporated  into the  total number  of plants for
Region II. For the continental United States, Region II contains 240 plants (22% of total).

    A further indication  of the geographic  concentration  of the U.S. pharmaceutical
industry  is the fact that five states have nearly 50% of all plants- New York (12%),
California (12%),  New Jersey (10%), Illinois (7%), and  Pennsylvania (6%). Not only is the
total number greater in these states,  but the plants are also  the largest in the industry.  As
shown in Figure 2.8B, these five states  and  Puerto  Rico contain nearly two-thirds of the
plants which have more then 100 employees.

    An interesting observation from the Census data is that the total number of establish-
ments  in the continental United States dropped from  1359 facilities  in 1958 to 1058 in
1972 (a decrease of 22%), but establishments with more than 20 employees increased from
403 to 416 during the same period (an increase of 3%). This shift is a further indication of
the smaller producer disappearing from the industry with the  larger manufacturers becoming
even more dominant factors.

     The number of employees in  the various sections of the pharmaceutical industry from
1947 to  1972 are  listed  in  Table  2.8B and  presented graphically in Figure 2.8C. The
industry employed a total of 129,300 workers  in 1972, 67,400 of which were production
workers. During  the period  1958 to  1972,  total  employment increased  by 26%,  while
production workers increased by 19%. This substantial increase in employment took place
during the period noted above in which total plants decreased - again an indication of the
concentration occurring within the industry.
                                        25

-------
                          TABLE 2.8A

ESTIMATED NUMBER OF PHARMACEUTICAL PLANTS {SIC 2831, 2833, AND 2834)
TOTAL NUMBER OF PLANTS AND THOSE WITH MORE THAN 100 EMPLOYEES1"


EPA Region
IV
X
IX
VI
IX
VIII
I
III
III
IV
IV
IX
X
V
V
VII
VII
IV
VI
I
III
I
V
V
IV
VII
VIM
VII
IX
I
II
VI
II
IV
VIM
V
VI
X
III
II
I
IV
VIM


State
Alabama
Alaska
Arizona
Arkansas
California
Colorado
Connecticut
Delaware
District of Columbia
Florida
Georgia
Hawaii
Idaho
Illinois
Indiana
Iowa
Kansas
Kentucky
Louisiana
Maine
Maryland
Massachusetts
Michigan
Minnesota
Mississippi
Missouri
Montana
Nebraska
Nevada
New Hampshire
New Jersey
New Mexico
New York
North Carolina
North Dakota
Ohio
Oklahoma
Oregon
Pennsylvania
Puerto Rico
Rhode Island
South Carolina
South Dakota


Total Plants1
( 7)
0
( 8)
( 2)
134
( 15)
16
( 4)
0
28
18
0
0
78
26
16
12
( 5)
( 11)
( 3)
23
31
39
( 21)
( 8)
44
0
9
( D
0
112
0
128
( 18)
0
34
( 5)
( 9)
69
42
( 4)
( 6)
( 2)


% of Total2
#
0
*
#
12
1
1
#
0
3
2
0
0
7
2
1
1
ป
1
*
2
3
4
2
*
4
0
#
*
0
10
0
12
2
0
3
*
*
6
4
#
*
*
Plants @
>100
Employees
0
0
0
0
18
1
6
0
0
1
3
0
0
13
9
3
1
0
0
0
2
2
10
2
1
10
0
2
0
0
45
0
26
5
0
5
0
1
19
16
0
2
0
% of Plants2
>100
Employees
0
0
0
0
8
*
3
0
0
#
*
0
0
6
4
1
#
0
0
0
*
*
5
*
*
5
0
#
0
0
21
0
12
2
0
2
0
#
9
7
0
#
0
                             26

-------
EPA Region     State
                                   TABLE 2.8A (Continued)
                           Total Plants1
   IV
   VI
   VIII
   I
   V
   VIII
Tennessee
Texas
Utah
Vermont
Virginia
Washington
West Virginia
Wisconsin
Wyoming

National Totals
Regional Totals
   I
   II
   III
   IV
   V
   VI
   VII
   VIM
   IX
   X
  16
  50
(   3)
   0
(  16)
(   7)
(   3)
  17
   0

1100

  54
 282
 115
 106
 215
  68
  81
  20
 143
  16


% of Total2
1
5
#
0
1
*
*
2
0
Plants @
>100
Employees
7
4
1
0
3
0
0
1
0
% of Plants2
>100
Employees
3
2
*
0
1
*
*
*
*
                                                               5
                                                              26
                                                              10
                                                              10
                                                              20
                                                               6
                                                               7
                                                               2
                                                              13
                                                               1
219

  8
 87
 24
 19
 40
  4
 16
  2
 18
  1
 4
40
11
 9
18
 2
 7
 *
 8
  1. Figures in parentheses are Arthur D. Little, Inc., estimates, based on 1967 Census of Manufactures and
    Dun and Bradstreet 1974 data; all others from 1972 Census of Manufactures (Preliminary).
  2. 'designates less than 1%.

   Sources:  Arthur D. Little, Inc., estimates and Census of Manufactures.
                                             TABLE 2.8B

                                        Number of Employees

                                       SIC 2833
1947
1954
1958
1963
1967
1972
Total
2,987
3,965
3,692
5,800
7,400
9,800
Production
Workers
NA
NA
2,567
3,600
4,800
5,500
Total
13,097
11,541
10,246
8,100
8,400
8,700
Production
Workers
NA
NA
6,640
5,300
5,600
5,300
Total
65,143
76,555
82,000
85,100
102,000
110,800
Production
Workers
NA
NA
45,708
45,900
55,200
56,600
Total
81,227
92,061
95,938
99,000
117,800
129,300
Production
Workers
NA
NA
54,915
54,800
65,600
67,400
   ^Source: Census of Manufactures

-------
Ni
oo
           Hawaii

             0
Puerto Rico (II)

     42
             N.B.: Numbers in parentheses are Arthur D. Little, Inc., estimates; Roman numerals designate EPA regions.


            ^Sources: Arthur D. Little, Inc., estimates and Census of Manufactures, 1972 (preliminary).
                                                             FIGURE 2.8A   NUMBER OF PLANTS1

-------
     Alaska
       0
to
VO
    Hawaii
      0
Puerto Rico (II)
     16
         N.B.:  Roman numerals designate EPA regions.
          Source:  Arthur D. Little, Inc., estimates.
                                                 FIGURE 2.8B  NUMBER OF PLANTS (> 100 EMPLOYEES)1"

-------
    140,000

    130,000 _

    120,000 -

    110,000

    100,000

     90,000
>.   80,000
_o
a
E
^   70,000
-o    60,000
     50,000

     40,000

     30,000

     20,000

     10,000
    SIC 2834  Pharmaceutical
    SIC 2833  Medicinal Chemicals and Botanical Products
    SIC 2831  Biological
    2834
     2833
      2831
       2834
              2834,2833,2831	

                        2834	
                                              Production Employees
  Total Employees
 	   2833
  Total Employees
 —   2831
  i   I  i   i  i  i
     Production Employees
         1947

           t
                 1954       1958

Source: Census of Manufactures
1963
1967
                          1972
        FIGURE 2.8C  PHARMACEUTICAL EMPLOYMENT TRENDS BY SIC CODES1"
                                         30

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3.0 WASTE CHARACTERIZATION IN THE PHARMACEUTICAL INDUSTRY

3.1 SELECTION AND APPLICATION OF HAZARDOUS WASTE CRITERIA

3.1.1  Background Information for the Selection of Hazardous Wastes

     In the studies covering various industries, the individual contractors were asked to:

     ".  .  identify and describe  the wastes generated by each industry which pose a
    potential health  or  environmental hazard upon final disposal. In performing his
    analysis,  the  contractor should pay particular attention to wastes which contain
    any of the following specific substances, or types of substances: asbestos, arsenic,
     beryllium, cadmium, chromium,  copper,  cyanides, lead,  mercury, halogenated
     hydrocarbons, pesticides,  selenium, and zinc. EPA  believes these substances, on
     the basis of initial  analysis, to have the potential for producing serious public
     health and environmental problems when  contained in wastes for disposal. Other
     wastes, believed by the contractor  to  be of a hazardous nature, such as  car-
     cinogens, should also be identified. "

     To identify the wastes  that pose a potential health or environmental hazard upon final
disposal, we had to develop a set of criteria to select the hazardous wastes generated by the
pharmaceutical industry. Whereas some industries have only a few well defined inorganic
substances to  classify, the pharmaceutical industry manufactures or purchases an estimated
15,000  inorganic and organic chemicals to  make its formulated pharmaceutical products.
Potential hazards of these chemicals range from essentially nonhazardous to highly hazard-
ous due to such characteristics as flammability or toxicity.

     We studied  other hazard classification schemes to assist in developing criteria for
selecting potentially hazardous and highly hazardous wastes generated in the pharmaceutical
industry, but found no universally applicable scheme for classifying the types of hazards and
the degree to  which  they are  hazardous. Each classification scheme was selected to meet
specific needs. Industrial toxicologists selected  criteria to assist them in  handling the toxic
materials produced in industry, and public health toxicologists assembled criteria to assist
the physician  in treating acute poisoning by various chemicals and commercial products.
Classification  schemes designed  to aid  the  physician in treating acute poisonings were
usually developed on the  basis of LDS 0 values alone, while the industrial hygienist was often
more  concerned with the toxicity of inhaled vapors, irritation to the skin, allergic reactions,
and flammability of products.

    While none of the other systems have addressed  the same problems that the Office of
Solid  Waste Management Programs will face, the Coast Guard addressed a related problem in
the safe handling  of  materials in bulk water transportation. During 1965-66 the  National
                                         31

-------
Academy of Sciences (NAS) developed an initial evaluation system for the Coast Guard.*  In
this  system the substances were  rated  on a  simple numerical scale of 0, 1, 2,  3 or 4,
indicating an increasing degree of hazard in each of 10 categories describing different types
of hazards (flammability, human toxicity, etc.). The publication was revised from  time to
time;the current  edition is  dated  1970 with additions to September 22,  1972. Comments
were received from overseas sources including the Intergovernmental Maritime Consultative
Organization (IMCO),  the Netherlands, and the United Kingdom, suggesting the need for
further extension and  amplification of the guidelines to define the ratings more precisely.
Thus in 1974  the  NAS submitted a  revised publication, "System for Evaluation of the
Hazards of Bulk  Water Transportation of Industrial Chemicals," which brought the grade
classifications for human toxicity and  aquatic toxicity into agreement with grade classifica-
tions developed by IMCO and one hazard category (effect on amenities) was dropped. The
suggested classification scheme now has nine hazard categories as follows: (1) fire,  (2) skin
and  eyes,  (3)  vapor inhalation, (4) gas inhalation,  (5) repeated inhalation, (6) human
toxicity, (7)  aquatic toxicity, (8) water reaction, and (9) self reaction. The same rating scale
of 0, 1, 2, 3 and 4 was retained and used for all hazard categories.

     We also examined the IMCO  system  which was developed by the Joint  Group  of
Experts on the Scientific Aspects of Marine Pollution to review the environmental hazards
of transporting substances  besides  oil. In contrast to the NAS  system which has  nine
categories of hazards, the IMCO system has only five categories:  (1) bio-accumulation, (2)
damage to living  resources, (3)  oral intake hazard to  human health, (4)  skin  contact and
inhalation hazard to human health, and (5) reduction of amenities.

3.1.2 Selection of Criteria for Classification of Potentially Hazardous Substances from
      the Pharmaceutical Industry

     Classification  of  materials as  hazardous or  nonhazardous  is  an arbitrary process.
Whether or not a substance is hazardous depends on its quantity, concentration, location,
and  the species affected.  Even air and water can be hazardous in certain  situations. For
example, air injected into a vein may cause a fatal  air embolism. Likewise water can be fatal
if too much water gets into the lungs by blocking access of air to the lungs and seriously
disrupting  the  ionic balance of  the  blood.  On  the  other  hand,  a  substance  such  as
hydrochloric acid, which can be fatal if ingested in concentrated form, can  also be beneficial
in dilute solutions for patients who have a deficiency of normal hydrochloric acid secretions
in the stomach.

     Despite the difficulties  of developing a universally applicable scheme  for  grading
hazardous  materials, materials with the highest potential for environmental damage and
human hazard  can  be identified for various handling or disposal techniques. Theoretically,
such a classification scheme should take in all possible hazards. In observing the pragmatic

"Described  in  NAS publication No.  1465, "Evaluation of the Hazard  of Bulk Water Transportation of
  Industrial Chemicals - A Tentative Guide."
                                         32

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approaches taken by IMCO, NAS-Coast Guard, and the Hazardous Substances Branch of
EPA's Office of Water Planning and Standards, it is apparent that firm decisions had to be
made to eliminate or exclude certain hazard categories. For example, effects on amenities
was eliminated in the 1974 NAS proposed system and bio-accumulation was not included as
a hazard  category. Likewise, the IMCO scheme did not include consideration of flamma-
bility in its hazard ratings, presumably because it is concerned with dumping of materials
from ships on  the high  seas  where toxicity  is a more  important consideration  than
flammability.
     Because of  the wide range of hazards  considered in the NAS scheme, and because of
the extensive data that had been collected for the scheme, we proposed that the 1974
modification suggested to the  Coast Guard by NAS be  used as a basis for evaluating the
hazards of materials for disposal on land. Initially, we suggested classifying substances which
fell into hazard grades 3 and 4 in any category of the NAS scheme as highly hazardous and
those in grades  1  and 2  as moderately hazardous as  shown in Table 3.1.2A. Another
contractor  (TRW, Inc.)  suggested  expansion  of  the NAS-Coast Guard  classification  to
include bio-accumulation to toxic levels and addition of substances that are  carcinogenic,
(oncogenic,  teratogenic, or  mutagenic.  Since the classification scheme developed for this
(preliminary study of hazardous wastes would not bind  EPA  to the same criteria, the Office
|of Solid Waste Management Programs, ADL, and TRW agreed that both contractors would
!use the expanded classification scheme for the pharmaceutical and organic chemical indus-
jtries, but  with a  modification involving the water pollution hazards.  The criteria for highly
hazardous  wastes were retained and, therefore,  included any substances falling into  hazard
i grades 3 or 4 in any  category  of the NAS classification scheme. Criteria  for moderately
hazardous  wastes included any substance falling in grades 1 or 2 in any category, except that
under the "water  pollution" heading substances falling  in  grade 1   were  considered non-
hazardous  unless they presented a hazard upon collection. We thus have nine graded criteria
to use in making preliminary judgments  in evaluating  the hazard of a given material.  In
addition, bio-concentratable materials are raised to the next higher hazard classification and
suspected carcinogens* are rated as Grade 4, highly hazardous. A summary of the classifica-
tion criteria is presented in Table 3.1.2A with  the boundaries between the  three  hazard
classifications (highly hazardous, moderately  hazardous, and essentially nonhazardous)
delineated by heavy lines. A more detailed  explanation of the criteria for hazard grades in
each of the nine categories is given in Appendix A.

     When one attempts  to apply the classification scheme developed above to a specific
industrial  situation, other precautions must  be observed. The problems of quantity and
concentration arise immediately when we consider the inorganic chemicals (heavy  metals
and fluorides, for example) that are usually considered to be toxic. The assumption that any
exposure  to a toxic  chemical  is harmful  at any dose is erroneous; for many  chemical
substances a deficiency is known to be every bit as injurious as an excess.

     Several examples illustrate  that substances can be nutritional at one level and toxic at
another. For example, fluorine is essential for life (Table 3.1.2B)  and is a demonstrated
growth factor in rats. A  fluorine deficiency leads to tooth decay, but in slight excess this
 *Does not include list of "suspected  carcinogens" published by NIOSH in  the Federal Register, 48,
 No. 121, pp 26,390-26,496, June 23, 1975. NIOSH is asking for information on the carcinogenicity of
 compounds on this list.                     oo

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                                                           TABLE 3.1.2A




                                         SUMMARY OF HAZARD EVALUATION CRITERIA
Etsentially
1 Priority II
Moderately Hazardous
Priority !•
Highly Hazardous
Hazard Categories
G 1 II III IV V VI
R
A Fire Health Water 1
ซ n
g E Skin and Vapor Gas Repeated | Human
3 Eyes Inhalation Inhalation Inhalation Toxicity
T>
ป Not
ฃ Applicable
o 0 All not All not
Non-combust- described described OSHA> LD50>
iWe below below 1000 ppm 5000 mg/kg
1
FPcc > 140ฐ F Corrosive Depressants, All not OSHA LD50
(60ฐC) to eyes asphyxiants described 100-1000 ppm 500-5000 mg/kg
below
I
i
2 FPcc
100ฐF-140ฐF Corrosive LC50 LC50 OSHA LD50
(37.8ฐ -60ฐC) to skin 200-2000 ppm 200-2000 ppm 10-100 ppm 50-500 mg/kg
3 (37.8ฐC) LD50
FPcc < 1 00ฐ F 20-200 mg/kg
BP>100ฐF 24-hr, skin LCSO 50^200 ppm LC50 OSHA LDSO
„ (37.8ฐC) contact or 0.5-2 mg/K 50-200 ppm 1-10 ppm 5-50 mg/kg
| 4 (37.8ฐC)
FPcc<100ฐF LD50<20mg
BP < 100ฐF 24-hr, skin LCSO < 50 ppm
(37.8ฐC) contact or<0.5mg/K LC50<50ppm OSHA<1ppm LDso<5mg/kg
VII VIII IX
'Dilution Reaction
Aquatic 1 Water 1
Toxicity Reaction Serf-Reaction
Insignif.
Hazard
T Lm > 1 000 mg/K No appreciable
self-reaction
TLm e.g., CI2 May polymerize
1 00- 1 000 mg/e with low heat
evolution
'^ Contamination
may cause
e.g., NH3 polymerization;
TLm no inhibitor
10-100 mg/K required
May polymerize;
requires
TLm 1-10 mg/K e.g.. Oleum stabilizer
Self-reaction
may cause
explosion or
TL < 1 mg/K e.g., S03 detonation
'Priorities are discussed in Subsection 3.1.3




Note:  Bio-concentratable materials are raised to next higher hazard classification. Suspected carcinogens are rated as Grade 4.

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                                            TABLE 3.1.2B
     BIOLOGICAL FUNCTIONS AND TOXICITIES OF SELECTED ELEMENTS
   Element                  Biological Function*

 Hydrogen             Constituent of water and organic
                         compounds
 Boron                Essential in some plants; function
                         unknown
 Carbon               Constituent of organic compounds
 Nitrogen              Constituent of many organic
                         compounds
 Oxygen               Constituent of water and organic
                         compounds
 Fluorine              Growth factor in rats; possible
                         constituent of teeth and bones
 Sodium               Principal extracellular cation
 Magnesium            Required for activity of many
                        enzymes
 Silicon                Shown essential in chicks; pos-
                        sible structural unit in
                        diatoms
 Phosphorus            Essential for biochemical synthesis
                        and energy transfer
 Sulfur                Required for proteins and other
                        biological compounds

 Chlorine              Principal extracellular anion
 Potassium             Principal cellular cation
 Calcium               Major component of bone; required
                        by some  enzymes
 Vanadium             Essential in  lower plants; certain
                        marine animals and rats
 Chromium            Essential in  higher animals; related
                        to action of insulin

 Manganese            Required for activity of several
                        enzymes
 Iron                  Most important transition metal ion
                        essential  for hemoglobin and
                        many enzymes
Cobalt                Required for activity of several
                        enzymes; in vitamin Bj 2
Copper               Essential in oxidative and other
                        enzymes and hemocyanin
Zinc                  Required for activity of many
                        enzymes; deficiency causes
                        anemia

Selenium              Essential for liver function
Molybdenum          Required for activity of several
                        enzymes
Tin                   Essential in rats; function
                        unknown
Iodine                Essential constituent of thyroid
                        hormones
                Toxldty"
 Used in insecticides and rat poisons;
 fluorides are protoplasmic poisons,
 removing essential body calcium inter-
 fering with enzyme reactions causing
 death from respiratory or cardiac failure
High plasma levels can result in respira-
tory depression and death
Quite toxic, especially as V20S dust

Carcinogenic in rats and mice; industrial
exposure has resulted in dermatitis, skin
ulcers, liver injury, and lung cancer.
Industrial exposure to dust has resulted in
a neurological syndrome and a pneumonitis
Excessive doses have caused severe symptoms
and a high proportion of deaths, especially
in children; actdosts,  cardiovascular
collapse and tissue damage to the gastro-
intestinal tract, liver and kidneys
Produces polycythemia, nephritis, etc.

Excessive doses damage liver, kidneys,
capillaries, and central nervous systems
Relatively nontoxic to mammals; yet causes
illness due to inhalation of Zn compounds
High toxicity, similar to Te and As; Even
natural levels cause serious disease (blind
staggers) in cattle; inhibits enzyme
function
lodism in some persons; irritation of
mucous membranes and gastrointestinal tract
 'from E. Frieden, Scientific American, Vof 227, No. 1, p 52 (July 1972).

"from J.R. DiPatma (ed.), Drill's Pharmacology in Medicine, (3rd ed.), McGraw-Hill
  Book Co., New York (1965).                           ^ c

-------
same element  produces an unsightly mottling of tooth enamel. In large excess it is a very
dangerous poison — the active ingredient, in fact, in some insecticides and rat poisons.
     Another example is zinc. Many enzymes require this element yet it can be an industrial
health  hazard and has been responsible for fish kills. The list of chemical elements essential
to life  is growing fast. It includes eight other "toxic heavy metals" - vanadium, chromium,
manganese, iron, cobalt, copper,  molybdenum, and tin -  which were listed by Frieden in
1972 (cf. Table 3.1.2B).
3.1.3 Application of the Classification Scheme to Categorize Wastes from
      the Pharmaceutical Industry as Priority I or Priority II
      Potentially Hazardous Wastes

     As was discussed in Section 3.1.2, the toxicity or degree of hazard presented by a given
waste  depends on  many factors.  In  this preliminary survey of hazardous wastes from  the
pharmaceutical industry potentially destined  for land disposal, we  were unable to make
final judgments on the degree of  "hazard" for wastes from the industry. We recognize that
more information  will  be required  on a plant by plant  basis before the hazards at an
individual plant can be  evaluated. In this report, we have focused on the "potential hazard"
in a given waste, choosing to label the potentially highly hazardous materials as Priority I
Hazardous Wastes, and the potentially moderately hazardous materials as Priority II Hazard-
ous Wastes.

     Priority I hazardous wastes include  all "elementary" toxic materials, viz.,  materials
which are potentially harmful,  regardless of their state of  chemical combination. Priority I
hazardous wastes also include materials which owe their hazardous properties to their mole-
cular arrangement and which fall in hazard grades 3 or 4 in Table 3.1.2A.

     Priority II hazardous wastes owe their hazardous properties to their molecular arrange-
ment and fall in hazard grades 1 or 2 in  Table 3.1.2A.

     All other process wastes are considered essentially nonhazardous in this study if they
fall in  the essentially nonhazardous section of Table 3.1.2A.

     A list of Priority  I inorganic chemicals was made up and used  during interviews as a
checklist  to see whether the plant had any of these materials in its waste (see Table 3.1.3A).
As the study proceeded, we found that we had to make some judgments as to whether cer-
tain wastes had significant concentrations of "hazardous" metals,  as  trace quantities of
metals can be found in almost any waste. Because of the approximately 15,000 active ingre-
dients used in the pharmaceutical industry, a similar list for organic compounds was im-
practical. The  industry also  uses some quantity of practically every organic solvent com-
mercially available, either in its  R&D groups or production  plants. As will be described later,
wastes from these solvents are incinerated. In this preliminary study we were not attempting
to catalog all possible components of waste streams, but were merely trying to identify
major  hazardous wastes. In general, we were looking for information on waste solvents,  still
bottoms,  and  solid wastes such as process "muds" or presscakes that were discharged from
the  plants manufacturing active medicinal ingredients. Representative solvents and  still
bottoms containing these solvents are characterized in Table 3.1.3B.
                                         36

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                                        TABLE 3.1.3A

                              PRIORITY I HAZARDOUS WASTES


                              Inorganic Elements and Compounds


       Mercury 1                                             Molybdenum (molybdates)
       Cadmium? on first proposed toxic pollutant list*            Nickel
       Cyanide )                                             Nitrites
       Antimony                                             Osmium
       Arsenic                                               Selenium
       Azides                                                Silver
       Barium                                               Thallium
       Beryllium                                              Tin
       Chromium (chromates)                                  Uranium
       Cobalt                                                Vanadium
       Copper                                               Zinc
       Fluorides                                              Radioactive elements
       Lead

       *Published in the Federal Register, 38FR 35388, December 27,1973.
                                       TABLE 3.1.3B

                    CHARACTERIZATION OF TYPICAL WASTE SOLVENTS
                  OR STILL BOTTOMS CONTAINING THE LISTED CHEMICALS

                   Priority I                             Priority II
               (Highly Hazardous)                   (Moderately Hazardous)

               Acetone                            Ethylene Glycol
               Acetonitrile                            Monomethyl Ether
               Amyl Acetate                       Heptane
               Benzene                            Methylene Chloride
               Butanol                             Naphtha
               Butyl Acetate
               Chloroform*
               Ethanol
               Ethylene Dichloride
               Isopropyl Alcohol
               Methanol
               Methyl Isobutyl Ketone
               Toluene
               Xylene

'Chloroform would normally be in the Priority II classification, but possible carcinogenic action
 its shift to Priority I.
                                            37
causes

-------
     Anyone considering  landfilling of returned  Pharmaceuticals or  disposal of  active
ingredients is concerned with the possible hazardous properties of the ingredients. Formu-
lated Pharmaceuticals and most  active medicinal ingredients are not hazardous because of
flammability, reactivity with water, self-reactivity, or corrosiveness to skin or eyes. Likewise
these products  do not usually produce vapors that are toxic on inhalation. The principal
hazard categories that would place these Pharmaceuticals or ingredients in the hazardous
classification are  aquatic toxicity (TLm), oral toxicity (LDSO), bio-concentration or car-
cinogenicity. It is unlikely that the Food and Drug Administration would leave a  pharma-
ceutical on the market for general use  that is a known carcinogen. There are essentially no
data on  the TL   values of these compounds and on  their bio-concentration in natural
flora and fauna. However, there  are extensive data  on the oral toxicity of these compounds
in test animals.

     We  therefore decided to evaluate the toxicity  of the most common products in five of
the  largest selling pharmaceutical categories: analgesics,  antibiotics,  ataractics, cardio-
vasculars, and hormones. The oral LD5 0 values of  typical compounds under each  pharma-
ceutical  category are listed in Table 3.1.3C.  As indicated in the summary at the end of
Table  3.1.3C, 48 out of  66  compounds  were in toxicity grade  1  (LD50 of 500  to 5000
mg/kg — essentially nonhazardous), 17 of the 66 were in grade 2 (50-500 mg/kg — moder-
ately  hazardous)  and only  one compound  was  in  grade 3 (5  to 50 mg/kg —  highly
hazardous). While the pharmaceutical ingredients sometimes may have a high activity for
man when they are injected or ingested, the most active ones are usually dispensed in  highly
diluted forms so that only a small percentage of active  ingredient is present in the dosage
form.  Although some of the  active ingredients can  qualify as moderately hazardous,  we do
not consider the  typical mix  of  returned goods that would  actually 'be  disposed of on land
to be  hazardous.  It is highly  unlikely that the diluted ingredients would be ingested. Never-
theless, some companies have a few products (such  as mercurial ointments) that they  screen
out of their returned goods to ensure that the discarded material is environmentally accept-
able. If  a company takes the conservative position that all returned goods and discarded
products are considered as moderately hazardous until they are examined, the handling and
disposal  of these compounds can be done without hazard to personnel or the  environment.

3.2  WASTE GENERATION DATA DEVELOPMENT

3.2.1  Approach to the Problem of Obtaining Valid Industry  Hazardous Waste Data

     No  Federal  law  has  yet been passed requiring industry to obtain  and  report data on
hazardous materials produced as wastes destined for land disposal. To conduct this study it
was therefore imperative to obtain the voluntary cooperation of companies that represented
a significant portion of the U.S. production of pharmaceutical products. Fortunately, the
Pharmaceutical Manufacturers Association (PMA) supported the planned attempt to  obtain
useful information on which EPA's Office of Solid Wastes Programs could  base its  future
planning and programs. The PMA Environmental Control Committee lent us  its support and
assisted in obtaining the cooperation of several major pharmaceutical producers.
                                         38

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                       TABLE 3.1.3C

TYPICAL TOXICITIES OF PHARMACEUTICAL ACTIVE INGREDIENTS
       AS MEASURED BY ORAL LD50 ON MICE AND RATS*

                          Oral LD50 (mg/kg)
Drug Class
Analgesics













Compound Mouse
A
B 815
C
D
E
F 18
G
H
I
J 693
K
L 84
M
N
Rat
2404
1500
4025
748
542

170
95
887

1650

1890
1600
Reference
1
2,3
4
4
5
1
6
7
8
9
10
5
1
11
    Antibiotics
A
B
C
D
E
F
G
H
I
J
K
L
M
N
0
P
Q
R
>3750
                            2618
                            4600
                          >2880
                             808

1188
2500
3400
3000

2372
2000

1447
>4000

4800
300
807
3579
3550
702
12
1
13
1
12
14
1
15
16
1
17
12
18
1
1
1
1
1
   *Table references follows table.
                            39

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TABLE 3.1.3C (Continued)
            Oral LD50 (mg/kg)
Drug Class
Ataractics













Cardiovasculars














Hormones



Compound
A
B
C
D
E
F
G
H
I
J
K
L
M
N
A
B
C
D
E
F
G
H
I
J
K
L
M
N
0
A
B
C
D
Mouse

126

148-176

>515

980

150
1250

1350
330



213



292

300
680

890



>2500
1737
950
Rat Reference
433 19
548 20,1
710 1
346-460 21
840 , 1
22
710 23
1552 24,1
318 19
25
1800 4,26
995 1
740 27,26
28
56 1
2600 1
1 000 29
30
2221 1
1100 4
1750 1
31
>80 32
440 33,34
300 35
2500 26
36
1000 26
3200 4
>300 4
37
2952 1
1


































Oral LDSO Summary of Typical Classes of Pharmaceuticals
(Classified
Toxicity Grade 4 (0-5)
Analgesics 0
Antibiotics 0
Ataractics 0
Cardiovasculars 0
Hormones 0
Total 0
by lower of
3 (5-50)
1
0
0
0
_0_
1
rat or mouse toxicity values)
2 (50-500)
3
1
6
6
J_
17
1 (500-5000)
10
18
8
9
_3_
48
0 (> 5000)
0
0
0
0
_p_
0
         40

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                                REFERENCES TO TABLE 3.1.3C

 1.  Toxicol. Appl. Pharmacol., 18, 185, 1971. (TXAPA9 - Toxic Substance List, 1973)
 2.  Toxicol. Appl. Pharmacol., 23, 537, 1972. (TXAPA9 - Toxic Substance List, 1973)
 3.  J. Pharmacol. Exp. Ther., 99, 450, 1950. (JPETAB - Toxic Substance List, 1973)
 4.  Merck Index. (12VXA4 - Toxic Substance List, 1973)
 5.  J. Pharmacol. Exp. Ther., 134, 332, 1961. (JPETAB - Toxic Substance List, 1973)
 6.  J. Pharmacol. Exp. Ther., 103, 147, 1951. (JPETAB - Toxic Substance List, 1973)
 7.  J. Pharmacol. Exp. Ther., 92, 269, 1948. (JPETAB - Toxic Substance List, 1973)
 8.  Food Cosmet. Toxicol., 2, 327, 1964. (FCTXAV - Toxic Substance List, 1973)
 9.  Arch. Int. Pharmacodyn. Ther., 190, 124, 1971. (AIPTAK- Toxic Substance List, 1973)
10.  Toxicol. Appl. Pharmacol., 7,  240, 1959. (TXAPA9 - Toxic Substance List, 1973)
11.  J. Pharmacol. Exp. Ther., 89, 205, 1947. (JPETAB- Toxic Substance List, 1973)
12.  Spector, W.S., ed. Handbook of Toxicology, Volume I: Acute Toxicities. W.B. Saunders Co.
     (Philadelphia), 1956.
13.  Toxicol. Appl. Pharmacol., 8,  398, 1966. (TXAPA9 - Toxic Substance List, 1973)
14.  Toxicol. Appl. Pharmacol., 21, 516, 1972. (TXAPA9 - Toxic Substance List, 1973)
15.  Toxicol. Appl. Pharmacol., 10, 402, 1967. (TXAPA9 - Toxic Substance List, 1973)
16.  J. Antibiot,  19, 30, 1966. (JANTAJ - Toxic Substance List, 1973)
17.  Toxicol. Appl. Pharmacol., 6,  746, 1964. (TAP- Journal)
18.  Acta Pol. Pharm., 24, 451, 1967. (APPHAX - Toxic Substance List, 1973)
19.  Toxicol. Appl. Pharmacol., 21, 315, 1972. (TXAPA9 - Toxic Substance List,  1973)
20.  Mouse - Physicians Desk Reference (PDR), 1974 and Proc. Eur. Soc. Study Drug Toxicity, 8,
     177, 1967. Rat-Toxicol. Appl. Pharmacol., 181, 185, 1971 (PSDTAP and TXAPA9 - Toxic
     Substance List, 1973)
21.  Physicians Desk  Reference (PDR),  1974
22.  J. Pharmacol. Exp. Ther., 727, 318, 1959. (JPETAB - Toxic Substance List, 1973)
23.  Am. Ind. Hyg. Assoc. J., 30, 470, 1969. (AIHAAP - Toxic Substance List, 1973)
24.  Mouse - J. Pharmacol. Exp. Ther., 723, 75,  1960. Rat- Toxicol. Appl. Pharmacol., 18, 185,
     1971. (JPETAB  and TXAPA9  - Toxic Substance List, 1973)
25.  Toxicol. Appl. Pharmacol., 27, 302, 1972. (TXAPA9 - Toxic Substance List,  1973)
26.  Barnes, C.C., Eltherington, L.G., Drug Dosage in Laboratory Animals — A Handbook, Univ. of
     California Press, Berkeley, 1965. (DDLA- Toxic Substance List, 1973)
27.  Smith, Kline and French Laboratories (Philadelphia ) — Mouse. Barnes, C.C., Eltherington,
     L.G., Drug Dosage in Laboratory Animals —  A Handbook. Univ. of California Press, Berkeley,
     1965) (SKFL and DDLA - Toxic Substance List, 1973)
28.  J. Pharmacol. Exp. Ther., 727, 318, 1959. (JPETAB -  Toxic Substance List, 1973)
29.  J. Pharmacol. Exp. Ther., 128, 22, 1960. (JPETAB - Toxic Substance List,  1973)
30.  Toxicol. Appl. Pharmacol., 7,  598, 1965. (TXAPA9 - Toxic Substance List, 1973)
31.  J. Pharmacol. Exp. Ther., 779, 580, 1971. (JPETAB -  Toxic Substance List, 1973)
32.  Arch. Ital. Sci. Farmacol., 6, 153, 1937. (AISFAR - Toxic Substance List, 1973)
33.  J. Pharm. Pharmacol., 727, 179,  1960. (JPPMAB - Toxic Substance List, 1973)
34.  Arch. Int. Pharmacodyn. Ther., 180, 155, 1969. (AIPTAK -  Toxic Substance  List, 1973)
35.  Ann. N.Y. Acad. Sci.,  707, 1,068, 1963. (ANYAA9 - Toxic Substance List, 1973)
36.  Toxicol. App. Pharmacol., 27,  253, 1972. (TXAPA9 - Toxic Substance List, 1973)
37.  Klin. Wochenschr., 18,  156, 1939. (KLWOAZ - Toxic Substance List, 1973)
                                            41

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     Because the industry had never had to report detailed composition of waste streams,
we  realized that mailing of questionnaires would not  produce usable  information. We
therefore chose  to conduct in-depth interviews  and plant inspections at the plants of the
cooperating companies. We visited the principal production plants of  companies repre-
senting 27 percent of total U.S. sales of ethical Pharmaceuticals. These plants represented an
even higher percentage of  the active ingredient production of the industry. All facilities
visited had multiple  operations so that good representative information was available  on
R&D, fermentation,  biological products, organic synthesis, extraction of animal glands and
formulation and packaging operations in the United  States,  including Puerto Rico. Infor-
mation given to us in the  interviews and by letter was  checked and confirmed with the
companies. From the collected data we extrapolated to obtain information applicable to the
entire industry.

     During the  course of the study we also visited eight  landfills and four contractors that
were  treating wastes, principally by incineration. We also  interviewed 11  contractors  by
telephone to confirm information obtained from plant visits.

     As explained in Section 2.0 of this report, the SIC  codes of the U.S. Department of
Commerce do not exactly  follow functional divisions of  the  pharmaceutical industry. For
example,  we  were  interested in  obtaining information on  R&D wastes and  the  R&D
category does not have a SIC code. Another complication in data collection from the plants
was that many of the pharmaceutical plants producing active ingredients were  diversified,
i.e., some parts  of the manufacturing  complex produced materials for animal feeds, cos-
metics,  pesticides, fine organic chemicals,  etc., as well as medicinal ingredients. For this
study we have attempted to isolate  those  wastes that are  associated only with the phar-
maceutical production.

     The information that  we collected on plant visits was categorized under three of the
four functional  divisions of the pharmaceutical  industry: (1) Research and Development,
(2) Production  of Active  Ingredients, and (3)  Formulation  and Packaging. The fourth
functional  division, Marketing and Distribution, did not dispose of significant quantities of
process wastes or hazardous wastes, as damaged or outdated goods were normally returned
to the formulation plants for disposition.

     As indicated in Section 2, we considered plants listed as 2831 and 2833 under the
production  of active ingredients category and plants listed as 2834 under the formulation
and packaging category.

3.2.1.1  Wastes from  Research and Development Installations

     Based  on surveys conducted by the  Pharmaceutical Manufacturers Association that
show a total of approximately 23,000 personnel employed in research and development
(R&D) activities in its member  firms, we estimate that total pharmaceutical R&D personnel
                                         42

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amount to about 25,000. About one-half of the R&D staff is made up of scientific and
professional people and the other half is about  equally  divided between technical and
supporting staff.

     R&D  activities  are often concentrated in research centers  run by the industry that
employ from 200 to over 2000 R&D personnel so that sizable quantities of wastes may be
generated in these centers. On the other hand, some R&D activities are dispersed throughout
the individual companies so only a  few R&D  personnel may be in a given plant, and the
R&D wastes may not be segregated.

     Depending on the type of research being done the wastes from these activities may
involve a heavy use of solvents in one installation while at  another installation most of the
work may  involve tests  on  animals. Thus  in one case there  will be waste solvents to be
disposed of and in the other there will be test animals to be incinerated. We found that the
average mixed solvent waste at  the  installations  we visited was  about 66 liters  per
man-year or a yearly total of approximately 1500 metric tons in the United States.

     Other hazardous wastes occurred in much smaller amounts than the solvents and were
usually handled as specified by the "Laboratory Waste  Disposal Manual" issued by the
Manufacturing Chemists' Association. Heavy metal wastes, such as mercury or mercury salts,
were often stored until a sufficient quantity was on hand to sell to a reprocessor.

3.2.1.2 Wastes from the Production of Active Ingredients

     In addition to the active ingredients that it  produces itself, the pharmaceutical industry
purchases many of its active ingredients from chemical companies that are not really in the
pharmaceutical industry. Most of the plants listed under SIC 2831 (Biological Products) are
a part of the pharmaceutical industry and manufacture active ingredients consumed by the
industry. On the other hand, many of the products listed under "Medicinal Chemicals" by
the U.S. Tariff Commission are manufactured  by chemical companies that are not in the
pharmaceutical business. A good  example of the latter is choline chloride in the "Medicinal
Chemicals" category,  which is made almost entirely by chemical companies, but which is
used  almost entirely  in animal  feed production. We have subtracted  substances such as
choline and other materials that are made mostly by the chemical companies  to arrive at
the active ingredient production that could be assigned to SIC code 2833. We estimate that
the pharmaceutical industry's 1973 production  of organic medicinal ingredients, excluding
antibiotic production, was no more than 34,000 metric tons  (75 million pounds).

     In the subsections that follow, we discuss methods of active ingredient production and
the generation of process and hazardous wastes. We have selected the processes shown from
the open literature, and they are  typical of industry practice, but do not refer to a specific
company's installation.
                                         43

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     3.2.1.2.1  Synthetic Organic Medicinal Chemicals

     The production of organic medicinal chemicals may involve the chemical (or biologi-
cal) modification of an antibiotic, botanical, or drug from animal sources, or it might be the
complete chemical synthesis of a complex chemical, such as vitamin  A, whose  synthesis
starts with acetone,  acetic acid,  acetylene, and methyl vinyl ketone. Unlike the "heavy
chemicals," those chemicals which are. produced by the chemical industry in thousands of
tons annually, the total annual production of any given organic chemical medicinal might
only be 1  or 2 tons.  Heavy chemicals are produced in continuous processes and generate a
uniform waste stream, but many different medicinals are produced in single batches which
causes a wide variation in their waste streams.

     The amount of process waste generated per ton of product will vary greatly, depending
on the number of synthesis steps, the yield in each step, and the solvents used. The chemical
synthesis may only require a two-step synthesis with recovery of unreacted  raw materials,
such as in  aspirin production, or as  many as 13 steps as  in the production of vitamin A.
With  an  overall yield  of  over  80%,  less than 0.2 kg  of organic residue waste would  be
generated  per kg of aspirin, whereas the overall yield in the production of vitamin A might
be as low as 15-20%, thus generating  as much as 7 kg of organic waste per kg of product.
The by-product organic residue waste material is separated from the main product by any of
a number  of  methods such as  extraction,  distillation, precipitation, crystallization,  or
filtration,  and may  be  recovered  as  hard still bottoms,  chemical  muds, or in a solvent
solution. This  residue may still contain residual hazardous organics such as hydroquinone,
pyridine, or oxalic acid.

     Wastewater from  the production of organic medicinal chemicals (containing up to
several thousand ppm of biodegradable organics such as isopropanol, acetone, ethanol, or
acetic  acid) must be treated to meet effluent  requirements.* This wastewater is usually
treated biologically, such  as  an activated  sludge treatment, either  on-site  or in local
municipal treatment systems. This biological treatment, in turn,  generates from 0.3 to 0.7
kg  of biological sludge solids per  kg of  organic solids  removed, the remainder  being
converted to carbon dioxide and water by the biological sludge organisms.

     The volume of solvent waste generated depends on the degree to  which the solvent is
contaminated, to what  extent solvent recovery is practiced, and the type of reaction and
solvent required. Some reactions, such as hydrogenation, may require no solvent at all; some
may use ethanol or acetic acid which is diluted and discharged to biological treatment, while
still others may use toluene or benzene which must be recovered or incinerated. A "typical"
synthetic organic medicinal chemical production process might be summarized as shown in
Figure 3.2.1.2.1.
*State or Federal.
                                         44

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         Raw Materials
         (5,000,000 kg)
                                      Finished Medicinal Products
                                           (500,000 kg)
Recycle
                    I vents        Aqeous Wastes
                 000,000kg)       (1,400,000kg)
                                   (solids)
      Waste Solvents
       (400,000 kg)
Biological Wastewater
     Treatment
Solid Wastes (dry)
  (300,000 kg)
                                   Biological
                                     Slud9e  **          /
                               (700,000 kg) (solids)        /
                                              V
                        Incineration
                                                                     Landfill
FIGURE 3.2.1.2.1   TYPICAL SYNTHETIC ORGANIC MEDICINAL CHEMICAL PROCESS
                                         45

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     Based on interviews and waste figures provided us by the industry, we have estimated
the average  quantities of waste generated per ton of product as shown in Table 3.2.1.2.1.
The production of aspirin will  generate less waste than the averages given in this table while
the production  of certain tranquilizers and  vitamins will generate more waste per ton of
product.  We believe that the averages we present in Table 3.2.1.2.1 represent the waste
generated for a typical or "average" mixture of synthetic organic medicinal products.


     The wastes  as  shown in this  table are segregated into solvents, organic residues,
biological sludge,  solid inorganic  wastes containing materials such as filter aid and carbon
and heavy metal wastes.


     Most of the hazardous waste generated  in the synthesis of organic medicinal chemicals
is organic in nature (composed of hydrogen, oxygen, carbon, and nitrogen) and is generally
disposed of. by  incineration.  A  limited amount of heavy-metal wastes,  such as those
containing mercury, chromium, copper, arsenic, and zinc, is also generated, however.


     Zinc waste generally occurs  in  pharmaceutical  chemical  production as metallic  zinc,
zinc oxide, or  zinc  chloride.  Metallic zinc is used as  a  reducing agent  and its salts as a
catalyst.  It  is  usually recovered  (for disposal  or recycle) from the reaction  mixture by
filtration. The waste zinc salts are recovered by precipitation or solvent evaporation.


                                       TABLE 3.2.1.2.1

                    ESTIMATED AVERAGE OF CHEMICAL WASTES GENERATED IN
                          ORGANIC MEDICINAL CHEMICAL PRODUCTION*

                                                                 Kilogram of Waste per
     Non-Hazardous Waste                                        Metric Ton Product (dry basis)

       - Biological Sludge                                           1400* (14,000 wet)
          (from Organic Chemical Wastewater Treatment)
       — High Inert Content Wastes (Filter and, Activated Carbon)              100

                                           Kilogram of Waste per          Heavy Metal Content
                                            Metric Ton Product       (kg Per Metric Ton Product
     Hazardous Wastes**                           (dry basis)                  of Waste)

     — Halogenated Solvent                            100
     — Non Halogenated Solvent                        700
     — Organic Chemical Residues
       (Tars, Muds, Still Bottoms)                        400
     — Contaminated High Inert Content Wastes
       (Filter and, Activated Carbon)                      50
     - Solid Heavy-Metal Wastes
       Zinc                                          70                      30
       Arsenic                                       15                      0.3
       Chromium                                    0.7                      0.3
       Copper                                      0.1                      0.04
       Mercury                                      0.02                     0.01

      *From 2800 kg of solids in organic chemical wastewater.
     "Contains some heavy metal, corrosive chemical, or flammable solvent

      Source:  Interviews and A.D. Little, Inc., estimates.


                                           46

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     To put the 2,200 metric tons/yr of zinc waste landfilled by the pharmaceutical in-
dustry in perspective, an  estimated 36,000 metric tons of zinc oxide annually finds its way
into landfills throughout the United States as photocopy paper.

     Arsenic  wastes are  generated  in the pharmaceutical  industry  as a  by-product  of
arsenical production and  where arsenic compounds are used as catalysts or oxidizing agents.

     We do not believe  there  is widespread use of chromium or chromium salts in the
pharmaceutical industry.  The oxide is used in the heavy chemical industry as one of many
catalysts for hydrogenation and oxidation, and as  an oxidizing agent in  some organic
chemical syntheses. However, many  of  these oxidation (dehydration) reactions can be
conducted, using other oxidizing agents, such as  chlorates, peroxides or permanganates. In
the one case where we know that chromium is being used in the pharmaceutical industry,
the chromium waste is recovered by precipitation  and filtration and then sold.

     We know of only one pharmaceutical company which produces a copper waste,  and it
is presently disposed of by deep-well injection.

     We  estimate  that  organic  mercury  wastes containing  about 270 kg of elemental
mercury  are  produced by the pharmaceutical industry annually. A limited number of
pharmaceutical companies produce the mercurial products which include nitromersol and
thimerosal. These companies take considerable care to ensure that mercury is removed from
the plant wastewater effluents.

     There are a number of processes available for the removal of mercury from wastewater.
Ion exchange, solvent extraction, carbon adsorption, sulfide precipitation, cementation, and
reduction/precipitation have  all been  used with varying degrees of success. The  type of
mercury-removal process that should  be  used for a specific application depends on the
following:

     •   Concentration of mercury in the wastewater;

     •   Maximum allowable concentration of mercury in effluent;

     •   Chemical form  of the mercury to be removed;

     •   Type and quantity of other chemical constituents in the wastewater; and

     •   Desirability of recovering metallic mercury.

     According to our investigations, reduction/precipitation processes are  being used in-
creasingly where the  wastewater flow  rate is relatively small and intermittent. Mercury is
recovered either as pure metallic mercury or as an  amalgam.
                                         47

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     In the most common  reduction/precipitation  process, which is currently being com-
mercialized, a caustic solution of sodium borohydride (NaBH4) is mixed with the mercury-
containing wastewater  where the ionic mercury is directly reduced to  metallic mercury
which rapidly precipitates out of solution. The following reaction occurs:

     4 Hg2+ + BH^ + 8 OH~ = 4 Hg + B(OH)^ + 4 H2O

     If the mercury solution is in the form of an organic complex, the driving force of the
reduction reaction may not be sufficient to break the complex. In that case, the wastewater
must be chlorinated prior to the reduction step to break down the metal-organic bond.

     When elemental mercury recovery  is not desired, the reduction process can be used to
form mercury amalgams to produce a  less hazardous solid waste for ultimate disposal by
encapsulation and landfill.

     3.2.1.2.2 Inorganic Medicinal Chemicals

     Antacids make up a major share of inorganic medicinal chemical production. Generally
antacids have magnesium hydroxide or  aluminum hydroxide as their primary active ingredi-
ent.  These antacids are produced  by  precipitating a  water-insoluble compound  from a
solution of a  soluble aluminum or magnesium salt by a sodium salt. Some formulations also
include  magnesium trisilicate,  calcium  carbonate,  sodium bicarbonate,  alumina gel, and
bismuth  aluminate. The waste stream generated contains no toxic metals or salts and is
usually  a solution of sodium  chloride or sodium  sulfate.  Bad batches  of antacid active
ingredient may  occasionally be produced, and these  are either reprocessed or disposed of by
landfilling, but they would also be considered nonhazardous.

     We did find one toxic  metal-containing waste generated in the production of inorganic
medicinal chemicals. This  waste  contains about  0.2%  selenium  and amounts to about
160,000 kg annually.

     The pharmaceutical industry  produces  several laxatives of botanical origin  such as
senna, cascara,  and  a  synthetic organic medicinal, phenolphthalein. However, milk of
magnesia (magnesium hydroxide suspension) is the principal inorganic laxative. The produc-
tion of  magnesium hydroxide  for this  use would also generate aqueous sodium sulfate or
sodium chloride.

     Active ingredients for many other inorganic medicinals are purchased for products such
as mouthwashes, throat  lozenges,  and topical medicinals, such as the mercurials, zinc oxide
ointments, and  foot powders. Since these purchased active ingredients are produced by the
chemical industry (rather than the pharmaceutical industry), the only waste containing
these purchased ingredients is that generated in the compounding and packaging of pharma-
ceutical preparations.
                                        48

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3.2.1.2.3 Fermentation Products (Antibiotics)

     Most commercial antibiotics  are the products of living microorganisms, such as fungi
(molds)  or bacteria. The  crude antibiotic produced by the microorganism is recovered from
the fermentor broth (a water solution containing nutrients) by extraction, precipitation, or
adsorption, depending on the type of antibiotic. Bacitracin,  the penicillins, cephalosporins,
and erythromycins are usually recovered  from the filtered broth by solvent extraction.
Chlortetracycline is  recovered  by  solvent  extraction  of  the  whole  broth (containing
mycelium) or filtered broth. Streptomycin is recovered from the filtered broth by ion ex-
change.  Oxytetracycline  is recovered  from the  filtered broth  by precipitation with a
quaternary ammonium compound.

     Following recovery  from the  fermentor broth,  the antibiotic is purified, in most cases,
by several stages of re crystallization. Other antibiotics, such as the semi-synthetic penicillins
and cephalosporin derivatives, are  produced by chemically modifying antibiotics  produced
by fermentation.

     The production of antibiotics results in the generation of several large waste streams:
the  filtered  micro-organism (mycelium*); the  filtered, extracted, fermentor broth; and
contaminated solvent generated in the solvent recovery operation.

The fermentor broth is sometimes  concentrated and sold as an animal feed supplement, but
in most cases the fermentor broth  and other  wastewater streams are treated biologically to
meet effluent requirements.  The 0.3  to 0.7 kg of biological sludge generated per kg of dis-
solved organics removed in wastewater treatment is either landfilled or incinerated.

  A good example of  antibiotic production (and a  large  volume  product)  is penicillin  as
shown in Table 3.2.1.2.3 and Figure 3.2.1.2.3.

     Commercial penicillin is produced by the submerged-culture fermentation process in
which  a strain of Penicillium mold is grown in an aerated, stirred tank, the fermentor, in a
water medium. This medium contains carbohydrates (starches, sugars) as an energy source,
nitrogen  in the form of ammonium salts or corn-steep liquor solids for  mycelium  cell wall
protein,  and trace minerals, such  as magnesium, which are necessary  for  growth. Rapid
growth of the mycelium takes place during the first  24 to 48 hours and the production of
penicillin takes place from 24 to 120 hours.
 *The term mycelium should be reserved for describing the thread-like growth of molds, such as Penicillium,
 or the analagous growth in Actinomyces. However, the term is commonly used in the industry to designate
 the mixture of cells, filter aid, undigested grain solids, etc., that is filtered off and discarded from all types
 of fermentations, including bacterial fermentations that do not produce true mycelia.
                                          49

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                                       TABLE 3.2.1.2.3

                TYPICAL ANTIBIOTIC PRODUCTION PLANT (PROCAINE PENICILLIN G)

              A.   Annual Production        950,000 kg
              B.   Waste Characterization

                                                      Weight per 1000 kg Product
                  Non-Hazardous Waste      Stream No.        Dry        Wet
                    Mycelium                 ฉ          2,300kg   10,000kg
                    Biological sludge            ฎ          3,500kg   35,000kg

                  Non-Hazardous Waste to Biological Treatment
                                                      Liters per 1000 kg Product
                    Waste fermentation broth     @                56,000
                    Crystallization water         @                   100
                    Phosphate buffer solution     ฉ                 3,000
                    Crystallization water         ฉ                   100
                    Potassium chloride solution    (ง)                 4,000

                  Hazardous Waste
                                                      Liters per 1000 kg Product
                    Solvent Waste Concentrate    (2)                 1,200
                      Solvent (butyl acetate)                         600
                      Dissolved organics (fats, protein)                 600
      Source:  Arthur D. Little, Inc., estimates.
      Carbohydrate is  fed  to the fermentor over the course of the fermentation as an energy
source  for the mycelium. After the initial mycelium growth phase, a  precursor,  such as
phenylacetic  acid or its salts, is added to increase production of a specific type of penicillin.
The mold uses this precursor directly in producing the penicillin. With phenylacetic acid, the
yield of penicillin G is greatly increased.

      The strain of penicillium, the exact  composition of the growth medium,  the yield of
penicillin,  and some  details of the purification  of the penicillin are  trade secrets of the
manufacturers. The penicillin produced and recovered from the  fermentation may also be
chemically modified to produce one of many commercial penicillins, but the fermentation
process for initially producing the basic penicillin is generally the same.

      A typical penicillin production process (Figure 3.2.1.2.3) consists of the initial fermen-
tation in which the antibiotic is produced by the micro-organism, the recovery of the crude
antibiotic  from the fermentation  broth by several stages of solvent and  aqueous buffer
extraction, crystallization of  the  crude  antibiotic, and finally the sterilization  of the
antibiotic. The same process steps  are used  by  many producers, but  the exact conditions of
pH and temperature and extraction procedures (type of extractor, type of solvent, etc.) will
vary- from  producer to producer. Likewise there was some variation in quantity of mycelium
waste reported by  our industrial  contacts. Nonetheless we believe that  the  system for
penicillin production, as shown in Figure 3.2.1.2.3, is representative of industry practice and
is representative of the types and quantities of waste generated in penicillin production and
antibiotic production  in general.

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                                             Sodium Phenylacetate
                                                   (300 kg)
                                                                                                                 Clarifier Broth
                                                                                                                pH 7.0 and 25ฐ C
    Corn Steep Liquor Solids
    Hydrolyzed Starch
    Glucose
    Ammonium Nitrate
    Magnesium Sulfate
                                                                                            (10,000 kg]Y Wet
                                                                                               Mycelium Waste
                                                                                              (2,300 kg dry solids
         Makeup Butyl Acetate
             (700 liters
     Butyl Acetate
     Solvent Waste
      (1200 liters
                                              Butyl Acetate
                                        3900 liters        7000 liters
                                                                                                                 Broth at pH 7.0
                                                                                                                  and 4ฐC
      600 kg Butyl Acetate
      600 kg Solids
                                                                                                    5% Phosphate Buffer
                                                                                                    Solution at pH 7.5 or
                                                                                                  Potassium Acetate Solution
                                                                                                       (3000 liters)
                                                                                   Water Solution of
                                                                                   Penicillin at pH 6.5-6.8
       Waste Fermentation Broth
            (56,000 liters)
            (6700 kg solids
  Phase to Disposa
  (100 liters)
                                                                              Water Phase to
                                                                              Solvent Strip
                                                                              and Disposal
                                                                              (3002 liters
                                                                                 5
Procaine Penicillin Product
      (1000kg)
                                                                                                      Butyl Acetate
                                                                                                      Solution of
                                                                                                      Penicillin
                                                                              Potassium Acetate
                                                                                  (200 kg)
                         Potassium Chloride
                         Water Waste j g
                         (4000 liters)
                         (leOkgKCI)
                                                                               Solvent Waste to
                                                                                utyl Acetate
                                                                               Recovery
                                                                               (120 liters)
                                                                                                                       Water Phase to  C 1J
                                                                                                                      Solvent Stripping
                                                                                                                        and Disposal
                                                                                                                        (100 liters
                                                                  Crude Potassium Penicillin
                                                                      (700 kg)
                                                                                                                                         ฉ
Sources:
          Brunner, Elder, Prescott, Rehm, Standen, Underkofler, Webb and Arthur D. Little, Inc., estimates
          (see Bibliography at end of Section).
             FIGURE 3.2.1.2.3    REPRESENTATIVE PROCESS FOR ANTIBIOTIC PRODUCTION
                                       (PROCAINE PENICILLIN G)

                                                                       51

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     Nutrients necessary for mycelia growth and penicillin production are dissolved in water
to form the fermentation medium which is  then sterilized by heat, either before or after
being added  to  the fermentor. Then the medium  is cooled  to near room temperature
(20-24ฐC) and inoculated with a concentrated culture of the Penicillium organism, about 5%
by volume. The  inoculated medium is agitated by a turbine-type impeller and compressed,
sterile air necessary for the growth of  the mycelium is  sparged into the fermentor. After
24 hours the mycelium has grown to  near its maximum concentration in the fermentor and
penicillin  production by the mycelium increases  rapidly. Penicillin production  continues
with supplemental additions of carbohydrates and a precursor to the end of the  fermenta-
tion cycle, about 5 days, when the penicillin reaches near maximum concentration. At this
point the fermentor is harvested and  the  mycelium  is filtered  from  the  spent  growth
medium  (broth).  The  filtered broth is  chilled  to prevent  penicillin  deterioration  and
acidified to liberate penicillic acid which is extracted by  a water-immiscible solvent such as
butyl or  amyl  acetate. The waste broth from  this extraction  may  be neutralized  and
discharged to a biological treatment system  or  concentrated for sale as an animal feed
supplement. The solvent containing the penicillin is extracted with an  alkaline  buffer to
form the sodium or potassium salt and remove it  from  the solvent into a water solution. At
this  point the  crude sodium  or  potassium salt  may be precipitated  out directly with a
solvent, or acidified and re-extracted by a water-immiscible solvent followed by neutraliza-
tion and  crystallization. Finally, the crude salt  is redissolved in water passed through a
sterile filter to a mix tank where it is combined with a sterile precipitating agent, and the
insoluble sterile  salt is recovered  by  centrifuging and then dried in a vacuum drier. As an
alternative to recovery as the potassium or procaine  salt, the penicillin may be chemically
modified  to  other penicillin derivatives before sterilization. In this report, the chemical
modification of antibiotics  is considered to  be  part  of the organic  medicinal chemical
segment of the industry.

     Since the medium in which this  living organism, the mycelium, is grown  is not toxic
to the organism, the spent medium would also be expected to have low toxicity. This is
generally  true.  The mycelium  from  the  spent medium  (fermentor broth) is incinerated,
landfilled, or used as a soil builder. Some  states require that mycelium have a solid content
of 30% or more before it is landfilled, since higher concentrations of water might cause
leaching of hazardous materials from  other substances in the landfill. To increase  the solids
content of the mycelium from penicillin production, a filler such as sawdust may be added.
Mycelia from other antibiotic fermentations contains filter aid which  is necessary for the
filtration of the  more gelatinous mycelia produced in these fermentations, and this increases
the solids concentration to an acceptable level.

     The  extracted, acidified  fermentation broth must  be neutralized before it  can be
disposed of by one of several  methods such as incineration, biological treatment, or
concentration and sale as an animal feed  supplement. In the case of biological treatment, the
resulting sludge must  also  be disposed of by incineration or landfill. In figure 3.2.1.2.3 we
have assumed biological treatment of the spent broth and other wastewater streams.
                                         52

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     The only hazardous wastes resulting from antibiotic production are the waste solvents
which contain  organic  material from the  extracted  broth  and which  are generated in the
recovery of the major portion of the solvent used in the process. In this  report, any chemical
wastes from antibiotic modification are considered to be part of synthetic organic medicinal
chemical production.

     3.2.1.2A  Botanicals

     The Pharmaceuticals produced from plant material — leaves, bark, and roots — include
the  alkaloids  such  as  quinine and reserpine,  plant  steroids for  chemical  synthesis  of
cortisones and oral contraceptives, and laxatives such  as emodin from cascara bark.

     3.2.1.2.4.1 Alkaloid Production from Botanicals Alkaloids are usually defined as basic
(alkaline),  nitrogenous  botanical  products which produce  a  marked  physiological  action
when administered  to  animals. Commercial  alkaloids include quinine, emodin (a  cascara
alkaloid), reserpine, and vincristine (a new anticancer drug).  The alkaloid content  of the
plant material can vary greatly. For example, quinine is present in amounts of up to  10% in
cinchona bark, while vinscristine is present in Vinca rosea (periwinkle) leaf in a concentration
of only about 0.02%.
     A process flow sheet for the production of a (alkaloid) botanical medicinal from plant
material is presented  as Figure 3.2.1.2.4.1, and Table 3.2.1.2.4.1  summarizes the  waste-
streams. The dried, ground plant material (roots, bark, seeds,  or leaf) is generally extracted
with an acidified water-miscible solvent  such as alcohol and  this leachate, in turn, is ex-
tracted with a water-immiscible solvent such  as ethylene dichloride. Variations in this pro-
cedure  include: (1) using an aqueous  solvent mixture of water and alcohol for the initial
extractions, and (2)  concentration of the  initial alcohol  extract before the  second (liquid-
liquid) extraction, transferring the alkaloid into the water-immiscible solvent.

     The equipment used for the initial extraction  may be a series of stirred tanks, each
followed by a  filter to remove the plant  material, or a series of vessels with wire  screen
supports to hold the  plant material while  the leaching  solvent is  changed  after each
extraction.

     The crude alkaloid is recovered from  the second (water-immiscible) solvent by vacuum
evaporation and  further purified by crystallization, precipitation, ion exchange, or chrom-
atography.

     Waste solvent containing plant extract is the hazardous waste generated in the extrac-
tion of the crude alkaloids  from plant materials.  (The subsequent  conversion of these
alkaloids to other derivatives may create additional hazardous  wastes, but these  wastes
would be included in organic medicinal chemical production.) The extracted plant material
waste must be steamed, however, to remove residual solvent  that would otherwise pose a
fire hazard.
                                          53

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                                                 Dried Leaves, Root, Seeds or Bark
                                                             (330 kg)
0
Wet Plant
 Material
 (660 kg)
To Landfill
                                                                                    60% wt Methanol
                                                                                    40% wt Water
                                                                                    (3500 liters)
                                                    Recovered Methanol/Water
                                                           (130 liters)
                                        Filter
                                        and
                                    Concentrate
                 Steam (200 kg)
                  Chlorinated Solvent
                       (700 liters)
              Makeup
            Chlorinated
              Solvent
              (7 liters)
            Sodium Hydroxide
                 (10kg)
                                                                                Methanol/Water
                                                                                 (2100 liters)
                                                                  Concentrated Methanol/Water
                                                                             Extract
                                                                             (11 00 liters)
                                    Immiscible
                                     Solvent
                                     Exchange
              Chlorinated
                Solvent
               Recovery
                                                                                Methanol/Water
                                                                                  (1100 liters)
                                                                  Alkaloid in
                                                                  Chlorinated
                                                                 . Solvent
                                                                          Methanol/
                                                                           Water
                                                                          (3200 liters)
                                                          Crude Alkaloid
                                                             Recovery
                                                       (vacuum evaporation)
                                     Crude Alkaloid
(2)  Waste
   Chlorinated
     Solvent
    (7 liters)
                                                                                           Organic Acid
                                                                                              (40 kg)
                                                                                                                     Makeup
                                                                                                                  Methanol/Water
                                                                                                                    (300 liters)
                                                                         Methanol/Water
                                                                            Recovery
                                                                                                 ฉ
                                                                               i
                                                            Precipitation
                                                         Chromatography
                                                         or Ion Exchange
                                                                1
                                                                              Solvent
                                                                               Waste
                                                                              (30 liters)
                                                                                Solvent Waste (130 liters)
                                                                                    40 kg Methanol
                                                                                      20 kg Water
                                                                               .  70 kg Plant Extract and
                                                                                   Organic Acid Salt
                                                           Active Alkaloid
                                                               (1 kg)
                 Source: Forbath, Manske, Nobler and Arthur D. Little, Inc., estimates. (See Bibliography)
                 FIGURE 3.2.1.2.4.1 REPRESENTATIVE PROCESS FOR BOTANICAL MEDICINALS
                                      (PLANT ALKALOIDS)
                                                           54

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                                    TABLE 3.2.1.2.4.1

    TYPICAL PLANT FOR PRODUCING BOTANICAL MEDICINALS (PLANT ALKALOIDS)
A.   Annual Production

B.   Waste Characterization
     Non-Hazardous Waste
        Wet botanical material
680kg
                                       Stream No.
                   Weight per kg Product
                      Dry

                    330kg
                  Wet
                 660kg
                                                      kg per kg
                                                  Botanical Material  Quantity per kg Product
     Hazardous Waste
        Halogenated solvent
        Methanol — water concentrate
        Non-halogenated solvent

   Source: Arthur D.  Little, Inc., estimates.
  ฎ
0.03
0.36
0.06
                                                                      Liters
  7
130
 30
                                        kg
  9
120
 20
                                          55

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     The solvent waste generated in the initial extraction will contain alcohol, water, and
dissolved plant extract (resins, fats, etc.). In the second step of alkaloid isolation, extraction
of the alkaloid from the aqueous leaching solvent into a water-immiscible solvent, much of
the water-soluble organic material is left behind in the aqueous solvent. Consequently, not
as much of this second solvent (e.g., chlorinated solvent) becomes waste in this process.

     In the final purification steps  (e.g., crystallization, precipitation)  of the  alkaloid,
additional waste solvent is generated.

     3.2.1.2.4.2 Steroid Production from  Botanicals Most of the  steroid products now
produced commercially  were originally extracted from animal organs, requiring tons  of
animal organs to produce a few grams of hormone. When the structures of the various hor-
mones and other steroids were determined  and synthesis routes were developed, it became
possible to produce many  of these hormones commercially on a large scale from steroids
present in plant materials.  Soybeans  and Mexican yams now  supply the  steroids stigmas-
terol and diosgenin, respectively, used in the commercial production of cortisone derivatives
and oral contraceptives.

     In 1964,  over  70% of  the  cortical hormones  were produced  from diosgenin from
Mexican  yams.  Since  a  high export  tax must be paid  in Mexico on shipments of  crude
product, the diosgenin is extracted from the yams and purified or converted to other steroid
derivatives before export to the United States. Stigmasterol is produced in the United States
by the solvent extraction of soybean oil distillation residue. Table 3.2.1.2.4.2 summarizes the
wastestreams and Figure 3.2.1.2.4.2  shows a representative  flow diagram for the  latter
process.

                                  TABLE 3.2.1.2.4.2

                TYPICAL PLANT FOR PRODUCING BOTANICAL MEDICINALS
                      (STIGMASTEROL FOR HORMONE SYNTHESIS)

       A. Annual Production of Stigmasterol                   130 Metric Tons

       B. Waste Characterization                       Weight per MT Product
           Non-Hazardous Waste
            Fused Soybean Steroid Ingots                     5000 kg
     Still bottoms from  soybean oil refining, which contain around 20% Stigmasterol and
about  45%  )3-sitosterol,  are dissolved  in  a  hot solvent  mixture of hexane and ethylene
dichloride.  About  1000 kg of 97%  Stigmasterol product  and 5000 kg  of  residue are
generated from 6000 kg  of feed steriods through a series of crystallizations from a solvent
mixture of 63% ethylene dichloride and 37% hexane by volume. In each crystallization step,
                                         56

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           10,000 kg Heptane
           35,000 kg Ethylene Bichloride
     j-
    Solvent
    Drying
                Recycled Solvent
                Recycled Solvent
                                            Ingot Casting of
                                            Molten Steroids
                                   Fused Soybean Waste
                                     Steroid Ingots
                                       (5000 kg)
                                           Solvent Recovery
                                            Steroid Melting
                                         Steroid
                                         Solution
Crystallization
   Filtration
                                         Steroid
                                         Solution
                                           1
                                                             Filter Cake
                                             Feed Dissolving
                                              and Filtering
                                  Residue from Soybean
                                       Oil Refining
                                       (6000 kg)
                                         Steroid
                                         Solution
                 Filter Cake
   Dissolving
Crystallization
   Filtration
                                           1000 kg Stigmasterol
                                   Raw Material for Hormone Production
Sources: Poulos et al and Arthur D. Little, Inc., estimates. (See Bibliography)
  FIGURE 3.2.1.2.4.2  REPRESENTATIVE PROCESS FOR BOTANICAL MEDICINALS
                      (STIGMASTEROL FOR HORMONE SYNTHESIS)
                                        57

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successively purer stigmasterol is crystallized out by cooling the hot (60ฐ C) solvent solution
to 30ฐC. The crystals of stigmasterol are recovered by filtration and then redissolved in the
solvent  mixture for the next  crystallization. At the end  of the  process, the 97% pure
stigmasterol containing 45-50% solvent is dried in a vacuum oven to less than 0.06% solvent.

     Unlike many other of  the  extraction processes, the  production of the steroid raw
material, stigmasterol, does not generate a hazardous waste  stream, but instead generates a
solid waste of fused plant material steroids. The waste residue of soybean steroids from this
extraction  process  is fused at 160ฐC which, after cooling to a solid  mass,  is  stored  or
landfilled.  As  an  alternative,  this mixture  of  steroid  residues  (containing  about 50%
/3-sitosterol) can be processed for recovery of the /3-sitosterol which also can be used as a
steroid raw material. The other major steroid raw material source, diosgenin from Mexican
yams, is imported from Mexico.

     In January 1975, G.D. Searle & Company announced plans to produce raw material for
steroid synthesis by  fermentation of the steroid, (3-sitosterol. Some of the 0-sitosterol which
was formerly a waste product may thus be recycled to produce other products.

     The conversion of  these steroids  to cortisone and oral contraceptives is done by a
combination of fermentation and chemical synthesis steps. The wastes  generated in these
conversion steps  is included as part  of the production of synthetic  organic medicinal
chemicals (Section 3.2.1.2.1).

     3.2.1.2.5  Medicinals from Animal Glands

     The major medicinal products obtained from animal glands are insulin from beef and
hog pancreas and  heparin from lung tissues. Since the extraction processes are similar, we
will use insulin production as an  example. On a small scale in the laboratory, insulin can be
extracted from the  pancreas by acidic water  alone, but on a commercial  scale  this is
impractical, so acidic 90% denatured alcohol is used. A process for commercial production
of medicinals from  animal glands (insulin) is presented in  Figure  3.2.1.2.5, and Table
3.2.1.2.5 summarizes the wastestreams. The ground glands are extracted with acidic ethanol
or methanol  and  the extract recovered from  the ground  glands  by centrifugation  or
filtration. Neutralization of the extract with concentrated ammonium hydroxide to pH 8.0
precipitates extraneous protein. A stronger alkali, such as sodium hydroxide, or too high a
pH will  decompose the insulin. The  precipitated extraneous protein is filtered, and  the
extract  is  acidified  and  then concentrated to  about a seventh of its original volume  by
vacuum evaporation at 20ฐC. The concentrated extract is raised quickly to 50ฐC to release
solubilized fats, then  cooled  to 20ฐC. The fats are skimmed and recovered for soap
manufacture and the extract filtered to remove additional precipitated protein. Crude insulin
is precipitated by dissolving sodium chloride in the concentrated clarified  extract.

     The crude insulin is further purified by redissolving the insulin in acidic water and
iso-electric precipitation at pH 5.2 and 4ฐC. In a final step, zinc  insulin is prepared  by
                                         58

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                                       Ground Glandular Material
                                             (3200 kg)
36% Hydrochloric Arid
(80 kg)
Alrnhnl Makpnp
(200 liters)
1


Recovered Solvent
(700 liters)
( Ethanol
•j Methanol
/Water
J) Waste Solvent
(350 liters) ^
( Water
•j Alcohol
/ Fats, Oils
(7000 liters) ^
Ethanol
Methanol
Water
Hydrochloric
Acid
Recycled
Ethanol
Methanol
Water
(5500 liters)
Solvent
Recovery
^
Sol
St
i
Sodium Chloride^
(240 kg) *
sent

1
Extraction
pH 2.5
\
r
Centrifugation
(clarification)
1
!
Neutralization
pHS.O
\
i
Filter
\
!
Acidification
PH3.0
1

Evaporation
at 20ฐC
Heat to 50ฐC
1
1000 liters
,pH 2-2.5
Skim Tank
Cool to 20ฐC
i
r
Filter
!
i
Crude
Insulin
Precipitation
'

Extracted
Rendered
Pancreas (3000 kg)
for Fat Recovery CO
Sold as Feed Protein
Cone. (30?
Ammomur
(110
Precipitate
Aid to Lar
(160 kg w
(80 kg sol
Sulfuric
(65 kg)
Disso
ar
Precip
@ 50ฐC t
(D
Fats to
( 140 kg)
Precipitated
Protein and
Filteraid tow
	 *• (4)
Landfill W
(40 kg wet)
(20 kg solids)
4)
n Hydroxide
kg)
d Protein andFilter
dfill (2)
n)
ds)
kg Purified Bulk Zinc Insulin
Water
Iving
itation <0.2 kg)
t
i i
Water Waste
(80 liters) (5)
(60 liters)
0.04 kg Sulfuric Acid
! r
Dissolving and
Isoelectric Sodium Hydroxide
	 * Precipitation (0.04 kg)
Crude at pH 5.2, 4ฐC
(1.2kg)
i
70
Water
r
iters (V)
Waste
                    Ammonium Sulfate
                   Sodium Chloride Waste
                       (400 kg) (?)
Sources:  Standen. Webb, and Arthur D. Little, Inc., estimates. (See Bibliography)
FIGURE 3.2.1.2.5   REPRESENTATIVE PROCESS FOR MEDICINALS FROM ANIMAL GLANDS
                   (INSULIN - 1  KG OF PRODUCT)
                                             59

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                                       TABLE 3.2.1.2.5

          TYPICAL PLANT FOR PRODUCING MEDICINALS FROM ANIMAL GLANDS (INSULIN)
         A.   Annual Production
284kg
         B.   Waste Characterization

                Non-Hazardous Waste
                  Rendered pancreas
                  Protein and filter aid
                  Recovered fats
                  Protein and filter aid
                  Ammonium sulfate/sodium
                   chloride
                Insulin precipitation wastewater
                                        Stream
                                          No.
           kg per
         kg Animal
          Glands
         (Dry Wt.)
           0.94
           0.025
           0.04
           0.006
           0.125

           0.022
                                                                 kg per kg Product
      Dry
      3000
        80
       140
        20
       400
Wet



160

 40


 70
                                                              Quantity per kg Product
                                                                  Liters     kg
                Hazardous Waste
                  Waste solvent concentrate     (
                  (Ethanol, methanol, water,
                   fats, oils)
                  Precipitation wastewater      (
                  (May contain traces of zinc)

        Source:  Arthur D.  Little, Inc., estimates.
           0.10
           0.025
     350
                                  320
      80      80
(1-5 gm Zn per kg product)
redissolving the insulin in acidified water and then adding zinc acetate to precipitate zinc
insulin, or  plain  insulin  may  be precipitated by  using acetone. The  solution  of sodium
chloride in water and alcohol is solvent-stripped to recover solvent and is then discarded.

     The  extracted glands are rendered to  recover fat  (and remove alcohol) and then are
sold as animal feed protein. The precipitated protein containing filter aid is landfilled.

     The  hazardous wastes generated in this process are the solvent concentrate (containing
fats and oils) left behind when the aqueous  alcohol is recovered in the solvent recovery
system and the wastewater from insulin precipitation which may contain traces of zinc salts.
(Treatment of this wastewater with alkali would precipitate any zinc as the hydroxide which
can then be removed by filtration.)

     3.2.1.2.6 Biologjcals

     The  biological products listed in SIC code 2831 include vaccines,  toxoids,  serum, and
human blood fractions.  The vaccines (such as influenza vaccine) are produced by growing
virus mutants in chicken egg embryos, extracting the egg with a salt solution, and precipitat-
ing the active antigen with ammonium sulfate for use in vaccine production. Most toxoid
production today is effected by tissue cell culture  of the virus, followed by formaldehyde
treatment  of the  culture medium  to give the toxoid.  Salk-type poliomyelitis toxoid is
produced by this method.                   50

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     Tetanus antiserum is produced from the blood of a horse that has been infected with
the tetanus organism. While the horse itself remains healthy and active, tetanus antibodies
are produced in its bloodstream.

     Human  blood plasma  contains a  series  of protein fractions that have  commercial
medicinal use.  Included in  these protein fractions are antihemophilic globulin (to arrest
severe hemorrhaging),  gamma-globulins (for prevention of hepatitis, measles, chicken pox,
and tetanus), thrombin (for blood coagulation), and albumin (for treating shock).

     The two major classes of biologicals produced in the United States today  are  virus
vaccines from chicken egg embryos and human blood fractions. A typical process for human
blood fraction production is described  below.  Whole blood  is  received from donors (or
obtained from placentas following childbirth) and the cells are removed (by centrifugation)
to yield plasma. The sterile plasma may be used as is, or processed further to produce blood
protein fractions. These protein fractions  are precipitated from the plasma at -5ฐC by adding
ethanol containing sodium  acetate-acetic  acid  buffer in steps to increase the ethanol
concentration and lower the  pH. The number  of steps and pH at each stage are dependent
on the "method" of fractionation used and the  protein fractions desired. The final step of
Method 6  (outlined in Figure 3.2.1.2.6) is precipitation of  albumin at pH 5.2  and 40%
ethanol.  Following this final precipitation,  there is generally  less than 2% of the original
plasma protein left in solution.

     The cells from the whole blood can be removed and discarded; they are removed for
recovery of erythrocytes (red cells) for therapeutic treatment or, as in more recent practice,
returned to the donor.

     The production of commercial quantities of plasma protein fractions does not require
very large equipment. A typical fractionation facility may handle a batch size of 500 liters
of plasma (from over 1500 donors) with a maximum in-process volume of 2000 liters. From
1943-1963, an average of 50,000 liters per year of plasma were fractionated.

     After  the  final  precipitation, the  diluted plasma contains  about 40%  ethanol by
volume, less  than  1% salts  (sodium acetate,  chloride, phosphate, carbonate) and about
0.03% protein. This would  generate a total waste stream of about 240,000 liters (60,000
gal.) per year of watery waste containing 40% ethanol.

     This waste can be (1) diluted and treated biologically, (2)  the ethanol can be recovered
and the residual liquor treated biologically, or (3) concentrated and incinerated. About 12
kg of diatomaceous earth per 500 liters of plasma are also used in this process as .filter aid.
If placentas are used,  when  discarded, they are  incinerated. The other unwanted  solids or
solutions are usually discharged to the  sanitary  sewer and are  handled by the liquid waste
treatment system.
                                         61

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ethanol 8% pLASMA
temp. -3ฐC

etha
temf
protein 5.1%
pH 7.2

Supernatant I
nol 25% 1
>. -5ฐC


,
Precipitate 1
Fibrinogen
(for treatment of hemophili
protein 3.0%
pH
6.9
1

             Supernatant ll+lll
                                                                   Precipitate ll+lll
ethanol
temp.
protein
pH
                -5ฐC
                1.6%
                5.1
                                                                   Immune Globulins
                                                           (for prevention of hepatitis, measles)
              Supernatant IV-1
                                                             Precipitate IV-1
ethanol
temp.
protein
pH
                40%
                -5ฐC
                1.0%
                5.8
                                                                       a-Globulin
             Supernatant IV— 4
                                                                   Precipitate IV-4
        ethanol   40%
        temp.    —5ฐC
        protein   0.8%
        pH      4.8
                                                                   a- and jS-Globulins
             Supernatant V
                                                                         1
                                                                     Precipitate V
           Aqueous Ethanol Waste

                     \
                                                     ethanol  10%  |     Albumin
                                                     temp.    —3ฐC   (for treatment of
                                                     protein  3%     traumatic shock)
                                                     pH      4.5
               Supernatant
                                                                      Impurities
        ethanol  40%
        temp.    —5ฐC
        protein  2.5%
        pH      5.2
                                                                          \
                Supernatant
                                                               Albumin
           Aqueous Ethanol Waste

      Source:  A. Standen, Kirk-Othmer  Encyclopedia of Chemical Technology.  (See Bibliography)
FIGURE 3.2.1.2.6  DIAGRAMMATIC REPRESENTATION OF METHOD 6 BLOOD FRACTIONATION

                                                62

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3.2.1.3  Pharmaceutical Preparations (SIC 2834)

     Pharmaceuticals  are  prepared in dosage forms  such as tablets, capsules,  liquids, or
ointments from the bulk Pharmaceuticals  and biologicals of SIC codes 2833 and 2831 and
from other purchased raw materials. The methods used to manufacture these dose forms of
Pharmaceuticals are described below:

     •    Tablets —  The flowsheet for production of coated and uncoated tablets is
          shown  in  Figure 3.2.1.3A. The active  ingredient, filler, and  binder are
          weighed, blended, and granulated. Additional  binder, of filler, is added, if
          required,  and the tablets are produced  in  a  tablet press machine.  Some
          tablets  are coated by tumbling with a coating material and drying. The filler,
          (usually starch,  sugar, etc.) is required to dilute the active medicinal to the
          proper  concentration, and binder (such as corn syrup or starch) is necessary
          to  bind the  tablet  particles together.  A  lubricant, such  as magnesium
          stearate, may  be added for proper tablet machine operation.  The  dust
          generated during  the mixing and tabletting operation  is collected and is
          usually recycled directly in the  same batch.  Broken tablets are generally
          collected and recycled to the granulation operation in a subsequent lot.

          After the tablets have been coated and dried, they are bottled and packaged.
          A small amount  of  breakage does occur during  this operation,  and this
          does generate some nonhazardous solid waste.

     •    Capsules —  Empty hard gelatine  capsules are produced by machines that dip
          rows of rounded metal dowels into a molten gelatine solution and then strip
          the  capsules from the dowels after the capsules have cooled and solidified.
          Imperfect empty  capsules are remelted  and reused,  if possible, or sold for
          glue manufacture. Most pharmaceutical companies  purchase empty capsules
          from a  few specialist producers.

          Capsule filling and packaging operations are shown in Figure 3.2.1.3B. The
          active  ingredient and any filler are mixed and  sometimes granulated before
          being poured into the empty gelatine capsules by machine. The filled capsules
          are then bottled and packaged. As in the case of tablet production, some dust is
          generated. This is recycled and small amounts disposed of. Some glass and
          packaging waste from broken bottles and cartons results from this operation.

     •    Liquid  Preparations  - The first  step in liquid preparation is weighing the
          ingredients  and  then dissolving' them in water.  Injectable  solutions are
          packaged in bottles and heat- or bulk-sterilized by sterile filtration and then
          poured into sterile bottles. Oral liquid  preparations are bottled directly
          without subsequent  sterilization.  There are small amounts of liquid wastes
          generated  in  this process  that  go to the  sewer.  Solid wastes  are  non-
          hazardous and consist of broken bottles and some packaging waste.

                                         63

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                                                                                                  Dust to
                                                                                                 Recycle or
                                                                                                   Waste
                         Raw Materials
                           Receiving
   Raw Materials
      Storage
                                                                                            A.
 Blending,
Granulating,
and Drying
                                                             Blending
                                                                                           Slugging
                                                                 Broken Tablets
                                                                   to Recycle
                                                                   or Waste
  Tablet
Compression
Foiling
                                                                                                                        Granulating
ON
                                Pan Coating
                               and Polistiing
              Tablet
             Counter
           Bottle
          Labeling
                                                                                                                                     f
           Packing
                      Finished
                       Goods
                      Storage
Shipping
       Broken Glass
         to Waste
        • Indicates Start of Alternate Process.

        Source:  Arthur D. Little, Inc.
                                                  FIGURE 3.2.1.3-A PHARMACEUTICAL TABLET PRODUCTION

-------
                                                                                       Dust to
                                                                                      Recycle or
                                                                                        Waste
        Raw Materials
         Receiving
Raw Materials
   Storage
Blending
                                Capsule Filling
Capsule Printing
                            F-'oiling
                                                                                                       Granulating
                                                                                                           and
                                                                                                          Drying
                                                Capsule
                                                Counter
                                         Bottle
                                        Labeling
                                    Packing
            Finished
             Goods
            Storage
      Shipping
   Broken Glass
    to Waste
• Indicates Start of Alternate Process.

Source:  Arthur D. Little, Inc.
                                              FIGURE  3.2.1.2-B  PHARMACEUTICAL CAPSULE PRODUCTION

-------
     •   Ointments and Salves — Ointment production is outlined in Figure 3.2.1.3C.
         The active ingredients (zinc oxide, antibiotic, cortisone, or other) are mixed
         and then blended with thickening agents such as  petroleum jelly or lanolin.
         The ointment or salve is then injected into tubes or jars and packaged.

     FDA regulations  require that all formulations be tested to assure that they contain the
proper concentration of active ingredient, and that all active ingredient have been accounted
for. For this  reason, and because of the value of the product, a concerted effort is made by
the pharmaceutical  companies to convert as much active ingredient into final product as
possible.  This requires as much reprocessing of  product  as possible  and the complete
"running out" of active ingredient  during  production  of the pharmaceutical preparations.
Some formulated material is sent to the sewer in cleanup operations, but typically only a
few  kilograms per  day of  material may  be disposed  of as solid  waste  from a large
formulation and packaging operation.

     The largest source of waste material that  has to be handled at any given time is from
recalled lots of Pharmaceuticals. The recall  may be due to company action in discontinuing
a product,  or due to some product deficiency, such as  a  loss of potency. In the latter case,
the FDA may enter the picture and  require a recall of the  questionable lot. Products may
also  be recalled due  to mislabeling or product mixups. Some of the" recalls are readily
correctable and the  product  can then be reshipped. In  other cases it is necessary to destroy
the entire lot. The waste generated in these operations  is  about 85% broken glass and waste
packaging materials and only about 15%  product waste.  The product waste, in turn, is
estimated to contain only about 20% active ingredient on the average.

     We estimate that the U.S. pharmaceutical industry disposes of approximately 10,000
metric tons  of returned goods annually, primarily consisting of packaging materials and
dilute active ingredient. There are also occasional batches of material that must be rejected
due to cross-contamination, decomposition,  and so forth, that must be disposed of. Certain of
the active ingredients and some formulations  in bulk  form may be hazardous enough to
warrant special disposal. We estimate that approximately 500  metric tons per year fall into this
hazardous category for disposal from plants in SIC 2834.

     In addition, we estimated that 75,000 metric tons of general rubbish are produced by the
packaging and shipping sections of the industry. These rubbish wastes consist mostly of glass,
paper, wood,  rubber, aluminum and the like. We estimate that only a small fraction of 1 per-
cent of this  material  consists of active  ingredient.  The material is disposed of in regular
municipal landfills, together with cafeteria wastes, office wastes, and  so forth. For purposes of
this study we do not consider that this waste should be categorized as a "process waste."

3.2.1.4 U.S. Pharmaceutical Industry Process Wastes and Projections to 1977 and 1983

             3.2.1.4.1  Annual Waste of Pharmaceutical Industry

             Tables 3.2.1.4.1 A and B present our estimates of hazardous and non-hazardous
       wastes generated by the pharmaceutical industry in 1973 and their distribution in
       the EPA regions. The quantities  of each type of waste for the various products were
                                         66

-------
                                     Raw Materials
                                       Receiving
Raw Materials
   Storage
                                                                     Blending or
                                                                    Homogenizing
0\
-J
Tube or Jar
   Filler
                                                                                                       Labeling
Packing



Finished
Goods
Storage
^^

(
Shipping

Damaged Tubes
or Jars
to Waste
-n ... , , , . 	
                Indicates Start of Alternate Process.
        Source:  Arthur D. Little, Inc.
                                               FIGURE 3.2.1.3-C  PHARMACEUTICAL OINTMENT PRODUCTION

-------
                                                                                                  TABLE 3.2.1.4.1.A
                                                         PHARMACEUTICAL INDUSTRY WASTE  GENERATION ESTIMATE  FOR
                                                                                                                                                                 1973'
                                                                                                                                                                                   Metric Tons Waste (1973)
                Industry Segment
a\
co
                      Solvent
                      Animals (Incinerated)
                      Heavy Metals (Coniract Disposal)
                SIC Code 2833:  Production of Active ingredients
                   Organic Medicinal Chemicals (34,000 Metric Tons/Yr)
                      Biological Sludge (from Wastewater Treatment)
                      High  Inert Content Waste — Non-Hazardous {Filter aid, activated carbon)
                      High  Inert Content Waste - Hazardous [Contaminated filter aid, activated carbon)
                      Organic Chemical Residue {Tars, muds, still bottoms)
                      Halogenated Solvent
                      Non-Halogenated Solvent
                      Heavy Metal Wastes
                         Zinc
                         Arsenic
                         Chromium
                         Copper
                         Mercury
                   Inorganic Medicinal Chemicals
                      Heavy Metals (i.e., selenium)
                  Antibiotics (by Fermentation, 10,000 Metric Tons/Yr)
                     Mycelium (plus filter aid and sawdust)
                     Biological Sludge (from wastewater treatment)
                     Waste Solvent Concentrate
                  Botanicals (Plant Alkaloids, 2,000 Metric Tons/Yr Plant Material)
                     Wet Plant Material
                     Aqueous Solvent Concentrate
                     Halogenated Solvent
                     Non-Halogenated Solvent
                                                                                                           66 liters/researcher
                                                                                                     Total for R&D
      Tons/Ton Product
            1.4
            0.1
            0.05
            0.4
            0.1
            0.7

            0.070
            0.015
            0.001
          < 0.001
          <0.001

Total for Organic  Medicinal Chemicals
   Rounded to
                                                                                                     Total for Inorganic Medicinal Chemicals
   7.5 tons (dry wt)/ton antibiotic
   3.5 tons/ton antibiotic
   1.2 tons/ton antibiotic

Total for Fermentation (Antibiotics)
   1 ton (dry basis) per ton plant material
   0.36 ton/ton plant material
   0.03 ton/ton plant material
   0.06 ton/ton plant material

Total for Plant Alkaloids (Botanical)
Non-Hazardous
Dry Basis Wet Basis
-
47,600 476,000
3,400 6,800









51,000 482^00
51,000 480,000


75,000 300,000
35,000 350,000
-
110,000 650,000
2,000 4,000
- -
-
-
Hazardous
Dry Basis
1,600
1,500

1,700
13,600
3,400
23300
2,200
450
20
4
1
45,175
45,000
200
200
_
_
12,000
12,000

720
60
120
Wet Basis "
1,500
1,500

3,400
13,600
3,400
23,800
2,200
460
20
4
1
46,875
47,000
200
200
_
-
12,000
12,000

850
60
120
                                                                                                                                                                     2,000
                                                                                                                                                                                     4,000
                                                                                                                                                                                                     900
                                                                                                                                                                                                                  1,030

-------
                                                                             TABLE 3.2.1.4.1.A (Continued)
                                                                                                                                                                           Metric Tons Waste (1973)
Industry Segment

   Botanicals (Plant Steroids, 150 Metric Tons/Yr Stigmasterol)
       Fused Plant Steroid Ingots
    Medicinals from Animal Glands (8000 Metric Tons Glands/Yr)

       Extracted Animal Tissue
       Fats or Oils
       Filter Cake (contains precipitated protein)
       Aqueous Solvent Concentrate
 SIC Code 2831: Biological Products
       Aqueous Ethanol Waste from Blood Fractionation
       Antiviral Vaccine
       Other Biologicals (Toxoids, serum)
 SIC Code 2834: Pharmaceutical Preparations (Formulation, Packaging and Returns)
    Total Returned Goods (Primarily packaging material and dilute active ingredient)
    Contaminated or Decomposed Active Ingredient
   5 tons/ton Stigmasterol

Total for Plant Steroids


   Tons/Ton Animal Glands
            0.940
            0.044
            0.031
            0.100

Total for Medicinals from Animal Glands

Total for Production of Active Ingredients (SIC Code 2833)


   5 liters/liter plasma



Total for Biological  Products SIC Code 2831
                                                                                          Total for Pharmaceutical Preparations

                                                                                          Totals for all Industry Segments

                                                                                          Rounded to:
Non-Hazardous
Dry Basis
750
750
7,500
350
250
8,100
172,000
-
-
10,000
10,000
181.850
1 82,000
Wet Basis
750
750
7,600
350
500
8,350
1,143,000
-
-
10,000
10,000
1,153,000
1 ,1 53,000
Hazardous
Dry Basis
-
800
800
59,000
250
300
200
750
500
500
61,650
62,000
Wet Basis*

-
1,600
1,600
62,000
600
300
200
1,100
500
500
65,100
65,000
*Wet weight estimates are given for all wastes. The two wastes that typically have the highest moisture content are biological sludge and mycelium from fermentations. Where the wet waste estimates are the same as
 on the dry basis, the waste is usually disposed of with only a minor amount of moisture. However, disposal practices vary from plant to plant, depending on the form in which the waste is produced.
 Source: Arthur D. Little, Inc., estimates.

-------
                                                  TABLE 3.2.1.4.1B




                       DISTRIBUTION OF PHARMACEUTICAL INDUSTRY WASTE GENERATION (1973)1
                                                                     Metric Tons Waste
Regions 1 & II
Industry Segment
R&D
Synthetic Organic
Medicinals




Fermentation
(Antibiotics)

Botanicals



Animal Source



Biologicals

Formulation, Packaging,
Returned Goods
Heavy Metal Wastes from
Organic and Inorganic

Waste Type
Solvent
Biological Sludge
Inert Wastes
Contam. Inerts
Halogenated Solvents
Non-Halogenated Sovent
Organic Residues
Mycelia (Dry Basis)
Biological Sludge
Waste Solvent Concen.
Plant Material
Aqueous Solvent
Halogenated Solvent
Non-Halogenated Solvent
Animal Tissue
Fats or Oils
Filter Cake
Aqueous Solvent
Waste Solvent
Other
Returned Goods
Active Ingredient

Non-Haz.
_
28.600
2,000
-
-
-
-
34.000
15,000
-
1,200
-
-
"
4.400
200
140
-
-
-
4,400
-

Haz.
780
_
-
1,000
2.000
14.300
8,200
-
-
5,000
-
420
30
60
_
-
-
500
25
50
_
220

Region III
Non-Haz.
_
4.800
300
-
-
-
-
7,500
3.600
-
200
-
-
"
740
35
30
-
-
-
1,100
-

Haz.
_
-
-
150
300
2.400
1.400
-
-
1.200
-
100
10
20
Region IV Region
Non-Haz. Haz. Non-Haz.
_ _ _
4.800 - 7.100
300 - 500
150 -
300 -
2,400
1,400
30,000
14.000
- - -
200 - 300
50
5 -
u Region VI
-HjJ Non-Haz. Haz.
420 - 60
400
50
200 - -
500-50
3.600 _ 150
2.100 - 50
_ _
-
4.800
— _ _
100 __
10 __
Region VII
Non-Haz.
_
700
100
-
-
-
-
1,000
700
-
_
-
-
Haz.
60
_
-
100
100
350
160
^
_
200
_
_
_
10- 20__ __
740 - 1.200 -
-
-
80
25
50

60

35 - 50
30 - 40
80 -
25 -
50 -
1.000 - 1.800
50 -

- -
- -
120
60
120
300
90-15

200
15
5
-
_
-
500
-


-
_
50
50
100
_
25

Region VIII Region IX
Non-Haz. Haz. Non-Haz. Haz.
- - - 180
1.200
150
- - 100
- - 150
- 600
- - - 300
2,500
1.700
- - 800
100
50
- - - 5
10
- 220 -
- 15
	 	 e
70
65
- - - 130
900
40

Region X Total
Non-Haz. Haz. Non-Haz. Haz.
- - - 1.500
47.600
3,400
- 1,700
- - - 3,400
- - - 23,800
- - - 13.600
75,000
35,000
- - - 12,000
2,000
- - - 720
- - 60
- - - 120
7.500
- - 350
- - 250
- - 800
- - 260
- - - 500
10,000
- - 500



lapnd: Non-Haz. - = Non Hazardous
Haz. - Hazardous
Total
Is for All Industry Segments
Rounded to:
2,900
181,850 61.850
182.000 62.000
Arthur D. Little. Inc., estimates.

-------
        extrapolated to an annual (1973) basis from data gathered at the plants visited using
        the following three methods:

     1.    Production of a given pharmaceutical product at the plants visited compared
          to total industry production in the United States;

     2.    Value of production of a pharmaceutical product at the plants visited as a
          percentage of annual total value of that product in the United States; and

     3.    Generation of  a  given waste as related  to total value of production  or
          number of production employees.

     We estimated the total annual quantity  of  solvent waste  originating from  R&D
operations on the basis of quantities generated per researcher at the facilities we visited.
Since test animals  are routinely  incinerated on-site and the amount of heavy metal waste is
very small and disposed of by waste disposal contractors,  we did not include figures for
these wastes in this table.

     The  production  of organic  medicinal chemicals creates waste solvents, chemical tars
and residues, wet filter  aid or carbon, some heavy metal waste, and biological sludge from
on-site or off-site  biological treatment of water-soluble organic compounds, such as acetic
acid or alcohol. The wet filter  aid or  carbon may be non-hazardous or  may contain
contaminating materials such as solvent, corrosives or heavy metals that render it hazardous.
(The  heavy metal contents of  the heavy metal wastes listed  in  Table 3.2.1.4.1 A were
presented earlier in Table 3.2.1.2.1.)Many pharmaceutical companies also  produce crude
antibiotics and growth  stimulants such as arsanilic acid for the animal feed industry, but
these products are not listed as part of SIC code  2833. Several companies are also producers
of some heavy chemical fermentation products, such as  citric and itaconic acid, but these
again are not part of SIC code  2833.

     Inorganic, medicinal, chemical, active-ingredient production  usually generates non-
hazardous aqueous waste salt  solution and little or no solid hazardous waste. In addition, a
large portion of the active ingredients for manufacture of inorganic medicinals is purchased
from the heavy chemicals industry.

     Fermentation  is used  for  the  production  of  most crude antibiotics, for  chemical
conversion of some steroids, and for the production of some industrial heavy chemicals. The
fermentation,  product recovery, and purification processes result in considerable quantities
of non-hazardous  wastes, such as mycelia and spent nutrient broth. The main hazardous
waste generated is a solvent  concentrate. This  waste contains organics  from recovery of
solvent used in the product recovery  and purification sections of the process. The weight of
dry mycelia waste  per ton of  product is considerably higher for other antibiotics than it is
for penicillin,  since it is necessary to use a significant amount of filter aid to remove the
mycelia from the broth and the yields of some of the other antibiotics per ton  of mycelia is
                                         71

-------
lower. Some State regulations also require a minimum solids content of the mycelia waste
for landfill  disposal, so an additional filter such as sawdust must be added to increase the
solids content.
     The extraction of botanicals, such as roots and leaves, and animal organs, such as
pancreas glands or lung tissue for alkaloid, steroid, and hormone products, respectively, is
usually accomplished using acidic aqueous alcohol and often requires a second halogenated
solvent in the purification process. These solvents are recovered for reuse,  thus generating a
waste solvent concentrate. The wet  botanicals are disposed of by landfill, but the animal
organ by-products (extracted glands and fats) are sold when possible.
     The quantities of returned goods and active ingredients disposed of were projected as
being proportional to the total value of production.

     The major wastes generated in  the production of biologicals include aqueous alcohol
and  dissolved salts  from human blood plasma fractions and formaldehyde-egg waste from
antiviral production. There is a limited amount of production of  other biologicals, such as
horse serum products  and toxoids, but the total  production of  biologicals is quite small
compared to the production of other Pharmaceuticals.

     Heavy  metal wastes occur mostly in the production of organic medicinal chemicals. In
some cases,  such as the selenium waste, the waste  stream is unique to one process and one
manufacturer. In  other cases, there  are several producers that have a similar waste heavy
metal (mercurials), and yet other heavy metal wastes, such as zinc compounds, are found
throughout  the industry. This factor was taken into consideration in estimating the annual
generation of each of these heavy metal wastes.

     In Table 3.2.1.4.IB  we have apportioned the waste  generation figures for the whole
United States, as  listed in Table 3.2.1.4.1 A, among the various EPA  regions. Our estimates
of waste generation distribution are based on production figures for antibiotics, synthetic
organic medicinals, and biologicals of the pharmaceutical companies in these regions. Waste
generation from R&D facilities was estimated from PMA data showing locations of R&D
personnel. Location of major formulation and packaging facilities  was used to estimate
distribution  of returned goods. Regions I and II were combined in  Table 3.2.1.4.IB to avoid
disclosure of confidential information  on production  or waste stream data on plants in
Region I which has only one large plant in SIC 2833.

     Waste generation on a state-by-state basis is presented in Table 3.2.1.4.1C. Regional
and national totals  are also given. State totals for heavy metals are not estimated because of
the difficulty in estimating the specialized use of these materials in individual plants. State
estimates for mycelium waste generation have also been  omitted, because only 16 major
fermentation installations produce antibiotics in the continental United  States. Seven states
have only one. plant each, one state has two, one state has. three, and only one state has four
major plants. Again, state-by-state figures on mycelium production would divulge, confiden-
tial information on several companies. Many  states have  so few people employed in the
pharmaceutical industry that the waste is considered insignificant, and  blanks therefore
appear in the table. The reason for the spotty distribution is apparent when one considers
that  SIC  code  2833 (which contributes almost all the hazardous and nonhazardous waste
from the industry) contains only 54 installations that have more than 20  employees each.
                                         72

-------
                                           TABLE 3.2.1.4.1C

ESTIMATED DISTRIBUTION OF WASTE GENERATED BY THE PHARMACEUTICAL INDUSTRY IN 1973
                                     (annual metric tons — dry basis)

State
IV Alabama
X Alaska
IX Arizona
VI Arkansas
IX California
VIII Colorado
Connecticut
II Delaware
V Florida
V Georgia
X Hawaii
X Idaho
V Illinois
V Indiana
VII Iowa
VII Kansas
V Kentucky
VI Louisiana
1 Maine
II Maryland
Massachusetts
V Michigan
V Minnesota
V Mississippi
VII Missouri
VIII Montana
VII Nebraska
IX Nevada
1 New Hampshire
1 New Jersey
VI New Mexico
1 New York
V North Carolina
VIII North Dakota
V Ohio
VI Oklahoma
X Oregon
III Pennsylvania
II Puerto Rico
1 Rhode Island
IV South Carolina
VIII South Dakota
IV Tennessee
VI Texas
VIII Utah
1 Vermont
III Virginia
X Washington
III West Virginia
V Wisconsin
VIII Wyoming
National Totals
Region Totals

1
II
III
IV
V
VI
VII
VIII
IX
X
Notes: 1. Includes R&D so
2. Includes biologic
3. Dry wt x 2 = we


Halogenated*
Solvent Waste
-
-
330
_
200
-
40
60
_
_
300
330
30
—
-
10
_
-
_
200

-
110
—
20
-
-
1,600

800
100

70
-
-
270
200
—
-
_
100
100
—
_
40
-
-
30
-
4,940

200
2,600
310
300
930
110
160

330
_

vent wastes
a! product organic w
weight


Non-Haloganata
Solvent Waste
:
-
1,600
_
1,400
-
400
500
_
_
2.900
3,100
130
—
_
10
_
-
_
1,900

-
440
—
80
-
-
11,000

6,000
900

600
-
-
3,300
2,000
—
-
_
800
140
-T-
_
550
-
-
200
-
37,950

1.4IXJ
19,000
3,850
2,600
8,700
150
650

1.600
_

4. Dryw
astes. 5 Dry w
6. Includ
7. Dryw
Hazardous
Organic
d (Chemicals)
Residues
-
-
430
—
500
-
250
200
—
_
760
810
50
—
-
5
—
-
_
450

-
170
—
30
-
-
4,700

2,300
550

150
-
-
1,250
750
—
-
—
450
45
-
_
200
-
-
50
-
14,100

500
7,750
1,450
1,450
2,220
50
250

430
_

x 10 = wet weight
t x 1.2 = wet weight
es filter cake tor animal
t x 4.35 = wet weight

Contaminated3
High Inerts
Waste
-
-
100
_
100
-
25
25
_
_
70
70
20
—
-
-
—
-
_
40

-
70
—
10
-
-
500

300
50

10
-
-
130
100
—
-
—
50
-
—
_
20
-
-
10
-
1,700

100
900
150
150
200
_
100

100
_



source pharmace


Active
:
-
40
—
20
-
5
5
—
-
30
30
5
—
-
-
—
-
_
20

-
20
—
-
-
-
120

60
20

10
-
-
50
20
-
-
—
20
15
—
—
10
-
-
-
-
500

'Al
200
60
50
90
15
25

40
_



uticals.


Heavy
Motals
-
„
-
_
_
„
_
-
_
_
_
_
_
_
_
_
_
_

_

_
_
_
_
_
_
_

__
_

_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
_
2,900

—
-
_
_
_
_
-

_
_






Total
Hazardous *
-
—
2,500
_
2,220
_
720
790
_
_
4,060
4,340
235
_
_
25
_
_
_
2,610

_
810
_
140
_
_
17.920

9,460
1,620

840
_
_
5,000
3,070
_
_
_
1,420
300
_
_
820
_
_
290
_
59,190

2,220
30,450
5,820
4,550
12,140
325
1,185

2,500
_

•(excludes
metals)



Biological4
Sludge
-
90
2,900
—
3,000
-
500
500
—
-
7,000
7,600
700
—
-
40
—
600
600
4,600

800
700
—
-
-
-
24,200

12,000
1,500

1,500
-
-
6,500
3,800
—
500
_
1,000
270
—
—
1.100
-
200
400
-
82,600

J.600
40,000
8,400
4,800
21,100
400
1,400

2,900
_





Non-Haz
Plant Material5
Animal Tissue
Fats, Oil

-
330
—
400
-
100
100
—
-
500
560
110
—
-
-
—
70
100
340

200
70
—
35
-
-
3,200

1,600
300

110
„
-
800
500
—
100
—
200
-
—
_
100
-
30
50
-
9,905

500
5,300
1,000
1,000
1,560
_
215

330
_





ardous
High Inerts3-
Waste
(Non-Haz.)

10
150
—
100
-
30
30
—
-
180
190
50
—
-
10
—
20
100
120

50
35
—
20
-
-
1,140

600
120

40
-
-
250
200
—
20
—
80
30
—
_
50
-
10
10
-
3,645

200
1,940
330
330
540
50
105

150
_






6
Returned
Goods
-
70
900
_
300
-
100
100
—
_
600
650
100
—
-
30
—
80
100
400

200
300
—
100
-
-
2,400

1,200
300

120
-
-
850
400
—
100
—
200
200
—
_
140
-
30
30
-
10,000

400
4,000
1,100
1,000
1,800
300
500

900
_






Mycolium
-
-
-
_
-
-
-
-
_
_
_
_
-
_
_
_
_
_
_
_

_
-
_
_
_
-
-

-
-

-
-
-
-
-
—
-
—
-
-
—
_
-
-
-
-
_ -
75,000

—
-
_
_
_
_
_

_
_





                                                                                                                     Nonhazardous*
                                                                                                                         170
                                                                                                                        4,280
                                                                                                                         730
                                                                                                                         730
                                                                                                                       8,280
                                                                                                                       9,000
                                                                                                                        770
                                                                                                                        900
                                                                                                                       5,460

                                                                                                                       1,250
                                                                                                                       1,105
                                                                                                                      15,400
                                                                                                                       2,220
                                                                                                                       8,400
                                                                                                                       4,900
                                                                                                                       1,480
                                                                                                                        500
                                                                                                                        270
                                                                                                                        490

                                                                                                                     106,150

                                                                                                                       4,700
                                                                                                                      51,240
                                                                                                                      10,830
                                                                                                                       7,130
                                                                                                                      25,000
                                                                                                                        750
                                                                                                                       2,220

                                                                                                                       4,280
                                                                                                                     excludes
                                                                                                                     mycelium)

-------
     3.2.1.4.2 Typical Types of Pharmaceutical Hazardous Wastes and Their Properties

     Table 3.2.1.4.2  lists the typical types of hazardous waste materials discharged from
pharmaceutical operations. The physical, chemical, and biological properties of the hazard-
ous constituents of these wastes are listed in Appendix B.

     3.2.1.4.3 Projections of Pharmaceutical Process Wastes to 1977 and 1983.

     Medicinal  ingredient production  in  the  United  States has increased at  an annual
compounded rate  of 6.3%  for the past  20 years. Also, prescription numbers  have been
increasing at approximately the same rate. However, we note that production has  sometimes
slackened during recessions,  and thus we anticipate that the present energy shortages and
disruptions of the economy  may have an  adverse effect on medicinal ingredient production
in the immediate  future. We  are  therefore projecting  waste increases on the basis of a 3
percent compounded rate until 1977. We expect passage of a National Health Care Act in
1976 and believe that growth will then be slightly above historical trends. We have therefore
projected waste growth from 1977 to 1983  on the basis of a 7 percent compounded rate.
Final effluent guidelines  have  not  been set for the pharmaceutical industry. We examined
the preliminary recommendations  for the industry and concluded that the guidelines will
not add  to the tonnage of wastes to be landfilled from  air and wastewater treatment pro-
cesses. Projections  of hazardous and non-hazardous wastes by industry segments for 1977
and 1983 are shown in Table 3.2.1.4.3A. The totals of hazardous and non-hazardous waste
generated in 1973 and the waste generation factors for each waste (metric tons of waste per
metric ton of product or raw material) were developed earlier in  Table 3.2.1.4.1 A  and
Section 3.2.1.2.1.  The projected distribution of wastes by state  was calculated from Ta-
ble 3.2.1.4.1C by using the same 3 percent and 7 percent compounded rate referred to above.
Estimates of state  data  for  1977 are presented in Table 3.2.1.4.3B  and for  1983 in
Table 3.2.1.4.3C. Due to rounding, totals of the various tables may not agree exactly.
                                         74

-------
                                  TABLE 3.2.1.4.2
                         SUMMARY OF TYPICAL TYPES OF
                PHARMACEUTICAL HAZARDOUS WASTE MATERIALS*
Antibiotics (Penicillin, Tetracyclines, Cephalosporins)
   Recovery Solvents
     Amyl acetate
     Butanol
     Butyl acetate
     Methylisobutyl ketone
Alkaloids (Quinine, Reserpine, Vincristine) from Plant Material
Purification Solvents
   Butanol
   Acetone
   Ethylene Glycol Monomethyl Ether
   Extraction Solvents
      Methanol
      Acetone
      Ethanol
      Chloroform
      Heptane
      Ethylene Dichloride
Crude Steroids from Plant Material
   Still bottoms (Soybean Oil Residue)
Medicinals from Animal Organs (Insulin, Heparin)
      Ethanol
      Methanol
      Acetone
Synthetic Organic Medicinals
   Typical Solvents
     • Acetone
      Toluene
      Xylene
      Benzene
      Isopropyl alcohol
      Methanol
      Ethylene Dichloride
      Acetonitrile
   Organic Residues (Still Bottoms, Sludges,
    Polymers, Tars)
      Terpenes
      Steroids
      Vitamins
      Tranquilizers
Blood Plasma Fractions
   Solvent
      Ethanol

 Source: Arthur D. Little, Inc., estimates.
Purification Solvents
   Ethylene Dichloride
   Naphtha
   Methylene Chloride
   Benzene
Inert Solids (Generally Non-Hazardous)
   Activated Carbon
   Filter Aid
   Filter Cloths
Heavy Metals
   Copper
   Mercury
   Arsenic
   Selenium
   Zinc
   Chromium
Salts
   Sodium Acetate
   Sodium Chloride
   Sodium Phosphate
                                         75

-------
                                                                                TABLE 3.2.1.4.3A

                                ESTIMATES OF  PHARMACEUTICAL INDUSTRY GENERATED WASTES FOR 1973,  1977 AND 1983*
                                                                         (All Figures in Metric Tons Per Year)
                                                                            1973
                                                                                                                              1977
                                                                                                                                                                                1983
Industry Segment


R&D
   Solvent
                 Total R&D
SIC Code 2833: Production of Active Ingredients
   Organic Medicinal Chemicals (34,000 Metric Tons/Yr)
      Biological Sludge (from wastewater treatment)
      High Inert Content (filter aid, carbon)
      Contaminated High Inert Content (i.e., filter aid and solvent)
      Organic Chemical Residues {tars, mud, still bottoms)
      Halogenated Solvent
      Non-Halogenated Solvent
      Heavy Metal Wastes
        Zinc Compounds
        Arsenic Compounds
   "~-J   Chromium Compounds
        Copper Compounds
        Mercury Compounds

                 Total for Organic Medicinal Chemicals
                 Rounded to:

   Inorganic Medicinal
      Heavy Metals (i.e., selenium waste)

   Antibiotics (by  Fermentation, 10,000 Metric Tons/Yr)
     Mycelium (plus filter aid and sawdust)
     Biological Sludge
     Waste Solvent Concentrate

                Total for Antibiotics
                Rounded to:

   Botanicals (Plant Alkaloids, 2,000 Metric Tons/Yr Plant Material)
     Wet Plant Material
     Aqueous Solvent Concentrate
     Halogenated Solvent
     Non-Halogenated Solvent

                Total for Plant Alkaloids

  Botanicals (Plant Steroids, 150 Metric Tons/Yr Stigmasterol)
     Fused Plant Steroid  Ingots
Non-Hazardous
Dry Basis Wet Basis
-
-
47,600 476,000
3,400 6,800
- —
51,000 482,800
51,000 480,000
-
75,000 300,000
35,000 350,000
1 1 0,000 650,000
110,000 650,000
2,000 4,000
Hazardous
Dry Basis
1,500
1,500
1,700
13,600
3,400
23,800
2,200
450
20
4
1
45,175
45,000
200
12,000
12,000
12,000
720
60
120
Wet Basis f
1,500
1,500
3,400
13,600
3,400
23,800
2,200
450
20
4
1
46,875
47,000
200
1 2,000
12,000
12,000
850
60
120
                                                          2,000
                                                                     4,000
                                                                                     900
                                                                                              1,030
Non-Hazardous
Dry Basis Wet Basis

-
53,600 536,000
3,800 7,600
- _
a7,400 543,600
57,000 540,000
-
84,400 338,000
39,400 394,000
123,800 732,000
1 24,000 730,000
2,250 4,500
Hazardous
Dry Basis
1,900
1,900
1,900
15,300
3,800
26,800
2,500
500
22
4
1
50,827
51,000
225
13,500
13,500
14,000
810
70
140
Wet Basis*
1,900
1,900
3,800
15,300
3,800
26,800
2,500
500
22
4
1
52,727
53,000
225
1 3,500
13,500
14,000
960
70
140
                                                                                                            2,250
                                                                                                                       4,500
                                                                                                                         840
                                                                                                                                     1,020
Non-Hazardous
Dry Basis Wet Basis

-
80,400 804,000
5,700 11,400
- -
- -
- -
- —
_ _
- -
- —
- -
- -
86,100 815,400
86,000 815,000
-
127,000 508,000
60,000 , 600,000
— -
187,000 1,108,000
190,000 1,100,000
3,400 6,800
- —
- —
-
Hazardous
Dry Basis
2,700
2,700

-
2,900
23,000
5,700
40,000
3,700
750
35
6
1
76,092
76,000
350
_
-
20,000
20,000
20,000
_
1,200
100
200
Wet Basis*
2,700
2,700

—
5,800
23,000
5,700
40,000
3,700
750
35
6
1
78,992
79,000
350
_
-
20,000
20,000
20,000
_
1,400
100
200
                                                                                                                                                              3,400
                                                                                                                                                               1,000
                                                                                                                                                                          6,800
                                                                                                                                                                          1.0OO
                                                                                                                                                                                        1,400
                                                                                                                                                                                                   1,700

-------
                                                                                      TABLE 3.2.1.4.3A (Continued)
Industry Segment


   Medicinals from Animal Glands (8,000 Metric Tons Glands/Yr)
      Extracted Animal Tissue
      Fats or Oils
      Filter Cake (Containing protein)
      Aqueous Solvent Concentrate

                 Total Medicinals from Animal Glands

       Total for Production of Active Ingredients (SIC Code 2833)

SIC Code 2831:  Biological Products
      Aqueous Ethanol Waste from Blood  Fractionation
      Antiviral Vaccine
      Other  Biologicals

                 Total for Biological Products

SIC Code 2834:  Pharmaceutical Preparations
      Returned Goods
      Contaminated or Decomposed Active Ingredient
                  Totals for All Industry Segments
                  Rounded to:
Non-Hazardous
Dry Basis
7,500
350
250
8,100
172,000
-
Wet Basis1
7,500
350
500
8,360
1,143,000
-
Hazardous
Dry Basis
800
800
59,000
250
300
200
Wet Basis1
1,600
1,600
62,000
600
300
200
Non- Hazardous
Dry Basis
8,400
400
280
9,080
193,000
-
Wet Basis1
8,400
• 400
560
9,360
1 ,285,000
-
Hazardous
Dry Basis
900
900
67,000
280
350
225
Wet Basis1
1,800
1,800
70,000
680
350
225
Non-Hazardous
Dry Basis
12,500
600
420
13,520
294,000
-
Wet Basis1
12,500
600
840
13,940
1,937,000
-
Haza
Dry Basis
1,350
1,350
99.000
400
500
350
rdous
Wet Basis1
2,700
2,700
103,000
1.000
500
350
                                                                 10,000
                                                                             10,000
181,850   1,153,000
182,000   1,153,000
                                                                                                                      1 1 ,300
                                                                                                                      1 1 ,300
                                                                                                                                  11,300
                                                                                                                                  11,300
                                                                                            61,650
                                                                                            62,000
65,100
65,000
204,300   1,836,300
204,000   1,836,000
70,445
70,000
73,755
74,000
                                                                                                                                                                            17,000
 17,000
311,000
310,000
                                                                                                                                                                                        17,000
   17,000
1,954,000
1,954,000
                                                                                                                                                                                                        1,250
                                                                                                                                                                                                         900
103,850
1 04.000
                                                                                                                                                                                                                    1,850
    900
108,450
108,000
'Source:  Arthur D. Little, Inc., estimates.
 Wet weight estimates are given for all wastes.  The two wastes that typically have the highest moisture content are biological sludge and
 mycelium from fermentations. Where the wet waste estimates are the same as pn the dry basis, the waste is usually disposed of with only
 a minor amount of moisture. However, disposal practices vary from plant to plant, depending on the form in which the waste is produced.

-------
                                            TABLE 3.2.1.4.3B

PROJECTED DISTRIBUTION BY STATE OF WASTES GENERATED BY THE PHARMACEUTICAL INDUSTRY IN 1977
                                      (annual metric tons — dry basis)


Halogenated"
Slate S
V Aldbama
X Alask;.
IX Arizona
VI Arkansas
X Cahlorm,]
VIII Colorado
Connecncui
II Delaware
V Florida
V Georgia
X Hawaii
X Idaho
V Illinois
V Indiana
VII Iowa
VII Kansas
IV Kentucky
VI Louisiana
1 Maine
III Maryland
1 Massachusetts
V Michigan
V Minnesota
IV Mississippi
VII Missouri
VIII Montana
VII Nebraska
IX Nevada
1 New Hampshire
II New Jersey
VI New Mexico
H New York
V North Carolina
VIM North Dakota
V Ohio
VI Oklahoma
X Oregon
1 I Pennsylvania
II Puerto Rico
1 Rhode Island
IV South Carolina
VIM South Dakota
IV Tennessee
VI Texas
VIII Utah
1 Vermont
HI Virginia
X Washington
III West Virginia
V Wisconsin
VIII Wyoming
National Totals
Region Totals
1
II
Ml
IV
V
VI
VII
VIM
IX
X
tes: 1. Includes R&D solver
2. Includes biological p
1 UUat iiuciinht ~ Hrv we





370

220

45
70


340
370
35

_
10
_
_
__
220
_
_
120
_
20
_
_
1,800
_
900
110

80
-
_
300
220
-
-
_
110
110
_.
_
45
-
_
35
-
5,530

220
2,920
345
335
1,045
120
175
-
370
_
t waste
rortuct organic
iaht x 2.

Nan Halogens




_
1.800
_
1.600
_
450
560

_
3,300
3,500
150
-

10
__
_

2,100
_
_
490
_
90
_
_
12,400
_
6,760
1,000
—
680
-
-
3.700
2,200
-
-
_
900
160
-
—
620
-
-
220
-
42,690

1,600
21,360
4.320
2,910
9,800
170
730
-
1,800

5.
wastes 6.
7.
Organic" Co
n laminated
ed (Chemical) High Inert* A




_
480

560
_
280
220
_
_
860
910
55
-
_
6
__
_
_
510
_
_
190
_
35
_
_
5,300
_
2.600
620
_
170
-
-
1,400
840
—

-
510
50
-
_
220
-
-
55
-
15.871

560
8,740
1,620
1,630
2,505
56
280

480

Wet weight = dry weight
Includes filter cake from
Wet weight = dry weight
Plant Material5
ctiwe Heavy
Waste Ingredient Metals




110

110
_
30
30
_
_
80
80
20
-

-
_
_
_
45
_
_
80
_
10
_
_
560
_
340
55
_
10
__
-
150
110
-
-
_
55

-
_
20
-
_
10
-
1,905

110
1.010
170
170
225
_
110
-
110

x-1.2.
animal source pha
x 4.35.




.45
_
20
_
6
6
_
_
35
35
6
-
_ —
-
_
_ _
_
20
_ —
_
20
_ _
_
_ -
_ _
130
_ __
70
20
_ __
10
- _
—
55
20
_
-
- _
20
15
- __
_
10
-
_ _
-
-
543 3,260

20
220
65
52
100
15
26
- -
45
—

rmaceuticals.
Total
Hazardous'

_
_

2,805
_
2,510
_
811
886
_
_
4.615
4,895
266
-
_
26
_
_
_
2,895
_
_
900
_
155
_
_
20.190
_
10,670
1,805
_
950
_
_
5,605
3,390
_
_
_
1.595
335
_
_
915
_
_
320
-
66,539

2.510
34,250
6,520
5,097
13,675
361
1,321
-
2.805
—

' (excludes
metals)
Biological4
Sludge


_
100
3,300
_
3,400
_
560
560
_
_
7.900
8,600
790
-
_
45
_
680
680
5,200
_
900
790
_
_
_
_
27.200
_
13,500
1,700
_
1.700
-
_
7,300
4,300
-
560
_
1,100
300
-
_
1,200
-
220
450
-
93,035

4,080
45.000
9.400
5,380
23,850
445
1,580
-
3,300
—


Animal Tissue,
Fats, Oil

_
_
„
370
_
450
_
110
110
_
_
560
630
120
-
_
_
_
80
110
380
_
220
80
_
40
_
_
3,600
_
1.800
340
_
120
-
_
900
560
-
110
-
220
-
-
_
110
—
35
55
-
11.110

560
5,960
1,125
1,110
1,745
—
240
—
370
—


High Insets"
Waste
(Non-Hal.)'

_

10
170
_
110
_
35
35
_
_
200
210
55
-
_
10
_
20
110
130
_
55
40
_
20
—
-
1,300
—
680
130
_
46
-
—
280
220
-
20
-
90
35
—
_
55
-
10
10
-
4,085

220
2,200
365
365
595
55
115
—
170
—



Returned
Goods Mynllum
_
_ —
_ —
80
1,010
- —
340
— —
110 -
110
- —
- —
680
730
110
~ -
— —
35
__ —
90
no -
450
— —
220
340
— —
110
— —
— —
2.700
— —
1.350
340
_ —
130
— —
— —
960
450
— —
110
— —
220
220
— —
— —
160
— —
35
35
-
1 1 .235 84.000

450
4,500
1.245 -
1,110
2,025
335
560
— —
1,010 -
— —



Total
Non-Hazsrdouj-
_
~
—
190
4,850
—
4,300
—
815
815
—
—
9.340
10.T70
1.075
~
—
90
—
870
1,010
6,160
—
1,395
1.250
—
170
—
—
34,800
—
17,330
2.610
—
1,996
—
—
9,440
5,530
—
800
—
1,630
555
—
—
1,525
—
300
550
~
119,465

5,310
57.660
12.135
7.965
28.215
835
2,495
—
4.860
	

"(excludes
mycelium)

-------
                                                    TABLE 3.2.1.4.3C
PROJECTED DISTRIBUTION BY STATE OF WASTES GENERATED BY THE PHARMACEUTICAL INDUSTRY IN 1983
                                             (annual metric tons — dry basis)



State
Alabama
Alaska
Arizona
Arkansas
California
Colorado
Connecticut
Delaware
Florida
Georgia
Idaho
Illinois
Indiana
Iowa
Kansas
Kentucky
Louisiana
Maine
Maryland
Massachusetts
Michigan
Minnesota
Mississippi
Missouri
Montana
Nebraska
Nevada
New Hampshire
New Jersey
New Mexico
New York
North Carolina
North Dakota
Ohio
Oklahoma
Oregon
Pennsylvania
Puerto Rico
Rhode Island
South Carolina
South Dakota
Tennessee
Texas
Utah
Vermont
Virginia
Washington
West Virginia
Wisconsin
Wyoming
nal Totals
Regional Totals
1
II
111
IV
V
VI
VII
VIII
IX
X
Notes: 1. Inc
2. Inc
3. Wei
4. Wei


Halogenated*
Solvent Waste
_
_
_
_
560
_
340
_
70
100
_
510
560
50
-
_
15
_
_
-
340
_
_
190
-
30
_
_
2,700
_
1,300
170
_
120
_
-
460
340
_
_
_
170
170
_
-
70
-
_
SO
-
8,315

340
4,340
530
510
1,580
185
270
—
560
-
ludesR&D solvent wast
ludes biological product
[ weight = dry weight x
[ weight = dry weight x


Non-Halogenated
Solvent Waste
_
_
-
_
2,700
-
2,400
_
680
840
„
4,900
5,200
220
-
_
15
_
~
-
3,200
_
_
740
-
130
_
_
18,600
_
10,100
1,500
_
1,000
-
-
5,600
3,400
_
_
-
1,300
240
-
-
930
-
-
340
_
64,035

2,400
32,100
6,530
4,320
14,640
255
1,090
—
2,700
-
es.
r organic wastes.
2.
10.
Hazardous
Organic3
(Chemical)
Residues
_
_
_
_
730
_
840
_
420
340
_
1,300
1,400
85
-
_
10
—
_
_
760
_
_
290
_
50
_
_
7,900
_
3,900
930
_
250
_
-
2,100
1,300
_
_
_
760
80
_
-
340
-
_
85
_
23,870

840
13,100
2,440
2,450
3,795
90
425
_
730
-
5. Wet weight
6. Includes fil-
7. Wet weight


Cant am! naiad3
High Inerts
Waste
_
_
_
_
170
_
170
_
40
40
_
120
120
30
-
_
_
_
_
-
70
_
-
120
-
15
_
_
840
_
510
85
_
15
_
-
220
170
_
_
-
85
—
-
-
30
-
-
15
_
2,865

170
1,520
250
250
340
-
165
—
170
-
= dry weight x 1.2.
ter cake from animal s(
= dry weight x 4.35.



Active
Ingredient
_
_
_
_
70
_
30
_.
10
10
_
50
50
10
-
_
_
_
_
-
30
_
_
30
_
-
_
_
200
_
100
30
_
15
_
_
80
30
_
_
_
30
25
_
-
16
-
_
-
_
815

30
330
95
80
145
25
40
—
70
-

Jurce pharmai




Heavy Total
Metals Hazardous*

_ _
_ „
-_ _
4,230
_ _
3,780
_ _
1 ,220
1 ,330
I I
6,880
7,330
395
_ _
_ _
40
_ _
_ _
__ „
4,400
_ _
__ _
- 1 ,370
_ _
225
_ _
_ _
30,240
_ _
- 15,910
2,715
_ _
1 ,400
_ _
_ _
8,460
5,240
_ _
_ _
_ _
2,345
- 515
_ _
_ „
1,385
_ _
_ _
490
_ _
4,900 99,900

3,780
51,390
9,845
7,610
20,500
555
1,990
— _
4,230
- -
* (excludes r
ceuticals. "(excludes r




Biological*
Sludge
_
_
-
150
4,900
-
5,100
_
840
840
_
11,800
12,800
1,200
-
_
70
-
1,000
1,000
7300
—
1,300
1.200
-
-
-
-
40,900
_
20,300
2,500
_
2,500
-
-
1 1 ,000
6,400
_
840
-
1,700
460
-
-
1,900
-
340
680
-
139,520

6,100
67,600
14,240
8,020
35,580
680
2,400
_
4,900
-
netals)
nycelium)


Non-Haz
Plant Material5
Animal Tissue,
Fats, Oil
_
_
-
-
560
-
680
_
170
170
_
840
950
190
-
_
-
-
120
170
570
_
340
120
-
60
-
-
5,400
—
2,700
510
—
190
-
—
1,300
840
_
170
—
340
-
-
-
170
-
50
85
_
16,695

850
8,940
1,640
1,700
2,635
—
370
_
560
-




ardous
High Inerts3-6
Waste
(Non-Haz.)
_
-
-
15
250
-
170
—
50
50
_
300
320
85
-
-
15
-
30
170
200
—
85
60
-
30
-
-
1,900
—
1,000
200
—
70
-
-
420
340
—
30
-
130
50
-
-
85
-
15
15
-
6,085

340
3,240
550
545
905
80
175
_
250
-






Returned
Goods
_
-
-
120
1,500
-
510
—
170
170
_
1,000
1,100
170
-
-
50
-
130
170
680
—
340
510
—
170
—
-
4,000
—
2,000
510
—
200
-
-
1,400
680
—
170
-
340
340
-
-
240
-
50
50
-
16,770

680
6,680
1,820
1,700
3,030
510
350
_
1,500
-




                                                                                                                                                Total
                                                                                                                                             Non-Hazardous,
                                                                                                                                                   285
                                                                                                                                                 7,210
                                                                                                                                                  1,230
                                                                                                                                                  1,230
                                                                                                                                                 13,940
                                                                                                                                                 15,170
                                                                                                                                                  1,645
                                                                                                                                                  1,280
                                                                                                                                                  1,510
                                                                                                                                                  9,250

                                                                                                                                                  2,065
                                                                                                                                                  1,890

                                                                                                                                                   260


                                                                                                                                                 52,200

                                                                                                                                                 26,000
                                                                                                                                                  3,720
                                                                                                                                                 14,120
                                                                                                                                                  8,260
                                                                                                                                                  2,510
                                                                                                                                                   850
                                                                                                                                                   455
                                                                                                                                                   830

                                                                                                                                                179,070

                                                                                                                                                  7,970
                                                                                                                                                 86,460
                                                                                                                                                 18,250
                                                                                                                                                 11,965
                                                                                                                                                 42,150
                                                                                                                                                  1,270
                                                                                                                                                  3,795

                                                                                                                                                  7,210

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                        DATA SOURCES FOR SECTION 3.1

A. GENERAL SOURCES

        Manufacturers'  Technical Bulletins - This is usually the best single source of
general information about the compound.

        Material Safety  Data  Sheets - Provided  by the manufacturer using the U.S.
Department of Labor Form OSHA-20 or an approved modification.

        Code of  Federal  Regulations - Office of the Federal Register,  Archives  and
Record Service, Washington, D.C., 1972. Titles 46 (Shipping) and 49 (Transportation) in the
most recent revision available.

        Chemical  Safety Data Sheets — Manufacturing Chemists  Association, Washington,
D.C.

        Industrial Safety Data Sheets — National Safety Council, Chicago, Illinois.

        International Maritime Dangerous  Goods Code — Inter-Governmental Maritime
Consultative Organization  (IMCO), London,  1972.

        Petroleum Products  Handbook -  V.B. Guthrie (ed.), McGraw-Hill, New York,
1960.

        Glossary of Terms Used in Petroleum Refining — 2nd edition, American Petroleum
Institute, New York, 1962.

        The Handling and  Storage of Liquid Propellants - Office of Defense Research and
Engineering, U.S. Government Printing Office, Washington, D.C., 1963.

        Industrial Chemicals - W.L. Faith, D.B. Keyes, and R.L. Clark, 3rd edition, Wiley,
New York, 1965.

        Chemical  Technology of Petroleum - W.A. Gruse and D.R. Stevens, 3rd edition,
McGraw-Hill, New York, 1960.

        Chemical  Rocket/Propellant Hazards - CPIA Publication No. 194, Vol. Ill, 1970.

        Organic Solvents - J.A. Riddick and W.B. Bunger, 3rd edition, Wiley-Interscience,
New York, 1970.

        Transport of Dangerous Goods - (4 vols) United Nations, New York, 1970.
                                        80

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         Kirk-Othmer Encyclopedia  of Chemical Technology- 1st edition (1947-1960)
and 2nd edition (1963-1970), Interscience-Wiley, New York.

         Evaluation of the Hazard of Bulk Water Transportation of Industrial Chemicals, A
Tentative Guide - National Academy of Sciences, Washington, D.C., 1970; includes supple-
ment with additions to September 1972.

         System for Evaluation of the Hazards of Bulk Water Transportation of Industrial
Chemicals — National Academy of Sciences, Washington, D.C., 1974.

B. HEALTH HAZARDS

         Industrial  Hygiene  and  Toxicology — F.A. Patty, 2nd edition,  Vol. II, Inter-
science, New York, 1963.

         Toxicity and  Metabolism of  Industrial Solvents — E. Browning,  Elsevier, New
York, 1965.

         Practical Toxicology of Plastics — R. Lefaux, CRC Press, Cleveland, Ohio, 1968.

         Industrial  Toxicology — L.T.  Fairhill, Williams and Wilkins,  2nd  edition, Balti-
more, Maryland, 1957.

         Toxicology of  Drugs  and Chemicals —  W.B.  Deichmann and  H.W. Girarde,
Academic Press, New York, 1969.

         Clinical Toxicology of  Commercial Products — M.N. Gleason, et al., 3rd edition,
Williams and Wilkins, Baltimore, Maryland, 1969.

         Handbook of  Toxicology:  Acute Toxicities  of Solids, Liquids  and Gases to
Laboratory Animals — W.S. Spector, Saunders, Philadelphia, Pa., 1956.

         Occupational  Diseases: A   Guide to Their Recognition — U.S. Department of
Health, Education, and Welfare, Public Health Service Publication No. 1097. Superintendent
of Documents, Washington, D.C., 1964.

         First Aid Textbook - American National Red Cross, Washington, D.C.,  1972.

         Electrical Safety Practice: Odor Warning for Safety - Monograph 113 Instrument
Society of America (ISA), Pittsburgh, Pa., 1972.

         Toxic Substances- Annual List 1973-  H.E.  Christensen, U.S. Department of
Health, Education, and Welfare, Superintendent of Documents, Washington, D.C., 1973.
                                         81

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        Encyclopedia of Occupational Health and  Safety, Two Volumes, International
Labour Organization, Geneva, 1972.

        Fawcett, H.H.,  Toxicity vs. Hazard, pages 279-289, and Foulger, J.H., Effect of
Toxic Agents, pages 250-278, in Fawcett and Wood, Safety and Accident Prevention in
Chemical Operations, Interscience, Wiley, New York, 1965.

        Murphy, Sheldon C., The Toxicity of Pesticides and Their Metabolites, pages
313-335, in Degradation of  Synthetic Organic Molecules  in the Biosphere— Natural,
Pesticidal,  and Various Other Man-Made  Compounds, Proceedings of a Conference,  San
Francisco, California, June 12-13, 1971, Committee on Agriculture and the Environment,
ISBN 0-309-02046-8, National Academy  of  Sciences, 2101 Constitution  Avenue, N.W.,
Washington, D.C. 20418,  1972.

C. FIRE HAZARDS

        The Fire and Explosion  Hazards of Commercial Oils —  W. Vlachos and C.A.
Vlachos, Vlachos and Co., Philadelphia, Pa., 1921.

        1972 Annual  Book  of ASTM Standards —  American  Society  for  Testing and
Materials, Philadelphia, Pa., 1972.

        Fire Protection Guide on Hazardous Materials — 5th edition, Nos. 325A, 325M, 49,
491M, and 704M, National Fire Protection Association (NFPA), Boston, Mass.,  1972.

        Fire Protection Handbook — G.H.  Tryon (ed.), 13th edition, National Fire Protec-
tion Association (NFPA), Boston, Mass., 1969.

        Handbook of Industrial Loss Prevention — 2nd edition, Factory Mutual Engineering
Corp., McGraw-Hill, New York, 1967.

D. WATER POLLUTION

        Water Quality Criteria Data Book - Vol. 1 - Organic Chemicals (1970) and Vol.
2- Inorganic Chemicals (1971), Vol.  5- Effect of Chemicals on Aquatic  Life (1974),
United States Environmental Protection Agency, Superintendent of Documents, Washing-
ton, D.C.

        Engineering  Management  of Water Quality - P.H. McGauhey, McGraw-Hill, New
York, 1968.

        The BOD of Textile   Chemicals  - Proceedings of the American  Association of
Textile Chemists and Colorisis, American Dyestuff Reporter, August 29, 1966, p. 39.

        Biodegradable Surfactants for the Textile Industry - American Dyestuff Reporter,
January 30, 1967.

                                       82

-------
       Water  Quality Criteria - J.E. McKee and M.W. Wolf, 2nd edition, California State
Water Quality Control Board, Sacramento, California, 1963.

       Water  Quality Criteria — National Technical  Advisory Committee, Federal Water
Pollution Control Administration, Washington, D.C., 1968.

       OHM-TADS  (EPA) - The  Oil and Hazardous Materials Technical Assistance Data
System (OHM-TADS) has been developed by the Environmental Protection Agency (EPA)
to provide information on  physical and chemical properties, hazards, pollution character-
istics, and shipping information for over 800 hazardous materials. OHM-TADS consists of a
computerized  data base which can be accessed from terminals at the 10 EPA Regional
Offices and  from EPA Headquarters in Washington,  D.C. The system can provide either
information  on  specifically requested properties  for a  material, or it can print all the
information in its files for that material.

       Water  Quality Characteristics of Hazardous Materials,  4 Volumes, —  R.W. Hann,
Jr. and Paul A. Jensen, Environmental Engineering Division, Civil Engineering Department,
Texas A&M University, College Station, Texas, 1974.
                                         83

-------
      BIBLIOGRAPHY FOR ANIMAL ORGAN EXTRACTS AND BIOLOGICALS

ANIMAL ORGAN EXTRACTS

    Standen, A. (editor), Kirk-Othmer Encyclopedia of Chemical Technology, 2nd Edit.,
Vol. 11 (1966) pp. 838-845.

    Webb, F.C., Biochemical Engineering, D. Van  Nostrand Co., London (1964), pp.
539-540.

BIOLOGICALS

    Standen, A. (editor), Kirk-Othmer Encyclopedia of Chemical Technology, 2nd Edit.,
Vol. Ill (1966)pp. 576-601.

    Webb, F.C.,  Biochemical Engineering, D.  Van Nostrand Co.,  London (1964) pp.
449-450.
                                   84

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                        DATA SOURCES FOR SECTION 3.2

                BIBLIOGRAPHY FOR ANTIBIOTIC MANUFACTURE

PENICILLIN

     Brunner, R., G. Machek, E.  Brandl and   A. Schmid, Die Antibiotica Band I Die
Grossen Antibiotica Verlag Hans Carl, Nurnberg (1962) pp. 285-376.

     Elder, Albert L. (editor), "Centrifugal Solvent Extraction" in The History of Penicillin
Production, Chemical Engineering  Progress Symposium Series, No.  100, Vol. 66 (1970),
American Institute of Chemical Engineers, Chap. VI.

     Prescott,  S.C., and  C.G. Dunn,  Industrial   Microbiology, 3rd Edit.,  McGraw-Hill
(1959), pp. 77-784.

     Rehm,  Hans-Jurgen,  Industrielle Mikrobiologie, Verlag Springer, Berlin (1967) pp.
159-180.

     Standen, A. (editor), Kirk-Othmer Encyclopedia of Chemical Technology, 2nd Edit.,
Vol. 14 (1967) pp. 688-707.

     Underkofler, L.A., and Richard Hickey, Industrial Fermentations, Vol. II, Chemical
Publishing Co., New York (1954) pp. 226-384.

     Webb,  F.C., Biochemical Engineering, D. Van  Nostrand  Co., London (1964) pp.
549-550,645-661.

TETRACYCLINE

     Rehm, Hans-Jurgen,  Industrielle  Mikrobiologie,  Verlag Springer,  Berlin (1967) pp
215-219.

     Forbath, T.P., "Tetracycline:  Engineered to Market," Chemical Engineering,  (March,
1957) pp. 228-231.

BACITRACIN AND ERYTHROMYCIN

     Underkofler, L.A. and Richard Hickey, Industrial Fermentations, Vol. II, Chemical
Publishing Co., New York  (1954) pp. 304-308,316-318.
                                       85

-------
                 BIBLIOGRAPHY FOR BOTANICAL MEDICINALS

ALKALOIDS

    Forbath, T.O., "Liquid Extraction Commerciallizes Reserpine" Chemical Engineering
(April, 1957) pp. 230-233.

    Manske,  R.H.F., The   Alkaloids, Vol. I,  Chap. I "Sources of  Alkaloids and  their
Isolation."

    Nobler, Carl  L., Chemistry of Organic Compounds, 2nd Edit., W.B. Saunders, Co.
(1957) pp. 648-655.

STEROIDS

    Nobler, Carl L.,  Chemistry  of Organic Compounds, 2nd Edit.,  W.B. Saunders, Co.
(1957) pp. 868-872.

    Krieg, Margaret B., Green Medicine, Rand McNally (1964) pp. 269-291.

    Poulos, Arthur; J.W. Greiner and G.A. Fevig. "Separation of Sterols by Countercurrent
Crystallization," Industrial and Engineering Chemistry,  Vol. 53, No. 12 (December 1961)
pp. 949-962.

    Underkofler,  L.A., and Richard Hickey, Industrial Fermentations, Vol. II, Chemical
Publishing Co., New York (1954) pp. 398-410.
                                       86

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4.0 TREATMENT AND DISPOSAL TECHNOLOGIES

4.1 BACKGROUND

     Approximately 244,000 metric tons of land-destined process wastes (dry weight basis)
are generated annually by the pharmaceutical industry.* The amount of hazardous wastes
generated is about 25 percent of the total waste, or 61,000 metric tons per year. The waste
generation rate  is expected to grow  to nearly 400,000 metric tons of total wastes per year
and to 100,000  metric tons of hazardous wastes per year by 1983.

4.2 DESCRIPTION OF PRESENT TREATMENT AND DISPOSAL TECHNOLOGIES

     Approximately 85 percent  of current total wastes generated and 60 percent of current
hazardous wastes generated  are estimated to  be  both treated and then disposed  of by
contractors. Of the  current  total wastes generated,  ADL estimates that 60 percent,  or
150,000  metric tons, are disposed of on land.  About 9 percent, or 5600 metric tons,  of
current hazardous wastes generated  are disposed of on land. These percentages reflect the
extensive use of incineration by  the pharmaceutical industry both on-site and by contractors
off-site. Where possible, materials are recovered for  reuse. Secure chemical landfills and
encapsulation techniques are now being  used — and will most probably be in the future —
for the disposal of heavy metal  wastes which are too dilute or contaminated for recovery,
and general process wastes of a non-hazardous nature.

     The current process waste treatment and disposal methods are briefly described  in
Section 4.2.1; for each hazardous  waste identified  in  Chapters, current  treatment and
disposal  practices are discussed in Sections 4.2.2 to  4.2.6. Section 4.2.7  describes the
treatment and disposal methods discussed in the sections on hazardous waste treatment and
disposal.

4.2.1  Present Treatment/Disposal Technologies for General Process Wastes
      (Hazardous and Non-hazardous)

4.2.1.1 Research and Development

     Numerous  large pharmaceutical companies have research and development operations.
In fact, there are currently 25,000 researchers within the industry.

     The wastes from this industry section include:

     •   waste solvents and still bottoms, and
     •   test animals.
*See Table 3.2.1.4 for summary  of total process  wastes  and  potentially hazardous wastes for the
 pharmaceutical industry in 1973.

                                        87

-------
     Waste solvents and still bottoms (1500 metric tons annually) are either disposed of by
contract incineration, or are company-incinerated, if the research facility is located near
pharmaceutical manufacturing operations with liquid incineration capability.

     Test animals  are either rendered or incinerated. Large animals are rendered with the
bones converted to bonemeal. Small animals are usually incinerated and the inert ash is sent
to a landfill. Often these small animals are either autoclaved or frozen, if the animals are not
to be incinerated immediately.

4.2.1.2  Production of Active Ingredients (SIC 2831 and 2833)

     4.2.1.2.1   Organic Medicinal Chemicals

     Pharmaceutical companies manufactured about 75 million pounds of organic medicinal
chemicals in 1973.* The wastes from these operations include:

     •    waste solvents, halogenated and non-halogenated;

     •    organic chemical residues;

     •    biological sludge (from organic chemical wastewater treatment);

     •    heavy metals, and

     •    high inert content wastes such as filter cakes.

     With the  exception of the biological sludge and part of the high inert content wastes,
they are  all hazardous wastes.  The present  methods  of hazardous waste  treatment and
disposal are discussed in more detail in Sections 4.2.2 through 4.2.6.

     The  pharmaceutical industry  recovers a  large amount (95  percent or more)  of its
process  solvents for reuse. Those solvents that are considered wastes come from solvent-
recovery operations. Essentially  all of these waste  solvents are incinerated, either on-site or
by contractors off-site.  Organic chemical residues  are usually incinerated, although some
operations are sending them to landfills off-site.

     ADL surveyed  about 25 to 30 percent of the pharmaceutical companies' production
capacity of organic chemicals for this  study.  Of  those visited, half had on-site biological
treatment of waste water; 90 percent disposed of the resulting sludge in off-site landfills.

     Heavy metals are used as catalysts, oxidants, and product  ingredients in the production
of  organic medicinal  chemicals. A  limited  amount  is used within the pharmaceutical
industry (see Section 3.2.1.2.1).  The locations using heavy metals are also limited. The heavy
metal wastes are handled in various ways, including recovery off-site and encapsulation and

*See Section 3.2.1.2.
                                         88

-------
landfill  in a separate section of a landfill. These methods are discussed further in Section
4.2.5.

     The properties  of the  high inert content wastes vary greatly. ADL estimates that as
much as 30 percent of those materials are potentially hazardous because of flammability,
corrosiveness, or toxicity. The remaining 70 percent are innocuous materials, such as filter
aid and water or charcoal and water, which are usually landfilled. Of the 30 percent that are
potentially hazardous  some are considered  potentially hazardous from the  standpoint  of
flammability because of the presence of solvent. These can be rendered non-hazardous by
incineration. About 25 companies incinerate this material. The remainder of the potentially
hazardous waste must be landfilled with special precautions because they contain material
such as heavy metals. These cannot be incinerated.

     4.2.1.2.2 Inorganic Medicinal Chemicals

     Since most  inorganic  medicinal-chemical active ingredients  are purchased  from
sources outside the pharmaceutical industry, there is  little  waste produced in this industry
section. Preparations such as stomach antacids are, however, generally produced within the
pharmaceutical industry. While the majority of the process waste leaves with the water
effluent, there may  infrequently  be reject  materials, such as aluminum  hydroxide  or
magnesium hydroxide. These wastes may be landfilled.

     The only hazardous waste stream we found in this industry segment was a waste which
contained about 0.2 percent selenium. The waste, about 160,000 kg per year, is in its most
insoluble form, the sulfide, when it is disposed of by a contractor in a state-approved secure
chemical landfill.

     4.2.1.2.3 Fermentation Products

     When active ingredients such as antibiotics are produced by fermentation, three types
of wastes that are destined for land disposal are also produced.* They are:

     •    Mycelia;
     •    Biological sludge from spent broth treatment;
     •    Solvent concentrate (hazardous waste, see section 3.2.1.2.3).

     Because there are few companies involved in  fermentation and most of the operations
are large  scale, ADL was  able  to study  about 65 percent of  the U.S. fermentation
production  capacity. The volumes of waste from such operations represent a significant
problem to the industry.
 h Figure 3.2.1.2.3 shows the waste generation from a typical fermentation product - penicillin.


                                          89

-------
     Of the  estimated 75,000  metric tons  of mycelia  (on a dry basis) produced by
fermentation operations each year, ADL estimates that 85  to  90  percent of the waste is
land-disposed  at some off-site location. Of the remainder, some portions are incinerated or
used as soil builders. In the past, ocean dumping was used for mycelia disposal, until 1972
EPA regulations  on ocean dumping halted this practice temporarily by invoking stricter
requirements on analysis of wastes prior to permit renewals. A typical large operation has on
the order of 25,000 to 45,000  metric tons of mycelia to dispose of each year.  Since this
material is wet (generally 25 to  35 percent solids after dewatering), it must be disposed of
immediately to eliminate odor problems.

     Many disposal methods have been investigated. When mixed with 1 percent lime, for
example,  mycelia can  be used as a soil  builder. It can  also be incinerated, but  the water
content is too high for the operation to be cost-effective. Although this  waste is not
considered hazardous, it is indeed a problem for the industry.

     Waste broth solids are high-volume materials which can either be disposed of as a waste
or can be changed to a useful by-product. About 72,000 metric tons are produced annually
by fermentation operations. Until stricter effluent restrictions were placed on fermentation
operations, the spent broth was usually treated biologically, producing a sludge that was
landfilled. Approximately 0.5 kg of biological  sludge is produced for each kg of waste broth
solids. Since  the  spent broth  contains a  significant  amount  of  food value,  it  can be
concentrated by  evaporation and sold as a molasses substitute in animal feeds.  Still some
operations handle  the  broth as a waste  either because  the capital investment  for  the
equipment is too great, or because there is no market for the concentrate. None of those
operations producing the broth concentrate are making a profit, just breaking even at best.
On the other hand, they do not have the significant cost of biologically treating the high
BOD waste.  Occasionally  the  waste  broth   is incinerated,  even  though  incineration is
expensive because of the relatively low-Btu content of the waste broth.

     The third type of waste, the solvent concentrate, which is a waste product  of solvent
recovery operations, contains as much as 50 percent by weight of organic solids.  About 50
million pounds of the concentrate is produced annually by fermentation operations within
the United States.  Sixty-five percent of the pharmaceutical industry  fermentation produc-
tion capacity was  surveyed.  The  waste solvent concentrate at all  these locations was
incinerated either on-site or by contractors off-site. Because of the similar nature of the other
plants  in  this industry, we  estimate that all  of this waste is currently being incinerated,
either  on-site or by contractors off-site. Because this  waste is flammable,  it is considered
hazardous. Disposal is discussed further in Section 4.2.2.2.3.

     4.2.1.2.4 Botanicals

     Medicinal active ingredients, such as alkaloids and steroids, are  obtained from plant
material. The  wastes potentially destined for land disposal  are listed below, the last two
being hazardous:
                                         90

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     •    Moisture-laden plant material,

     •    Waste solvent (50 percent solids and 30 percent water), and

     •    Waste chlorinated hydrocarbons.

     A  typical alkaloid operation* produces  1820 kg per day of wet waste plant material
and  operates  250 days per year. This totals  to  454 metric tons per year of  waste plant
material. The waste is steamed to remove residual solvent and is then sent to sanitary landfill
off-site.

     Three types of solvents are used in the extraction process to produce alkaloids. The one
used in the  initial extract  ends up with  water, plant  extract,  and organic  acid  salts
after solvent-recovery  operations. This  waste solvent  is  either incinerated on-site  or by
contractors off-site. A  second water-immiscible, chlorinated solvent, is used to extract the
alkaloid from the first solvent. More of the chlorinated solvent can be recovered than the
first solvent which contains most of the water-soluble organic material after extraction. But,
since this second solvent is chlorinated, problems can develop if it is incinerated  without the
proper  precautions. The  amount of chlorinated solvent is only 5 cubic meters (1,250
gallons) per year for the typical plant, five percent of the total solvent. This amount is small
enough to drum for contractor incineration. We estimate that 60 percent of each of the two
waste solvents are incinerated on-site and the remainder off-site by contractors. A third waste
solvent  is non-halogenated.

     4.2.1.2.5 Drugs from Animal Sources

     Medicinal products such as insulin or heparin are obtained from animal sources. The
wastes from these operations that are destined for land disposal include:

     •    rendered organs or animal tissue;
     •    fats and oils;
     •    filter cake, containing precipitated protein; and
     •    aqueous solvent (hazardous waste, see Section 3.2.1.2.5).

The  typical extraction operation** will dispose of 839 metric tons of organs or animal tissue
annually in the production of 284 kg of active ingredient. Two methods of disposal are used
interchangeably in most  operations. When a market exists, the waste product  is sold as a
protein-source feed for animals; otherwise it is disposed of in a sanitary landfill. The fats (40
metric tons per year)  are recovered for sale to  soap manufacturers. The filter cake (25.5
metric tons per  year), which  contains precipitated protein, is landfilled or incinerated if the
operation is near other  pharmaceutical operations with incineration capability.
'Figure 3.2.1.2.4.1 presents the flow scheme of waste generation for a typical alkaloid operation.
* Figure 3.2.1.2.5 describes the waste generation in a typical operation extracting glandular materials.


                                         91

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     The hazardous waste from the operation in which medicinals are obtained from animal
glands is a waste solvent emanating from the solvent-recovery system. A typical operation
produces 91 metric tons (25,000 gallons) of waste solvent annually, a generation rate of 350
liters  per  kilogram of product. These  solvents,  which contain 50 percent water and 25
percent organic solids, are incinerated either on-site or by a contractor off-site.

     4.2.1.2.6 Biological Products

     Some pharmaceutical companies manufacture biological products such as blood prod-
ucts, vaccines, serums and toxoids. The wastes from these operations include:

     •    Aqueous solvent waste;
     •    Miscellaneous incineratable wastes; and
     •    Filter material.

ADL  estimates that SIC 2831 has 500 metric tons of hazardous waste. Most of this amount
is considered hazardous because  of its  flammability.  All hazardous wastes are incinerated
either on-site  or by  contractor off-site. The filter material contains only traces of protein
and can be landfilled.

4.2.1.3 Formulation and Packaging (SIC 2834)

     The  wastes  from  the  formulation and  packaging segment   of the  pharmaceutical
industry are returned  goods and reject material.* The  total  returned goods and  reject
material from this segment annually are indicated below:

     •    Glass, paper, water, etc.     10,000 metric tons
     •    Active ingredient             500 metric tons

Normal trash waste from the formulation and packaging segment of the industry is handled
in much the same way as in other industries. Paper, cartons, and the like, not identifiable as
the company's own can be recycled  through salvage dealers, while materials bearing the
company's name are either shredded or incinerated on-site.

     Returned goods are handled specifically  by the formulating and packaging operations
of a company. "Controlled drugs," such as narcotics, must be destroyed in  the presence of
Drug  Enforcement Agency (DEA) personnel, according to the regulation which is presented
on the  next page. Other Pharmaceuticals are handled in a method detailed by the specific
company  and  Pharmaceuticals recalled by the FDA may be required to be destroyed under
FDA  observation. Generally, non-salvageable goods  are crushed on-site and then sent to
landfill. Smaller percentages are either incinerated or are slurried with water  which is sent to
an activated sludge treatment facility.
*Section 3.2.1.3 discusses waste generation in this industry segment.
                                         92

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                        federal  Regulations;  . Disposal of Controlled    Pharmaceuticals'
                 ง 1307.15   Incidental  manufacture  of
                     controlled substances.
                   Any registered manufacturer who, In-
                 cidentally but necessarily, manufactures
                 a controlled substance as a result of the
                 manufacture of  a controlled substance
                 or basic class of controlled substance for
                 which he is registered and has been  is-
                 sued an individual manufacturing quota
                 pursuant to Part 1303 of this chapter (if
                 such substance or class is listed in sched-
                 ule  I or II) shall be exempt from the
                 requirement of registration pursuant to
                 Part 1301  of this chapter and, if  such
                 incidentally manufactured substance is
                 listed in schedule I or II, shall be exempt
                 from the requirement  of an individual
                 manufacturing quota pursuant to Part
                 1303 of this chapter, if such substances
                 are  disposed  of  in  accordance  with
                 ง 1307.21.
                   DISPOSAL OF CONTROLLED SUBSTANCES
                 ง 1307.21   Procedure for  disposing  of
                     controlled substances.
                   (a)  Any  person in possession  of any
                 controlled substance and desiring or re-
                 quired to dispose of such substance may
                 request  the Regional Administrator of
                 the Administration  in the  region  in
                 which the person is located for author-
                 ity  and instructions  to dispose of  such
                 substance. The request should be made
                 as follows:
                   (1)  If the person  is a registrant re-
                 quired to make reports pursuant to Part
                 1304 of this chapter, he shall list the con-
                 trolled  substance or substances which
                 he desires to dispose of on the "b" subpart
                 Oi the report normally filed by him, and
                 submit three copies of that subpart to
                 the Regional Administrator  of the Ad-
                 ministration in his region;
                   (2)  If the person is a registrant not
                 required to make reports pursuant to
                 Part 1304 of this chapter, he shall list the
                 controlled substance or substances which
                 he desires  to dispose of on  DEA Form
                 41. and submit three copies of that form
                 to the Regional Administrator in his reg-
                 ion; and
                   (3)  If the person is  not a registrant,
                 he shall submit to the Regional Admin-
                 istrator a letter stating:
                   (1) The  name and  address  of the
                 person;
                   (il)  The name and quantity of each
                 controlled substance to be disposed of;
                   till)  How the applicant obtained the
                 substance,  If known; and
                   (iv)  The name, address, and registra-
                 tion number,  if  known, of the person
                 who possessed the controlled substances
                 prior to the applicant, if known.
                   (b) The Regional Administrator shall
                 authorize and instruct the applicant to
                 dispose of the controlled substance in
                 one of the following manners:
   (1)  By transfer to person registered
 under the Act and authorized to possess
 the substance;
   (2)  By delivery to an agent of  the
 Administration  or to  the nearest office
 of the Administration;
   (3)  By destruction in the  presence of
 an agent of the Administration or other
 authorized person; or
   (4)  By such other means  as  the Re-
 gional Administrator may determine to
 assure that the substance does not  be-
 come available to unauthorized persons.
   (c)  In the event  that a  registrant
 is required regularly to dispose of con-
 trolled substances, the Regional Admin-
 istrator  may authorize the registrant to
 dispose  of such  substances,  in  accord-
 ance with paragraph (b) of this section,
 without  prior approval of the Adminis-
 tration in each instance, on the condi-
 tion that the registrant keep records of
 such disposals  and file periodic reports
 with the Regional Administrator sum-
 marizing the disposals made by the regis-
 trant. In granting such  authority, the
 Regional Administrator may place such
 conditions as he  deems proper on the
 disposal  of controlled substances, includ-
 ing the method of disposal and the fre-
 quency and detail of reports.
   (d)  This section shall not be construed
 as  affecting or altering in any way the
 disposal  of controlled substances through
 procedures provided in laws and regula-
 tions adopted by any State.
 [36 F.B.  7801, Apr.  24. 1971, as  amended at
 37 FJt. 16922, Aug. 8, 1972]
 ง 1307.22  Disposal of  controlled sub-
     stances by the Administration.
  Any controlled substance delivered  to
 the Administration under ง 1307.21  or
 forfeited pursuant to section 511 of the
 Act (21  U.S.C. 881) may be delivered to
 any department, bureau, or other agency
 of the United States or of any State upon
 proper application addressed  to the Ad-
 ministrator, Drug Enforcement Adminis-
 tration, Department of Justice, Washing-
 ton, D.C. 28083. The  application shall
 show the name, address, and official title
of the person or agency to whom the con-
trolled drugs are to be delivered,  includ-
ing the name and quantity of the sub-
stances  desired  and  the purpose for
which  intended.  The  delivery of such
controlled drugs shall be ordered by the
Administrator, if,  in his opinion, there
exists a medical or scientific need there-
for.
'''Source:      Code  of Federal Regulations,  No. 21,  Food and Drugs,  Part 1300  to  end.

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     Reject  material from formulation is  very  limited. Because of the value of the raw
materials involved, potentially faulty batches of Pharmaceuticals are reformulated to meet
specifications. When  a material  cannot be  upgraded, the "bad  batches" are either in-
activated, by neutralization, for  example, and  sent through  biological treatment, or are
landfilled or incinerated, depending upon the nature of the material.

     (For the purpose of this study, a portion of the returned goods and reject material have
been  segregated as  potentially  hazardous wastes.) Section  4.2.4 provides a more detailed
discussion on present  treatment  and disposal technologies of the  potentially hazardous
wastes resulting from the returned goods and reject material, Section 4.5.5 describes Level I,
II, and III technologies for treating and disposing of returned goods and reject material from
formulation.

4.2.1.4 Marketing and Distribution

     Wastes from marketing and distribution merely represent large volumes of paper, wood,
and  cardboard. Since there are no process wastes from this segment of the industry and
returned goods are normally  sent back to the  formulation  and packaging facilities, this
segment of the industry has not been studied further,

4.2.1.5 Pharmaceutical Operations in Puerto Rico,

     An organization  called Fomento  was set  up by the Puerto Rican  government to
encourage industry  to settle in Puerto Rico and to provide assistance to those companies in
the  areas of siting, employment, and services,  such as electricity, water, and regional
wastewater treatment. Industries investigating the attractive tax-break offers in the mid-'60's
were  also told that, should they settle in an area like Barceloneta  (about 40 miles west of
San Juan) adequate regional wastewater treatment facilities would be provided. The planned
completion  date has slipped a  little. It was planned to  be on stream in 1974, but it will
probably not be in operation until mid-1975. Therefore, pharmaceutical companies involved
have had to ocean-dump their process wastewater, because they are not permitted to send it
to the nearby Manati River.

     Numerous U.S. and European  pharmaceutical  firms  were encouraged to construct
operations in Puerto Rico.  Since the  early '60's, the number of these installations has been
growing rapidly. At present, we estimate that as many as 42 plants have been constructed
and  are now in operation. These operations have severe impacts on the pollution control
problems of the area.

     Solid waste  disposal sites  are provided by the local municipal governments in Puerto
Rico  (see Figure 4.2.1.5 for outline of current facilities). In the past these disposal sites have
simply been dumps with open burning of trash. The Puerto Rican Environmental Quality
Board (EQB) is pressuring the  municipalities to  upgrade the disposal sites and to provide
sanitary landfills.  The EQB does not consider two of the sites - the Manati dump and the


                                        94

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                                           o Sanitary Landfill

                                           o Dumps Converted to
+                                            Sanitary Landfill
 Source:  Environmental Quality Board of Puerto  Rico.
o Approved Lands


n Open Dump with Burning
                                                              • Lands Under Study
                                    FIGURE 4.2.1.5  SOLID WASTE DISPOSAL FACILITIES IN PUERTO RICOt

-------
 Barceloneta landfill — to be satisfactory for disposal  of chemical wastes. But the EQB
 considers a third site — the landfill at Mayagiiez — suitable for chemical wastes. In addition
 a new site has been recommended between Barceloneta and Arecibo in the Cana Tiburones
 area which the  EQB  feels will be satisfactory for chemical waste disposal. We visited the
 Manati,  Barceloneta,  and Mayagiiez disposal  sites. The Manati dump clearly is  not satis-
 factory for chemical  disposal and is currently no longer being so used. The Barceloneta
 landfill is currently being used for chemical waste disposal and, on casual examination, it
 appears that the site  could  be upgraded to serve as .a satisfactory site for chemical waste
 disposal.  However, studies by  the EQB indicate that  subsurface drainage to the nearby
 Manati River would be excessive, and hence the EQB is attempting to stop the municipality
from  accepting  chemical wastes.  There may be a problem  for several  months as the
pharmaceutical companies were assured of municipally operated solid waste and  liquid
waste facilities. The Mayagiiez landfill appears to be well located, well run, and should be
satisfactory for chemical waste disposal. There is at least one company available to recover
and incinerate solvents on a contract basis in the Barceloneta area.

     The  Commonwealth of Puerto Rico appears presently to be making good progress in
improving the handling of solid wastes, but regulations and facilities have lagged behind U.S.
mainland practices. An excerpt  from  a development  plan  for a  proposed  Solid  Waste
Management Authority is presented on the following page.

4.2.2 Present Treatment/Disposal Technologies for Waste Solvents

     Small companies and R&D installations in  isolated  areas are currently disposing of
some solvents by landfill, but the trend is to incinerate waste solvents. Depending upon local
conditions, outside contractors may be used for waste incineration by both large and small
companies, or large companies may choose to install their own incinerators. Table 4.2.2
summarizes the disposal methods used for waste solvents  in the pharmaceutical industry.

     Incineration is an environmentally adequate means of waste solvent disposal.*  Where
 quantities of halogenated solvent  are incinerated the use  of scrubbing to minimize the air
 pollution risk should be investigated.

4.2.2.1  Research and Development

     Since there is no measurable unit of production  for the research and development
operations, the  amount of wastes has been estimated on  the basis of  the  number of
researchers.  Although  the degree of recovery is not well known for this  segment of the
industry,  solvents are commonly  distilled  for reuse. The 25,000  members of the R&D
section of the industry produce approximately 1500 metric tons of mixed waste solvents
each year. This  number is based upon  an  extrapolation using  data supplied to ADL by a
number of comoanies.

*Tables 4.5.1-A and 4.5.1-B describe the various levels of treatment and disposal technologies used for
 waste-solvent disposal in the pharmaceutical industry.
                                       96

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          A Plan for  Hazardous Waste Disposal in Puerto Rico1"
                 The proposed Authority should have the sole responsi-
               bility  in Puerto Rico for processing,  recovery, disposing,
               and storing of hazardous and toxic wastes, in order to pro-
               vide uniform and reliable control. The  proposed Authority
               should serve  as a servicing agent for all producers of
               hazardous and toxic wastes. Sites and  handling techniques
               conforming to Puerto Rico Environmental Quality Board
               and Federal standards should be established.  Special user
               fees should be  charged producers of  these wastes, based
               upon difficulty and expense of providing this service. The
               service should  not only be self-liquidating financially, but
               produce a replacement  fund for facilities and equipment.
               Program Recommendations
                 Currently,  Federal standards governing  hazardous and
               toxic wastes are still pending, and patterning a program for
               Puerto Rico  according  to  these standards appears specu-
               lative.  Nevertheless, enough is  now  known  about  types
               and classes of these wastes to begin forming directions for
               Puerto Rico.  Therefore,  the  following  steps  should be
               taken  to  initiate an operating  capability for  handling
               hazardous and toxic wastes by  the proposed Authority.
                    1. Conduct  an island-wide survey to determine the
                 types,  amounts, and locations of hazardous and toxic
                 waste  production.   Identification  of  present storage
                 sites should be made as well.
                    2. Investigate and evaluate existing Commonwealth
                 of  Puerto  Rico and  Federal  regulations applicable to
                 hazardous and toxic wastes.
                    3. Develop a plan which can bo  implemented by the
                 Authority  for handling hazardous  and toxic wastes in
                 Puerto  Rico. The plan  should consider such aspects as:
                    (a)   Land disposal methods
                    (b)   Disposal facility locations
                    (c)   Topographical and geological conditions
                    (d)   Drainage control
                    (e)   Protection of water supplies
                    (f)   Handling hazards and protection
                    (g)   Transportation and unloading
                    (h)   Security
                    (i)   Personnel training and safety
                    (j)   Records and monitoring
                    (k)   Technologies of processing and storing
                    (I)   Prevention of accidental catalytic reactions
                    (m)  Abandonment of sites

                     4.  An  adjunct to this plan should be a  locational
                  plan showing  desirable locations for  new  industries
                  which  may  have hazardous  and toxic substances as a
                  manufacturing by-product.  These  locations should be
                  amenable  to the environment. Industries  producing
                  hazardous and toxic wastes should be prohibited from
                  any location not specified for this purpose. The indus-
                  trial location plan should be developed and implement-
                  ed   in  conjunction  with the Environmental Quality
                  Board, Fomento, Department of   Natural  Resources,
                  the Planning Board, and the Department of Health.
                    5.  All  plans developed  for  hazardous  and  toxic
                 wastes  must comply with regulations of the Environ-
                 mental Quality Board, the Environmental Protection
                 Agency and other applicable  Commonwealth of Puerto
                  Rico standards.
'''Source:    Proposed  Solid Waste Management,Environmental Quality  Board, Puerto Rico.

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                                        TABLE 4.2.2
                           WASTE SOLVENT DISPOSAL METHODS1
      Industry Segment
   Total
 Hazardous
   Waste
(metric tons
 per year)
                                                      Current Disposal Methods
                                                      On-Site
                                                Off-Site
Incineration
Incineration
 At Nearby
 Company-
  Owned
  Facility
Other*
Incineration by
  Contractor
 R&D                             1,500          -         450

 Active Ingredient Production

  Organic Medicinal Chemicals
   Halogenated solvent               3,400          800        -
   Non-halogenated solvent          23,800        9,300

  Inorganic Medicinal Chemicals        0            —          -
  Fermentation products            12,000        5,000        —
  Botanicals
   Aqueous solvent                 1,000          400        -
   Halogenated solvent                 50            5        —
   Non-halogenated solvent            120           50        —
  Drugs from Animal Sources           800          260        —
  Biologicals                         250          100        -

 Formulation & Packaging              0            —          —

 Total                            42,920       15,915       450
                                                 1,050
                                      40
                                      40
                                                 2,600
                                                14,500
                                     7,000

                                      600
                                       45
                                       70
                                      500
                                      150
                                    26,515
 "Treatment in on-site biological wastewater treatment facility or in municipal system.
  Source:  Interviews and Arthur D. Little, Inc., estimates.

     R&D installations surveyed were  either  sending waste  solvents  to contractors for
incineration off-site (about 70 percent is  estimated to be disposed of in this manner), or were
incinerating  them in nearby company-owned  facilities.  The  Laboratory Waste Disposal
Manual published by the Manufacturing Chemists' Association, Inc., suggests incineration
for even very small amounts  of solvents. Incineration of these  waste solvents is an environ-
mentally adequate disposal technique.

4.2.2.2 Production of Active Ingredients (SIC 2831 and 2833)

     When the pharmaceutical industry  was much smaller, most pharmaceutical companies
discarded waste solvents and  still bottoms in  dumps  or landfills.  With the increased
production of active ingredients, greater difficulty in finding  suitable  landfills, and more
                                           98

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stringent state  and local government controls, incineration is being increasingly employed
for disposal of waste solvents.

     4.2.2.2.1  Organic Medicinal Chemicals

     We  estimate that all  waste solvents  from solvent-recovery  operations used  in  the
production of organic medicinal chemicals are disposed of by incineration. Approximately
half  of the larger pharmaceutical companies have some on-site incineration capacity, even
though they  may send more  troublesome wastes, such as halogenated solvents, to off-site
contractors.  Others continue  to  utilize outside contractors; however, some  additional
pharmaceutical companies are currently  planning on-site incineration.  For this study, ADL
surveyed about 25 to 30 percent of the production capacity of organic medicinal chemicals
of the pharmaceutical companies. Since  the production of active ingredients is centered in
the larger pharmaceutical companies, such disposal methods as found  would also extend to
the part of the industry not interviewed.

     There are about 10,100  metric tons per year of on-site incineration capacity. This
figure is  predicated on the  basis of 27,200 metric tons of solvent for the pharmaceutical
companies involved in organic  medicinal  chemical  production. Not all of the in-place
incinerator capacity can adequately handle  air  and water pollution control for all waste
solvents.  Often, because of stack emissions or potential equipment corrosion, halogenated
solvents are not handled in  on-site incinerators.  Since liquid incinerators are relatively new
to the pharmaceutical industry, potential problem wastes are often sent to outside contrac-
tors  for incineration.

     Off-site  incineration techniques range  from excellent to poor.  There are  numerous
contract  disposal and recycling operations  across the country that are well designed and
operated.

     4.2.2.2.2  Inorganic Medicinal Chemicals

     There are  no known significant amounts of waste solvents or organics from this industry
section.*

     4.2.2.2.3  Fermentation Products

     The disposal of solvents used in fermentation operations is in the form of a solvent
concentrate from the solvent-recovery  operations. This  material, which may  contain  as
much as 50 percent of organic solids, is hazardous, mainly because of its flammability.
'Section 3.2.1.2.2 discusses wastes from this industry segment.


                                          99

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     Approximately 12,000 metric tons of waste solvent concentrate  from fermentation
operations is disposed of annually. We  estimate that all of the concentrate is incinerated
either  on-site or by  contractors off-site. The trend is toward on-site  incineration. Some
plants  which are currently sending these  materials out to contractors for disposal have
incineration units being designed, on order, or under construction. This incineration is very
straightforward, as is evidenced by the number of on-site units.

     The study encompassed approximately 65 percent of the U.S. fermentation capacity.
On the basis of the estimated 12,000 metric  tons per year of waste solvent concentrate,
there is approximately 5000 metric tons per year of on-site incineration capacity. Most of
the in-place  incinerators  have adequate air and water pollution control equipment. This
essentially  means particulate control only. However, since most fermentation operations are
also associated  with  other active ingredient manufacturing operations, there is generally
co-incineration of the wastes which may dictate additional pollution control requirements.
Approximately 7000 metric tons (1.5 million gallons) per year is sent to  outside contractors
for incineration. A typical charge for this material would be $0.30 per gallon.

     4.2.2.2.4 Botanicals

     Nearly  1200  metric tons (310,000 gallons) of waste  solvent are estimated to be
disposed of annually by operations producing botanicals. Three types of solvent wastes are
produced  in extracting alkaloids  from  plant  material. The first  solvent waste is a non-
halogenated solvent concentrate containing water plant extract and organic acid  salts.  The
second solvent waste is a concentrate of the water-immiscible chlorinated solvent used to
extract the alkaloid from the  first solvent. The third, a non-halogenatedlsolvent waste, is
generated in the purification of the crude alkaloid. The first ends up both with water, plant
extract, and organic acid  salts and as a more concentrated non-halogenated solvent stream.
The second is used to extract the  alkaloid from the first solvent. Water-immiscible chlori-
nated solvents are used for the second solvent. The chlorinated solvent is five percent of the
total.  These waste solvents are either  incinerated on-site or by  contractors off-site. We
estimate that 60 percent are incinerated by contractors off-site.

     4.2.2.2.5 Drugs from Animal Sources

     The waste solvent  from the operation of obtaining medicinals from animal glands is an
aqueous solvent containing as much as 50 percent  water and 25 percent organic solids. The
800 metric tons (220,000 gallons) of waste solvent are generally incinerated or,  when the
amount is small, treatment in a biological wastewater treatment facility provides environ-
mentally adequate disposal.

     4.2.2.2.6 Biologicals

     Much of the solvent  from biological operations is recoverable. An industry total of 250
metric tons  (60,000  gallons) must be  disposed  of from biological operations. It is in-
cinerated  on-site or by contractors off-site. We estimate that  60 percent is  handled by
contractors off-site.

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4.2.3 Present Treatment/Disposal Technologies for Organic Chemical Residues

     In many instances, little is known about the constituents in organic chemical residues.
The recovery operations which produce many of them are used for many various solvents
and products.  The residues may contain contaminants that have been removed from the
product, non-reclaimable product,  and other materials.  Since these residues are so varied,
the trend in  the pharmaceutical industry  has been to incinerate them. Extensive testing will
be  needed if these materials are to continue  to be landfilled. Table 4.2.3 shows the total
organic chemical residues and indicates the various methods by which they are disposed.

                                       TABLE 4.2.3

                     ORGANIC CHEMICAL RESIDUE DISPOSAL METHODSt

                                                        Current Disposal Methods
                               Total Hazardous
                                                    On-Site                   Off-Site
                                  Waste      	  	
                              (metric tons per                        Incineration by     Landfill
      Industry Segment              year)	 Incineration  Other*      Contractor    by Contractor

 R&D                              Nil

 Active Ingredient Production

   Organic medicinal chemicals       13,600.        5,440     1,360     3400 min.         3400 max.
                                                                   6800 max.

   Inorganic medicinal chemicals       Nil            —         —           —             —
   Fermentation products             Nil            —         —           —             —
   Botanicals                       Nil            -         —           -             —
   Drugs from animal sources          Nil            —         —           —             —
   Biologicals                       Nil            -         -           -             —

 Formulation & Packaging             0             —         —       	~        	~	
 Total                            13,600         5,440     1,360     3400-6800      < 3,400

 *About 10 percent of the residues are disposed of on-site by other methods, such as mixing with plant waste-
  water prior to its treatment
 ^Source: Interviews and Arthur D. Little, Inc. estimates.
4.2.3.1 Research and Development

     Organic chemical residues  from research and  development are  disposed  of with the
waste solvents. This means that  they are either sent for incineration by a contractor, or are
incinerated  in  company-owned facilities that  are associated  with the manufacturing opera-
tions.
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4.2.3.2  Production of Active Ingredients

     4.2.3.2.1 Organic Medicinal Chemicals

     Organic chemical residues from organic medicinal chemical production are generally
incinerated.  Approximately  40  percent  of  the active  ingredient producers have on-site
incineration for their residues. This is becoming increasingly true since these residues are
seen as potential problems. Consequently, plant personnel are removing less solvent than the
common previous practice to maintain pumpability for liquid type incineration. Another 25
to 50 percent utilize off-site incineration  contractors. Tracing the ultimate disposal of these
materials is difficult. Some are incinerated by the contractor, while others are landfilled in
containers by the contractor. In addition, about another 10 percent utilize other methods of
disposal, such as mixing with plant wastewater prior to its treatment.

     4.2.3.2.2 Inorganic Medicinal Chemicals

     There are no organic chemical residues from these operations.

     4.2.3.2.3 Fermentation Products

     The solvent concentrate from fermentation operations is discussed as a waste solvent in
this report  (see Section 4.2.2.2.3).

     4.2.3.2.4 Botanicals

     There  are no significant amounts of organic  chemical residues from this industry
segment. They are either handled with waste solvents or are sent to biological treatment or
landfill.

     4.2.3.2.5 Drugs from Animal Sources

     There  are no significant amounts of organic  chemical residues from this industry
segment. They are either handled with waste solvents or are sent to biological treatment or
landfill.

     4.2.3.2.6 Biologjcals

     There  are no significant amounts of organic  chemical residues from this industry
segment. They are either handled with waste solvents or are sent to biological treatment or
landfill.
                                          102

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4.2.4 Present Treatment/Disposal Technologies for Potentially Hazardous High
      Inert Content Wastes (Such as Filter Cakes)

     While high inert content wastes may show up in small amounts in the R&D segment of
the industry, by far the bulk occurs  in the  production of organic medicinal active ingre-
dients. Generally, they  are handled in the same manner no  matter which type of active
ingredient is being produced. Most are landfilled, but a growing percent is being incinerated
to remove  the organic portion. The ash is then landfilled. Table 4.2.4 shows the  total high
inert content wastes and indicates the various methods by which they are disposed.

     Approximately 75  percent  of  the solid materials, such as filter cake  and filter paper
from  organic medicinal  chemical production,  are  disposed  of in landfills. Most of these
landfills  are  either municipal or  private commercial facilities located off-site, and they are
generally operated as sanitary landfills. The industry has been careful to avoid bad publicity
that might accompany poor disposal  techniques. Another 25 percent of the solids  of this
type are  incinerated either on-site or off-site.

                                        TABLE 4.2.4

                     HIGH INERT CONTENT WASTES DISPOSAL METHODS*
      Industry Segment
                                         Total
                                       Hazardous
                                         Waste
                                      (metric tons
                                       per year)
                    Current Disposal Methods
               On-Site
             Incineration*
                                   Off-Site
         Incineration'*
                        Landfill
 R&D

 Active Ingredient Production

    Organic medicinal chemicals
    - Waste containing flammables only
    - Waste containing heavy metals or
       corrosives
 Total
                                         Nil
 850
 850

1,700
                  225
225
                                 200
               200
                           425
                           850*
1,275
      oene waste is neutralized, or the heavy meta, is precipitated,ซ, <,„ place,Mna
    secure chemical landfill. Nearly 40 percent is placed untreated ,n a secure chem.cal landf.ll, often
    capsulated in drums. The remainder goes to general landfill locations.
  Source: Interviews and Arthur D. Little, Inc., estimates.
                                           103

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4.2.5 Present Treatment/Disposal Technologies for Heavy Metal Wastes

     ADL has surveyed pharmaceutical  active ingredient manufacturers producing an esti-
mated 20 to 40 percent of the heavy metal wastes. Table 4.2.5 shows the total heavy metal
wastes and indicates the various methods by which they are disposed.

                                      TABLE 4.2.5

                       HEAVY METAL WASTE DISPOSAL METHODS*

                                   Total Hazardous   	Current Disposal Methods	
                                       WaStC        On-Site                Off-Site
                                    (metric tons
      Industry Segment                  per year)                    Recovery        Landfill*

 R&D                                   Nil            -              x             -

 Active Ingredient Production

   Organic medicinal chemicals              2,675          —             575            2,100
   Inorganic medicinal chemicals             200          —             —               200
 Total                                   2,875          -             575            2,300

 *Heavy metal is converted to its most insoluble form,and is generally drummed and placed in a secure
  chemical landfill.
 Source:  Interviews and Arthur D. Little, Inc., estimates.

     With the exception of recovered  R&D wastes and  some large amounts of zinc and
chromium wastes that are sent off-site for recovery, the heavy metal wastes are usually too
dilute or contaminated for recovery. The number of facilities using heavy metals  within the
pharmaceutical industry is  limited. Production appears to be  exclusively  with  the larger
companies. Most  non-recovered heavy metal wastes are landfilled. Zinc oxide is a relatively
stable and insoluble form of zinc, and much of the landfilled zinc takes this form.

     Arsenic is landfilled in drums with the  surrounding soil conditioned with  lime to
inhibit its change to a soluble form in case a drum develops a leak. The landfilled selenium
wastes are dilute  (an estimated 0.2 percent selenium sulfide). Mercurial wastes, generally as
amalgams, are landfilled.  A number  of heavy  metal wastes are deep-well disposed in
Michigan where state approval can be obtained.

4.2.6 Present Treatment/Disposal Technologies for Returned Goods and Reject Material
      from Formulation

     Returned goods  (as described in Section 3.2.1.3) are handled specifically  by the
formulating and packaging operations of a company. Table 4.2.6 shows the total returned
goods and reject material and indicates the various methods by which they are disposed.
                                         104

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                                       TABLE 4.2.6

            DISPOSAL METHODS FOR RETURNED GOODS AND REJECT MATERl AL*

                                   Total Hazardous          Current Disposal Methods
                                        Waste               On-Site                 Off-Site
                                     (metric tons
      Industry Segment                   per year)     Incineration     Other*         Landfill**

 Formulation and Packaging                   500           50          100             350

  * Material is crushed and slurried with water, and the resulting slurry is sent to a biological wastewater
   treatment facility.
 ** The waste is crushed on-site to form a sludge or cake before it is sent to off-site landfill.
  Source: Interviews and  Arthur D. Little, Inc., estimates.
      Handling the amounts of Pharmaceuticals that have been returned - for instance because
 they have reached their expiration date - requires  care.  Some returned goods can be
 salvaged, but of the returned goods that are non-salvageable,  somewhere  in the  range of
 60-80 percent are crushed in  special equipment on-site  to form a sludge or cake,  which is
 then sent to  a landfill off-site.  The remainder is  either incinerated on site, or crushed and
 slurried with  water  which is sent to an activated sludge treatment facility on-site, while the
 glass, metal, rubber, and cardboard are sent to a landfill off-site.  Numerous types of crushers
 are used. Some of the  names include Somat, Wascon, Rodeva, and Cumberland.

      The disposal  of  Pharmaceuticals in  landfills raises many  questions.  Dosage  levels in
 medicines are generally measured in milligrams; nevertheless, because many of the products
 may  have biological or  physiological effects on the environment and on man, disposal of
 these wastes  must be  carefully controlled. Because of the Drug Enforcement Agency's strict
 regulation on  the disposal of  controlled substances, there  is little  chance  that controlled
 materials would be scavengable from any landfilled wastes.

     Fearing the possibility of bad publicity  from the scavenging of a returned good, each
 pharmaceutical firm  has extended  the care in  handling controlled  substances  (such as
 narcotics) to the disposal of non-controlled substances as  well. Representatives of the
 company witness the  destruction of returned goods, whether on-site or off-site, to ensure
 that no tablet, vial, capsule, or the  like is scavengable. To this extent, the disposal practices
 of the industry are excellent. Yet, little is known of the effect of such items on the landfill
and  the potential for  hazardous quantities to leach into groundwater or streams. In this
 study, in an attempt to  provide  some basis from which to work, we used the toxicity of the
active ingredients to assess the hazard.* However,  additional work in this area is advisable.
'Section 3.1.3 discusses the properties of these materials.
                                          105

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4.2.7 General Description of Treatment and Disposal Technologies

     Treatment  processes should reduce  the  volume, separate  components, detoxify, and
recover as much as possible for reuse. In  general, no single process can adequately perform
these functions.  Table 4.2.7-A presents those treatment and disposal technologies found
within the pharmaceutical industry, and each is discussed in the subsections which follow.

     In order to fully utilize the information obtained in the study,* those processes which
treat liquid  effluent streams have  been  viewed  as  waste-producing steps rather  than as
waste-treatment steps. Table 4.2.7-B presents the processes, their functions, and the types of
wastes treated.

4.2. 7.1 Segregation of Wastes

     There  is great  need to  segregate wastes to obtain optimum waste  treatment and
disposal. Not only is segregation necessary for recovery, treatment, and disposal, it is also
necessary for safe handling, transport, and treatment. Use of a system of chemical compati-
bility which was developed  by the National Academy of Sciences has been proposed for use
as a  guide for the compatibility of waste  materials.** Usually the same handling techniques
are required for wastes as for the raw materials.

4.2. 7.2 Incineration of HalogenatedandNon-halogenated Solvents

     When  high-energy  content solvents  with  small amounts  of water and solids persist
through normal  process-recovery operations, they are often destroyed by thermal oxidation
at high temperatures in liquid injection  incinerators. These units typically operate  at or
above 1800ฐF and with sufficient  turbulence and time to  destroy solvents effectively. If
combustion  is controlled, by  means of excess air, for  example, no  air pollution  control
devices are  needed for solvents containing only carbon, hydrogen, and  oxygen. However,
these liquid injection incinerators are being increasingly equipped with air pollution control
systems, because solvents often contain either suspended and dissolved solids or substances
which could  react to form noxious gases, such as hydrogen chloride, sulfur oxides, and
nitrogen oxides.
 *We had difficulty in tracing all disposal steps, and considerable overlap with the work on the water
   effluent guidelines' study being prepared by Roy F. Weston, Inc., occurred.
 'Witt, Philip A., Jr. "Disposal of Solid Wastes," Chemical Engineering, October 4, 1971, p. 61.
                                         106

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                                           TABLE 4.2.7-A

                    FUNCTIONS AND WASTE TYPES OF CURRENTLY USED
                HAZARDOUS WASTE TREATMENT AND DISPOSAL PROCESSES
         Process
                        Functions Performed
                                                                     Types of Waste
   Chemical Treatment:
   —  Oxidation of sludges
                        Detoxification
   Thermal Treatment:
   —  Incineration of solvents
   —  Incineration of solids
                        Volume reduction,
                        detoxification,
                        disposal
•  Biological Treatment:
   —  Activated sludge or
      other biological
      treatment

•  Disposal/Storage:
   —  Land burial
                        Detoxification
                        Disposal
   —  Deep-well injection
                        Disposal
 Inorganic chemical with/without
   heavy metal
 Organic chemical with/without
   heavy metal
Organic chemical without heavy
   metal
Biological
Flammable
Explosive
Organic chemical
   without heavy metal
Inorganic chemical with/without
   heavy metal
Organic chemical with/without
   heavy metal
Biological
Flammable
Explosive

Only liquids can be disposed of in
   this manner; all those listed for
   land disposal, with the excep-
   tion of explosives, are disposable
   in this manner with proper pre-
   cautions.
   —  Ocean dumping
                        Disposal
   —  Engineered storage

 Source:
                        Storage
Inorganic chemical with/without
   heavy metal
Organic chemical with/without
   heavy metal
Flammable
Explosive

All as in land burial
Colonna, R.A., and McLaren, C., "Appendix D. Hazardous Wastes," Decision-Makers Guide
in Solid Waste Management, Environmental Protection Agency, 1974, p. 146.
                                             107

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Process
                   TABLE 4.2.7-B
WASTE TREATMENT PROCESSES USED TO SEPARATE
     A WASTE1" DESTINED FOR LAND DISPOSAL
         Function                                 Resource Recovery
        Performed*        Types of Waste**            Capability
Physical Treatment:
   Carbon Sorption
   Dialysis
   Electrodialysis
   Evaporation
   Filtration
   FI occu I atio n/Settl i ng
   Reverse Osmosis
   Ammonia Stripping

Chemical Treatment:
   Calcination
   Ion Exchange
   Neutralization
   Oxidation
   Precipitation
   Reduction

Thermal Treatment:
   Pyrolysis
   Incineration

Biological Treatment:
   Activated Sludge
   Aerated Lagoon
   Waste Stabilization Ponds
   Trickling Filter

Disposal/Storage:
   Deep-well Injectiont
Se
Se
Se
Se
Se
Se
Se
Se

Se, De
De
De
Se
De
VR.De
De, Di
1,3,4
1,2,3,4
1,2,3,4,6
1,2
1,2,3,4
1,2,3,4
1,2,4,6
1,2,3,4
1,2
1,2,3,4
1,2,3,4
1,2,3,4
1,2,3,4
1,2
3,4,6
3,6,7,8
          De
          De
          De
          De
          Di
3
3
3
3
1,2,3,4,6,7
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
                                                        Yes
No
No
No
No
No
  *Se — segregation
  De — detoxification
   VR — volume reduction
   Di — disposal
 ** 1.  Inorganic chemical without heavy metal
   2.  Inorganic chemical with heavy metal
   3.  Organic chemical without heavy metal
   4.  Organic chemical and heavy metal
   5.  Radiological1^
   6.  Biological
   7.  Flammable
   8.  Explosive
  t    A waste is formed either when solids must be filtered out, or when a substance must be precipitated
      out because of chemical incompatibility with substances underground.
tt    Use and disposal of radiological wastes within the pharmaceutical industry is not discussed in this
      report.
Source:  Colonna, R.A. and McLaren, C., "Appendix D. Hazardous Wastes," Decision-Makers Guide in
        Solid Waste Management, Environmental Protection Agency, 1974, p. 146.
                                           108

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     The  most  common air  pollution control device for removing  acidic gases  is a wet
scrubber like the venturi. A significant operating cost for these incinerators may be incurred
in providing the caustic scrubbing liquors for the venturi such as lime, sodium hydroxide, or
ammonia  for removal of halogens from off-gases.  Disposal of the scrubber liquors is usually
via introduction into wastewater treatment systems. This means that a significant load of
dissolved  solids may be imposed. Although the effectiveness of liquid injection incinerators
may vary widely in the destruction of solvent-type wastes, the efficiency of destruction is
relatively  high in a properly operated incinerator. In general, the liquid injection incinerators
need auxiliary fuel for solvents with low heating values. Consequently, the disposal  costs are
inversely  related to the  heating values of the wastes:  the higher  the heating value of the
solvent, the lower  the disposal cost. Some waste solvents can be recovered for their fuel
value.  The wastes then have  a net  worth; thus increasing attention is being given to their
recovery,  especially by some of the contract waste disposers that have sophisticated systems
for recovery and conversion. Instead of paying for the disposal of some waste solvents, they
can be sold.  However, the industry often uses high heating value  wastes (i.e., solvents) to
destruct low heating  value waste (watery wastes) in company-owned facilities. As regula-
tions regarding disposal become stricter, an increasing number of companies are contracting
for waste disposal. This  is true especially where a variety  of liquids as well as solid wastes
must be destroyed.

4.2. 7.3 Incineration of Solid Wastes

     The  incinerator  furnace  provides the environment for controlled combustion of solid
wastes with air. The waste is processed by controlled oxidation with the liberation of heat,
producing flue or combustion gases and a residue or ash. Most incineration furnaces have
either  a refractory hearth to  support the burning waste, or a variety of grate-type hearths
which  stroke the waste. Neither the stationary hearth nor the rotary kiln furnace systems
have grates. The typical stationary  hearth furnace has a refractory floor which may have
openings to let slightly pressurized air in  underneath the burning wastes.  Stationary hearth
furnaces are used for commercial and small industrial incinerators. For hospital wastes, they
are equipped  with auxiliary gas or oil burners to maintain the furnace temperature above
1200  to  1600ฐF.  At  these   temperatures,  the   combustible solids and  vapors will be
completely eliminated as long as high oxygen content  air is well dispersed  throughout the
gas. This may require auxiliary fuel burners in the  secondary combustion chamber.

     The  rotary kiln  incinerator has been used for several hundred years in the pyropro-
cessing industry. Unless special  provisions are made for air  or water cooling, the metal
cylinder is lined with refractory material to  prevent overheating of the metal. The move-
ment of the solids being processed is controlled by the speed of rotation of the kiln  which is
inclined toward  the  discharge end.  The rotary kiln normally requires  all the  air for
combustion to enter with the waste at the feed end.
                                          109

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     Because  of their versatility in handling solids, sludges, and  containers, rotary kiln
incinerators are being used increasingly for the thermal destruction of wastes. The incinera-
tors are used by a number of contractors and individual plants. Since the feed rates of wastes
cannot  be controlled closely, as is done in liquid injection incinerators, the rotary kiln
incinerator usually operates less  thermally efficient than the liquid injection incinerators to
ensure effective destruction while meeting air pollution regulations. However, these incinera-
tors are  especially sensitive to erratic conditions, such as the rupture of containers. Any
volatile substances which are released cause oxygen deficiencies in the reaction chamber and
consequently  smoke forms. Thus, extensive afterburner chambers and control methods are
required to prevent smoke.

     The most common off-gas cleaning systems for rotary kiln incinerators like those used
in liquid  injection incinerators are  wet  scrubbers.  Because of their versatility in  handling
different  forms of wastes, especially wastes with high heating values, use of the rotary kiln
incinerator is  expected to increase.  As in the case of the liquid injection incinerator, the
costs generally are inversely related to the heating value of the wastes; the higher the heating
value of the waste, the lower the  disposal  cost. Because tarry substances take longer to burn,
they will cost  more to dispose of than the non-tarry substances.

     Stationary grates have been used in incinerator furnaces for a long time. The original
stationary grates  consisted of metal bars or rails supported in  the masonry  sides of the
furnace chamber. Subsequently, these bars were replaced with cast metal or fabricated metal
grates with provisions for rotating the grate sections to permit dumping of the ash residue.
Such stationary grates are still used in many of the older incinerators.

     Mechanically operated grates installed in batch-type furnaces evolved from the station-
ary grates in batch-type furnaces. Many of the new, small-capacity incinerators still utilize
batch-fed furnaces either with stationary or mechanically operated grates. Although other
thermal  destruction systems such as multiple hearths or fluidized beds might  be  used for
waste disposal,  especially  sludges from wastewater treatment plants, filter cakes or centri-
fuge solids, these are not used much  in the pharmaceutical industry.

     Conventional incinerator furnaces  are  made from refractories  such as  fire bricks,
metals, and refractory-covered metals, such as castable or  fire brick refractory linings 1 to 9
inches thick.

     A rotary kiln furnace may be lined either with castable refractories or with kiln blocks.
Alternatively,  if the kiln is unlined, it must be cooled externally with air or water with an
optional water film on the inside of the cylinder. Since furnaces  are subject to temperature
changes, refractory  linings are  susceptible to damage from  spalling, fluxing,  or  slagging.
Corrosion must also be considered for any  incinerator furnace material whether refractory
or metal.
                                          110

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     Many incinerator design specifications require a secondary combustion chamber. In the
primary combustion chamber wastes are ignited, vaporized, and burned above the incinera-
tor grates. The secondary combustion chamber may consist of a separate  down stream
chamber wherein gases  emitted from the primary  chamber containing soot, hydrocarbons,
and other combustibles are burned. They will be completely eliminated as long as the gases
in the secondary combustion chamber are heated above  1500 to 1600ฐF. After complete
incineration of the waste, the ash residue drops into an ash chamber or chute from the end
of the grate or kiln,  directly  into a container, onto conveyors for disposal, or into water for
quenching and cooling.

     Wastewater at incinerator installations comes from various sources such as  chamber
sluicing, the quenching of ash, and parts of the ash conveyor system, the flue gas cooling
chamber,  or the flue gas scrubbers. Because of  the costs of water  treatment  facilities
required to prevent  water pollution, this wastewater flow is minimized.  For example,  ash
can be quenched with air near the discharge end of the grate or in a separate ash cooler; gas
can be cooled with a gas-to-air heat exchanger or by total evaporation of fine water sprays;
and dry dust collection systems can be used instead of wet ones.

     Acceptable ash  residue  can only  be  achieved  by prudent  operation.  This requires
teamwork  on  the part  of the entire staff. Materials must be mixed to  provide a relatively
homogeneous  feed stream. The furnace operator must constantly check and adjust the air
ratio, the degree of agitation, the temperature of the furnace, and the residence time of the
waste flowing through the furnace. Such an operation requires constant attention and, when
waste is  difficult to burn, waste flow may be reduced. Knowing the  composition of the
residue is important  as a diagnostic aid to detect operational problems, determine complete-
ness of combustion, and identify potential water pollutants.

     A well operated modern incinerator will burn out 97  percent of the combustible
materials. The  water solubility of the residue is of interest primarily to evaluate potential
groundwater pollution,  because this fraction  will, to some extent, be leached from the ash
over long periods of time and may contaminate groundwater. Such leaching may or may not
be harmful, depending upon  the materials which are dissolved and the rate of solution. In
general, the amount  of  water-soluble materials in the ash will be quite small and will reflect
the composition of  the waste burned and the operating practices of the incinerator. The
extent to  which groundwater contamination occurs depends primarily on the  fill operation,
the local rainfall, drainage patterns, and geology all  of which vary widely. Each fill site is
different.

     The organic-soluble fraction of the residue will support undesirable forms of life such
as insects, rodents, and  bacteria. If the level of these materials is found to be over 1 percent
of the residue  ash, the incinerator is not being operated properly. All organic materials are
combustible. Increased residence time in the furnace, high temperatures,  good agitation, and
proper air distribution will reduce these materials to  less than  1 percent of the residue ash.
To determine  if living organisms are in the ash, samples of the ash can be incubated. If
                                        111

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organisms are present, they should be classified to establish which fraction is pathogenic.
Fungi or bacteria indicate that burn out of the ash is not complete.

     The air pollutants associated with incinerators fall into three  categories: particulates
(both mineral and combustible), combustible gases (which  include carbon monoxide and
hydrocarbons), and  non-combustible  gases (including nitrogen oxides,  sulfur oxides, and
hydrogen chloride).

4.2.7.4  Land Disposal

     The disposal methods used by  many industries are those  used for residential and
commercial wastes: landfill and incineration. Landfills are either dumps, land burial opera-
tions, or  sanitary landfills.  Dumps and  land burial  operations  are  generally unsuitable
disposal methods, land burial being a dump that is covered. Sanitary landfilling is defined as
an engineering method of disposing of solid waste on land in a manner that minimizes
environmental hazards by spreading the waste in thin layers, compacting the wastes to the
smallest practical volume,  and applying the compacting cover material  at the end of each
operating day.

     Where land is available, a sanitary landfill is usually more cost-effective than incinera-
tion  for disposing of solid wastes.  A  number of pharmaceutical companies are located in
areas where land availability is not a  problem. On the other  hand, in  areas such as New
Jersey, there is increased difficulty in locating landfill operations willing to accept industrial
wastes.

     Current practice dictates that the potential sanitary landfill site be examined for soil
condition  and proximity of groundwater.  Because so little  is known of the properties of
chemical wastes in landfills,  an effective monitoring system for toxic waste disposal  areas
may  become a routine requirement.

     A  safety hazard exists with landfilling organic waste. Fires  and explosions occur in
landfills which handle liquid organics. Further, the California  Water Pollution Control Board
found that water that has gone through landfilled incinerator ash will leach alkalies and salts
from the fill. Gases such as methane, ammonia, and hydrogen  sulfide  are produced in land
disposal areas. Because landfilling of materials with high water  content can produce adverse
effects within a landfill, States such  as Indiana and New Jersey are  considering, or have
instituted,  strict requirements on landfill operations.  As regulations on a  State and local
level  become effective, the number  of landfills accepting organic liquids is  expected to
decrease.

     Increased  consideration will  be  given to thermal destruction as regulatory agencies
establish more stringent rules and regulations for landfill  disposal.  There are economic
reasons  for landfill disposal. Costs of landfilling range  from $4 to $10/ton of solids because
of relatively low capital investment and energy requirements, while incineration costs fall in
                                         112

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the range of $25 to  $50/ton of solids. Incineration of solid wastes is capital- and energy-
intensive. Additional fuel is required when the wastes have low heating values. Therefore, in
spite  of increasing pressure to  minimize landfill, the  rapidly escalating energy costs and
capital investment requirements for thermal destruction will mean that landfill costs will
continue to be more economically attractive than thermal destruction.

     Secure chemical  landfills (i.e., lined landfills, limited to chemical wastes, with adequate
local soil conditions and often using leachate control) will probably be an important aspect
of long-term disposal of selected pharmaceutical  wastes. Inorganic salts  and other sub-
stances, such as metallic compounds,  which cannot be converted into innocuous substances
will  present  continuing disposal  problems.  The magnitude of these  problems will be
determined by the volume and toxicity of the substances. Among these problem wastes are
mercury, arsenicals, chromium,  copper, and  zinc. Since some of these substances, such as
mercury, arsenic, and zinc would be vaporized in thermal destruction facilities, and perhaps
widely  dispersed by  atmospheric transport, careful consideration must be given to the
methods for their disposal.  The  "concentrate and contain" philosophy of land disposal will
have to be exercised for these wastes which cannot be altered in toxicity or hazardousness.

4.2.7.5 Recovery for Reuse

     There are many processes for resource recovery. Important  factors in deciding which
method to use include type, form, and volume  of waste,  as well as the economics of the
processes.  Solvents are now recovered for economic reasons. Heavy metals, on the other
hand, may be removed to keep them out of the wastes to be disposed.

     Within the pharmaceutical industry, most recovery operations, with the exception of
solvent recovery, are  performed off-site by contractors. In our study, we found that firms
handling recovery were often reluctant to  discuss the source  and potential market for
recovered materials. The competition for recovery appears  to be great in areas such as New
Jersey and Illinois.

4.2. 7.6 Wet Oxidation

     Wet oxidation is oxidation of organic materials in  a liquid state under  high pressure at
moderate temperatures. Sulfur,  nitrogen, and halogen breakdown products are retained in
the liquid effluent. Waste treatment techniques, such  as wet oxidation, are found  infre-
quently in the pharmaceutical industry. However, this particular technique is used when the
total  energy content  of the wastes  is too low for  cost-effective incineration. In wet
oxidation a complex mixture of organic materials may be degraded to a more simple series
of components which are amenable to further treatment by well-established processes such
as biochemical treatment. This method is usually  employed for slurries and sludges with the
concomitant need to dispose of solids' which, of course, are much more stable and of less
potential environmental concern than the  original waste. This process may be a candidate
for those wastes  which have inhibitory effects on biochemical systems. Its utilization will
                                         113

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require an assessment of the specific waste compositions. Treatment costs range from $1 to
$20 per thousand gallons.

4.2.7. 7  Deep-well Injection

     Deep-well injection for disposal of industrial wastes became popular during the late
1950's.  Of the approximately 300 wells drilled in the United States, close to 200 are still in
use,  mostly in Texas and Michigan. To  be effective the wells must have  a complete and
permanent separation between  the stratum being used for  disposal and useful strata.  The
rock must have the desired porosity and permeability at the level the waste is to be injected.
Approximately 30 new wells are being built each year. Deep-well injection is  a method of
aqueous liquid waste disposal. It was investigated because a limited number of pharma-
ceutical plants manufacturing active ingredients use deep-well injection for their wastewater,
and  often solid wastes  are formed while preparing the liquid for injection. In addition, if
deep-well injection  were to be banned, these companies would have to find some alternate
method of disposal. The pollutants typically sent to deep-wells are difficult to remove using
standard biological methods. Chemical methods such as precipitation or adsorption would
probably be used, forming a potentially hazardous solid waste for land disposal.

     Since  Michigan's Department of Natural Resources officials have indicated that deep-
well injection will  continue, we investigated  only those solid wastes  produced prior to
injection to meet the limitations of deep-well disposal. That is, wastes must be compatible
with  the brine naturally occurring in the selected porous  rock stratum. If they are not
compatible, solids which can plug the pores of the rock will precipitate. For example, if the
stratum were a limestone, sulfates, phosphates, and aluminum salts would not be com-
patible.

4.3 ANALYSIS OF ON-SITE/OFF-SITE DISPOSAL METHODS

     The pharmaceutical industry makes extensive use  of waste disposal contractors. Eight-
five  percent of the pharmaceutical industry's  total  process waste  and  60 percent of the
hazardous wastes are disposed of off-site by contractors. Contractors either haul and  dispose
of the wastes, or in areas such as northern New Jersey, trucking firms transport the waste
from the pharmaceutical plant to the disposer. Within the State of New Jersey independent
licenses are granted for transporting wastes  and disposing of wastes.  Occasionally, the
pharmaceutical company delivers the waste to the disposal site.

     Waste disposal contractors  contacted  indicated that pharmaceutical companies segre-
gated their wastes and provided information, on the constituents' characteristics and recom-
mended handling techniques. Their work relationship  appears to be open and functional.
The  pharmaceutical companies take considerable care to ensure that reliable methods of
final disposal are used by their contract disposers. Hazardous wastes are usually landfilled in
areas of low soil permeability, and are often encapsulated and segregated from other wastes.
                                         114

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     Contract disposers are very visible and are rapidly coming under the strict regulations
of air, water, and  hazardous waste authorities. Because contract  disposal operations are
susceptible to shutdowns that  can  last  hours  or  months, the larger pharmaceutical com-
panies are tending toward installation of their own liquid and solid incineration capacity.

     A large  amount  of the general process wastes, such as mycelia from  fermentation, is
landfilled. Most of the landfilling is handled by  private  commercial operations. In total,
about 80 percent of the pharmaceutical industry process  wastes disposed of by contractors
are landfilled.  Some  of the remaining wastes are recovered, but most  are incinerated.
Eighty-five percent of the hazardous  waste  handled by contractors  are incinerated  or
recovered. Most of this waste is solvent.  While  some contractors are set up to recover
valuable  products from this waste, most  is incinerated. Most of the remainder  of  the
hazardous wastes  are landfilled. These  wastes include  potentially hazardous high inert
content wastes, such as filter cakes, and heavy metal wastes.

     Of those  hazardous process wastes  disposed of on-site, all except 8 percent  are
incinerated either in liquid injection incinerators or in solid-waste incinerators.

     Table 4.3  summarizes  current  on-site/off-site disposal  methods  and  indicates  the
amount of wastes by specific category.

4.4 SAFEGUARDS USED IN DISPOSAL

     Numerous safeguards were found to be used in waste disposal. Table 4.4 summarizes
the use of the various  safeguards.

4.5 TREATMENT AND DISPOSAL TECHNOLOGY LEVELS AS APPLIED TO LAND-
    DESTINED HAZARDOUS WASTE STREAMS FROM THE PHARMACEUTICAL
    INDUSTRY

     The various levels of technology within the  pharmaceutical industry are described in
this subsection for those hazardous waste streams identified in Section 3. They are described
on the basis of EPA definitions for the industry studies:


     Technology Level I-This level encompasses the  broad  average of technologies
     which are currently used in typical facilities. There may be more than one Level I
     technology used by the facilities in an industry section. Although the possible
     variations within a technology  are often numerous, Level I is defined broadly to
     distinguish  between  technologies such as incineration and  landfill or chemical
     landfill and sanitary landfill.
                                         115

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                                                                                TABLE 4.3

                                                       ANALYSIS OF ON-SITE/OFF-SITE DISPOSAL METHODS™
                                                                                                              Current Disposal Methods
  Industry Segment

  •   R&D
           Solvent
           Animals
           Heavy metals
  •   Active Ingredient Production
      — Organic medicinal chemicals
           Non-halogenated waste solvent
           Halogenated waste solvent
           High inert content wastes
           — containing flammables only
           — containing heavy metals or corrosives
           Heavy metal wastes
           Organic chemical residues
     — Inorganic medicinal chemicals
           Heavy metal wastes
     — Fermentation Products
           Waste solvent concentrate
     — Botanicals
           Aqueous solvent
           Waste halogenated solvent
           Non-halogenated solvent
     — Drugs from animal sources
           Aqueous alcohol
     — Biologicals
           Aqueous alcohol
           Antiviral vaccines
           Other biologicals (toxoids, serum)
  •  Pharmaceutical Preparations

  Total
Total Hazardous Waste
 (metric tons per year)    Quantity
       1,500
      23,800
       3,400

         850
         850
       2,585
      13,600

         200

      12,000

       1,000
          50
         120

         800

         250
         300
         200
         500

      62,005

On^Site
Incineration Other
Quantity
450
X
—
9,300
800
225
—
-
5,440
-
5,000
400
5
50
260
100
100
—
50
22,180
% Quantity %
30
X**
—
40
24
26
_ _ _
_ _ _
40 1,360*** 10
_
42
40
10
40
33 40 5
40
33 100* 33
200 r 100
10 100 20
36 1 ,800 3


(incineration
Quantity
1,050
—

14,500
2,600
200
-
—
5,100
-
7,000
600
45
70
500
150
100
_
-
31,915
%
70
-

60
76
24
-
—
38
-
58
60
90
60
62
60
33
_
-
51
Off-Site (Contractors)
Landfill
Quantity %

— -


— -
425 50
850 100
2,010 78
1 ,700 1 2
200 1 00
-
	 	
— —
- -
-
_
	 	
_ _
350 70
5,535 9

Recovery*
Quantity %

- -
x —

- -
_ _
— —
575 22
- —
-
-
	 —
— -
- -
-
_
	 —
_ _
- -
575 1
   *Solvent recovery is a very common practice on-site at pharmaceutical plants; it has been excluded from this study as a waste treatment process.  The recovery discussed here is heavy metal
    recovery from waste.
 **Small animals are often autoclaved if they cannot be incinerated immediately.
***Dilute and sent to on-site biological wa'stewater trealjnent.
t   Autocfaved.
tt  Source: Interviews and Arthur D. Little, Inc., estimates.

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                                                       TABLE 4.4
                                   USE OF SAFEGUARDS IN DISPOSAL OPERATIONS7
Type of Safeguard and Related Waste

•  Segregation of wastes;
     Hazardous
•  Reduction of water content;
     Mycelia (non-hazardous)
•  Detailed handling instructions;
     Hazardous
•  Careful and informative labelling
    of  waste containers;
     Hazardous
•  Drummed disposal of hazardous
    wastes in landfills;
     High inert content wastes
     Heavy metal wastes
     Organic chemical residues
•  Sealed landfills;
     High inert content wastes
     Heavy metal wastes
     Organic chemical residues
•  Soil conditioning to inhibit conver-
    sion of a heavy metal waste to a
    a water soluble form;
     High inert content wastes
     Heavy metal wastes
 Amount of
Waste (Metric
Tons per Year)
    62,000

   300,000

    62,000


    62,000
     1,275
     2,010
     1,700

     1,275
     2,010
     1,700
       425
     2,010
Percent of Waste
 Disposed Using
   Safeguard
     100

     100

     100


      80
      50
     100
      60

      50
     100
      50
        0
      20
Estimated Number
   of Locations
   Where Used
        54

        19*

        54


        43
        15
        15
        32

        15
        15
        27
         0
         2
                                                                                                             ExtensJveness
                                                                                                                of Use
   Very

   Very

   Very


   Very
   Moderate
   Very
   Moderate

   Moderate
   Very
   Moderate
No examples found
  Slight
 *This number only includes principal fermentation installations.

 ^ Source:  Interviews and Arthur D. Little, Inc., estimates.

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     Technology  Level II- This level  includes the best technologies which are cur-
     rently used in at least one pharmaceutical facility,  that is, they are the soundest
     treatment or disposal methods on a commercial scale from an environmental and
     health standpoint. In some cases the technologies may be the same as in Level I.
     Pilot and bench-scale installations are not considered.

     Technology Level III - This level includes the technologies which are necessary to
     provide  adequate health and  environmental protection. Existing pilot or bench-
     scale processes that have high potential for meeting the needs of the industry if
     scaled up are considered.

     Tables  4.5.1-A through  4.5.5  describe the technology  levels and provide relevant
information such as current usage of the identified levels of technology, present adequacy,
future adequacy based upon waste stream volume, composition, suitability for retrofit, non
land-related environmental impact such as  energy and water requirements, residual wastes
finally disposed of on land, problems,  limitations and reliability of the technology, imple-
mentation time, and environmental impact.

     As a basis for calculating  the number of facilities employing various treatment and
disposal  technologies,  we  estimated  that  approximately 54 company  operations  large
enough to have significant wastes  participate in the manufacture of pharmaceutical active
ingredients. Another 175 operations large enough to produce  significant wastes formulate
and package these and other ingredients into final pharmaceutical preparations. The derived
estimates of facilities using the various treatments appear  in the following sections.

4.5.1  Treatment  and Disposal Levels for Halogenated and Non-Halogenated Waste Solvents

     ADL estimates that 39,470 metric tons of non-halogenated waste solvents are gener-
ated annually by  the pharmaceutical industry.  This amount includes 1500 metric tons from
research and  development, 23,800 metric tons from organic medicinal chemicals, 12,000
metric tons from the production of fermentation  products, 1000  metric tons of aqueous
solvent concentrates (720 metric tons on a dry basis) from the production of botanicals and
an additional  120 metric tons  of  non-aqueous solvents from  botanicals, 800 metric tons
from  the production of drugs from animal  sources, and  250 metric tons from  the produc-
tion of biologicals.

     In our survey of the industry, we found  that  approximately 50%  of the industry
facilities had  onsite incineration capability; the remainder used contractor incineration to
dispose of these solvent wastes. These two treatment technologies, therefore, are defined as
Level I in Table 4.5.1-A. Both of these disposal techniques are  presently  adequate. A
limitation of this kind  of incineration is  that liquid incinerators cannot handle a high
inorganic salt content waste.

     Because  there are a number of contractors who provide energy and resource recovery
at their own  sites, we have included this technology in  our  Level II discussion. By energy
recovery   we  mean  that  the  contractor  has the capability  to  produce steam during
                                         118

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                                   TABLE 4.5.1-A
                 TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
                    FOR NON-HALOGENATED WASTE SOLVENTS*

Amount of Waste:*  39,470 Metric Tons per Year

Hazardous, Physical, and Chemical Properties of Waste: Flammable organic liquid.
   Technology
   Current Usage
   — Percent of Industry
     Facilities
   — Number of Facilities
   Risk
   —  Risk from Fires or
      Explosions
   —  Transport Risks
   - Pollution Risk
   Present Adequacy

   Future Adequacy

   Residual Waste**
   Reliability of Technology
   Limitations or Problems
   Suitability for Retrofit
   Non-Land Related Impact

   Implementation Time
      Level I

1) Incineration on-
   site
2) Contractor in-
   cineration
      Level II

1) As Level I
2) Includes energy
   and resource re-
   covery at the
   contractor's site.
1) 50
2) 50
1) 27
2) 27
1) 50
2) 12
1) 27
2) 6
Moderate

Minimized with
on-site incinera-
tion
Minor
1) Excellent
2) Excellent
1) Good
2) Good
0
1) Good
2) Many reliable
   contract dis-
   posal firms
1) Cannot handle
   high inorganic
   salt content
2) Same as 1) above
Excellent
None, excepting
salt plume
1) Two years
2) Minimal
Moderate

Minimized with on-
site incineration

Minor
1) (2) Excellent

1) Good
2) Excellent
0
As Level I
    J
   Level III

 1) As Level I***
 2) As Level 11***
0
As Level I
None

Technology not
yet proven for salt
removal by scrubbing
  *Generated, i.e., prior to treatment or disposal (see Table 4.2.2).
 **Finally land disposed.
***With scrubber for salts when they are present in concentrations that require scrubbing.

 Source:  Interviews and Arthur D. Little, Inc., estimates.

                                         119

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incineration of  the waste. Resource recovery is  possible if the contractor produces  a
low-grade, salable fuel from the various waste solvents that he collects. We estimate that
approximately 12% of the pharmaceutical facilities are currently using contractors which
are using energy and resource recovery techniques.

     The Level III technology is the same as Levels I and II, except that a scrubber is added
to handle salts when they are present in concentrations that require scrubbing. Although
there have  been numerous  attempts to work out this technological  problem, there is
currently no proven method for complete salt removal by scrubbing. In Table 4.5.1-B we
discuss the treatment and disposal technology levels for halogenated waste solvents. There
are approximately 3450 metric tons of halogenated waste solvents generated annually in the
pharmaceutical industry. These materials are usually flammable and the halogen is typically
chlorine.

     In our survey of the industry,  we found that those facilities which had incineration
capability onsite  either diluted the halogenated solvents with their other solvents, or they
had  them incinerated by a contractor.  Those plants which had no incineration capability
onsite also had their waste solvents incinerated by contractor. In both cases, the contractor
had  the capability for scrubbing forHCl. We have estimated that about 35% of the industry's
facilities with this kind of solvent waste were diluting and incinerating  onsite. In so doing
they  were meeting current air pollution control regulations.  A specific limitation on this
kind  of incineration, however, is that it tends to corrode the incinerator. Because we had
identified offsite  facilities which used incineration and energy- and resource-recovery tech-
niques, we have included energy and resource recovery as a technology level within Level II.
About 10%  of pharmaceutical industry facilities utilize offsite contractor incineration with
energy  and  resource recovery. As  long as care  is taken  to maintain  proper  operating
conditions, Level I and Level II technology provides adequate waste disposal.

     It takes approximately two years to design and install an onsite incinerator within  a
pharmaceutical plant. However, there is an adequate supply  of reliable  contract disposal
firms in  most areas of the country.  Also, under Level I we believe that the incineration
onsite that is accomplished by dilution  of  the halogenated solvent with other solvents is
satisfactory, because  the use of halogenated solvents within  the  pharmaceutical industry
does not constitute a major portion of the solvents.

4.5.2 Treatment and Disposal  Levels for Organic Chemical Residues

     Based  on  its 1973  production  level,  we estimate that  the  pharmaceutical industry
generates 13,600  metric  tons of organic chemical residues annually. By far the majority of
these residues results from the production of the active ingredients used in organic medicinal
chemicals. We further estimate that about 10% of these residues are disposed of onsite by
methods other than incineration; for  example, by mixing the residue with plant wastewater
prior to its treatment. We have not cited this method as a unique technology level because
we found it to be used for only a small amount of waste within a given plant, and only when
                                         120

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                                   TABLE 4.5.1-B

                 TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
                      FOR HALOGENATED WASTE SOLVENTSt

Amount of Waste:*  3450 Metric Tons per Year

Hazardous, Physical, and Chemical Properties of Waste: Flammable, Chlorinated Organic
           Liquid.
                                   Level I
                        Level 11
   Technology
•  Current Usage
   —  Percent of Industry
      Facilities
   —  Number of Facilities
•  Risk
   —  Risk from Fires or
      Explosions
   —  Transport Risks

   -  Pollution Risk

•  Present Adequacy

•  Future Adequacy

•  Residual Waste**
•  Reliability of Technology
•  Limitations or Problems
•  Suitability for Retrofit
•  Non-Land Related Impact
•  Implementation Time
1) Incineration on-  1) as Level I***
   site (diluted with
   other solvents)
2) Contractor incin- 2) With energy and
   eration with        resource recovery
   scrubbing for HCI
                        Level III
                     1) as Level I
                                                                     2) as Level 11
1) 35
2) 65
1) 19
2) 35

1) Moderate
2) Moderate
Minimized by on-
site incineration
1) Moderate
2) Slight
Good

Good

Nil
Good
1) Corrosion and
   pollution may
   occur at high
   percentage
   chlorine.
Good
1) Two years
2) Minimal
1) 35
2) 10
1) 19
2)  5

1) Moderate
2) Moderate
Minimized by on^site
incineration
1) Moderate
2) Slight
1) Good
2) Excellent
1) Good
2) Excellent
Nil
Good
                                                Good
1) Two years
2) Minimal
  *Prior to treatment or disposal.
 **Finally land disposed.
***Assuming that the relatively small percentage of halogenated solvents will continue.

'''Source:  Interviews and Arthur D. Little, Inc., estimates.
                                       121

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the waste was compatible with the onsite treatment. The other methods currently used to
dispose of these residues are onsite and contractor incineration and landfill.

     Only the smaller facilities are likely to place  these materials in a landfill. We estimate
that 40% of the industry facilities use onsite incineration and another 40% use contractor
incineration. The  present adequacy of the incineration method  is  excellent,  while  the
landfill can  be defined as only fair. In many instances, little is known about the constituents
in organic chemical residues. For that reason  we have described the future adequacy of
the landfill  method as  poor. There is little residual waste  from the incineration of these
materials. Often the amount of solvent in the residue is maintained at a level that allows it
to remain pumpable, so that it can be incinerated in a liquid-feed incinerator. In the past,
the residue  was allowed to flow into a steel drum while still hot. As the material cooled, it
turned into  a hard, glassy substance which was then landfilled. A potential  for groundwater
contamination  is inherent in this method. With  Level II, either onsite or contractor incinera-
tion is recommended, and Level III is the same as Level II.

     Table 4.5.2 provides information on the contractor-recommended levels of treatment
and disposal of organic chemical residues.

4.5.3 Treatment and Disposal Levels for Potentially Hazardous High  Inert-Content Wastes,
      Such  as Filter Cakes

     To discuss these high inert-content wastes effectively, we divided such as filter cakes, in
two  classes, one  of which contains flammable  solvent, and the other  which contains
corrosives or trace amounts of  heavy metals.  Based on  information  obtained in  our
interviews, we  estimate that approximately  half of the wastes contains solvents and  the
other half heavy  metals and corrosives. These  materials are either semi-solid  or solid. The
inert content may be filter aid or materials, such as charcoal.

     In Table 4.5.3-A,  we discuss the wastes which contain flammable solvent. Currently,
about  one half of the plants generating this kind of waste send the material to contractor
landfill. The others have  some means of incinerating, generally in rotary kilns or multiple
hearth furnaces. The content  in  these wastes ranges from under five to as much as 60
percent solvent.

     The  present adequacy of the landfill method is only fair and its future adequacy  has
been determined to be poor because of the possibility of fires in the disposal area. On the
other hand,  incineration provides an excellent means of making the waste  inert as it burns
off all solvent and the only residual is the  inert ash. A facility for the incineration of these
materials would take about two years to design and install.

     For  Level II  technology, we are recommending  incineration as the  best method
currently used. Because it provides an environmentally acceptable method for disposing of
these materials, we have also stated that Level  III  should be incineration. In Table 4.5.3-B,
                                          122

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                                      TABLE 4.5.2
                 TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
                         FOR ORGANIC CHEMICAL RESIDUES*
 Amount of Waste:*     13,600 metric tons per year
 • Technology
 • Current Usage
   — Percent of Industry
      Facilities

   — Number of Facilities
 •  Risk
    — Risk from Fires' or
      Explosions
    — Transport Risks

    - Pollution Risk
 •  Present Adequacy

 •  Future Adequacy

 •  Residual Waste**
 •  Reliability of Technology

 •  Limitations or Problems
•  Suitability for Retrofit
•  Non-Land Related Impact


•  Implementation Time
      Level I

 1) On-site incinera-
   tion
 2) Contractor in-
   cineration
 3) Landfill1"

 1) 40
 2) 40
 3) 20
 1) 22
 2) 22
 3) 11

 3) Yes
                                                       Level 11
                         Level III
 1) On-site incinera-  as Level
   tion
 2) Contractor in-
   cineration
 1) 40
 2) 40

 1) 22
 2) 22
Moderate
2) Moderate
3) Moderate
3) Yes
1) (2) Excellent
2) Moderate
Nil
Excellent
3) Fair
1) (2) Excellent
3) Poor
1) (2) Minimal1'1'
1) (2) Good
3) Unknown
1) (2) None
3) Landfill ade-
   quacy unknown
1) Good1"1'1'
3) Potential
   groundwater
   pollution
1) Two years
Excellent

Minimal
Good

None


Good
Nil


1) Two years
   * Generated, i.e., prior to treatment or disposal.
 **Finally land disposed.
   tSince smaller facilities are more likely to use landfilling, it is included here.
 ttlf enough solvent remains to keep waste pumpable, it can be incinerated in liquid-feed
    incinerator with little residual waste.
tttHeated feed to existing liquid injection incinerator is possible.

* Source:  Interviews and Arthur D. Little, Inc., estimates.
                                       123

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                                 TABLE 4.5.3-A
                TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
         FOR POTENTIALLY HAZARDOUS HIGH INERT CONTENT WASTES*
                (such as filter cakes, which contain flammable solvent)

Amount of Waste:*    850 Metric Tons per Year

Hazardous, Physical, and Chemical Properties of Waste:  Flammable, Semi-Solid or Solid
          with High Inerts Contents
•  Technology

•  Current Usage
   - Percent of Industry
     Facilities
   — Number of Facilities

•  Risk
   — Risk from Fires or
     Explosions
   - Transport Risk
   - Pollution Risk
*  Present Adequacy

•  Future Adequacy

•  Residual Waste**

•  Reliability of Technology

•  Limitations or Problems
•  Suitability for Retrofit


•  Non-land Related Impact
•  Implementation Time
                                  Level I
                        Level II
                        Level III
1) Landfill
2) Incineration
1) 50
2) 50
1) 27
2) 27
1) Yes
Slight
1) Yes
1) Fair
2) Excellent
1) Poor
2) Excellent
1) All
2) Inert ash
1) Unknown
2) Excellent
Fire risk
1) Not recom*
mended
2) Good
Incineration as Level II
50
27
27
Minimal
Slight
Nil
Excellent
Excellent
Inert ash
Excellent
None
Good











2)  Two years
Two years
 *Prior to treatment or disposal
**Finally land disposed
   Source: Interviews and Arthur D. Little, Inc., estimates.
                                       124

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                                   TABLE 4.5.3-B
                TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
          FOR POTENTIALLY HAZARDOUS HIGH INERT CONTENT WASTES1"
               (such as filter cakes, which contain heavy metals or corrosives)

Amount of Waste:*    850 Metric Tons per Year

Hazardous, Physical, and Chemical Properties of Waste:  Toxic, Semi-Solid or Solids with
          high inerts content (may contain solvent)
                                   Level I
                        Level II
                                                                       Level III
   Technology
1) Secure chemical  Neutralize or prer   as Level II
   landfill           cipitate heavy
2) Sanitary land-    metal, then place
                                fill
                             1) 40
                             2) 40
                             1) 22
                             2) 22

                             Slight
                   in secure chemical
                   landfill

                   20

                   11


                   Slight
                             Slight to moderate   Slight
                             1) Slight           Slight
                             2) Moderate***
                             1) Good
                             2) Fair
                             1) Fair
                             2) Poor
                             All
                             1) Good
                             2) Fair
                             1) (2) Soil con-
                                ditions
                  Good

                  Good
   Current Usage
   — Percent of Industry
     Facilities
   — Number of Facilities
•  Risk
   —  Risk from Fires or
      Explosions
   —  Transport Risks
   —  Pollution Risk

•  Present Adequacy

•  Future Adequacy

•  Residual Waste**
• 1 Reliability of Technology

•  Limitations or Problems

•  Suitability for Retrofit
•  Non-Land Related Impact
•  Implementation Time
   *Prior to treatment or disposal.
 **Finally land disposed.
***Anaerobic conditions can occur in sanitary landfill which will dissolve heavy metals and
    make them mobile.
                  More stable
                  Good

                  Soil conditions
 Source: Interviews and Arthur D. Little, Inc., estimates.
                                        125

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we  outline our  evaluation of treatment and disposal of those high inert-content wastes
which contain corrosives or trace amounts of heavy metals. We estimate that the pharma-
ceutical industry generates 850 metric tons of these wastes annually. Because they contain
corrosives, they are generally not incinerated.

     Because these materials  cannot be  incinerated, they  are currently  landfilled. We
estimate that about 40% of the facilities dispose of these wastes in sanitary landfills, which
means  that wastes other than chemical wastes are being  disposed of. We estimate that a
second  40% disposes  of these wastes in a  secure  chemical landfill that is both limited to
chemical wastes and has to be lined with some material to ensure that materials do not leach
into groundwater. The present adequacy of the sanitary landfill method is only fair and is
not recommended for future disposal. Anaerobic conditions can occur in  sanitary landfills
which will dissolve heavy metals and make them mobile.

     Secure chemical  landfills provide better environmental conditions, but even these can
create problems because of  local soil conditions.  Level II technology, which is currently
used by about 20% of the facilities, involves the neutralization  of the corrosive material or
precipitation  of the trace amounts of heavy metal. Then, the material which is less soluble
and less toxic is placed  in a  secure chemical landfill. Because of the nature of these wastes
and the inability to recover the trace amounts of heavy metal,  we  have recommended this
Level II treatment as Level III also.

4.5.4 Treatment and Disposal Levels for Heavy Metal Wastes

     ADL estimates that the pharmaceutical  industry generates 2875 metric tons of heavy
metal wastes  annually. Pharmaceutical facilities which produce these heavy metal wastes are
not common within the industry. In fact, we estimate that only 15 pharmaceutical plants
generate heavy metal wastes.  About 80% of these  facilities currently convert the heavy
metal wastes  into their most insoluble form, place  them in drums, and then bury them in a
secure  chemical landfill. All the plants we visited  that used  landfill for disposal used a secure
chemical landfill for their heavy  metal wastes. However, we believe that a small percentage
of the heavy metal wastes may  be placed  in normal sanitary  landfills. As  we mentioned
before,  anaerobic conditions can occur in  sanitary landfills which may dissolve the heavy
metals and make them mobile.

     About 20% of the  industry facilities  currently subject their heavy metal wastes to a
recovery process  at an  offsite contractor  location. From an environmental  control view-
point, this technique is excellent, since only a small  portion of the wastes is then disposed of
on land. The limitations of this kind of disposal include the economics of the recovery and
the market for the recovered  metal. For  Level  III,  we recommend  both the recovery as
described in Level II and engineered storage.  However, in  our survey, we did not  find any-
one utilizing  engineered storage. We include engineered storage  in this Level III technology
because there are some heavy metal wastes which  do not  lend  themselves to recovery and
therefore must be subjected to some secure method of disposal.
                                         126

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     Table 4.5.4 provides information on our recommended levels of treatment and disposal
of heavy metal wastes.

4.5.5 Treatment and Disposal Levels for Returned Goods and Reject Materials
      from Formulation

     ADL estimates that the pharmaceutical industry annually generates 500 metric tons of
waste from returned goods and reject material from formulation operations. The technology
most commonly used within the industry for handling these wastes is to crush the material
and dispose of it in a sanitary landfill. We estimated that approximately 60% of the industry
facilities use  this  method. Because more information is needed on the effects  of these
materials being landfilled, we  have  described their  present adequacy as good, but have
recommended other treatment for Level II.

     In Level II technology in our survey we  have found that these wastes were both being
incinerated by  either a contractor or at a company-owned  facility and also treated in an
onsite  biological  wastewater treatment  system.  Approximately 10% of these  facilities
currently use incineration  and  about 20% use the biological treatment. The residual from
the incineration is a non-hazardous ash.

     The  problems and limitations associated with these two methods involve the avail-
ability of either incineration or onsite biological treatment. We have described Level III to
be the same  as Level II, because we believe  these two methods provide environmentally
adequate methods  of disposal.

     Table 4.5.5 provides information on our recommended levels of treatment and disposal
of returned goods.
                                         127

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                                          TABLE 4.5.4

                     TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
                                FOR HEAVY METAL WASTES1"1"
     Amount of Waste:*  2875 Metric Tons per Year
   Technology
•  Current Usage
   — Percent of Industry
     Facilities
   — Number of Facil-
     ities^
•  Risk
   — Risk from Fires or
     Explosions
   — Transport Risks
   - Pollution Risk
•  Present Adequacy

•  Future Adequacy

•  Residual Waste**

•  Reliability of Technology
•  Limitations or Problems


•  Suitability for Retrofit
•  Non-land Related Impact
•  Implementation Time
         Level I
Convert heavy metal to
most insoluble form,
drum, and place in se-
cure chemical landfill***

           80

           12
         Level II
1) Recovery off-site
2) As Level I
1) 20
2) 80
1)  3
2) 12
         Level III
1) Recovery off-site
2) Engineered storage
1) 20
2)  0
1)  3
2)  0
Slightly
Moderate
Good
Good
All
Good
Soil conditions
D(2) Slight
1) Minimal
2) Moderate
1) Excellent
2) Good
1) Excellent
2) Good
1) Some
2) As Level 1
1) (2) Good
1) Market for heavy
1)(2) Slight
1) Minimal
2) Slight
1) (2) Excellent
1) (2) Excellent
1) Some
2) All


                             metal
                        2) Soil conditions
                        1) Minimal
                        1) Two years
   * Prior to treatment of disposal
  **Finally land disposed
 ***AII of the plants we visited that used landfill for disposal used a secure chemical landfill for their heavy
    metal wastes.  We believe, however, that a small percentage of the heavy metal wastes may be land-
    filled in sanitary landfills.
    15 pharmaceutical plants are estimated to have heavy metal wastes.
    Source:  Interviews and Arthur D. Little, Inc., estimates.
                                             128

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                                    TABLE 4.5.5
                TREATMENT AND DISPOSAL TECHNOLOGY LEVELS
             FOR POTENTIALLY HAZARDOUS RETURNED GOODS AND
                    REJECT MATERIAL FROM FORMULATION™
Amount of Waste:* 500 Metric Tons per Year
•  Technology
   Current Usage
   — Percent of Industry
     Facilities
   — Number of Facilities
•  Risk
   —  Risk from Fires or
      Explosions
   —  Transport Risks
   —  Pollution Risk
•  Present Adequacy
•  Future Adequacy
•  Residual Waste**
•  Reliability of Technology
•  Limitations or Problems
•  Suitability for Retrofit
•  Non-Land Related Impact
•  Implementation Time
     Level I
Crush on-site and
landfill  in sanitary
landfill.
60

122

None

None
Slight
Good
***
All
Good
     Level II
1) Incineration by
   contractor or at
   company-owned
   facility.
2) Treatment in on-
   site biological waste-
   water treatment
   system.

1) 10
2) 20
1} 15
2) 30

1) (2) None

1) (2) None
1) (2) None
1) (2) Excellent
1) (2) Excellent
1) 60 percent of waste
1) (2) Good
1) (2) Availability
   Level III
as Level 11
  *Prior to treatment or disposal.
 **Finally land disposed.
***More information needed.
  tNon-hazardous ash.

 ^Source: Interviews and Arthur D. Little, Inc., estimates.
                                       129

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                            GENERAL BIBLIOGRAPHY

                                    Section 4.0

Achinger, W. C. and L. E. Daniels. An Evaluation of Seven Incinerators, Proceedings of the
     1970 National Incinerator Conference, p. 32.

Adinoff, J. "Waste Disposal" Industry and Power, July 1953, p. 80.

Black & Veatch and  Rafael A.  Domenech & Associates.  "Industrial Waste  Survey,  Bar-
     celoneta Region, Puerto  Rico," Prepared for the Puerto  Rico Aqueduct and Sewer
     Authority, Commonwealth of Puerto Rico, July 1973.

Breaz, Emil. "Drug Firm  Cuts  Sludge  Handling  Costs,"  Water  and Waste Management,
     January 1972, p. A-22.

Bridge, D. P. and J. D. Hammel.  "Incinerator Design Specifically to Burn Waste Liquids and
     Sludges," Proceedings of 1972 National Incinerator Conference, p. 55.

Colonna, Robert A.,  and Cynthia McLaren. "Appendix D, Hazardous Wastes,"  Decision-
     Makers Guide in  Solid Waste Management,  Environmental Protection Agency, 1974,
     p. 146.

Danielson, C. N., W. G. Robrecht. "Deep-well Disposal of Chemical Wastes: Solid Backbone
     of a Total Waste Control Program."

Davis, Ken E.  and Rabey  J. Funk. "Deep-Well Disposal of Industrial Wastes," Industrial
     Wastes, Vol. 21, No. 1, January/February 1975, p. 28.

Eckenfelder, W. Wesley, Jr.,  and Edwin L.  Barnhart. "Biological  Treatment of Pharma-
     ceutical Wastes," Biotechnology and Bio engineer ing, Vol. IV, 1962, p. 171.

Heaney, Frank L., and Charles  V. Keane,  Solid Waste Disposal  (Camp, Dresser and McKee
     Company).

Hescheles, C. A. "Ultimate Disposal of Industrial Wastes," Proceedings  of 1970 National
     Incinerator Conference, p. 235.

Kroneberger, G. F. "Porteous Conditioning of Sludges for Improved Dewatering," Solid
     Waste Treatment, Vol. 68, No. 122, p. 176.

Kumar, J. and J. A. Jedlicka.  "Selecting and  Installing Synthetic Pond-Linings," Chemical
     Engineering, February 5,  1973, p. 67.
                                       130

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Laboratory  Waste Disposal Manual, Manufacturing  Chemists Association,  Revised July
     1974.

Lawson,  J.  Ronald, Michael L.  Woldman, and  Paul P. Eggermann.  "Squibb  Solves Its
     Pharmaceutical Wastewater Problem In Puerto  Rico," Chemical Engineering Progress
     Symposium Series, 1970, p. 401.

McGill, Douglas L., and Elbridge M. Smith. "Fluidized  Bed Disposal of Secondary Sludge
     High in Inorganic Salts," Proceedings of 1970 National Incinerator Conference, p. 79.

Mead, Berton  E., and William G. Wilkie.  "Leachate Prevention and Control from Sanitary
     Landfills,"  Presented  at  the  68th  National Meeting of the American Institute of
     Chemical Engineers, March 2, 1971, p. 1.

Melcher,  R. R. "Experience with Pharmaceutical Waste Disposal by Soil Injection," Speech
     presented at the American Chemical Society,  September 7, 1961.

"Ocean Dumping," Federal Register, Environmental Protection Agency, Part II, Volume 38,
     No.  94, May 16, 1973.

Proposed Solid  Waste Management Authority  Development Plan,  Solid Waste and  Noise
     Control Program, Office of the Governor, Commonwealth of Puerto Rico, p.  69.

Quane, D. E. "Air Pollution Control Techniques:  Reducing Air Pollution at Pharmaceutical
     Plants," Chemical Engineering Progress, Vol. 70,  No. 5, May 1974, p. 5.

Routson, R.  C. and R. E. Wildung.  "Ultimate Disposal of Wastes  to Soil,"  Chemical
     Engineering Progress Symposium Series, No. 97, Vol. 65, Winter, 1969, p. 19.

Rules of the Bureau of Solid Waste Management, New Jersey Department of Environmental
     Protection, July 1, 1974.

Santoleri, Joseph J. "Chlorinated Hydrocarbon  Waste Recovery and Pollution Abatement,"
     Proceedings of 1972 National Incinerator Conference, p. 66.

Scurlock, Arch C., Alfred W. Lindsey, Timothy Fields, Jr., and David R. Huber.  "Incinera-
     tion in Hazardous Waste Management,"  Division  of the Environmental Protection
     Agency, April 1974.

"Solid Waste Management in the Drug  Industry," Prepared for the Environmental Protec-
     tion Agency, 1973.

Sorg, Thomas J. "Industrial Solid Waste  Problems," AIChE Symposium Series, No. 122,
     Vol. 68, 1972, p. 1.
                                         131

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Stone, Ralph. "Sanitary Landfill Disposal of Chemical  Petroleum Waste," Solid Waste
     Treatment, AIChE Symposium Series, No. 122, Vol. 68, p. 35.

"Synthetic Organic Chemicals, United States Tariff Commission, United States Production
     and Sales, 1971, p. 101.

"The Form of Hazardous Waste Materials," Rollins Environmental Services, September 7,
     1972.

Walker,  William H. "Monitoring Toxic Chemicals in Land Disposal Sites," Pollution Engi-
     neering, September 1974, p. 50.

Witt,  Philip A., Jr. "Disposal of Solid Wastes," Chemical Engineering, October 4, 1971,
     p. 61.
                                        132

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5.0 COST ANALYSIS

5.1 BACKGROUND

     Total production of active ingredients within the pharmaceutical companies in 1973 is
estimated at  45,000 metric tons. Overall, production of these ingredients is expected to
grow at a rate of 3 percent per year through 1977 and at a 7 percent rate thereafter.* Waste
generated and  destined  for land  disposal in  1973 for the pharmaceutical industry  is
estimated at 244,000 metric tons per year. The hazardous waste represents about 25 percent
of the  total waste or 61,000 metric tons per year in  1973. Wastes are expected to grow to
400,000 metric tons per year of total wastes and  to 100,000 metric tons per year of
hazardous wastes by 1983. Approximately 85 percent of total wastes  and 60 percent of
hazardous wastes are estimated to be treated and disposed of by contractors.

     Approximately  54 company operations estimated to be large enough to have signifi-
cant wastes  participate in the manufacture of pharmaceutical active ingredients.  Another
175 operations large enough to produce significant wastes formulate and package these and
other ingredients into final pharmaceutical preparations. In order to calculate total industry
costs, we used the  above estimates of company operations in conjunction with  industry
production estimates and treatment and disposal costs per ton of product.

5.2 SUMMARY OF COSTS FOR CONTROLLED TREATMENT AND DISPOSAL OF
    LAND-DESTINED HAZARDOUS WASTES

     Tables 5.2-A,-B, and-C summarize the costs of end-of-pipe treatment and disposal
systems either currently in use or recommended for future use in pharmaceutical production
facilities.  No  costs  are  given  for in-process  changes  made to  minimize or  change the
hazardous character of the wastes. Because typical plants were used to develop an  estimate
of the  total industry cost of treatment and disposal of hazardous wastes, the total  industry
costs should be taken only as an indication of the order of  magnitude of such costs rather
than as the outcome of a detailed industry survey of the costs. Issues such as site specific
costs,  different products or product mixes, local disposal rates, and available  disposal
methods were  not  included in  this  estimate. Where it is  necessary to reflect different
economics of large versus small plants and separate hazardous waste streams, costs have been
developed typically for more than one plant in each industry section. These product-specific
analyses are presented in Tables 5.4.2.1 to 5.4.3.

5.3 RATIONALE AND REFERENCES USED IN COST ESTIMATING

     Eighty-five percent of the total pharmaceutical industry process waste are disposed of
through contractors. The onsite disposal facilities are liquids incinerators and solids  incinera-
tors. However, almost 70  percent of the incineration  capability are located offsite with
contractors. There  is, however, a trend toward onsite incineration. In our survey, we
contacted numerous  pharmaceutical  companies that had  recently  installed incineration

*The industry growth rate is discussed in Section 2.7.
                                        133

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capacity or were planning installation. Because of the patterns of offsite disposal, costs in
this report have usually been determined for representative plants on the basis of contractor
disposal. In addition, there is information presented  on the cost of onsite incinerators for
solids. The data are presented for various size ranges. Installation  of these units is usually
determined by individual company location  and policy. Where industry in an area is sparse,
there may be limited availability  of contractor  incineration. On the other hand, in some
areas, pharmaceutical companies may find  an adequate supply of disposers, but find that
they are constantly on the  brink of being shut down  by local regulatory agencies for air or
water regulation violations. These pharmaceutical companies may decide in favor of onsite
incineration to ensure that they have a reliable disposal method.
                                      TABLE 5.2-A

                   PERSPECTIVE ON THE PHARMACEUTICAL INDUSTRY:
                                      COSTS PERUIV
                                      ($/metric ton)
TREATMENT AND DISPOSAL COSTS PER UNIT OF HAZARDOUS WASTE*
            Product Category                       Level I     Level II    Level III

            •  Bulk Active Ingredient
            —  Organic Medicinal Chemicals
                 Non-halogenated waste solvent          68        68         68
                 Halogenated waste solvent             184        184        184
                 High inert content wastes              26        43         43
                 Heavy metal waste                    50        50         60
                 Organic chemical residues             100        100        100
            —  Inorganic Medicinal Chemicals
                 Heavy metal waste                    50        50         60
            —  Fermentation Products
                 Waste solvent concentrate             120        120        120
            —  Botanicals
                 Aqueous solvent                    144        144        144
                 Waste halogenated  solvent             180        180        180
                 Non-halogenated waste solvent          68        68         68
            —  Drugs from Animal Sources
                 Aqueous alcohol                    142        142        142
            -  Biologicals
                 Aqueous alcohol                    142        142        142
                 Antiviral vaccine                     30        30         30
                 Other biologicals (toxoids, serum)        30        30         30
            •  Pharmaceutical Preparations               28        67         67

             Source: Arthur D. Little, Inc., estimates.
                                           134

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                            TABLE 5.2-B

       PERSPECTIVES ON THE PHARMACEUTICAL INDUSTRY:
     HAZARDOUS WASTE TREATMENT AND DISPOSAL COSTSปf

                                                  Estimated
                                          Total Annual Costs ($000)**
Product Category                           1973      1977       1983

•  Bulk Active Ingredient
—  Organic Medicinal Chemicals
     Non-halogenated waste solvent          1,620      1,820      2,585
     Halogenated waste solvent               630       705      1,000
     High inert content wastes                 45         80        110
     Heavy metal wastes                     145       160        275
     Organic chemical residues               1,360      1,530      2,170
—  Inorganic Medicinal Chemicals***
     Only one hazardous waste identified       -         -         -
—  Fermentation Products
     Waste solvent concentrate               1,440      1,620      2,300
—  Botanicals
     Aqueous solvent                       145       160        230
     Halogenated waste solvent                10         10         15
     Non-halogenated waste solvent            10         10         15
—  Drugs from Animal Sources
     Aqueous alcohol                       115       130        180
—  Biologicals
     Aqueous alcohol                        35         40         60
     Antiviral vaccines                        10         10         15
     Other biologicals (toxoids serum)           5         10         10
•  Pharmaceutical Preparations                 15         40         50
   Partial Total"1"                           5,585      6,325      9,015

   *Based on average treatment costs and pharmaceutical industry waste esti-
    mates.
 **December 1973 dollars.
***lncluded  in heavy metal wastes under organic medicinal chemicals
+Excludes R&D costs.

 Source: Arthur D. Little, Inc., estimates.
                                135

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                                      TABLE 5.2-C

                   PERSPECTIVES ON THE PHARMACEUTICAL INDUSTRY:
             COST IMPACTOF HAZARDOUS WASTE TREATMENT AND DISPOSAL

                                                         Estimated Hazardous Waste
                                                       Control Cost as Percent of Price*
   Product Category

   • Bulk Active Ingredient
        Organic Medicinal Chemicals
        Inorganic Medicinal Chemicals'
        Fermentation Products
        Botanicals
        Drugs from Animal Sources
        Biologicals
   1973
Selling Price
   $/kg
    22


    44
   *##
   **#
   #**
Level I


0.2%

0.34%
                                                                 Level II
             Level III
  0.22%     as Level 11

as Level I     as Level I

as Level I     as Level I
     * Manufacturers selling price in the case of pharmaceutical preparations; value of sales, that
       is, the net selling value FOB plant or warehouse, or delivered value, whichever represents
       the normal practice for bulk active ingredient.
    **  Representative data not available because most inorganic medicinal ingredients that might
       produce a hazardous waste are purchased from the chemical industry.
   ***  Data not available; the selling  price of  many  of these products is stated  in terms  of
       biological activity.

    Source: Arthur D. Little, Inc., estimates.
     In each of the representative operation cost analyses, typical  plant situations  are
identified in terms of production capacity, process waste load, hazardous waste load, and
product  value. Annual capital  costs have  been assumed to be  a  constant  percentage (10
percent of fixed investment). Depreciation costs have been  calculated on the straight-line
method (10 percent per year) over 10 years, even though the physical life is longer. Taxes
and  insurance are  included as 1-1/2 percent of the capital  investment.  All estimates  are
reported in December 1973 dollars. The Engineering News Record (ENR) Construction Cost
Index (1158) and the Chemical Engineering (CE) Plant Cost  Index (148.2) have been used
to prepare these  estimates.  Land  requirements for onsite treatment are  not significant;
therefore, no cost  allowance has been made.  Offsite treatment and disposal land require-
ments  are not considered directly. Land costs are included in the  contractor's charges.
Cost-effectiveness relationships are implicit in the calculation of these costs, together with
the technology levels achieved. For example, when considering a  small pharmaceutical plant,
the use of contractor disposal is more cost-effective because  of the economies of scale and
the potential for energy  and  resource  recovery. With  larger  pharmaceutical  operations,
onsite and offsite incineration have approximately equal cost-effectiveness. The major issue
in these instances would be the availability  of capital.
                                          136

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     Table 5.3-A presents costs for transporting wastes for offsite disposal:


                                        TABLE 5.3-A

                             COST OF TRANSPORTING WASTES1"
             Distance	Liquids 	               Solids
             (miles)          ($/m3)             ($/1000gal)            ($/metric ton)

                5             0.92                3.50                   1.85
               10             1.02                3.85                   2.10
               20             1.48                5.60                   2.70
               40             1.94                7.35                   3.40
               50             2.03                7.70                   3.70

             Source: Arthur D. Little. Inc., estimates.
A number of contractors were contacted in this study, primarily in EPA Regions II and V
where concentrations of the pharmaceutical industry are found. Table 5.3-B summarizes the
information obtained, supplemented and checked by ADL estimates.  No  factors are in-
cluded for areas of the country, as no obvious differences were found in our analysis.

                                        TABLE 5.3-B

                 CONTRACT DISPOSAL CHARGES FOR HAZARDOUS WASTES*


                    Method                           $/Metric Ton

                    General Landfill*                        8
                    Secure Chemical Landfill**               17
                    Approved Secure Landfill***              30
                    Incineration
                       Non-halogenated solvents (organic
                       content 85% and over)                 90
                       Solids                               30
                    Neutralization (or precipitation of
                    components) of Wastes                  30
                     **.
                    ***
Operated as sanitary landfill.
Lined landfill limited to chemical wastes.
Lined landfill limited to hazardous wastes with monitoring.
                    tSource:  Interviews and Arthur D. Little, Inc., estimates.
                                           137

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     Also, the costs for offsite disposal vary, depending upon the amount of waste to be
disposed, the collection frequency, and the onsite storage facilities. Figure 5.3-A gives an
example  of how these factors affect costs.  Figure  5.3-B  presents capacity ranges and
investment costs for industrial solid waste incinerators, and Table 5.3-C presents background
information. Figure 5.3-C gives operating costs in terms of dollars per metric ton.

5.4 COSTS FOR TREATMENT AND DISPOSAL OF HAZARDOUS WASTES

5.4.1  Research and Development

     The hazardous wastes produced within the R&D  section of the industry include both
waste solvents and test animals. Waste solvents can be incinerated either by contractors or in
company-owned facilities for  about $0.30 per gallon.  A research facility  with 100 re-
searchers will produce about 2000 gallons of waste solvent annually. The cost of incinerat-
ing that waste will be approximately $600 annually.

     Most pathological incineration capacity for test animals  within the R&D section of the
industry is installed. It is not discussed here.

5.4.2 Production of Active Ingredients (SIC 2831 and 2833)

J. 4.2.1  Organic Medicinal Chemicals

     Of the 27,200 metric tons of waste solvent produced by  the pharmaceutical companies
in the manufacture  of organic  medicinal chemicals, about  10,100 metric tons per year can
be  incinerated onsite  by the  industry. Onsite incineration capacity  and  its associated
pollution control equipment (both air and water) are expected to increase.

     Offsite contractors dispose of the remainder of the waste solvent, about  17,100  metric
tons per year.  After surveying  the disposers, we found the typical charge for incineration of
pharmaceutical waste solvents to be $0.20 to $0.35 per gallon for a solvent of medium-range
Btu content,  depending mainly on the Btu content. The purer solvents can potentially be
recovered and sold, reducing the disposal charge, or used as a fuel for the incineration of
wastes with a higher water content. Those lower Btu content wastes may vary from $0.35 to
$0.60 per gallon for those with high water content; perhaps up to $1.00 for those with high
chlorine content as well.

     Since the actual quantities of medicinals which are produced in an operation are often
difficult to determine, we based  the plant size on  the number of production workers. A
typical operation producing organic medicinal chemicals has 300 production workers. In
other industries, the production is related to the number of production workers. That ratio
remains relatively  constant from  plant to plant  within  an  industry. Within the pharma-
ceutical industry, where the number of intermediate production steps can range from 1 to
                                        '138

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        100
"o
Q
     s   10
           0.1
                            1               10
                         Metric Tons (dry solids)/day
                                                        100
           Source: Arthur D. Little, Inc., estimates
    FIGURE 5.3-A   IN-PLANT STORAGE AND LANDFILL CHARGES1"
     400,000

     300,000

     200,000
     100,000



      50,000

      30,000
                       Semi-batch Incinerator
                                 V
             300
                                                      10,000
                  1000    2000
              Incinerator Capacity (Ib/hr)
*ENR Construction Cost Index: 1158
Source: Arthur D. Little, Inc., estimates.
 FIGURE 5.3-B  GENERAL INDUSTRIAL SOLID WASTE INCINERATION
                CAPACITY RANGES AND IN VESTMENT COSTS*1
   o
   U  c
      30
      25

      20
ฐฃ  15
         10
                                Single Shift Operation
               Two-shift Operation
                   I   I   I  I  J_
                                               I    I   l
              500          1000          2000            4000
                         Solid Waste (metric tons/year)
           "Includes capital-related charges.
           Source: Arthur D. Little, Inc., estimates.
         FIGURE 5.3-C  GENERAL INDUSTRIAL SOLID WASTE
                        INCINERATION OPERATING COSTS**
                                 139

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                                  TABLE 5.3-C
     CAPITAL INVESTMENT FOR INDUSTRIAL SOLID WASTE INCINERATION7
Capacity                                600 Ib/hr
Annual Capacity (single-shift operation)     450 tons*
Type                                       Batch
Capital Cost
    Incinerator                            $25,000
    Freight                                 2,000
    Installation  (includes foundations,
    electrical, plumbing, oil storage)           5,000

Total Fixed Capital Investment (FCI)
Engineering @ 10% of FCI
Contractor's Fee @ 7% of FCI
Contingency @ 15% FCI
 Total                                    $42,000
 1200 Ib/hr
900 tons**
   Batch

  $45,000
    3,000

    8,000
   2500 Ib/hr
 1875 tons***
Semi-Automatic

   $100,000
      5,000

     15,000
32,000
3,000
2,000
5,000
56,000
5,000
3,000
8,000
120,000
12,000
8,000
18,000
  $72,000
   $158,000
      *410 metric tons
     **820 metric tons
    ***1700 metric tons
     Installation costs for an incinerator within an operating plant are lower than those for
     for an incinerator located in areas where these facilities are not already available.

     Source:  Arthur D. Little, Inc., estimates.
                                      140

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15, we studied the various plants for which production figures were available and found that
for operations of approximately the same complexity the production per production worker
stays  relatively  constant also.  Ratios varied from 8000 pounds per year per production
worker* to  30,000 to  40,000  pounds  per year per  production worker for  large-scale
operations making relatively simple products such as aspirin.

     The  costs  of treatment and  disposal of hazardous wastes  from organic medicinal
chemical active  ingredient  production for a typical plant of  300 production workers are
presented in Tables 5.4.2.1-A,-B,-C, and  -D. There are smaller  operations in the industry
ranging down to almost 100 production workers. Few facilities can operate with fewer than
this number. Some of the larger operations  employ close to 1000 production workers. The
problems and the associated costs per amount of waste are generally of the same magnitude
as the typical plant.

5.4.2.2 Inorganic Medicinal Chemicals

     No individual costs have  been developed  for the treatment and disposal of inorganic
medicinal chemical  wastes. We found only one  hazardous  waste  in  our  survey. We have
included its treatment and  disposal cost  in the overall number for the organic medicinal
chemical hazardous waste treatment and disposal cost. We have estimated that the treatment
and disposal cost for this waste is approximately $50 per metric ton.

5.4.2.3 Fermentation Products

     As we have indicated in Tables  5.4.2.3-A  and -B, although the plant size varies, both
the large and small plants incur the same  average treatment  and disposal cost of 14^/kg of
product and $120/metric ton  of waste to dispose of a material which is a waste solvent
concentrate containing about 50% solids.

5.4.2.4 Botanicals

     We have identified three hazardous wastes from  the production of botanicals, specifi-
cally alkaloids. These materials are  an aqueous solvent with 50%  solids, a halogenated waste
solvent, and a non-halogenated waste solvent. Each of these waste streams was disposed of
by incineration.  Although there are onsite facilities for  incineration of these wastes, as our
example we have chosen a  typical  plant  which is using incineration by contractor offsite.
The  average treatment  and disposal  costs of these wastes range from  $68/metric  ton  of
waste for  the non-halogenated  waste solvent to $144/metric ton of waste for the aqueous
solvent  to a high of $180/metric ton of waste for the halogenated waste solvent. Tables
5.4.2.4-A, -B, and  -C  describe the  costs associated  with  a typical botanical production
operation.
' For operations making widely diverse products in batch operations where many products were made only
 once per year with the production lasting anywhere from one day to three months.
                                        141

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5.4.2,5  Drugs from Animal Sources

     For our typical plant we have chosen a plant with 20 employees manufacturing insulin.
The hazardous waste stream from this production facility is an aqueous alcohol with organic
solids. It is typically 25% alcohol, 25% solids, and 50% water. This waste is disposed of by
incineration by a contractor off site. The costs average $50/kg of product  or $142/metric
ton of waste. Table 5.4.2.5 describes the costs associated with a typical operation in which
drugs are produced from animal sources.

5.4.2.6  Biologicals

     Producing plasma  protein  fractions represents a typical  production  scenario  for  a
biological products plant. We have based our estimates of disposal costs on such a plant. The
representative production capacity for this plant is a 500-liter batch of input plasma. The
associated hazardous waste load  from  this batch is  about 2500 liters  of aqueous alcohol.
This corresponds to a hazardous waste  load per unit of production of 5 liters of waste per
liter of  plasma. This results in an average treatment and disposal cost of 40^/liter of input
plasma. Table 5.4.2.6 describes the costs associated with a typical biological operation.

5.4.3 Formulation and Packaging (SIC 2834)

     Finished pharmaceutical preparations  are made  in the formulation  and packaging
operation.  The hazardous waste  stream  from this operation consists of a  portion of the
returned goods and reject materials. A  typical plant would have 200 production employees
and would operate 250  days per year. Because of the variety of products, it  is difficult to
assign a representative plant capacity to these operations. We have therefore  described the
plant capacity both  in  terms of the value of shipments  and the value  added in that
processing operation. The representative plant we have chosen has  $11,000,000 value added
and  a $14,000,000 value of the shipments. The average product value added annually per
employee is $55,000; the average value of shipment annually per employee is  $70,000. The
hazardous waste load from this facility annually is about 18 metric tons of returned goods
and reject material. Under Level I technology, which is described as  crushing this material
onsite and having a contractor handle the landfill and the sanitary landfill offsite, the cost
amounts to about $28 per metric ton of waste. Incineration of this waste by a contractor
offsite raises the average treatment and disposal cost to $67 per metric ton of waste.

     Table 5.4.3  describes the  waste volume and treatment costs of a  typical formulation
and packaging operation.
                                        142

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                                 TABLE 5.4.2.1-A

                       TREATMENT AND DISPOSAL COSTS:
      ACTIVE INGREDIENT PRODUCTION; ORGANIC MEDICINAL CHEMICALS
             WASTE STREAM - NON-HALOGENATED WASTE SOLVENT1"

         Plant description:  plant with 300 employees
         Representative production schedule, days/year:                 250
         Representative plant capacity: million kg/year:                1.0
         Average product value per unit of production, $/kg               22
         Process hazardous waste load in million kg/year:
            Waste solvent, non-halogenated;                            0.7
            Waste solvent, halogenated;                               0.1
            Potentially hazardous high inert content wastes;             0.05
            Heavy metal waste                                        —
            Organic chemical residues                                0.4
         Hazardous waste load (Non-halogenated waste solvent)
           million/kg year:                                           0.7
         Hazardous waste load per  unit of production:  kg/kg            0.7

                                                        Levels of Treatment
Cost-($)                                        Level I      Level)I       Level III
Transportation                                     1,000    as Level I     as Level
Contract disposal charges                           46,400
Total Annual Costs                                47,400
Average Treatment/Disposal Cost
 per Unit of Production, $/kg                       $0.047
 per metric ton of waste                           $68
Level I   - Incineration by contractor off-site
Level II — as  Level I
Level III — as  Level I

 Source: Arthur D. Little, Inc., estimates.
                                       143

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                                  TABLE 5.4.2.1-B

                       TREATMENT AND DISPOSAL COSTS:
      ACTIVE INGREDIENT PRODUCTION; ORGANIC MEDICINAL CHEMICALS
                WASTE STREAM - HALOGENATED WASTE SOLVENT1"

          Ptant'description: plant with 300 employees
          Representative production schedule, days per year              250
          Representative plant capacity: million kg/year:                 1.0
          Average product value per unit of production, $/kg               22
          Process hazardous waste load in million kg/year:
            Waste solvent, non-halogenated;                            0.7
            Waste solvent, halogenated;                                0.1
            Potentially hazardous high inert content wastes;              0.05
            Heavy metal waste                                         —
            Organic chemical residues                                  0.4
          Hazardous waste load (halogenated waste solvent)
           million kg/year:                                            0.1
          Hazardous waste load per unit of production: kg/kg             0.1

                                                        Level of Treatment

Cost - ($)                                        Level I      Level  II      Level III

Transportation                                         160   as Level I     as Level  I
Contract disposal charges                            18,280
 Total Annual Costs                                18,440
Average treatment/disposal cost
 per unit of production,                            $0.018/kg
 per metric ton of waste                            $184
Level  I  — Incineration by  contractor off-site
Level  II — as Level  I; with energy and resource recovery at contractor's site
Level  III-as Level  II

 Source: Arthur D. Little,  Inc., estimates.
                                       144

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                                   TABLE 5.4.Z1-C

                         TREATMENT AND DISPOSAL COSTS:
       ACTIVE INGREDIENT PRODUCTION; ORGANIC MEDICINAL CHEMICALS
    WASTE STREAM: POTENTIALLY HAZARDOUS HIGH INERT CONTENT WASTESt
           Plant description:  plant with 300 employees
           Representative production schedule, days per year
           Representative plant capacity: million kg/year:
           Average product value per unit of production, $/kg
           Process hazardous waste load: million kg/year:
             Waste solvent, non-halogenated;
             Waste solvent, halogenated;
             Potentially hazardous high inert content wastes;
             Heavy metal waste
             Organic chemical  residues
           Hazardous waste load (potentially hazardous high inert
            content wastes), million kg/year:
           Hazardous waste load per unit of production:  kg/kg
                    250
                   1.0
                     22


                   0.7
                   0.1
                   0.05

                   0.4

                   0.05
                   0.05
                                                          Levels of Treatment
Cost-($)

 Transportation Cost
 Contractor Incineration Charge
 Contractor Landfill Charge
 Neutralization Cost
 Contractor Secured Landfill Charge

   Total Annual Costs
 Average treatment/disposal cost

  per unit of production

  per metric ton of waste
Level I
 1,529
1000kg

 $26
Level II
163
730
198
—
438
163
730
198
730
438
 2,259
 $1.53      $2.26
1000kg

 $43
Level III
                        as Level 11
 Level I   — Incineration by contractor off-site for solvent containing waste; disposal by contractor
            in secure chemical landfill for waste containing corrosives or trace amounts of
            heavy metal.*\
 Level II  — Incineration by contractor off-site for sol vent contain ing waste; treatment (neutrali-
            zation) by contractor prior to disposal by contractor in secure chemical landfill for
            waste containing corrosives or trace amounts of heavy metal.
 Level 111  — as Level 11
 *lf this plant were to landfill the solvent containing waste (as described in Table 4.5.3-A) and
  landfill  the waste containing corrosives or trace amounts of heavy metal, then the associated
  costs for treatment and disposal would be $0.77 per 1000 kg product ($13 per metric ton of
  waste).
 ^Source:   Arthur D. Little, Inc., estimates.
                                        145

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                                  TABLE 5.4.2.1-D

                        TREATMENT AND DISPOSAL COSTS:
      ACTIVE INGREDIENT PRODUCTION; ORGANIC MEDICINAL CHEMICALS
                WASTE STREAM - ORGANIC CHEMICAL RESIDUES*

          Plant description:  plant with 300 employees
          Representative production schedule, days/year:                 250
          Representative plant capacity: million kg/year:                 1.0
          Average product value per unit of production: $/kg              22
          Process hazardous waste load in million kg/year:
            Waste solvent, non-halogenated;                            0.7
            Waste solvent, halogenated;                                0.1
            Potentially hazardous high inert content wastes;              0.05
            Heavy metal waste                                          —
            Organic chemical residues                                  0.4
          Hazardous waste load  (organic chemical residues)
           million kg/year:                                            0.4
          Hazardous waste load per unit of production: kg/kg             0.4


                                                         Levels of Treatment

Cost - ($)                                          Level I       Level II       Level III

Transportation                                        600      as Level I      as Level  I
Contract disposal charges                            39,400
 Total Annual Costs                                 40,000
Average treatment/disposal cost
 per unit of production                             $0.04/kg
 per metric ton of waste                            $100

Level I  —  Incineration by contractor off-site*
Level II — as'Level I  ,
Level III - as Level  I

*lf this plant were to  landfill these wastes as described in Table 4.5.2, the associated costs
 for treatment and disposal would be $0.0034 per kg product ($8.50 per metric ton of waste).
 Larger facilities, such as the one described on this page, do not landfill these residues.
 Source:  Arthur D. Little, Inc., estimates.
                                        146

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                               TABLE 5.4.Z3-A

ACTIVE INGREDIENT PRODUCTION; FERMENTATION PRODUCTS; PENICILLIN
      WASTE STREAM - WASTE SOLVENT CONCENTRATE (50%SOLIDS)t

       Plant description:  small plant (with solvent extraction)
       Representative production schedule, days per year:             350
       Representative plant: 200,000-gallon fermentor capacity.
        Product, million kg/year:                                  0.95
       Average product value per unit of production, $/kg              22
       Hazardous waste load (waste solvent concentrate, 50% solids),
        million kg/year:                                          1.14
       Hazardous waste load per unit of production: kg/kg            1.20
                                                       Levels of Treatment
Cost - ($)

Transportation
Contract disposal charges
  Total Annual Costs
Average treatment/disposal cost
 per unit of production
 per metric ton of waste

Level  I  — Incineration by contractor off-site
Level  II — as Level I
Level  III — as Level I

* Source: Arthur D. Little, Inc., estimates.
Level I
           Level II
  1,730   as Level I
133,000
134,730

$0.14/kg
$120
                                                                      Level III
                                                                      as Level I
                                     147

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                                 TABLE 5.4.2.3-B

                       TREATMENT AND DISPOSAL COSTS:
   ACTIVE INGREDIENT PRODUCTION; FERMENTATION PRODUCTS; PENICILLIN
        WASTE STREAM - WASTE SOLVENT CONCENTRATE (50% SOLIDS)1"

         Plant description:  large plant (with solvent extraction)
         Representative production schedule, days per year:              350
         Representative plant: 600,000-gallon fermentor capacity
           Product, million kg/year:                                   2.9
         Average product value per unit of production, $/kg               22
         Hazardous waste load (waste solvent concentrate,  50%
           solids), million kg/year:                                     3.48
         Hazardous waste  load per unit of production:  kg/kg            1.20
                                                        Levels of Treatment
Cost - ($)                                        Level I     Level II      Level III

Transportation                                     5,280   as Level I      as Level I
Contract disposal charges                          406,000
  Total Annual Costs                              411,280
Average treatment/disposal cost
  per unit of production                            $0.14/kg
  per metric ton of waste                           $120

Level I  — Incineration by contractor off-site
Level II - as  Level  I
Level 111 - as  Level  I

Source:  Arthur D. Little, Inc., estimates.
                                      148

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                                TABLE 5.4.2.4-A
                      TREATMENT AND DISPOSAL COSTS:
         ACTIVE INGREDIENT PRODUCTION; BOTANICALS; ALKALOIDS
WASTE STREAM - AQUEOUS SOLVENT WITH SOLIDS (30% SOLVENT, 20% WATER,
                                 50%SOLIDS)t

         Plant description: typical size industrial plant with 20
                           employees
         Representative production schedule, days  per year:             250
         Representative plant capacity, kg/year:                       680
         Average product value per unit of production, $/kg           11,000
         Process hazardous waste load in thousand  m3/year:
            Aqueous solvent with 50% solids                         0.09
            Halogenated waste solvent                              0.005
            Non-halogenated waste solvent                           0.020
         Hazardous waste load  (aqueous solvent with solids 30%
          solvent, 20% water, 50% solids) thousand m3/year:           0.09
         Hazardous waste load per unit of production: m3/kg           0.13

                                                       Levels of Treatment
Cost - ($)                                       Level I     Level II       Level III
Transportation                                      160    as Level I     as  Level I
Contract disposal charges                          12,500
  Total Annual Costs                             12,760
Average treatment/disposal cost
 per unit of production                            $18.8/kg
 per metric ton of waste                           $144
Level  I  — Incineration by contractor off-site
Level  II — as Level  I
Level  111 - as Level  I

* Source: Arthur D.  Little,  Inc., estimates.
                                      149

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                                 TABLE 5.4.24-B

                      TREATMENT AND DISPOSAL COSTS
          ACTIVE INGREDIENT PRODUCTION; BOTANICALS; ALKALOIDS
               WASTE STREAM - HALOGENATED WASTE SOLVENT*

    Plant description: typical size industrial plant with 20  employees
    Representative production schedule, days per year:                            250
    Representative plant capacity: kg/year:                                      680
    Average product value per unit of production, $/kg                         11,000
    Process hazardous waste load in thousand  m3/year:
       Aqueous solvent  with 50% solids                                       0.09
       Halogenated waste solvent                                             0.005
       Non-halogenated waste solvent                                         0.020
    Hazardous waste load (halogenated waste solvent, thousand
      m3/year):                                                            0.005
    Hazardous waste load per unit of production:  m3/kg                        0.007


                                                       Levels of Treatment
Cost - ($)                                        Level I    Level II       Level III

                                                          as Level I     as Level I
Transportation                                       20
Contract disposal charges                             1,000
 Total Annual Costs                                1,020
Average treatment/disposal cost
 per unit of production                            $1.5/kg
 per metric ton of waste                           $180
Level   I  — Incineration by contractor off-site
Level  II  — as Level I
Level III  — as Level I

 Source:  Arthur D. Little, Inc., estimates.
                                      150

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                                 TABLE 5.4.2.4-C

                       TREATMENT AND DISPOSAL COSTS:
          ACTIVE INGREDIENT PRODUCTION; BOTANICALS; ALKALOIDS
             WASTE STREAM- NON-HALOGENATED WASTE SOLVENT*

          Plant description: typical size industrial plant with 20
                           employees
          Representative production schedule, days per year:                250
          Representative plant capacity, kg/year:                           680
          Average product value per unit of production, $/kg             11,000
          Process hazardous waste load in thousand m3/year:
           Aqueous solvent with  50% solids                             0.09
           Halogenated waste solvent                                  0.005
           Non-halogenated waste solvent                              0.020
          Hazardous waste load (non-halogenated waste solvent,
           thousand m3/year):                                        0.020
          Hazardous waste load per  unit of production: m3/kg            0.03

                                                        Levels of Treatment

Cost - ($)                                        Level I    Level II       Level III

Transportation                                        80    as Level I      as Level I
Contract disposal charges                            1,040
 Total Annual Costs                                1,120
Average treatment/disposal cost
 per unit of production                            $1.60/kg
 per metric ton of waste                           $68
Level  I  — Incineration by contractor offsite
Level  II — as Level I
Level  111 — as Level I

* Source: Arthur D. Little, Inc., estimates.
                                       151

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                                 TABLE 5.4.2.5

                      TREATMENT AND DISPOSAL COSTS:
  ACTIVE INGREDIENT PRODUCTION; DRUGS FROM ANIMAL SOURCES; INSULIN
         WASTE STREAM - AQUEOUS ALCOHOL WITH ORGANIC SOLIDS
                    (25% ALCOHOL, 25%SOLIDS, 50% WATER)T

         Plant description: typical size industrial plant with 20
                          employees
         Representative production schedule, days per year:               250
         Representative plant capacity, kg/year:                          284
         Average product value per unit of production, $/kg             11,000
         Hazardous waste load (aqueous alcohol with  organic solids,
          25% alcohol, 25% solids, 50% water), thousand m3/year:         0.10
         Hazardous waste load per unit of production: m3/kg               0.35
                                                       Levels of Treatment
Cost - ($)                                       Level I      Level II      Level III

Transportation                                     400     as Level I      as Level I
Contract disposal charges                           13,900
 Total Annual Costs                              14,300
Average treatment/disposal cost
 per unit of production                           $50/kg
 per metric ton of waste                          $142
Level I  — Incineration by contractor off-site
Level 11 - as Level I
Level III - as Level I

 Source:  Arthur D. Little, Inc., estimates.
                                     152

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                                  TABLE 5.4.2.6

                       TREATMENT AND DISPOSAL COSTS:
          ACTIVE INGREDIENT PRODUCTION; BIOLOGICAL PRODUCTS;
                          PLASMA PROTEIN FRACTIONS
                      WASTE STREAM - AQUEOUS SOLVENT*
         Plant description:  typical size industrial plant
         Representative production schedule, days/year                  250
         Representative production capacity: 500-liter batch of
          input plasma
         Average product value per unit of production, $/kg              N.A.*
         Hazardous waste load (aqueous alcohol, liters/batch)            2,500
         Hazardous waste load per unit of production:  liters/liter
          of plasma                                                   5


                                                       Levels of Treatment

Cost-($)                                       Level I     Level II      Level III
                                                                          I
Contract disposal charges per batch                    200      as Level I     as Level
Average treatment/disposal cost                 $0.40/1 iter of
 per liter of plasma                            input plasma

Level I   — Incineration by contractor off-site
Level II  - as Level I
Level III — as Level I

*N.A. = not available

 Source: Arthur D. Little, Inc., estimates.
                                      153

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                                  TABLE 5.4.3

                       TREATMENT AND DISPOSAL COSTS:
 FORMULATION AND PACKAGING (FINISHED PHARMACEUTICAL PREPARATIONS)
          WASTE STREAM- RETURNED GOODS AND REJECT MATERIAL*

         Plant description:  plant with 200 employees
         Representative production schedule, days/year:                    250
         Representative plant capacity: $11 million value added
                                    $14 million value of shipments
         Average product value added per employee, $/year              $55,000
         Average value  of shipments per employee,  $/year               $70,000
         Hazardous waste load, returned goods and reject material,
          metric tons/year                                               18
          kg/year/employee                                             90
                                                       Levels of Treatment
Cost-(S)                                       Level I     Level II       Level
Crushing                                           100       -         as Level II
Transportation                                     200       200
Landfill Charge                                     200       -
Incineration Charge                                 —        1,000

 Total Annual Costs                                500      1,200
Average treatment/disposal cost
 per metric ton of waste                          $27.80     $66.70
 per pound of waste                              $0.013      $0.03

Level I   - crush on-site and landfill in sanitary landfill off-site by contractor
Level II  — Incineration by contractor off-site
Level III-as Level II

 Source:  Arthur D. Little, Inc., estimates.
                                     154

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                                  APPENDIX A*

                       DESCRIPTION OF HAZARD GRADES

                          HAZARD CATEGORY I - FIRE

Grade 0       Insignificant Hazard: Includes chemicals that are essentially noncombustible.

Grade 1       Slightly  Hazardous: Includes  chemicals  having  a closed-cup flash  point
              above 140ฐF (60ฐC).

Grade 2       Hazardous:  Includes combustible chemicals having a closed-cup flash point
              below 140ฐF (60ฐC) and above 100ฐF (37.8ฐC).

Grade 3       Highly Hazardous:  Includes flammable liquids having a closed-cup flash
              point below 100ฐF (37.8ฐC) and a boiling point under standard conditions
              above 100ฐF (37.8ฐC).

Grade 4       Extremely Hazardous: Includes volatile liquids or liquefied gaseous materials
              having a flash point below 100ฐF (37.8ฐC) and a boiling point below 100ฐF
              (37.8ฐC).
*National Academy of Sciences Hazard Classification Scheme.
                                        155

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        HAZARD CATEGORY II - LIQUID CONTACT WITH SKIN AND EYES

Grade 0       Insignificant Hazard: Liquids in this category are  all  those not  described
              below.

Grade 1       Slightly Hazardous:  Liquids that are corrosive to the eyes according to the
              definition  in  16 CFR  1500.3(c) (3) and the  test procedure in 16  CFR
              1500.42

Grade 2       Moderately Hazardous: Liquids in this category are:

              a. Liquids that  are corrosive according to the  test procedure  described in
              46 CFR 146.23-1.

              b. Materials that are transported as liquids at 140ฐF (60ฐ) or above.

              c. Liquefied gases that are capable of causing freeze burns.

Grade 3       Highly  Hazardous:  Liquids in this category have an LD50* of more than
              20 mg/kg of body weight when  administered by continuous contact for 24
              hours or less with the bare skin of rabbits, according to the test procedure
              described in 21 CFR Section 191.10 of the Code of Federal Regulations.

Grade 4       Extremely Hazardous: Liquids in this category have an LD50* of 20 mg/kg
              or less  or body weight when administered by continuous contact for 24
              hours or less with the bare skin of rabbits, according to the test procedure
              described in 21 CFR Section 191.10 of the Code of Federal Regulations.
*LD5o: that dose likely to kill one-half of a group of animals within 14 days.
                                       156

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Grade 0
 HAZARD CATEGORY III - INHALATION OF VAPORS
                 (Occasional Short-Term)

Insignificant  Hazard: Liquids in this category  are all those not described
below.
Grade 1       Slightly Hazardous: Liquids in this category cause dizziness and unsteadiness
              in 30 minutes or less upon exposure to an atmosphere saturated with vapor
              at 122ฐF(50ฐC).*

Grade 2       Moderately Hazardous: Liquids in this category have an LC50** in air of
              more than 200 ppm, but not more than 2000 ppm by volume of vapor; or
              more than 2 mg/1,  but not more than 20 mg/1 of mist when administered by
              continuous inhalation for one hour or less to  both male and female albino
              rats (young adults), provided the Coast Guard finds that such concentration
              is likely to be encountered by man under any reasonably foreseeable condi-
              tion of transportation.*

              Liquids in  this category may produce sufficient irritation of  the  eyes or
              respiratory tract to cause temporary incapacitation. This includes lachryma-
              tors and  those corrosive liquids as defined above in Hazard Category I that
              have a vapor pressure at 122ฐF (50ฐC) or 10 mm Hg or more.*

Grade 3       Highly Hazardous: Liquids in this category have an LC50** in  air of more
              than 50 ppm but not more than 200 ppm by volume of vapor, or more than
              0.50 mg/1, but  not more than 2  mg/1, of mist when  administered by con-
              tinuous inhalation  for one hour or less to both male and female albino rats
              (young adults), provided the Coast Guard  finds that  such  concentration is
              likely  to  be encountered by man under any reasonably foreseeable condi-
              tion of transportation.*

Grade 4       Extremely Hazardous:  Liquids in this  category  have  an LC50**  in air of
              50 ppm by volume or less of vapor, or 0.5 mg/1 or less of mist when admin-
              istered  by continuous  inhalation for  one  hour or less to both male and
              female albino rats (young adults), provided the Coast  Guard finds that such
              concentration is likely to  be encountered by man under any reasonably
              foreseeable condition of transportation.
 'During transportation emergencies involving liquids (ruptures, spills, etc.) the degree of personnel hazard
  is increased by rapid evaporation. If the ratio of the evaporation rate for the test material to that of
  n-butyl acetate at 122ฐF (50ฐC) under the same test conditions is 0.8 or less, the test material should be
  given the next higher rating with a notation to this effect. An appropriate  test procedure has been
  described.
**LC50: that concentration which, over a given period of time, is likely to kill one-half the test animal
  species.
                                         157

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                   HAZARD CATEGORY IV - GAS INHALATION

Grade 0       Grade 0 is not applicable since no gas has an insignificant hazard.

Grade 1       Slightly Hazardous: Gases in this category are all those not described below,
              since the release of a gas into  a confined  space  may  displace sufficient
              oxygen to create a significant hazard to life.

Grade 2       Moderately Hazardous: Gases in this category have an LC5 0 *  in air of more
              than 200 ppm, but not more than 2000 ppm, by volume of gas when admin-
              istered by  continuous inhalation for one hour or less to both male and fe-
              male albino rats (young  adults). Gases in this category may product suffi-
              cient irritation of the eyes or respiratory tract to cause temporary incapacita-
              tion. This includes lachrymators.

Grade 3       Highly Hazardous: Gases in this category have an LCSO*  of more than 50
              ppm,  but  not more than 200  ppm  as  described in  Grade 3 of Hazard
              Category III.

Grade 4       Extremely Hazardous: Gases in this category have  an LC5 0 *  of 50 ppm or
              less as described in Grade 4 of Hazard Category III.

          HAZARD CATEGORY V** - HAZARD RATING  FOR PREPARED
                      INHALATION OF GASES AND VAPORS

Grade 0       Insignificant Hazard: Materials in this category are all those not described
              below and having standards established by  the U.S. Department of Labor,
              Occupational  Safety and Health Administration (OSHA), as in 29 CFR Sub-
              part G, Section 1910.93, of 1000 ppm or more.

Grade  1       Slightly  Hazardous: Materials in this category have  standards established by
              OSHA of 100 ppm or more, but less than 1000 ppm.

Grade 2       Moderately Hazardous: Materials in this category have standards established
              by OSHA of 10 ppm or more, but less than 100 ppm.

Grade 3       Highly Hazardous: Materials in this category have standards established by
              OSHA of 1 ppm or more, but less than 10 ppm.

Grade 4       Extremely Hazardous:  Materials in this category have Occupational  Safety
              and Health Standards established by OSHA of less than 1 ppm.
  *LC50: that concentration which, over a given period of time, is likely to kill one-half the test animal
  species.
  *OSHA standards are applicable to a normal working situation, i.e., 8 hours per day, 5 days per week.
                                       158

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Grade

  0
   1
  2
  3
  4
            HAZARD CATEGORY VI - WATER POLLUTION RATING -
                               HUMAN TOXICITY
     Description

Insignificant Hazard
Slightly Hazardous
Moderately Hazardous
Highly Hazardous
Extremely Hazardous
       LD
          so
  Above 5000 mg/kg
  500-5000 mg/kg
  50-500 mg/kg
  5-50 mg/kg
  Below 5 mg/kg
             HAZARD CATEGORY VII - AQUATIC TOXICITY RATING
Grade
  0
  1
  2
  3
  4
     Description
 Insignificant Hazard
 Practically Nontoxic
 Slightly Toxic
 Moderately Toxic
 Highly Toxic
TLm Concentration
>1000mg/l
100-1000 mg/1
10-100mg/l
1-10 mg/1
<1 mg/1
             HAZARD CATEGORY VIM -WATER REACTION RATING

Grade 0      Insignificant Hazard: No known hazardous reaction with water.

Grade 1      Slightly Hazardous:  Chemical  or physical reaction with water may  occur.
             Unlikely  to  be hazardous under  conditions  of water transportation.
             Examples are  chlorine, bromine, ethylene oxide, propylene oxide, propionic
             anhydride, stabilized benzoyl chloride, and acetic anhydride.

Grade 2      Hazardous Reaction: Examples are anhydrous ammonia, hydrogen fluoride,
             and hydrogen chloride.

Grade 3      Highly Hazardous (Vigorous Reaction): Examples are oleum, 72%-98% sul-
             furic acid, ethyl trichlorosilane, and chloroacetyl chloride.

Grade 4      Extremely  Hazardous (Violent Reaction):  Likely if mixed with  water.
             Examples are  sulfur trioxide, chlorosulfonic acid, aluminum triethyl, unstab-
             ilized benzoyl chloride, methyl  trichlorosilane, and acetyl chloride.
                                      159

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               HAZARD CATEGORY IX - SELF-REACTION RATING

Grade 0       Insignificant Hazard: No appreciable self-reaction.

Grade 1       Slightly Hazardous: Chemicals known to undergo polymerization or other
              self-reaction under certain conditions.  Due  to  low reactivity or low heat
              evolution, they are unlikely  to lead to  a hazardous situation in bulk water
              transportation.

Grade 2       Hazardous:  Chemicals  that  may  undergo polymerization or other self-
              reaction if contaminated-by an initiator for such  process. The results may be
              hazardous. They are not considered to require  a stabilizer or inhibitor for
              safe shipment under normal conditions.

Grade 3       Highly Hazardous: Chemicals that may underto a hazardous self-reaction and
              are considered to require special handling, such as incorporation of a sta-
              bilizer or polymerization inhibitor to ensure safety in bulk water transporta-
              tion.

Grade 4       Extremely Hazardous:  Chemicals that  can undergo self-oxidation, and/or
              polymerization, possibly causing explosions or detonations.
                                        160

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                                   APPENDIX B

                  PROPERTIES OF HAZARDOUS CONSTITUENTS

                        EXPLANATION OF SPECIAL TERMS

     Several of the terms used in the following tables may not be clear to the average reader.
Therefore, we have prepared short explanations that will be useful in interpreting the data.

     •   Physical Form - The statement indicates whether the chemical is a solid,
         liquid, or gas  after  it  has  reached  equilibrium with its surroundings  at
         "ordinary" conditions of temperature and pressure (15ฐC and 1 atmo-
         sphere).

     •   Specific Gravity - The specific gravity  of  a chemical is the ratio of the
         weight of the solid or liquid to the weight of an equal volume  of water at
         4ฐC (or at some other specified temperature).

     •   Flash Point — The flash point is defined as the lowest temperature at which
         vapors above  a volatile combustible substance will ignite in air when exposed
         to a flame. Depending on the test method used, the  values given are either
         Tag  closed  cup  (C.C.)  (ASTM D56)  or  Cleveland  open  cup  (O.C.)
         (ASTM D93). The values give an indication of the relative flammability  of
         the chemical. In general, the open-cup value is  about 10ฐ to 15ฐF higher
         than the closed-cup value.

     •   Boiling Point at 1 Atmosphere —  This value is the temperature of a liquid
         when its vapor pressure is 1 atmosphere. For example, when water is heated
         to 100ฐC  (212ฐF), its  vapor pressure  rises to 1  atmosphere  and the liquid
         boils.

     •   Melting Point — The melting point is the  temperature  at  which a solid
         changes to a liquid.

     •   Chemical Composition — This has been limited to a commonly used  one-line
         formula.

     •   Molecular Weight -  The value given  is  the  weight  of a molecule of the
         chemical relative to a value of 12 for one atom of carbon.

     •   Heat  of Combustion  - The value is the amount  of heat liberated when the
         specified weight is burned in oxygen at 25ฐC. The products of combustion,
         including water, are  assumed to remain as gases; the value given is usually
                                        161

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         referred to as the  "lower heat value." The negative sign  before the value
         indicates that heat is given off when the chemical burns. Units are calories
         per gram.

    •    Solubility - The value represents the grams of a chemical  that will dissolve
         in 100 grams of pure water. Solubility usually increases when the tempera-
         ture increases. The following terms are used when numerical data are either
         unavailable or not applicable:

         "Miscible"  means  that the chemical mixes with water in all  proportions.
         "Insoluble" usually means that 1 gram of the chemical does not dissolve
         entirely in 100 grams of water.

    •    TL   (Aquatic Toxicity)  — TLm (Median Tolerance Limit) means that ap-
         proximately 50% of the  fish will die under the conditions  of concentration
         and time given.  The form of data presentation used by the Environmental
         Protection Agency's "Oil and Hazardous Material-Technical Assistance Data
         System  (OHM-TADS)" is used here. Reading from left to right and separated
         by slashes (/) are the following data:

         Concentration in parts per million  by weight (or  milligrams per liter) at
         which the chemical was tested;

         Time of exposure in hours;

         Name of the aquatic species studied (only data on fish are given here);

    •    TLV (Threshold Limit Value) — The  threshold limit  value is usually ex-
         pressed in units of parts per million (ppm) — i.e., the parts of vapor (gas) per
         million parts of contaminated air by volume at 25ฐC (77ฐF) and atmospheric
         pressure. For a chemical that forms a fine mist or dust, the concentration is
         given  in milligrams per  cubic  meter  (mg/m3). The  TLV is defined as the
         concentration of the substance in air that  can be breathed for five consecu-
         tive eight-hour workdays (40-hour  work  week) by most people without
         adverse  effect.* As some  people become ill after  exposure to concentrations
         lower than the TLV, this value cannot be used to define exactly  what is a
         "safe" or "dangerous" concentration.

    •    LDSO (Oral Toxicity) - The  term  LDSO signifies  that about  50% of the
         animals given the specified  dose by mouth will  die. All LDS 0 values listed
         are for rats.
'American Conference of Governmental Industrial Hygienists, "Threshold Limit Values for Substance in
 Workroom Air, Adopted by ACGIH for 1972."
                                        162

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                            TABLE B-1

                     PROPERTIES OF ACETONE

Physical & Chemical Properties
Physical form:  Liquid              Chemical composition: CH3COCH3
Specific gravity: 0.791             Molecular Weight: 58.08
Flash Point:  4ฐF O.C., 0ฐF C.C.     Heat of Combustion:  -6808 cal/g
Boiling point at 1 atm:  56.1ฐC       Solubility:  Complete
Melting point: -94.7ฐC             Odor:  Sweetish
Biological Properties
Toxicity:
TLm: 1 3,000 ppm/48 hr/mosquito fish
TLV: 1000ppm
LD50:  >5000 mg/kg

                            TABLE B-2

                  PROPERTIES OF ACETONITRILE

Physical & Chemical Properties
Physical form: Liquid              Chemical composition:  CH3CN
Specific gravity: 0.787             Molecular Weight:  41.05
FlashPoint:  42ฐF O.C.             Heat of Combustion: -7420 cal/g
Boiling point at 1 atm:  81.6ฐC       Solubility: Miscible
Melting point: 45.7ฐC              Odor: Sweet, ethereal
%CI:
Biological Properties
Toxicity:
TL  :  1150 ppm/24  hr/fathead minnow
TLV: 40 ppm
LD5 o :  500-5000 mg/kg
                               163

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                                  TABLE B-3

                       PROPERTIES OF AMYL ACETATE
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 0.876
Flash Point:  (n-) 91ฐF, C.C., (iso-) 69ฐF C.C.
Boiling point at 1 atm:  146ฐC
Melting point: <-100ฐC
% Cl:
Biological Properties
Toxicity:
TLm:
TLV: 100ppm
LD50:  >5000 mg/kg
Chemical composition: C
Molecular Weight:  130.19
Heat of Combustion: -7423 caI/g
Solubility: Insoluble
Odor: Banana-like
                                TABLE B-4

                           PROPERTIES OF BENZENE
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 0.879
Flash Point:  12ฐF C.C.
Boiling point at 1 atm: 80.1ฐC
Melting point:  5.5ฐC
% CL:

Biological Properties
Toxicity:
TLm: 20 ppm/24 hr/sunfish
TLV: 25 ppm
LDSO:  >5000 mg/kg
Chemical composition: C6H6
Molecular Weight:  78.11
Heat of Combustion:  -9698 cal/g
Solubility:  Insoluble
Odor: Aromatic
                                     164

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                          TABLE B-5

                PROPERTIES OF CHLOROFORM
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 1.49
Flash Point:  -
Boiling point at 1 atm: 61.2ฐC
Melting point:  -63.5ฐC
%CI:  89.09
Biological Properties
Toxicity:
TLm: -
TLV:  25 ppm
LD5 o :  >5000 mg/kg
                               Chemical composition: CHCI3
                               Molecular Weight:  119.39
                               Heat of Combustion:  —
                               Solubility:  Insoluble
                               Odor: Ethereal
                          TABLE B-6

            PROPERTIES OF CHROMIC ANHYDRIDE
Physical & Chemical Properties
Physical form:  Solid
Specific gravity: 2.70
Flash Point:  -
Boiling point at 1 atm:
Melting point:  —
                               Chemical composition: Cr03
                               Molecular Weight: 100.01
                               Heat of Combustion:  —
                               Solubility:  Very soluble
                               Odor:  -
Reactivity: Reacts with organic materials rapidly; may cause ignition

Biological Properties
Toxicity:
TLm: 52 ppm/96 hr/goldfish
TLV: -
LD5 o : 50-500 mg/kg
                              165

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                         TABLE B-7

           PROPERTIES OF COPPER SULFATE
Physical & Chemical Properties
Physical form: Solid
Specific gravity:  2.29
Flash Point: -
Boiling point at 1 atm:
Melting point: —
                            Chemical composition:  CuS04-5HaO
                            Molecular Weight: 249.7
                            Heat of Combustion: —
                            Solubility: Soluble
                            Odor:  -
Biological Properties
Toxicity:
Tl_m: 3.8 ppm/24 hr/rainbow trout
TLV: -
LDSO:  50-500 mg/kg
                         TABLE B-8

                  PROPERTIES OF  ETHANOL
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 0.790
Flash Point: 55ฐF C.C., 64ฐF O.C.
Boiling point at 1 atm: 78.3ฐC
Melting point: -114ฐC
                                      Chemical composition:  C2HSOH
                                      Molecular Weight: 46.07
                                      Heat of Combustion: -6425 cal/g
                                      Solubility: Miscible
                                      Odor:  Like whiskey
Biological Properties
Toxicity:
TLm: 250 ppm/6 hr/goldfish
TLV:  1000 ppm
LD50:  >5000 mg/kg
                            166

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                              TABLE B-9

                PROPERTIES OF ETHYLENE DICHLORIDE
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 1.253
Flash Point: 60ฐ F O.C., 55ฐ F C.C.
Boiling point at 1 atm: 83.5ฐC
Melting point: -35.7ฐC
%CI:  71.66

Biological Properties
Toxicity:
TLm: 150 ppm/*/pin perch
TLV: 50 ppm
LD50:  500-5000 mg/kg

*Time of exposure unknown.
                                 Chemical composition: CICH2CH2CI
                                 Molecular Weight: 98.96
                                 Heat of Combustion:  1900cal/g
                                 Solubility: Insoluble
                                 Odor:  Ethereal
                              TABLE B-10

       PROPERTIES OF ETHYLENE GLYCOL MONOMETHYL ETHER
Physical & Chemical Properties
Physical form: Liquid
Specific gravity:  0.966
Flash Point:  120ฐF O.C., 107ฐF C.C.
Boiling point at 1 atm:  124.5ฐC
Melting point: -85.1ฐC
                                   Chemical composition:  CH3OCH2CH2OH
                                   Molecular Weight:  76.10
                                   Heat of Combustion:  5,500 cal/g
                                   Solubility: Miscible
                                   Odor:  Mild ethereal
Biological Properties
Toxicity:
TLm: -
TLV: 25 ppm
LD50:  500-5000 mg/kg
                                167

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                           TABLE B-11

                    PROPERTIES OF HEPTANE
Physical & Chemical Properties
Physical form: Liquid
Specific gravity:  0.6838
Flash Point: 250ฐFC.C.
Boiling point at 1 atm:  98.4ฐC
Melting point: -90.6ฐ C
Chemical composition:  CH3(CH2)sCH3
Molecular Weight:  100.21
Heat of Combustion: -10,650 cal/g
Solubility: Insoluble
Odor: Gasoline
Biological Properties
Toxicity:
TLm: 4924/24 hr/mosquito fish
TLV: 500 ppm
LD50:  >15000mg/kg
                           TABLE B-12

              PROPERTIES OF ISOPROPYL ALCOHOL
Physical & Chemical Properties
Physical form:  Liquid
Specif ic:gravity: 0.785
Flash Point: 65ฐ F O.C., 54ฐ F C.C.
Boiling point at 1 atm: 82.3ฐC
Melting point: -88.5ฐC
  Chemical composition: CH3CH(OH)CH3
  Molecular Weight: 60.10
  Heat of Combustion:  -7,201 cal/g
  Solubility:  Soluble
  Odor:  Like ethyl alcohol
Biological Properties
TLm: 900-1 000 ppm/24 hr/chab
TLV: 400 ppm
LDSO: >5000 mg/kg
                              168

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                         TABLE B-13
                  PROPERTIES OF MERCURY

Physical & Chemical Properties
Physical form:  Liquid            Chemical composition:  Hg
Specific gravity: 13.55           Molecular Weight:  -
Flash Point:  -                  Heat of Combustion: -
Boiling point at 1 atm:  357ฐC     Solubility: Insoluble
Melting point: -38.9ฐC           Odor: -
Biological Properties
Toxicity:
TLm: 0.29 ppm/48 hr/marine fish
TLV: 0.05 ng/m3
LDSO: -
                         TABLE B-14
                 PROPERTIES OF METHANOL

Physical & Chemical Properties
Physical form:  Liquid              Chemical composition: CH3OH
Specific gravity: 0.792             Molecular Weight: 32.04
Flash Point:  59ฐF C.C., 61ฐF O.C.   Heat of Combustion:  -4677 caI/g
Boiling point at 1 atm:  64.5ฐC      Solubility:  Miscible
Melting point:  -97.8ฐC             Odor:  Faintly sweet
%CI: -
Biological Properties
Toxicity:
TLm: 250/4 hr/goldfish
TLV: 200 ppm
LDSo >5999mg/kg
                              169

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                                TABLE B-15

                PROPERTIES OF METHYL ISOBUTYL KETONE
Physical & Chemical Properties
Physical form: Liquid
Specific gravity:  0.802
Flash Point: 73ฐ F C.C., 75ฐ F O.C.
Boiling point at 1 atm: 116.2ฐC
Melting point: -84ฐ C
                                 Chemical composition: (CH3)2CHCH2COCH3
                                 Molecular Weight: 100.16
                                 Heat of Combustion:  -5800 caI/g
                                 Solubility: 2%
                                 Odor:  Pleasant ketonic
Biological Properties
Toxicity:
TLm: >1000ppm
TLV: 100 ppm
LD50:  500-5000 mg/kg
                                TABLE B-16

                  PROPERTIES OF METHYLENE CHLORIDE
Physical & Chemical Properties:
Physical form: Liquid
Specific gravity:  1.322
Flash Point: -
Boiling point at 1 atm: 39.8ฐC
Melting point: -96.7ฐC
%CI:  83.49

Biological Properties
Toxicity:
TLm:  -
TLV:  500 ppm
LD5 o:  500-5000 mg/kg
                                Chemical composition:  C
                                Molecular Weight:  84.93
                                Heat of Combustion: -
                                Solubility: Insoluble
                                Odor: Aromatic
                                   170

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                              TABLE B-17

            PROPERTIES OF NAPHTHA (STODDARD SOLVENT)
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 0.78
Flash Point:  110ฐFC.C.
Boiling point at 1 atm:  160-199ฐC
Melting point:  —
                                    Chemical composition:  (mixture)
                                    Molecular Weight: —
                                    Heat of Combustion: -10,100cal/g
                                    Solubility: Insoluble
                                    Odor:  Like kerosene
Biological Properties
Toxicity:
TLm: -
TLV: 200 ppm
LD50:  500-5000 mg/kg
                               TABLE B-18

                      PROPERTIES OF n-BUTANOL
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 0.810
Flash Point:  84ฐF C.C., 97ฐF C.C.
Boiling point at 1 atm:  117.7ฐC
Melting point: -89.3ฐC
                                    Chemical composition:  CH3(CH2)2CHOH
                                    Molecular Weight: 74.12
                                    Heat of Combustion: -7906cal/g
                                    Solubility: Slightly soluble
                                    Odor:  Alcohol-like
Biological Properties
Toxicity:
TLm: 1000ppm/29hr/goldfish
TLV: 100 ppm
LD50:  500-5000 mg/kg
                                  171

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                                 TABLE B-19

                     PROPERTIES OF n-BUTYL ACETATE
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 0.875
Flash Point:  99ฐ F O.C., 75ฐ F C.C.
Boiling point at 1 atm: 126ฐC
Melting point: -73.5ฐC
                                    Chemical composition:  CH3COO(CH2)3CH3
                                    Molecular Weight:  116.16
                                    Heat of Combustion:  -7294 cal/g
                                    Solubility: Insoluble
                                    Odor:  Fruity in low concentrations
Biological Properties
Toxicity:
TLm: -
TLV: 150-200 ppm
LDSO:  >5000mg/kg
                                TABLE B-20
                         PROPERTIES OF o-XYLENE
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 0.880
FlashPoint: 63ฐ F C.C., 75ฐ F O.C.
Boiling point at 1 atm: 144.4ฐC
Melting point:  -25.2ฐC
                                    Chemical composition: o-C6H4(CH3)2
                                    Molecular Weight: 106.16
                                    Heat of Combustion:  -9754.7 cal/g
                                    Solubility:  Insoluble
                                    Odor:  Benzene-like
Biological Properties
Toxicity:
TLm:  -
TLV:  100ppm
LD50:  50-500 mg/kg
                                    172

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                           TABLE B-21

                    PROPERTIES OF TOLUENE
Physical & Chemical Properties
Physical form:  Liquid
Specific gravity: 0.867
Flash Point:  40ฐF C.C., 55ฐF O.C.
Boiling point at 1 atm:  110.6ฐC
Melting point:  -95.0ฐC
                                    Chemical composition:  CgHjCHs
                                   •Molecular Weight: 92.14
                                    Heat of Combustion:  -9686 cal/g
                                    Solubility: Insoluble
                                    Odor:  Aromatic
Biological Properties
Toxicity:
TLm: 1180ppm/96hr/sunfish
TLV: 100 ppm
LD5 o :  > 5000 mg/kg
                           TABLE B-22

                  PROPERTIES OF ZINC CHLORIDE
Physical & Chemical Properties
Physical form:  Solid
Specific gravity: 2.91
Flash Point:  -
Boiling point at 1 atm: —
Melting point:  283ฐC
%CI: 52.03
Biological Properties
Toxicity:
TLm:  7.2 ppm/96 hr/bluegill
TLV:  1 mg/m3 (dust)
LD50:  50-500 mg/kg
                                    Chemical composition:  ZnC12
                                    Molecular Weight:  136.28
                                    Heat of Combustion: —
                                    Solubility: Soluble
                                    Odor: -
                                173

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                               GLOSSARY OF TERMS

Activated Sludge Treatment  - A wastewater treatment process in which  biological orga-
     nisms convert soluble and insoluble pollutants to biological mass (activated sludge)
     which is then usually removed from the treated wastewater by settling.

Active Ingredient  - The  chemical constituent in a medicinal which  is responsible for its
     activity.

Analgesics — Pain-relieving medicinals.

Ataraxics — Tranquilizers

Alkaloids - Basic (alkaline) nitrogenous botanical products which produce a marked physio-
     logical action when administered to animals (or humans).

Ampoule — A small, sealed-glass container for one dose of a sterile medicine to be injected
     hypodermically.

Antibiotic — A substance produced by a living organism which has  the power to inhibit
     multiplication of, or to destroy, other organisms, especially bacteria.

Biological  Products — In  the  pharmaceutical  industry, medicinal products derived from
     animals or humans, such as  vaccines,  toxoids,  antisera  and  human blood  frac-
     tions.

Blood Fractionation — The separation of human blood into its various protein fractions.

BOD — Biochemical Oxygen Demand —  A measure of the amount of oxygen required (and,
     therefore,  the concentration of the pollutants present) in the destruction of pollu-
     tant^) by  microorganisms (i.e., activated sludge).

Botanicals — Drugs made from a part of a plant, such as roots, bark, or leaves.

Capsules — A gelatinous shell used to contain medicinal chemicals; a dosage form for admin-
     istering medicine.

Chemical Residues - Waste materials, such as still bottoms and chemical process "muds"
     or waste slurries.

Control Technology — Method for treatment or disposal for wastes such as neutralization,
     landfill, and incineration.

Diatomaceous Earth — A fine material of uniform particle size used to aid in filtration.
                                        175

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Ethical Products - Pharmaceuticals promoted by advertising  to the medical, dental, and
     veterinary professions.

Fermentation  —  Decomposition or conversion of complex substances to other substances
     by enzymes produced by microorganisms.

Fermentor Broth - A slurry of microorganisms in water containing'nutrients (carbohydrates,
     nitrogen) necessary for the microorganism's growth.

Filter Cakes - Wet solids generated by the filtration of solids from a liquid. This filter cake
     may be a pure material (product) or a waste material containing additional fine solids
     (i.e., diatomaceous earth) that has been added to aid in the filtration.

Halogenated Solvent — An organic liquid chemical containing an attached halogen (chlorine,
     fluorine, etc.) used for dissolving other substances.

Hazardous High-Inert Content Wastes — Those  high inert content  wastes which  contain;
     corrosives, trace amounts of heavy metals, or  flammable solvents.

Hazardous Wastes  — No final judgments are intended  by such a classification. Additional
     information will be required before a definition of hazardous waste can be made.

Heavy Metals  — Originally defined as a group of metals including lead,  zinc, arsenic, mer-
     cury, selenium,  cadmium, and copper which  have an atomic weight greater than iron.
     In more  recent usage, the  toxic metals, chromium and  vanadium, are also considered
     to be "heavy (toxic) metals."

High-Inert Content Wastes —   Waste  materials  such as filter cakes which contain large
     amounts  of diatomaceous earth, filter  aid or activated  carbon used to remove color or
     trace impurities.

Hormone - Any of a number of substances formed in  the body which activate specifically
     receptive organs when transported to them by the body fluids.

IMCO System - Intergovernmental Maritime Consultative Organization hazardous material
     determination system.

Incineration — Burning under controlled combustion conditions.

Injectables - Medicinals prepared in a sterile (buffered) form suitable for administration by
     injection.

Iso-FJectric Precipitation - Adjustment of the pH (hydrogenion  concentration) of a solu-
     tion to cause precipitation of a substance from the solution.
                                         176

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Land-Destined Process Wastes — Solids, slurries and liquids currently or previously disposed
     on land. The term is used to distinguish these wastes from water or air effluents.

Land Disposal - Placing waste materials into the land in a specific manner as a method of
     treatment, storage, or disposal.

LDSO - A dosage level that is lethal to 50% of the test animals to which it is administered.

Medicinal Chemicals — Chemicals which have therapeutic value.

Mycelia —  A mass of filaments which constitutes the vegetative body of fungi. In the indus-
     try, the term is commonly used to designate the mixture of cells, filter aid, undigested
     grain solids, etc., that is filtered off and discarded from all types of fermentations.

Pharmaceutical — A medicinal chemical which has been processed into a stable useful dosage
     form.

Plasma  — The  fluid part of the lymph and of the blood, as distinguished  from the coi •
     puscles.

PMA — Pharmaceutical Manufacturers  Association, which represents  110 pharmaceutical
     manufacturing firms which,  in turn, account  for approximately 95 percent of the
     ethical Pharmaceuticals sold in the United States.

Priority I — Hazardous Waste — Includes all  "elementary" toxic materials, viz., materials
     which are potentially harmful, regardless  of their state of chemical combination. This
     also includes  materials which owe their hazardous properties  to their molecular
     arrangement — and which fall in hazard grades 3 or 4 in Table 3.1.2A.

Priority II — Hazardous Waste — These wastes owe their hazardous properties to their
     molecular arrangement and fall in hazard grades 1 or 2 in  Table 3.1.2A.

Proprietary  Products — Pharmaceuticals promoted by advertising  directly to the consumer.

Sanitary Landfill  — A sanitary landfill is  a  land  disposal site employing  an engineered
     method of disposing of solid wastes on land in a manner  that minimizes  environmental
     hazards by spreading the wastes in thin  layers, compacting the  solid  wastes to the
     smallest practical volume, and applying cover material  at the end  of each operating
     day.

Secure Chemical Landfill — A landfill that is lined and limited  to chemical wastes.

Serum — Blood serum containing agents of immunity, taken  from an animal made immune
     to a specific disease by inoculation; it is used as an antitoxin.
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SIC Codes - Standard Industrial Classification. Numbers used by the U.S. Department of
     Commerce to denote segments of industry.

Steroid —  Any  one of a large group of multicyclic ring chemical substances related to
     various alcohols occurring naturally in plants and animals.

Still Bottom - The residue remaining after distillation of a material. Varies from a watery
     slurry to a thick tar which may turn hard when cool.

Tablet — A small, disc-like mass of compressed medicinal powder used as a dosage form for
     administering medicine.

Technology Level I  - A  waste treatment or disposal method that is the broad average of
     technologies which are currently used in typical facilities.

Technology Level II - A waste treatment or disposal method  which is the best technology
     from an environmental and  health standpoint that is currently used in at least one
     pharmaceutical facility.

Technology Level III — A waste treatment or disposal method that provides adequate health
     and environmental protection.

TLm  — Median Tolerance Limit  — This measure  of aquatic toxicity means that approxi-
     mately 50 percent of the fish will die  under the conditions of concentration and time
     given.

Toxoid — Toxin treated to destroy its toxicity, but  still capable of inducing antibody forma-
     tion.

Vaccine — A preparation of dead or modified live virus or bacteria introduced into the body
     to produce immunity to a specific disease by causing the formation of antibodies.

Virus —  Any of a group of ultramicroscopic or submicroscopic infective agents that cause
     various diseases; viruses are capable of multiplying in connection with living cells.

Wastewater — Process water contaminated to such  an extent it  is not reusable in the process
     without repurification.
Also please note terms appearing in Appendix B.
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                                                    U. S. GOVERNMENT PRINTING OFFICE : 1976 623-300/498

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