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EPA310-R-97-6p5
September 1997
SECTOR
NOTEBOOKS
:EFV\ Qffice Of Compliance Sector Notebook Project
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
* WASHINGTON, D.C. 20460
NOV f 0 1997
THE ADMINISTRATOR
Message from the Administrator
Since EPA's founding over 25 years ago, our nation has made tremendous progress in protecting
public health and our environment while promoting economic prosperity. Businesses as large as
iron and steel plants and those as small as the dry cleaner on the corner have worked with EPA to
find ways to operate cleaner, cheaper and smarter. As a result, we no longer have rivers catching
fire. Our skies are clearer. American environmental technology and expertise are in demand
around the world.
The Clinton Administration recognizes that to continue this progress, we must move beyond the
pollutant-by-pollutant approaches of the past to comprehensive, facility-wide approaches for the
future. Industry by industry and community by community, we must build a new generation of
environmental protection.
The Environmental Protection Agency has undertaken its Sector Notebook Project to compile,
for major industries, information about environmental problems and solutions, case studies and
tips about complying with regulations. We called on industry leaders, state regulators, and EPA
staff with many years of experience in these industries and with their unique environmental issues.
Together with an extensive series covering other industries, the notebook you hold in your hand is
the result.
These notebooks will help business managers to understand better their regulatory requirements,
and learn more about how others in their industry have achieved regulatory compliance and the
innovative methods some have found to prevent pollution in the first instance. These notebooks
will give useful information to state regulatory agencies moving toward industry-based programs.
Across EPA we will use this manual to better integrate our programs and improve our compliance
assistance efforts.
I encourage you to use this notebook to evaluate and improve the way that we together achieve
our important environmental protection goals. I am confident that these notebooks will help us to
move forward in ensuring that — in industry after industry, community after community ~
environmental protection and economic prosperity go hap4 in hand. """"'
_
Carol M. Browner
RtcycUd/R*cycl*bl» • Printed with Vegetable OH Based Inks on 100% Recycled Paper (40% Postconsumer)
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Sector Notebook Project
Pharmaceutical Industry
EPA/310-R-97-005
EPA Office of Compliance Sector Notebook Project:
Profile of the Pharmaceutical Manufacturing Industry
September 1997
For sale by the U.S. Government Printing Office
Superintendent of Documents, Mail Stop: SSOP, Washington, DC 20402-9328
ISBN 0-16-049397-8
Office of Compliance
Office of Enforcement and Compliance Assurance
U.S. Environmental Protection Agency
401 M St., SW (MC 2221-A)
Washington, DC 20460
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Page iv intentionally left blank.
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Sector Notebook Project
Pharmaceutical Industry
Table of Contents
List of Tables vii
List of Figures viii
List of Acronyms ix
I. INTRODUCTION TO THE SECTOR NOTEBOOK PROJECT 1
A. Summary of the Sector Notebook Project 1
B. Additional Information 2
II. INTRODUCTION TO THE PHARMACEUTICAL INDUSTRY 3
A. Introduction, Background, and Scope of the Notebook 3
B. Characterization of the Pharmaceutical Industry 3
1. Product Characterization 5
2. Industry Size 6
3. Geographic Distribution 11
4. Economic Trends and International Competition 13
III. INDUSTRIAL PROCESS DESCRIPTION 17
A. Industrial Processes in the Pharmaceutical Industry 17
1. Research and Development 17
2. Production of Bulk Pharmaceutical Substances 19
3. Formulation, Mixing, and Compounding 32
B. Raw Material Inputs and Pollutant Outputs 38
1. Raw Materials 40
2. Air Emissions and Control Systems 43
3. Wastewater 46
4. Solid Wastes 50
C. Management of TRI Chemicals in the Production Process 51
IV. CHEMICAL RELEASE AND TRANSFER PROFILE 53
A. EPA Toxic Release Inventory for the Pharmaceutical Industry 57
B. Summary of Selected Chemicals Released 68
C. Other Data Sources 72
D. Comparison of Toxic Release Inventory Among Selected Industries 74
V. POLLUTION PREVENTION OPPORTUNITIES 77
A. Material Substitutions 79
B. Process Modifications 83
C. Good Operating Practices 87
D. Recycling, Recovery, and Reuse 90
E. Pollution Prevention Research 92
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Sector Notebook Project Pharmaceutical Industry
VI. SUMMARY OF APPLICABLE FEDERAL STATUTES AND REGULATIONS 93
A. General Description of Major Statutes 93
B. Industry Specific Requirements 105
C. Pending and Proposed Regulatory Requirements 110
D. Other Federal Regulations Affecting the Pharmaceutical Industry Ill
E. Other Statutes and Regulations Affecting the Pharmaceutical Industry 114
VII, COMPLIANCE AND ENFORCEMENT HISTORY 117
A. Pharmaceutical Industry Compliance History 121
B. Comparison of Enforcement Activity Between Selected Industries 123
C. Review of Major Legal Actions 128
1. Review of Major Cases 128
2. Supplementary Environmental Projects (SEPs) 129
VIII. COMPLIANCE ACTIVITIES AND INITIATIVES 131
A. Sector-related Programs and Activities 131
B. EPA Voluntary Programs 131
C. Trade Association/Industry Sponsored Activity 138
1. Environmental Programs 138
2. Summary of Trade Associations 140
IX. CONTACTS/ACKNOWLEDGMENTS/REFERENCES 143
Appendix A: Instructions for downloading this notebook A-l
Sector Notebook Project vi September 1997
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Sector Notebook Project
Pharmaceutical Industry
List of Tables
Table 1: Summary Statistics for the Pharmaceutical Industry 8
Table 2: Pharmaceutical Industry (SIC 283) Facility Size , 10
Table 3: Employment Size Distribution for Medicinals and Botanicals and Pharmaceutical
Preparations Establishments 10
Table 4: Top U.S. Pharmaceutical Companies by Sales 11
Table 5: Examples of Pharmaceutical Products by Bulk Manufacturing Process 20
Table 6: Pharmaceutical Dosage Forms 34
Table 7: Summary of Typical Material Inputs and Pollution Outputs in the Pharmaceutical
Industry 39
Table 8: Solvents Used in the Chemical Synthesis Process 41
Table 9: Solvents Used in Biological and Natural Product Extraction 42
Table 10: Solvents Used in Fermentation Processes 42
Table 11: Chemicals Discharged in Wastewater by the Pharmaceutical Manufacturing Industry 48
Table 12: Wastewater Treatment Technology Trends 49
Table 13: Source Reduction and Recycling Activity for the Pharmaceuticals Industry 52
Table 14: 1995 Releases for Pharmaceutical Facilities (SIC 2833 & 2834) in TRI 58
Table 15: 1995 Transfers for Pharmaceutical Facilities (SICs 2833 & 2834) in TRI 62
Table 16: Top 10 TRI Releasing Pharmaceutical Manufacturing Facilities 66
Table 17: Top 10 TRI Releasing Facilities Reporting Pharmaceutical
Manufacturing SIC Codes to TRI 67
Table 18: Air Pollutant Releases by Industry Sector (tons/year) 73
Table 19: Toxics Release Inventory Data for Selected Industries 76
Table 20: Five-Year Enforcement and Compliance Summary for the Pharmaceutical Industry 121
Table 21: Five-Year Enforcement and Compliance Summary for Selected Industries 124
Table 22: One-Year Enforcement and Compliance Summary for Selected Industries 125
Table 23: Five-Year Inspection and Enforcement Summary by Statute for Selected Industries 126
Table 24: One-Year Inspection and Enforcement Summary by Statute for Selected Industries 127
Table 25: Pharmaceutical Industry Participation in the 33/50 Program 133
Sector Notebook Project
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September 1997
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Sector Notebook Project Pharmaceutical Industry
List of Figures
Figure 1: Percent of Total Value of Shipments by Sector 8
Figure 2: Employment in-the Pharmaceutical Industry 9
Figure 3: Geographic Distribution of Pharmaceutical Facilities (SIC 2833 and 2834) 11
Figure 4: World Sales of Pharmaceuticals, 1995 14
Figure 5: Simplified Process Flow Diagram for Chemical Synthesis 22
Figure 6: Typical Design of a Kettle-Type Batch Reactor 23
Figure 7: Cross-Section of Typical Top-Suspended Centrifugal Filter 25
Figure 8: Cross-Section of Typical Tumble Dryer 27
Figure 9: Simplified Process Flow Diagram for Natural/Biological Extraction 29
Figure 10: Simplified Process Flow Diagram for the Fermentation Process 30
Figure 11: Simplified Process Flow Diagram for Compounding and Formulating 32
Figure 12: Summary of TRI Releases and Transfers by Industry 75
Sector Notebook Project viii September 1997
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Sector Notebook Project
Pharmaceutical Industry
List of Acronyms
AFS - AIRS Facility Subsystem (CAA database)
AIRS - Aerometric Information Retrieval System (CAA database)
BEFs - Boilers and Industrial Furnaces (RCRA)
BOD - Biochemical Oxygen Demand
CAA - Clean Air Act
CAAA - Clean Air Act Amendments of 1990
CDER - Center for Drug Evaluation and Research
CERCLA - Comprehensive Environmental Response, Compensation and Liability Act
CERCLIS - CERCLA Information System
CFCs - Chlorofluorocarbons
CO - Carbon Monoxide
COD - Chemical Oxygen Demand
CSI - Common Sense Initiative
CTM - Clinical Trial Material
CWA - Clean Water Act
D&B - Dun and Bradstreet Marketing Index
ELP - Environmental Leadership Program
EPA - United States Environmental Protection Agency
EPCRA - Emergency Planning and Community Right-to-Know Act
FDA - Food and Drug Administration
FIFRA - Federal Insecticide, Fungicide, and Rodenticide Act
FINDS - Facility Indexing System
HAPs - Hazardous Air Pollutants (CAA)
HSDB - Hazardous Substances Data Bank
IDEA - Integrated Data for Enforcement Analysis
IND - Investigational New Drug
LDR - Land Disposal Restrictions (RCRA)
LEPCs - Local Emergency Planning Committees
MACT - Maximum Achievable Control Technology (CAA)
MCLGs - Maximum Contaminant Level Goals
MCLs - Maximum Contaminant Levels
MEK - Methyl Ethyl Ketone
MSDSs - Material Safety Data Sheets
NAAQS - National Ambient Air Quality Standards (CAA)
NAFTA - North American Free Trade Agreement
NAICS - North American Industrial Classification System
NCDB - National Compliance Database (for TSCA, FIFRA, EPCRA)
NCP - National Oil and Hazardous Substances Pollution Contingency Plan
NDA - New Drug Application
NEIC - National Enforcement Investigation Center
NESHAP - National Emission Standards for Hazardous Air Pollutants
NO2 - Nitrogen Dioxide
NOV- Notice of Violation
NOX - Nitrogen Oxides
Sector Notebook Project
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September 1997
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Sector Notebook Project
Pharmaceutical Industry
NPDES - National Pollution Discharge Elimination System (CWA)
NPL - National Priorities List
NRC - National Response Center
NSPS - New Source Performance Standards (CAA)
OAR- Office of Air and Radiation
OECA - Office of Enforcement and Compliance Assurance
OPA - Oil Pollution Act
OPPTS - Office of Prevention, Pesticides, and Toxic Substances
OSHA - Occupational Safety and Health Administration
OSW - Office of Solid Waste
OSWER - Office of Solid Waste and Emergency Response
OW - Office of Water
P2 - Pollution Prevention
PCS - Permit Compliance System (CWA Database)
PhRMA - Pharmaceutical Research and Manufacturers of America
POTW - Publicly Owned Treatments Works
RCRA - Resource Conservation and Recovery Act
RCRIS - RCRA Information System
SARA - Superfund Amendments and Reauthorization Act
SDWA - Safe Drinking Water Act
SEPs - Supplementary Environmental Projects
SERCs - State Emergency Response Commissions
SIC - Standard Industrial Classification
SO2 - Sulfur Dioxide
SOX - Sulfur Oxides
TOC - Total Organic Carbon
TRI - Toxic Release Inventory
TRIS - Toxic Release Inventory System
TCRIS - Toxic Chemical Release Inventory System
TSCA - Toxic Substances Control Act
TSS - Total Suspended Solids
UIC - Underground Injection Control (SDWA)
UST - Underground Storage Tanks (RCRA)
VOCs - Volatile Organic Compounds
Sector Notebook Project
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September 1997
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Pharmaceutical Industry
Sector Notebook Project
I. INTRODUCTION TO THE SECTOR NOTEBOOK PROJECT
LA. Summary of the Sector Notebook Project
Integrated environmental policies based upon comprehensive analysis of air,
water and land pollution are a logical supplement to traditional single-media
approaches to environmental protection. Environmental regulatory agencies
are beginning to embrace comprehensive, multi-statute solutions to facility
permitting, enforcement and compliance assurance, education/ outreach,
research, and regulatory development issues. The central concepts driving the
new policy direction are that pollutant releases to each environmental medium
(air, water and land) affect each other, and that environmental strategies must
actively identify and address these inter-relationships by designing policies for
the "whole" facility. One way to achieve a whole facility focus is to design
environmental policies for similar industrial facilities. By doing so,
environmental concerns that are common to the manufacturing of similar
products can be addressed in a comprehensive manner. Recognition of the
need to develop the industrial "sector based" approach within the EPA Office
of Compliance led to the creation of this document.
The Sector Notebook Project was originally initiated by the Office of
Compliance within the Office of Enforcement and Compliance Assurance
(OECA) to provide its staff and managers with summary information for
eighteen specific industrial sectors. As other EPA offices, states, the regulated
community, environmental groups, and the public became interested in this
project, the scope of the original project was expanded to its current form.
The ability to design comprehensive, common sense environmental protection
measures for specific industries is dependent on knowledge of several inter-
related topics. For the purposes of this project, the key elements chosen for
inclusion are: general industry information (economic and geographic); a
description of industrial processes; pollution outputs; pollution prevention
opportunities; Federal statutory and regulatory framework; compliance
history; and a description of partnerships that have been formed between
regulatory agencies, the regulated community and the public.
For any given industry, each topic listed above could alone be the subject of
a lengthy volume. However, in order to produce a manageable document, this
project focuses on providing summary information for each topic. This
format provides the reader with a synopsis of each issue, and references if
more in-depth information is available. The contents of each profile were
researched from a variety of sources, and were usually condensed from more
detailed sources. This approach allowed for a wide coverage of activities that
can be further explored based upon the citations and references listed at the
end of this profile. As a check on the information included, each notebook
went through an external review process. The Office of Compliance
appreciates the efforts of all those who participated in this process who
Sector Notebook Project
September 1997
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Pharmaceutical Industry
Sector Notebook Project
enabled us to develop more complete, accurate and up-to-date summaries.
Many of those who reviewed this notebook are listed as contacts in Section
X and may be sources of additional information. The individuals and groups
on this list do not necessarily concur with all statements within this notebook.
I.B. Additional Information
Providing Comments
OECA's Office of Compliance plans to periodically review and update the
notebooks and will make these updates available both in hard copy and
electronically. If you have any comments on the existing notebook, or if you
would like to provide additional information, please send a hard copy and
computer disk to the EPA Office of Compliance, Sector Notebook Project,
401 M St., SW (2223-A), Washington, DC 20460. Comments can also be
uploaded to the Enviro$en$e World Wide Web for general access to all users
of the system. Follow instructions in Appendix A for accessing this system.
Once you have logged in, procedures for uploading text are available from the
on-line Enviro$en$e Help System.
Adapting Notebooks to Particular Needs
The scope of the industry sector described in this notebook approximates the
national occurrence of facility types within the sector. In many instances,
industries within specific geographic regions or states may have unique
characteristics that are not fully captured in these profiles. The Office of
Compliance encourages state and local environmental agencies and other
groups to supplement or re-package the information included in this notebook
to include more specific industrial and regulatory information that may be
available. Additionally, interested states may want to supplement the
"Summary of Applicable Federal Statutes and Regulations" section with state
and local requirements. Compliance or technical assistance providers may
also want to develop the "Pollution Prevention" section in more detail. Please
contact the appropriate specialist listed on the opening page of this notebook
if your office is interested in assisting us in the further development of the
information or policies addressed within this volume. If you are interested in
assisting in the development of new notebooks for sectors not already
covered, please contact the Office of Compliance at 202-564-2395.
Sector Notebook Project
September 1997
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Pharmaceutical Industry Introduction
EL INTRODUCTION TO THE PHARMACEUTICAL INDUSTRY
This section provides background information on the size, geographic
distribution, employment, production, sales, and economic condition of the
pharmaceutical industry. Facilities described within this document are
described in terms of their Standard Industrial Classification (SIC) codes.
H.A. Introduction, Background, and Scope of the Notebook
The Standard Industrial Classification (SIC) code established by the U.S.
Office of Management and Budget (OMB) to track the flow of goods and
services within the economy is 283 for the Pharmaceuticals industry. The
industry is further categorized by four 4-digit SIC codes consisting of:
Medicinals and Botanicals (SIC 2833)
Pharmaceutical Preparations (SIC 2834)
In Vivo and in Vitro Diagnostic Substances (SIC 2835)
Biological Products, except diagnostics (SIC 2836)
OMB is in the process of changing the SIC code system to a system based on
similar production processes called the North American Industrial
Classification System (NAICS). In the NAIC system, medicinals and
botanicals are classified as NAIC 325411 and pharmaceutical preparations are
classified as NAIC 325412.
According to the U.S. Census of Manufacturers, in 1992 the Medicinals and
Botanicals and Pharmaceutical Preparations categories accounted for 64
percent of establishments and 81 percent of the value of shipments in the
industry. In comparison, the In Vitro and In Vivo Diagnostic Products and
Biological Products categories are relatively small. Together they accounted
for the remaining 36 percent of establishments and 19% of the value of
shipments in the industry. In general, the industrial processes and subsequent
environmental impacts of the In Vitro and In Vivo Diagnostic Products and
Biological Products categories are different from those of the Medicinals and
Botanicals and Pharmaceutical Preparations categories. This notebook
concentrates on the two larger categories (SIC 2833 and 2834) within SIC
283.
H.B. Characterization of the Pharmaceutical Industry
As defined by its SIC Code, the pharmaceuticals industry (SIC 283) consists
of establishments that are primarily involved in fabricating or processing
medicinal chemicals and pharmaceutical products. The industry also includes
establishments that formulate pharmaceutical products and are involved in
grinding, grading, and milling of botanical products. The Census of
Manufacturers defines an establishment as a single physical location or a
Sector Notebook Project 3 September 1997
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Pharmaceutical Industry Introduction
facility where manufacturing occurs. If more than one distinct line of
manufacturing occurs at the same location, the Bureau of Census requires
separate reports for each activity.
Although the industry is part of the two-digit SIC code 28 for Chemicals and
Allied Products, it differs significantly from the rest of the chemicals industry
in its industrial processes and regulatory requirements. For example, in its
industrial processes, the pharmaceuticals industry uses more batch operations
than the chemicals industry as a whole. Since some of the bulk manufacturing
operations involve extracting relatively small, highly concentrated quantities
of active ingredients from much larger volumes of raw material, the industry's
production yield for these operations is correspondingly low.
The pharmaceuticals industry also receives extensive regulatory oversight by
the U.S. Food and Drug Administration (FDA). In 1996, the Center for Drug
Evaluation and Research, FDA approved 131 new drug applications (NDAs),
of which 53 were new molecular entities. According to the Congressional
Office of Technology Assessment (OTA) in 1993, it costs an average of $359
million to develop a new drug and complete the drug approval process. Total
drug development and agency review time averaged 15.3 years for drugs
approved from 1990 through 1995. More information on the typical industrial
processes and regulatory requirements of this industry is provided in Sections
HI and VI, respectively.
When a pharmaceutical company discovers a compound that may have
medical potential, the company usually applies for a patent. Patents are valid
for 20 years from the date of application. Any drug made from the compound
may be marketed only after approval by the federal Food and Drug
Administration (FDA). The drug development process, beginning with initial
toxicology testing, followed by clinical trials for safety and effectiveness, and
review of the application by the FDA averages fifteen years. When the
company's patent or period of exclusivity has expired, other companies may
rely on the original manufacturer's data on safety and effectiveness to obtain
approval to market a generic version of the drug. Companies wanting to
manufacture the same drug once it is off-patent are required to obtain FDA
marketing approval, based on evidence that the generic version is
"bioequivalent," i.e., differs in the rate and extent of drug absorption by no
more than 25 percent nor less than the 20 percent from the original drug
(FDA, 1996). While companies that specialize in the development and
marketing of brand-name, innovator drugs1 may have subsidiaries that
1 The term "brand name" is used interchangeably with "pioneer drug" or "innovator's drug product". The terms reflect
the fact that the drug product is the first to contain a particular active ingredient or ingredients to receive FDA approval
for a specified use. The term "generic" drug is used to describe a product that contains the same active ingredients but
not necessarily the same excipients (inactive ingredients) as a so-called "pioneer drug".
Sector Notebook Project 4 September 1997
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Pharmaceutical Industry
Introduction
manufacture generic products, most generic drug companies do not conduct
research intended to identify and develop innovator drugs (PhRMA, 1997).
Because of the high cost and time to approval, effective patent protection is
an essential component in the decision to invest in drug development and
marketing. This is especially true for international companies interested in
marketing drugs in several countries, each with its own approval procedure
and marketing requirements. While the International Conference on
Harmonization is proposing harmonized rules for drug registration and
approval for Europe, Japan and the United States, each country retains its
own approval system. In other countries, especially developing countries, the
issue of adequate patent protection is a central concern of pharmaceutical
manufacturers (PhRMA, 1997).
Discovery of new compounds followed by further research and development
(R&D) is one of the primary functions of the industry. The pharmaceutical
production process starts with an extensive research stage, which can last
several years. Following the discovery of a new drug that appears to have
efficacy in treating or preventing illness, pre-clinical tests and clinical trials are
conducted. Then a New Drug Application (NDA) is submitted to the FDA
for approval. According to a primary trade association for pharmaceutical
companies producing brand name drugs, the Pharmaceutical Research and
Manufacturers of America (PhRMA), it takes an average of 15 years to bring
a new drug to market, from time of discovery to approval (PhRMA, 1996).
It is only after FDA approval has been secured that market distribution in the
U.S. can begin.
The competition for discovering new drugs and bringing them to market is
extremely high. As a result, a significant proportion of the industry's sales are
reinvested into research and development (R&D). According to PhRMA,
total R&D expenditures, both domestically and abroad, by its members, will
be close to $19 billion dollars in 1997. PhRMA estimates that over 21% of
total sales will be reinvested into R&D by its members (PhRMA, 1997).
II.B.1. Product Characterization
The pharmaceutical industry manufactures bulk substance pharmaceutical
intermediates and active ingredients which are further processed into finished
products.
Medicinals and Botanicals (SIC 2833)
Companies in the Medicinals and Botanicals industry category are 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. The industry is made up of establishments or
Sector Notebook Project
September 1997
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Pharmaceutical Industry Introduction
facilities that manufacture products of natural origin, hormonal products, and
basic vitamins, as well as those that isolate active medicinal principals such as
alkaloids from botanical drugs and herbs (OMB, 1987). These substances are
used as active ingredients for the Pharmaceutical Preparations industry
category. Companies often produce both Medicinals and Botanicals and
Pharmaceutical Preparations at the same facility.
Pharmaceutical Preparations (SIC 2834)
The Pharmaceutical Preparations industry category is made up of companies
that manufacture, fabricate, and process raw materials into pharmaceutical
preparations for human and veterinary uses. Finished products are sold in
various dosage forms including, for example, tablets, capsules, ointments,
solutions, suspensions, and powders. These are 1) preparations aimed for use
mainly by dental, medical, or veterinary professionals, and 2) those aimed for
use by patients and the general public (OMB, 1987). A more in depth
discussion of these finished products is provided in Section III.A.3.
Pharmaceutical products also are often classified in terms of their availability
to the general public.
Both prescription and over-the-counter (OTC) drugs are available to the
public. Prescription drugs can be purchased only with a prescription from a
licensed health care professional authorized to prescribe, while OTC drugs
may be purchased without a prescription. The FDA will consider approving
the switch of a drug from prescription to OTC when the manufacturer
presents evidence that consumers can self-diagnose the condition for which
the drug is approved, i.e., cold or seasonal allergy, and directions for use can
be-written for the consumer (PhRMA, 1997).
//; Vivo and In Vitro Diagnostic Substances (SIC 2835) and Biological Products (SIC 2836)
The In Vivo and In Vitro Diagnostic Substances industry category (SIC 2835)
includes facilities that manufacture in vivo (tested inside a living organism)
and in vitro (tested outside of a living organism) diagnostic substances. They
produce chemical, biological, and radioactive substances used in diagnosing
and monitoring health. The Biological Products industry category (SIC 2836)
produces bacterial and virus vaccines, toxoids, serums, plasmas, and other
blood derivatives for human and veterinary use, other than in vitro and in vivo
diagnostic substances (OMB, 1987).
H.B.2. Industry Size
According to the U.S. Census of Manufactures for the pharmaceuticals
industry as a whole (SIC 283), in 1992 there were a total of 1,425
establishments employing 194,000 people (excluding Puerto Rico). It is
possible that some of the smaller facilities identified by the Census are actually
Sector Notebook Project 6 September 1997
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Pharmaceutical Industry
Introduction
sales, marketing or distribution centers in which no manufacturing operations
take place. Such possible misclassifications have no significant effect on the
census statistics other than on the number of companies and establishments.
(U.S. Department of Commerce, 1995) The value of total shipments was
over $67 billion (see Table 1). Pharmaceutical Preparations (SIC 2834) was
the largest sector in terms of number of facilities (48 percent), employment
(63 percent), and value of shipments (75 percent). The remaining facilities,
employment, and value of shipments were divided evenly among the
remaining sectors within the industry. One exception is the In Vivo and In
Vitro Diagnostic Products sector (SIC 2835) which claims a higher portion
of employment than SIC codes 2833 and 2836. Figure 1 displays the value
of shipments by sector, and Figure 2 displays employment by sector.
A relatively significant number of pharmaceutical establishments are located
in Puerto Rico. This is in part the result of the federal government's policy
decision to encourage job creation by offering tax incentives to manufacturers
to locate new plants in Puerto Rico. A 1996 tax law phases-out those tax
incentives over the next ten years.
The effects of the tax incentive are illustrated by the concentration of
pharmaceutical plants in Puerto Rico. According to the 1992 Economic
Census of Outlying Areas, which covers statistics for Puerto Rico, there were
a total of 88 establishments in Puerto Rico. Of these 88, 74 establishments
were in the Pharmaceutical Preparations industry, 8 were in the Medicinals
and Botanicals industry, and the remaining six establishments were in the In
Vitro and In Vivo Diagnostic Products industry, and the Biological Products,
except diagnostic substances industry. The total value of shipments of the 88
establishments located in Puerto Rico was about $12 billion. Pharmaceutical
Preparations accounted for about 92 percent of this. The pharmaceutical
industry in Puerto Rico employed about 25,000 people in the 88
establishments in 1992.
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September 1997
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Pharmaceutical Industry
Introduction
Table 1: Summary Statistics for the Pharmaceutical Industry
Industry
SIC 2833
SIC 2834
SIC 2835
SIC 2836
Total
50 STATES
Number of
Establishments
225
691
234
275
1,425
Number of
Companies1
208
585
205
193
1,191
Value of
Shipments
(millions of
dollars)2
6,438
50,418
6,838
3,974
67,668
Employment
(OOO's)
13
123
40
18
194
PUERTO RICO
Number of
Establishments
8
74
5
1
88
Value of
Shipments
(millions of
dollars)2
N/A3
11,097
477
N/A3
11,924
Employment
(OOO's)
N/A3
22
1
N/A3
25
Source: 1992 Census of Manufacturers, Industry Series: Drugs, US Department of Commerce, Bureau of the Census,
1995and1992EconomicCensus of Outlying Areas, Manufacturers: Puerto Rico, US Department of Commerce, Bureau
of the Census, 1994.
'Defined as a business organization consisting of one establishment or more under common ownership or control.
2 Value of all products and services sold by establishments in the pharmaceuticals industry.
'Certain census data are not available for Puerto Rico. Information is withheld to avoid disclosing data for individual
facilities.
Figure 1: Percent of Total Value of Shipments by Sector
75%
10%
Pharmaceutical Preparations
In Vitro and In Vivo Diagnostics
Medicinal sand Botanicals
Biological Products
Source: 1992 U.S. Census of Manufacturers.
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Pharmaceutical Industry
Introduction
Figure 2: Employment in the Pharmaceutical Industry
140
120-
100-
-s- 80 H
o
o
S. 60 -
40
20-
Pharm. Preparations
Biological Products
Medicinals and Botanicals In Vitro and In Vivo Diagnostics
Source: 1992 U.S. Census of Manufacturers.
As shown in Table 2, many facilities within the pharmaceutical industry are
small. Almost 70 percent of the facilities employ fewer than 50 people.
However, a relatively small number of large companies account for a large
portion of the total value of shipments, as well as employment. For example,
according to the 1992 U.S. Census of Manufacturers, only 36 facilities (less
than three percent) employed more than 1,000 people in the 50 states (i.e., not
including Puerto Rico). However, these 36 facilities accounted for over 38%
of the total value of shipments for the industry. In comparison, 968 facilities
(almost 70 percent) employ fewer than 50 people. However, these facilities
accounted for less than four percent of the industry's value of shipments.
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Pharmaceutical Industry
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Table 2: Pharmaceutical Industry (SIC 283) Facility Size1
Number of Employees
fewer than 10
10 to 49
50 to 249
250 to 999
1,000 or more
Total
Number of Facilities
479
489
292
129
36
1,425
Percent of Total
Facilities (%)
34
34
20
9.1
2.5
100
Percent of Total Value
of Shipments (%)
0.6
3.2
19
392
382
100
Source: 1992 Census of Manufacturers, Industry Series: Drugs, Bureau of the Census, 1995.
Does not include Puerto Rico - information withheld to avoid disclosing data for individual facilities.
2 Some information withheld to avoid disclosing individual facility data. Values may be somewhat higher.
Medicinals and Botanicals (SIC 2833) and Pharmaceutical Preparations (SIC 2834)
The establishment size distributions for Pharmaceutical Preparations and
Medicinals and Botanicals are similar (see Table 3). The Pharmaceutical
Preparations sector, however, has a somewhat higher proportion of large
facilities. As is the case with the pharmaceuticals industry as a whole, a
relatively small number of large establishments account for the majority of the
total value of shipments for the Pharmaceutical Preparations industry. Value
of shipment data is not available by establishment size for the Medicinals and
Botanicals sector.
Table 3: Employment Size Distribution for Medicinals and Botanicals and
Pharmaceutical Preparations Establishments 1
Number of
Employees
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Pharmaceutical Industry
Introduction
Table 4 lists the largest U.S. pharmaceutical companies in terms of U.S.
prescription sales.
Table 4: Top U.S. Pharmaceutical Companies by Sales
Rank
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Company
Glaxo Wellcome
Johnson & Johnson
American Home Products
Bristol-Myers Squibb
Merck & Co
Pfizer
Novartis
SmithKline Beecham
Lilly
Abbott
Schering-Plough
Hoechst Marion Roussel
Roche
Amgen
Bayer
1996 Rx Sales
(millions of dollars)
5,803
5,275
5,251
5,160
5,026
4,511
3,786
3,589
3,567
3,423
3,272
2,474
2,316
1,860
1,854
Source: IMS America,
II.B.3. Geographic Distribution
The U.S. Pharmaceuticals industry has traditionally been concentrated in New
Jersey, California, and New York (see Figure 3). These three states account
for about one third of the facilities, employees, and value of shipments.
Historically, the industry concentrated here because these were vocational
centers. Other states, such as Massachusetts, North Carolina and Maryland,
have seen recent growth in the Pharmaceuticals industry, especially in
biotechnology and research and development.
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Figure 3; Geographic Distribution of Pharmaceutical Facilities (SIC 2833 and 2834)
Source: 1992 U.S. Census of Manufacturers.
A significant number of pharmaceutical establishments are also located in
Puerto Rico. According to the 7992 Economic Census of Outlying Areas,
which covers statistics for Puerto Rico, there were a total of 88
Pharmaceuticals establishments in Puerto Rico accounting for almost $12
billion in shipments. Eighty two of these establishments were in the
Pharmaceutical Preparations and Medicinals and Botanicals sectors. These
establishments accounted for 11 percent of all employment and 15 percent of
the value of shipments for these sectors. The driving force behind the
Pharmaceuticals industry concentrating in Puerto Rico over the years are tax
incentives specifically directed at the industry.
Many U.S. firms have facilities abroad or own foreign companies in which
both R&D and production of Pharmaceuticals are conducted. According to
PhRMA, in 1996 its member firms employed close to 165,000 people
overseas in the production of prescription pharmaceuticals. Of these, about
42% were employed in Western Europe. The next largest region for overseas
employment by PhRMA member companies is Latin America and the
Caribbean, with 20 percent (PhRMA, 1996). Recently, a number of
pharmaceutical companies are moving production to Ireland. Similarly, many
foreign owned pharmaceutical firms operate pharmaceutical research and
development and production facilities in the U.S.
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II.B.4. Economic Trends and International Competition
Changes in the U.S. Health Care Industry
During the early 1990s the United States pharmaceutical industry faced major
challenges associated with the changing nature of health care delivery coupled
with intense market competition. In 1995 about 62 percent of prescriptions
were paid for by insuring third parties, up from 39 percent in 1990. Third
parties, including managed care organizations and Medicaid, consider cost in
choosing which drugs are approved for reimbursement. Techniques such as
substituting generic drugs for branded drugs are also used. Low priced
generic drugs rapidly capture a large share of prescriptions once the
originating drug's patent expires. Likewise, intense R&D rivalries between
companies now mean that new products may have major competition within
months after their FDA approval, as was the case for three competing
protease inhibitors approved between December 1995 and April 1996.
Companies have responded to shorter product life cycles and cost
containment pressures by forming an increasing number of strategic alliances
and merging. However, a steady stream of new product introductions has
contributed to steady industry growth driven by an increasing volume of
prescriptions. In 1997, research-based companies' net sales in the United
States are projected to reach $66.1 billion, a 5.5 percent increase over 1996
(PhRMA, 1997).
Consolidation of the Pharmaceuticals Industry
Competitive pressures are forcing many companies to restructure and form
mergers and strategic alliances. Increasing competition from both domestic
and foreign firms, as well as from the generic drug market, has forced mergers
between the larger pharmaceutical companies and mid-sized companies. In
1989, three major mergers occurred between large and mid-sized
pharmaceutical companies. In 1995, this number increased to seven. In 1996,
there were three mergers.
As a result of generic competition, some brand name firms are becoming
involved with companies that manufacture generic drugs by purchasing
existing companies, setting up their own generic drug ventures, or forming
partnerships (PhRMA, 1996). Also, many smaller biotech and R&D
companies are merging with large pharmaceutical companies. Strategic
alliances often involve domestic and foreign pharmaceutical companies,
biotech firms, university research centers, government agencies such as the
National Institute of Health, and contract research organizations. Such
mergers and alliances allow companies to draw upon each others' research
expertise, bring products to market more rapidly, and more effectively market
products once they are approved by FDA.
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Changes in Geographical Concentrations
An increasing number of establishments owned by U.S. companies are
locating outside the U.S. A number offerees are driving these changes,
including the growing international market for pharmaceutical products,
foreign registration requirements and patent laws, laws allowing sales only if
the products are manufactured in the country; and tax incentives.
International Trade and Competition
The U.S. pharmaceuticals industry accounts for about one-third of all
Pharmaceuticals marketed worldwide (see Figure 4). The major U.S. trading
partners are Europe, Japan, Canada, and Mexico. The largest importer of
U.S. pharmaceuticals is the European Community (EC). In 1993, the EC
alone imported nearly 50% of all U.S. exports (ITA, 1994). Canada and
Mexico combined imported 15 percent of all U.S. exports of pharmaceutical
products in 1993. The North American Free Trade Agreement (NAFTA),
however, has increased the volume of trade with Canada and Mexico in recent
years.
Although Japan still remains one of the largest importers of U.S.
pharmaceuticals, Japanese pharmaceutical companies have been investing
heavily in their own R&D, thereby reducing Japan's import share of U.S.
exports in recent years.
In 1993, European and Japanese pharmaceutical companies accounted for 27
percent and 22 percent of all pharmaceuticals marketed worldwide,
respectively (PhRMA, 1996). China and the countries of the former Soviet
Union are potentially large markets for U.S. pharmaceuticals. However,
China is also increasing its production of pharmaceuticals and the former
countries of the Soviet Union pose some major challenges for U.S. producers
in terms of testing and licensing regulations (International Trade
Administration, 1994).
Major issues affecting the international competitiveness of U.S.
pharmaceutical firms include price controls and intellectual property
protection abroad. Other trade barriers include foreign pricing systems that
favor locally produced pharmaceuticals, discriminatory registration
requirements, and requirements that foreign companies enter into joint
ventures with domestic firms.
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Figure 4: World Sales of Pharmaceuticals, 1995
Europe
27%
Australasia
1%
United States
30%
Japan
22%
Latin America
7%
Middle East
2%
Southeast
As ia& China
Canada 6%
3%
Source: Pharmaceutical Research and Manufacturers of America, 1997
based on data provided by IMS America, 1996.
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Pharmaceutical Industry
Industrial Process Description
HI. INDUSTRIAL PROCESS DESCRIPTION
This section describes the major industrial processes within the pharmaceutical
industry, including the materials and equipment used, and the processes
employed. The section is designed for those interested in gaining a general
understanding of the industry, and for those interested in the inter-relationship
between the industrial process and the topics described in subsequent sections
of this profile ~ pollutant outputs, pollution prevention opportunities, and
Federal regulations. This section does not attempt to replicate published
engineering information that is available for this industry. Refer to Section IX
for a list of reference documents that are available.
This section specifically contains a description of commonly used production
processes, associated raw materials, and the materials either recycled or
transferred off-site. This discussion, coupled with schematic drawings of the
identified processes, provides a description of where wastes may be produced
in the process. A more in-depth description of the major wastes produced by
pharmaceutical manufacturing can be found in Section III.B.
Additionally, it is important to understand the regulatory framework in which
pharmaceutical products are manufactured. To protect the public from unsafe
or ineffective pharmaceutical products, Congress established a stringent
regulatory system to control the research and development, manufacture and
marketing of pharmaceutical products. The US Food and Drug Administration
(FDA) was delegated the responsibility for: (i) evaluating the safety and
efficacy of new drugs; (ii) determining if the benefits of the drug outweigh the
risks and warrant approval for sale; and (iii) reviewing toxicological
performance of active pharmaceutical ingredients. For most new
pharmaceutical compounds, FDA oversight begins soon after the discovery
of the compound.
HLA. Industrial Processes in the Pharmaceutical Industry
The production of pharmaceutical products can be broken down into three
main stages: 1) research and development; 2) the conversion of organic and
natural substances into bulk pharmaceutical substances or ingredients through
fermentation, extraction, and/or chemical synthesis; and 3) the formulation of
the final pharmaceutical product.
HLA.1. Research and Development
New drug development involves four principal phases: Pre-Clinical Research
and Development; Clinical Research and Development; Review of New Drug
Application; and Post Marketing Surveillance. Pre-Clinical Research and
Development begins after a promising compound has been discovered and
isolated in the laboratory. In this phase, the compound is subjected to
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extensive laboratory and animal tests to determine whether the compound is
biologically active and safe. The average time to complete this phase is six
years.
After completing the Pre-Clinical Research and Development and before
testing the drug in humans, an application is filed with FDA known as an
Investigational New Drug Application (END). The application must show the
results of the pre-clinical testing and detail the plans for human clinical tests.
It must also contain information about the chemical structure of the
compound and a general description as to how the compound is
manufactured.
Clinical Research and Development is typically conducted in three phases,
with each phase involving progressively more people. The first phase, which
typically lasts about a year, is aimed at establishing the drug's safety and
involves a small number of healthy volunteers. The second phase, which lasts
about two years, helps the scientists determine the drug's effectiveness. In the
third phase, the drug is used in clinics and hospitals, and scientists must
confirm the results of earlier tests and identify any adverse reactions.
Altogether the three phases of Clinical Research and Development take about
six years.
In the first phase of Clinical Research and Development, a small amount of the
compound is manufactured in a pilot plant for use in the clinical trials. This
batch of compound is called Clinical Trial Material (CTM). At this time, the
manufacturing steps of the compound are also optimized and improved.
During this phase, attention to waste minimization considerations is most
effective.
After Clinical Research and Development is completed, the company files,
with the FDA, a New Drug Application (NDA) containing comprehensive
data about the compound. The NDA must include data to demonstrate that
the drug is safe and effective for use under the conditions described in its
labeling. FDA regulations require that the NDA contain specific and detailed
information on: the components and composition of the drug; the methods
and controls used in the manufacturing; processing and packaging of the drug;
and, data from all pre-clinical and clinical investigations. In 1993, the median
total approval time for NDAs was 21 months. This has been significantly
reduced and in 1996, the median total approval time for NDAs was 15
months.
Each step in the manufacturing process, and the identity and quality of each
ingredient used in the process, must be specified in the NDA and approved by
the FDA. Once the NDA is approved, certain changes cannot be made
without the filing and approval by the FDA of a supplemental application,
known as an SNDA. The level of reporting depends on the type of change
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and may require substantial investment of resources to implement. FDA
approval may take several years to obtain depending on the nature of the
change, and some changes even require new clinical studies.
Based on data from a 1995 study by the Center for the Study of Drug
Development at Tufts University, a pharmaceutical Research and
Development (R&D) facility discovering and developing a new medicinal
agent will evaluate approximately 5,000 to 10,000 compounds. About 250
of these substances may hold therapeutic promise and enter preclinical testing.
However, only about five will go on to limited human clinical testing.
Subsequently, only one, after 15.3 years of research and development, will be
introduced commercially as a new drug (PhRMA, 1997).
Basic research is responsible for identifying and isolating or synthesizing each
new chemical entity that will be evaluated for its potential therapeutic
effectiveness. Once a lead compound has been identified and characterized,
some 1,000 related chemical substances will be synthesized and studied by
laboratory assay systems. These assay systems are designed to identity which
compounds exhibit the most specific and potent biological effect. For each
compound tested, generally some 5-10 separate chemical reactions will be
needed to synthesize the compound. The results of biological testing will then
guide the direction of subsequent synthetic operations. If the results are
unsatisfactory, then the process starts anew.
Should a substance show promise in the laboratory assays, limited animal
studies are started. If there is no activity in the animal, other related
compounds will be evaluated or the program will be discontinued. Once
biologically active substances are identified, they will undergo further
chemical modification to refine their efficacy and safety.
Once an active candidate has been identified, it will be proposed for formal
development. Pharmaceutical development includes the evaluation of synthetic
methods on a larger scale and the assessment of various ways of formulating
the drug to provide optimum delivery. Up to this point, only small amounts
have been synthesized for evaluation. More will be needed for the extensive
animal testing required by FDA. Even larger amounts will be required for the
extensive clinical studies in humans required before federal approval.
ni.A.2. Production of Bulk Pharmaceutical Substances
Bulk pharmaceutical substances typically consist of structurally complex
organic chemical compounds which are manufactured via a series of
intermediate steps and reactions under precise conditions. These substances
are used in the manufacture of the dosage form of a formulated
pharmaceutical product and are manufactured by: (1) chemical synthesis; (2)
fermentation; (3) isolation/recovery from natural sources, or (4) a combination
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of these processes. Examples of different drugs produced by each of these
processes are presented in Table 5.
Table 5: Examples of Pharmaceutical Products by Bulk Manufacturing Process
Chemical Synthesis
Antibiotics
Antihistamines
Cardiovascular Agents
Central Nervous System (CNS)
Stimulants
CNS Depressants
Hormones
Vitamins
Natural Product Extraction
Antineoplastic Agents
Enzymes and Digestive Aids
CNS Depressants
Hematological Agents
Insulin
Vaccines
Fermentation
Antibiotics
Antineoplastic Agents
Therapeutic Nutrients
Vitamins
Steroids
Most pharmaceutical substances are manufactured utilizing "batch" processes.
In a batch process, a particular substance or "intermediate"2 is manufactured
in a "campaign" for periods ranging from a few days to several months until
sufficient material is manufactured to satisfy the projected sales demand. At
the end of the manufacturing campaign, another pharmaceutical intermediate
or substance is made. The same equipment with potentially different
configurations and the same operating personnel are often used to make a
different intermediate or substance, utilizing different raw materials, executing
different processes, and generating different waste streams.
When the same equipment is used for manufacturing different intermediates
and/or different bulk substances, the equipment is thoroughly cleaned and
validated prior to its reuse. Where cleaning of a specific type of equipment
is difficult or where a sufficient volume of a certain intermediate or bulk
substance is made every year, the equipment may be dedicated to the batch
manufacturing of a particular intermediate or bulk substance. Where the
equipment is dedicated to the production of successive batches of the same
intermediate or bulk substance, the equipment may not be washed and cleaned
between batches. Instead, the cleaning schedule will depend on whether there
is a potential for carryover of contaminants or degraded materials that could
affect the final product.
The specific methods and materials (e.g., water, steam, detergents, and/or
organic solvents) used to clean the equipment are based on the ability of the
cleaning process to remove residues of raw materials, intermediates,
precursors, degradation products, and isomers (FDA, 1996).
An intermediate is a material produced during a manufacturing process that must undergo further molecular
change or processing before it becomes a bulk pharmaceutical substance.
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Raw materials are checked for their identity and quality before use in the
manufacturing processes. Additionally, in-process testing, as well as quality
assurance/quality control (QA/QC) testing in onsite laboratories, is performed
during drug product manufacturing. In-process testing may include simple pH
measurements or checks on color, while QA/QC testing typically includes
more sophisticated analyses such as chromatography. "Upon completion of
the manufacturing operation, batch-production records are checked by
competent and responsible personnel for actual yield against theoretical yield
of a batch and to ensure that each step has been performed and signed for"
(McGraw Hill Encyclopedia of Technology).
Chemical Synthesis
Most of the compounds used today as pharmaceutical products are prepared
by chemical synthesis, generally by a batch process (Watthey, 1992).
Cardiovascular agents, central nervous system agents, vitamins, antibiotics,
and antihistamines are just a few examples of the bulk pharmaceutical
substances made by this process.
The manufacture of pharmaceutical compounds using chemical synthesis
involves a complex series of processes including many intermediate stages and
chemical reactions performed in a step-by-step fashion. Depending on the
process, the operator (or a programmed computer) adds reagents, increases
or decreases the flow rate of chilled water or steam, and starts and stops
pumps to draw the reactor contents into another vessel. At other stages in the
process, solutions may be pumped through filters or centrifuges, recycled
within the process, or pumped to recycling or disposal facilities. Co-products,
such as salts, may be sold for reuse. Spent acids, metals, and catalysts may
be recovered and reused onsite or sold for reuse.
The material from each intermediate step may be isolated and transferred to
the next step of the process for continued processing until the final compound
is derived. These steps may be all conducted at the same manufacturing site,
or if the intermediate is isolated, it may be transferred to another site for
further processing.
It is impossible to provide a single process flow diagram for this industry since
each bulk pharmaceutical substance is different in its manufacture and several
intermediates may be produced in a step-wise fashion prior to the manufacture
of the final active ingredient. However, an example chemical synthesis
process has been provided as Figure 5 to show the equipment used and where
wastes or emissions might be generated.
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Figure 5: Simplified Process Flow Diagram for Chemical Synthesis
Scaled -jacket
for cooling/heating
media
Source: Adapted from Economic Impact and Regulatory Flexibility Analysis of Proposed Effluent Guidelines for the
Pharmaceutical Manufacturing Industry, 1995.
Reactors
The most common type of reactor vessel is the kettle-type reactor. These
reactors typically range in capacity from 50 to several thousand gallons. The
vessels are made of either stainless steel or glass-lined carbon steel.
A diagram of a typical reactor vessel is shown in Figure 6. "Reactors are
equipped to provide a range of capabilities that may be required during the
batch reaction step. This equipment may include: a jacket for heating and
cooling, hookups for charging raw materials and for discharging the contents
of the reactor, an agitation and recycle line for mixing, control systems for
temperature and pressure, a condenser system for controlling vent losses, a
return line for refluxing condensables, a steam ejector for vacuum operation,
a nitrogen supply for padding and purging the reactor, and a manway for
taking samples and adding solid catalysts, reactants, and other solid materials
to the reactor" (USEPA 1993).
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Figure 6: Typical Design of a Kettle-Type Batch Reactor
Steam
Pressure
Relief Valve
Condensed ^. p-
Steam and J^
Organics
Solvent,
Raw Material,
and Reactant
Addition
Steam
Cooling Water
or Coolant
Cooling Water
or Coolant
!>
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Pharmaceutical Industry
Industrial Process Description
Reactors are often attached to process condensers to recover solvents from
process operations. They are also often attached to other air pollution control
devices to remove volatile organics or other compounds from vented gases.
Depending on the reaction being carried out, a reactor may also be attached
to a distillation column for solvent separation and recovery.
Separation
Several separation mechanisms are employed by the pharmaceutical industry
including extraction, decanting, centrifugation, and filtration. These
mechanisms may be employed jointly or individually, in multiple stages, to
separate the intermediate or bulk substance from the reaction solution and to
remove impurities. Crystallization is another common technique used to
separate the desired active ingredient or intermediate from the reaction
mixture. Because crystallization is widely used in conjunction with other
separation techniques, it is presented separately from the other separation
techniques shown in Figure 5 and discussed below.
Extraction. Extraction is used to separate liquid mixtures by taking advantage
of differences in the solubility of the mixture components. A solvent that
preferentially combines with only one of the components is added to the
mixture. "The resulting mixture consists of an extract (containing the
preferentially combined material) and a raffinate (containing the residual
phase). Extraction may take place in an agitated reaction vessel (mixer-
settler), in a vertical cylinder (where the solvent flows upward or downward
through the liquid mixture), or in a column with internals to mechanically
enhance the contact between the two liquid phases" (Crume et al., 1992).
Decanting. Decanting is a simple process used to separate mixtures of a liquid
and insoluble solid that has settled to the bottom of a reactor or settling
vessel. The liquid over the solid is either pumped out of the vessel or poured
from the vessel leaving behind the insoluble solid and a certain amount of
liquid.
Centrifugation. "Centrifuges are used to remove the intermediate or product
solids from a liquid stream" (USEPA 1979). Centrifuges work on the principle
of centrifugal force, in which an outward force is exerted on a rotating object.
Centrifuges are cylinders with rotating baskets within them. The sides of the
basket are perforated and covered with filter medium such as woven fabric or
metal. As the basket rotates, a slurry solution is fed into the centrifuge via an
inlet pipe. The centrifugal force pushes the slurry against the rotating basket,
forcing the liquid to pass through the perforations, and the solids or filter cake
to remain behind, accumulating on the sides of the basket. "After all of the
slurry has been fed to the chamber, a wash liquid may be introduced to force
the remaining slurry liquid through the cake and filter medium" (USEPA
1993). Once the centrifuge is turned off, the solids (i.e., the intermediates or
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Industrial Process Description
the final bulk substance) are scraped off the sides with an internal scraper or
manually scooped out. A diagram of a typical basket centrifuge is shown in
Figure 7.
Figure 7: Cross-Section of Typical Top-Suspended Centrifugal Filter
Motor
Slurry Inlet
Casing
Filtrate , ,
Discharge T Adjuslable Unloader
Knife
Wash Inlet
Solids Cake
Perforated Basket
Removable Valve Plate
Solids Discharge
Source: Adapted from Control of Volatile Organic Compound Emissions from Batch Processes, EPA Guideline Series, 1993.
The extremely high speeds and frictional forces involved in centrifuging,
combined with the potential build-up of combustible solvent vapors, create a
potential for an explosive environment to develop within the centrifuge. To
control this, an inert gas, usually nitrogen, may be introduced into the unit
before the slurry is fed in. "Centrifuges must be carefully operated to avoid
air infiltration by vortex entrainment. Therefore, they usually are operated
under nitrogen blanket and kept sealed under operation" (USEPA 1993).
VOC emissions may occur when purging the vessel before loading and
unloading (USEPA, 1993).
Filtration. Filtration is the separation of a fluid-solids mixture involving
passage of most of the fluid through a porous barrier (the filter medium)
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Pharmaceutical Industry Industrial Process Description
which retains most of the solid particulates contained in the mixture ((Perry's
1984). In the pharmaceutical industry, "filtration is used to remove solids
from a liquid, whether these solids be product, process intermediates, catalysts
or carbon particulates (e.g., from a decoloring step)" (USEPA 1979). Batch
filtration systems widely used by the pharmaceutical industry are the plate-
and-frame filter, cartridge filters, the nutsche filter, and combination
filter/dryers.
"The normal filtration procedure is simply to force or draw the mother liquor
through a filtering medium. Following filtration, the retained solids are
removed" (USEPA, 1979). The wet cake may then go through a reslurry
process where it is washed and filtered again. "This option is usually carried
out when a highly specialized product requiring high purity is desired or when
solvents were not removed as part of the original slurry filtration (USEP A,
1993).
Crystallization
After the reaction takes place, the intermediate or final bulk substance (which
is usually in solid form) can be separated from the reaction solution by
crystallization. Crystallization is one of the most common separation
techniques and is often used alone or in combination with one or more of the
separation techniques described above. In crystallization, a supersaturated
solution is created in which crystals of the desired compound are formed.
Supersaturation depends on the solubility of the desired compound. If the
compound's solubility increases with temperature, supersaturatiori can be
achieved by cooling the solution. If the solubility is independent of or
decreases with temperature, then evaporating a portion of the solvent will
create supersaturation. "If neither cooling nor evaporation is desirable,
supersaturation may be induced by adding a third component. The third
component forms a mix with the original solvent in which the solute is
considerably less soluble" (USEPA 1979). If crystallization is done through
cooling of a solution there will be relatively little VOC emissions, especially
if the equipment is fully enclosed. "However, when crystallization is done by
solvent evaporation in a vacuum environment, there is a greater potential for
emissions" (USEPA 1993). Further separation of the crystals from the
supersaturated solution can be done by centrifuging or filtration.
Purification
Once the intermediate or the bulk substance has been separated, it may need
to be purified. Depending on the intermediate or the bulk substance produced,
there may be several purification steps involved to produce the desired active
ingredient. In vitamin production, for example, there are at least three to four
purification steps. Purification typically is achieved through additional
separation steps such as those described above. Purification is often achieved
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through recrystallization. Washing with additional solvents and filtration may
also be used.
Drying
The final step in the chemical synthesis process is drying of the intermediate
or final bulk substance. Drying is done by evaporating the solvents from the
solids. Solvents released from drying operations may be condensed for reuse
or disposal (USEPA 1993).
There are several different types of dryers used by the pharmaceutical industry
including tray dryers, rotary dryers, drum or tumble dryers, or pressure filter
dryers. "The selection of the dryer type depends primarily on the
characteristics of the solid" (USEPA 1993).
Prior to 1980, probably the most common type of dryer used by the industry
was the vacuum tray dryer. In a vacuum tray dryer, "the filtered solid is
placed on trays which are then manually stacked on shelves in the dryer.
When the dryer is closed, the trays are heated to remove any liquids. A
vacuum is applied within the dryer so that drying can take place at lower
temperatures when needed" (USEPA, 1993).
More often today, tumble dryers or combination filter/dryers are used. In a
combination filter/dryer "the equipment not only acts as a filter, but can also
function as a product dryer after the slurry has been compressed and filtered
into cake form. Heat is introduced to the filter/dryer through a hot gaseous
medium which is blown up through the cake until the desired level of dryness
is achieved" (USEPA 1993). VOC emissions may occur since the gas will
entrain evaporated solvent which must be vented from the drying filter/dryer.
Tumble dryers consist of revolving conical shells ranging in capacity from 20
to 100 gallons. "The rotation of the dryer tumbles the product to enhance
solvent evaporation and may also perform a blending function" (USEPA
1979). These dryers may be operated under a vacuum or using hot air
circulation. When operated under a vacuum, heat is supplied through
conduction from heated surfaces. Some air will pass through the equipment
due to inward leakage. Thus, the vacuum exhaust will contain VOCs
(USEPA, 1993). A diagram of a simple tumble dryer is shown in Figure 8.
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Figure 8: Cross-Section of Typical Tumble Dryer
Cover
Chain Casing
Vacuum
Connection
Steam or
Hot Water
Inlet
Concrete
or Structural
Foundation
Source: Adapted from Control of Volatile Organic Compound Emissions from Batch Processes, EPA Guideline Series, 1993.
Natural and Biological Product Extraction
Natural product extraction, as the name suggests, involves isolating an active
ingredient from natural sources, such as plants, roots, parasitic fungi or animal
glands. This process is often used to produce allergy relief medicines, insulin,
morphine, anti-cancer drugs, or other pharmaceuticals with unique properties.
Blood fractionation, used to produce plasma, is also part of the natural
product extraction process (USEPA 1995). A simplified diagram of natural
product extraction processes and its associated wastes, is shown in Figure 9.
The desired active ingredient, usually present in raw materials at very low
concentrations, must be extracted for the final product. Therefore, a defining
characteristic of this process is that the volume of finished product is often an
order of magnitude smaller than that of the raw materials used. At each step
in the extraction process, the volume of material being processed is reduced
significantly. This inherent nature of the process makes it an expensive one
to utilize (USEPA 1995).
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Figure 9: Simplified Process Flow Diagram for Natural/Biological Extraction
Organic Solvents
(mcthelyne chloride,
chloroform, alcohol,
toluene)
Solvent vapors \
(phenol, chloroform, ';—
methelyne chlor.)
To Compounding
& Formulation
Source: Adapted from Economic Impact and Regulatory Flexibility Analysis of Proposed Effluent Guidelines for the
Pharmaceutical Manufacturing Industry, 1995.
Because of the large volume reductions involved, an assembly-line processing
method, consisting of several operation stations is used. At each subsequent
operation station, a little more of the inert material is removed and the active
ingredient is extracted. As the volume of material being processed decreases,
the size of the containers carrying the material also decreases, from containers
capable of carrying 75-100 gallons to, in some cases, laboratory size
equipment (USEPA 1995).
Active ingredients are recovered by precipitation, purification and solvent
extraction methods. In precipitation, solubility is changed by pH adjustment,
salt formation, or addition of an anti-solvent. Solvents are used as extractive
agents to remove the active ingredient from the raw materials, such as plant
and animal tissues. Solvents are also used to remove fats and oils, which may
contaminate the product (USEPA 1995). Such solvents remove the fats and
oils, without damaging the essential active ingredient(s) found in the raw
materials. Ammonia is also used in the extraction stages as a method of
controlling the pH when extracting from animal and plant sources.
Ammonium salts are used as buffering chemicals, and aqueous or anhydrous
ammonia is used as an alkalizing agent. The high degree of solubility of
ammonium salts prevents unwanted precipitation. Also, ammonium salts have
the advantage of not reacting with animal and/or plant tissues (USEPA 1995).
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Fermentation
Most steroids, antibiotics, and certain food additives (such as vitamins) are
commonly known Pharmaceuticals which are produced by fermentation. In
fermentation, microorganisms (e.g., bacteria, yeast or fungi) are typically
inoculated in a liquid broth supplemented with nutrients that are acclimated
to an environment (e.g., temperature, pH, oxygen), conducive to rapid
growth). These microorganisms produce the desired product (e.g., antibiotic,
steroid, vitamin, etc.) as a by-product of normal metabolism. Fermentation
involves three main steps: 1) inoculum and seed preparation, 2) fermentation,
and 3) product recovery. A diagram of a fermentation process and the wastes
produced in this process is shown in Figure 10.
Figure 10: Simplified Process Flow Diagram for the Fermentation Process
Gas
Nutrients
(sugars, starches) H20
Solvents or
Metal Salts
(MiBK, Cu, Zn)~
Organic Solvents
(acetone, MiBK, _
1,2-dichloroethane)
Sludge
(sugars,
starches, fermentation
broths, com steep
liquor)
. Active
Ingredient
To Compounding &
Formulation
Source: Adapted from Economic Impact and Regulatory Flexibility Analysis of Proposed Effluent Guidelines for the
Pharmaceutical Manufacturing Industry, 1995.
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Seed Preparation
The fermentation process begins with the introduction of the microbial strain
to a primary seed fermentation, which is commonly performed using shaking-
flask culture techniques at the laboratory scale. Once grown, the suspension
is then transferred to further seed stages, which may be additional flask
fermentations, stirred tanks or both. The purpose of this "seed-train" is to
generate enough inoculum for the production fermentor (typically 1-10% of
the production tank volume). Generally, special seed tanks are used for the
fermentor inoculum which are miniature versions (1-10% of size) of the
production fermentor. If a seed tank becomes contaminated, it is emptied,
sterilized, and reinoculated.
Fermentation
Once the fermentor inoculum is ready, it is charged into a sterilized fermentor.
During fermentation, the fermentor is usually agitated and aerated. The pH,
temperature, and dissolved oxygen content of the fermentation broth may be
monitored during fermentation. Fermentation may last from hours to weeks,
depending on the process. A fermentor "broth" is produced, which is then
filtered or centrifuged to separate out the solids (USEPA 1991).
Product Recovery
Filtration removes any larger residues from the broth, but it does not isolate
the active ingredient from the residues. This must be done by product
recovery processes. Product recovery is achievable through three different
methods: solvent extraction, direct precipitation and ion exchange, or
adsorption (USEPA 1995). Sometimes, the active material is contained
within the cells of the microorganism. Cell wall breakage by heat or
ultrasound, for example, may be required to recover the material.
In solvent extraction the active ingredient is removed from the aqueous broth
by contacting it with an organic solvent, in which the product is more soluble
than it is in water. Removal of the active agent from the solvent can be
achieved by crystallization (USEPA 1995).
The direct precipitation method of product recovery involves precipitation of
the active ingredient, as a metal salt from the broth using, for example, copper
(Cu) and/or zinc (Zn) as precipitating agents. The actual choice of the
precipitating agent depends on the properties of the desired active ingredient.
The broth is then filtered and the product is recovered from the solid residues
(USEPA 1991).
Additionally, ion exchange or adsorption may be used for product recovery.
Ion exchange resin (or alternatively, activated carbon) is contacted with the
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broth and the product adsorbs onto the resin. The product is recovered from
the resin by using a solvent or by washing the resin with an acidic or basic
solution. It is then crystallized.
III.A.3. Formulation, Mixing, and Compounding
"The primary objective of mixing, compounding, or formulating operations
are to convert the manufactured bulk substances into a final, usable form."
(USEPA 1995) Figure 11 shows a simplified process flow diagram for
compounding, formulation and packaging. Common dosage forms of
pharmaceutical products include tablets, capsules, liquids, creams and
ointments, as well as aerosols, patches and injectable dosages. Table 6 lists
common pharmaceutical dosage forms and their uses.
Figure 11: Simplified Process Flow Diagram for Compounding and Formulating
.-' Tablet
• Dust
Fugitive emissions,
vent emissions
Non-Contact
Cooling Water
Solvent
Emission - VOCs
Wastewater
(waste starches,
sugars
BOD.COD.TSS)
Exeipients &
Binders
(sugars, starches)
I Aqueous-based Solvents
Tableting &
Encapsulation
Active Ingredient
(Drug)
Tablets and
Capsules
Source: Adapted from Economic Impact and Regulatory Flexibility Analysis of Proposed Effluent Guidelines for the
Pharmaceutical Manufacturing Industry, 1995.
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As with the bulk manufacturing operations, many final products are produced
in batch utilizing a campaign regimen. At the end of the production campaign,
another product may be formulated and packaged using the same equipment
and the same personnel. Additionally, formulation and packaging is
performed in accordance with "good manufacturing practices" (GMP). GMP
is regulated by the FDA and sets forth the minimum methods to be used in,
and the facilities and controls to be used for the manufacture, processing,
packing, or holding of a drug to assure that such drug meets the safety
requirements and the quality and purity characteristics that it purports or is
represented to possess.
Following formulation, the finished product may be packaged at the same site
or it may be transferred to another site. Packaging includes placing the final
formulated products into containers, labeling, and preparing for shipping.
"The packaging components of a pharmaceutical product are vital to its safe
and effective use. Besides serving the patient as a convenient unit of use, the
composite package (unit container, labeling, and shipping components) must
provide appropriate identification and necessary information for proper use
including warnings and (pre)cautions and preservation of the product's
chemical and physical integrity" (Kirk-Othmer, 1994).
Batch production records are used and describe each manufacturing step in
detail. At various stages in the formulation and packaging process, quality
control checks are utilized. All raw materials are checked prior to use in a
process and the final dosage forms require a myriad of tests to assure
therapeutic benefit. For example, the content uniformity, color, homogeneity,
dissolution, stability, identity, and potency of the product must be determined
and meet stated ranges. Representative samples are collected at the end of the
formulation stage and submitted to the chemical and/or microbiological
laboratories for final assaying. Representative samples are also collected
during packaging operations. The quality control unit of the pharmaceutical
manufacturing company has the responsibility and authority to approve or
reject all raw materials, in-process materials, packaging materials including
containers, closures, and labeling materials, as well as the final product.
The equipment used to formulate and package the final product is cleaned,
maintained, and sanitized at appropriate intervals. Actual maintenance and
cleaning schedules and results are documented. As described under bulk
manufacturing, the methods, equipment, and materials used (e.g., water
wash, steam, detergents, organic solvents) to clean the equipment are
specified on a per product basis.
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Dosage
Form
powders, bulk
effervescent
insufflation
lyophilizcd
capsules
troches,
lozenges
compressed
tablets
pellets
coated tablets
syrups
spirits
collodions
parcnteral
solutions
ophthalmic
nasal
mouthwash,
gargles
inhalations
suspensions
emulsions,
lotions
ointments
pastes and
cerates
suppositories
Table 6: Pharmaceutical Dosage Forms
Constituents, properties
Solids
comminuted or blended, dissolved or mixed with water
CO2-releasing base ingredients
insufflator propels medicated powder into body cavity
rcconstitution by pharmacist of unstable products
small-dose bulk powder enclosed in gelatin shell, active ingredient plus diluent
prepared by piping and cutting or disk candy technology; compounded with
glycerogelatin
dissolved or mixed with water, great variety of shapes and formulations
for prolonged action
coating protective, slow release
Liquid Solutions
sweetener, solvent, medicinal agent
alcohol, water, volatile substances
pyroxylin in ether, medicinal agent (castor oil, camphor)
sterile, pyrogen-free, isotonic, pH close to that of blood; oily or aqueous
solution
sterile, isotonic, pH close to that of tears; viscosity builder
aqueous, isotonic, pH close to that of nasal fluids; sprays or drops
aqueous, antiseptic
administered with mechanical devices
Liquid Dispersions
powder suspended in water, alcohol, glycol, or an oil
oil-in-water or water-in-oil
Semisotid and plastic dispersions
hydrocarbon (oily), adsorptive water-washable, or water-soluble bases;
emulsifying agents, glycols, medicating agent
ointments with high dispersed solids and waxes, respectively
thcobroina oil, glyeinerated gelatin, or polyethylene glycol base plus medicinal
agent
Uses
external, internal
oral
body cavities
various uses including
parenteral and oral
internal
slow dissolution in mouth
oral and external
implantation
oral
flavoring agent, medicinal
flavor or medicinal
external for corns and
bunions
intravenous, intramuscular,
subcutaneous injection
eye treatment
nose treatment
refreshment, short term
bacterial control
medication of trachea or
bronchioles
oral dosing, skin application
oral, external or injection
external
external
insertion into body cavity
Source: Adapted from Zanowaik, P., 1995, "Pharmaceuticals " in Kirk-Othmer, Encyclopedia of Chemical Technology,
vol. 18, 4th edition.
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Tablets
Tablets account for the majority of solid medications taken orally in the
United States. "Tablets can be made to achieve rapid drug release or to
produce delayed, repeated or prolonged therapeutic action" (Kirk-Othmer,
1994). Tablets can be compressed or molded, and may be coated.
To prepare a tablet, the active pharmaceutical ingredient is combined with a
filler, such as sugar or starch, and a binder, such as corn syrup or starch. The
filler is added to ensure that the active ingredient is diluted to the proper
concentration. A binder is needed to bind tablet particles together. A
lubricant, such as magnesium sterate or polyethylene glycol, may be added to
facilitate equipment operation, or to slow disintegration or dissolution of the
active ingredient.
Tablets are produced by compression of powder blends or granulations. In
direct compression, the ingredients are blended and then compressed into the
final tablet without modifying the physical nature of the material itself. "The
most widely used and most general method of tablet preparation is the wet-
granulation method" (Remington, 1995). In wet granulation, the active
ingredient is powdered and mixed with the filler. This mixture is then wetted
and blended with the binder, forming a solution. Coarse granules form which
are mixed with lubricants such as magnesium stearate and then compressed
into tablets. Slugging or dry granulation is used when tablet ingredients are
sensitive to moisture or temperatures associated with drying or when the
tablet ingredients have sufficient inherent binding or cohesive properties. Dry
granulation includes weighing, mixing, slugging, dry screening, lubrication,
and compression. Slugging requires large heavy presses to compress larger
tablets, between 20-30 grams in weight. These large tablets are then ground
and screened to a desired mesh size then recompressed into final tablets
(USEPA, 1991).
Coating may be used to offer protection from moisture, oxygen, or light, to
mask unpleasant taste or appearance, and to impart distinctive colors to
facilitate patient recognition. "Enteric coatings are used to delay the release
of the active ingredient in the stomach and prolong therapeutic activity. The
latter are used for drugs that are unstable to gastric pH or enzymes, cause
nausea and vomiting, or irritation to the stomach, or should be present in high
concentrations in the intestines" (Kirk-Othmer, 1994). Coating is done in a
rotary drum. The coating solution is poured onto the tablets. In many
operations, aqueous coating solutions are now used instead of solvent based
(usually methylene chloride) solutions. As the drum rotates, the tablets
become coated. Once coated, they are dried in the drum and may be sent to
another rotary drum for polishing. Polishing works by the friction created
when the tablets rotate and rub against each other. Un-coated tablets may
also be polished.
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Capsules
Once the tablets pass quality control requirements, they may be held or sent
directly to packaging. Coated tablets are stamped with identifying information
(e.g., brand name, code number) in a rotary ink press.
After tablets, the most common solid oral dosage form is the capsule.
Capsules come in soft and hard shelled varieties. Hard capsules or "dry-filled"
capsules are formed by dipping metal pins into a solution of gelatin of a
specific temperature. The temperature controls the viscosity of the gelatin
and hence the thickness of the capsule walls. When the pins are removed
from the solution, a hard coating of gelatin forms on the pins. The coating is
dried and trimmed. "These capsules are filled by introducing the powdered
material into the longer end or body and the capsule and then slipping on the
cap." (Remington, 1995)
Soft shelled capsules are formed by placing two continuous gelatin films
between rotary die plates. As the plates are brought together, the two gelatin
films join and seal, forming the two halves of the capsule. As the two halves
join, the ingredients, which can be a liquid, paste or powder, are injected into
the capsules. "Commercially filled soft gelatin capsules come in a wide choice
of sizes and shapes: they may be round, oval, oblong, tube or suppository-
shaped" (Remington).
Liquid Dosage
In formulating a liquid product, the ingredients are first weighed and then
dissolved in an appropriate liquid. The solutions are mixed in glass-lined or
stainless steel vessels, after which they are stored in tanks before final
packaging. Preservatives may be added to prevent mold and bacterial growth.
If the liquid will be used for injection or ophthalmic use, sterilization is
required. In this case, the container, which has also been previously
sterilized/depyrogenated, is filled with liquid which has either been rendered
sterile by aseptic filtration in a sterile environment and/or the entire container
and its contents are terminally heat sterilized in an autoclave.
Ointments and Creams
Ointments are usually made by blending the bulk active ingredient with a base,
such as a petroleum derivative or wax. The mixture is cooled, rolled out, and
poured into tubes by machines and packaged (USEPA, 1991).
Creams are semisolid emulsions and are either oil-in-water or water-in-oil,
rather than being petroleum based. "Generally, the ingredients of the two
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phases are heated separately, then are mixed and stirred vigorously to achieve
emulsification" (Kirk-Othmer, 1994).
As with all other dosage forms, equipment is washed and cleaned based on
batch record requirements. However, because of the greasy nature of
ointment and cream production, cleaning often is done with detergents.
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Ifl.B. Raw Material Inputs and Pollutant Outputs
Pharmaceutical batch processes use numerous raw materials and generate
wastes and emissions. In general, the waste and emissions generated depend
on the raw materials and equipment used, as well as the manufacturing
process employed. In designing bulk manufacturing processes, consideration
is given to the availability of the starting materials and their toxicity, as well
as the wastes (e.g., mother liquors, filter residues, and other by-products) and
the emissions generated. A description of some of the considerations given
is provided in Section V, Pollution Prevention Opportunities.
When bulk manufacturing reactions are complete, the solvents are physically
separated from the resulting product. Due to purity concerns, solvents often
are not reused in a pharmaceutical process. They may be sold for non-
pharmaceutical uses, used for fuel blending operations, recycled, or destroyed
through incineration.
This section describes the raw materials and associated waste streams and
some of the more common technologies used to control these wastes. Much
of this information is summarized in Table 7.
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Table 7: Summary of Typical Material Inputs and Pollution Outputs in the Pharmaceutical Industry
Process
Chemical
Synthesis
- Reaction
- Separation
- Purification
- Drying
Natural Product
Extraction
Fermentation
Formulation
Inputs (examples of
some commonly used
chemicals provided)
Solvents, catalysts,
reactants, e.g. benzene,
chloroform, methylene
chloride, toluene,
methanol, ethylene glycol,
methyl isobutyl ketone
(MiBK), xylenes,
hydrochloric acid, etc.
Separation and extraction
solvents, e.g.. methanol,
toluene, hexanes, etc.
Purification solvents e.g..
methanol, toluene,
acetone, hexanes, etc.
Finished active drug(s) or
intermediates
Plants, roots, animal
tissues, extraction
solvents, e.g.. ammonia,
chloroform, phenol,
toluene, etc.
Inoculum, sugars,
starches, nutrients,
phosphates, fermentation
solvents, e.g.. ethanol,
amyl alcohol, methanol,
MiBK, acetone, etc.
Active drug, binders
(starches), sugar, syrups,
etc.
Air Emissions
VOC emissions from
reactor vents, manways,
material loading and
unloading, acid gases
(halogen acids, sulfur
dioxide, nitrous oxides);
fugitive emissions, from
pumps, sample
collections, valves, tanks
VOC emissions from
filtering systems which
aren't contained; and
fugitive emissions from
valves, tanks and
centrifuges
Solvent vapors from
purification tanks; fugitive
emissions
VOC emissions from
manual loading and
unloading of dryers
Solvent vapors & VOC's
from extraction chemicals
Odoriferous gases,
extraction solvent vapors,
particulates
Tablet dusts, other
particulates
Wastewater
Process waste waters with
spent solvents, catalysts,
reactants; pump seal waters,
wet scrubber wastewater;
equipment cleaning
wastewater; wastewater maybe
high in BOD, COD, TSS with
pH of 1-11.
Equipment cleaning wash
waters, spills, leaks, spent
separation solvents
Equipment cleaning wash
waters, spills, leaks, spent
purification solvents
Equipment cleaning wash ,
waters, spills, leaks
Equipment cleaning wash
waters, spent solvents
(ammonia); natural product
extraction wastewater have low
BOD, COD, TSS and pH of 6-
8.
Spent fermentor broth,
fermentation wastewater
containing sugars, starches,
nutrients, etc.; wastewater
tends to have high BOD, COD,
TSS and have pH of 4-8.
Equipment cleaning wash
waters (spent solvents), spills,
leaks; wash waters typically
contain low levels of BOD,
COD, TSS and have pH of 6-8.
Residual
Wastes
Reaction residues
and reactor bottom
wastes
Spent raw
materials (plants,
roots etc.)
Waste filter cake,
fermentation
residues
Particulates, waste
packaging,
rejected tablets,
capsules etc.
Source: Development Document for Proposed Effluent Limitations Guidelines and Standards for the Pharmaceutical
Manufacturing Point Source Category, US EPA, Washington, DC., February 1995.
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IH.B.l. Raw Materials
"The pharmaceutical manufacturing industry draws upon worldwide sources
for the myriad of raw materials it needs to produce medicinal chemicals.
Fermentation operations require many new raw materials falling into general
chemical classifications such as carbohydrates, carbonates, steep liquors,
nitrogen, and phosphorus compounds, anti-foam agents, and various acids and
bases. These chemicals are used as carbon and nutrient sources, as foam
control additives, and for pH adjustment in fermentation processes. Various
solvents, acids, and bases are also required for extraction and purification
processes.
Hundreds of raw materials are required for the chemical synthesis processes
used by the industry. These include organic and inorganic compounds and are
used in gas, liquid, and solid forms. Plant and animal tissues are also used by
the pharmaceutical manufacturing industry to produce various biological and
natural extraction products" (EPA, 1995).
Each manufacturing or formulation plant is special, differing from other
similar pharmaceutical plants in size, types of intermediates, bulk substances,
or products produced, amounts and types of solvents used, and thus, in the
raw materials used and wastes/emissions generated. Most bulk
pharmaceutical reactions require organic solvents to dissolve chemical
intermediates and reagents. Because of the high reactivity of many
pharmaceutical reagents and intermediates, pharmaceutical solvents must be
non-reactive, provide an environment which allows efficient heat transfer
during endothermic or exothermic reactions, and facilitate efficient electron
transfer. Often halogenated solvents, such as methylene chloride, provide the
optimum choice for pharmaceutical reactions. The most commonly used
solvent in the pharmaceutical industry is methanol, an oxygenated organic
solvent. Other common solvents used are ethanol, acetone, and isopropanol.
Tables 8, 9, and 10 show the typical solvents (and whether or not they are
priority pollutants or hazardous air pollutants) used in chemical synthesis,
biological and natural extraction, and fermentation processes, respectively.
Final bulk substances from the bulk manufacturing processes are used in
formulation operations, along with other raw materials or ingredients. The
production of these ingredients is described under Section III. A.2.
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Table 8: Solvents Used in the Chemical Synthesis Process
Chemical
Acetone
Acetonitrile
Ammonia (aqueous)
n-Amyl acetate
Amyl Alcohol
Aniline
Benzene
2-Butanone (MEK)
n-Butyl acetate
n-Butyl alcohol
Chlorobenzene
Chloroform
Chloromethane
Cyanide
Cyclohexane
o-Dichlorobenzene (1,2-
Dichlorobenzene)
1 ,2-Dichlorobenzene
Diethylamie
Diethyl Ether
NJ-J-Dimethyl acetamide
Diethylamine
NJN-Dimethylaniline
N,N-Dimethylformamide
Dimethyl sulfoxide
1 ,4-Dioxane
Ethanol
Ethvl acetate
Priority
Pollutant Under
the Clean
Water Act
X
X
X
X
X
X
X
Hazardous
Air Pollutant
under the
Clean Air Act
X
X
X
X
X
X
X
X
X
X
Chemical
Ethylene glycol
Formaldehyde
Formamide
Furfural
n-Heptane
n-Hexane
Isobutyraldehyde
Isopropanol
Isopropyl acetate
Isopropyl ether
Methanol
Methylamine
Methyl cellulose
Methylene chloride
Methyl formate
Methyl isobutyl ketone
(MiBK)
2-Methylpyridine
Petroleum naphtha
Phenol
Polyethylene glycol
600
n-Propanol
Pyridine
Tetrahydrofuran
Toluene
Trichlorofloromethane
Triethylamine
Priority
Pollutant
Under the
Clean Water
Act
X
X
X
Hazardous
Air Pollutant
under the
Clean Air
Act
X
X
X
X
X
X
X
X
X
x
Source: adapted from
Manufacturing Point
Development Document for Proposed Effluent Guidelines and Standards for the Pharmaceutical
Source Category, 1995 and US Environment Laws, 1994.
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Table 9: Solvents Used in Biological and Natural Product Extraction
Chemicals
Acetone
Acctonitrilc
Ammonia (aqueous)
n-Amyl acetate
Amyl alcohol
n-Butyl alcohol
Chloroform
1 ,2-Dichlorocthanc
Dicthylaminc
Dicthyl ether
N,N-Dicthylformamide
Dimethyl sulfoxide
1 ,4-Dtoxane
Ethanol
Ethvl acetate
Priority
Pollutants
under the Clean
Water Act
X
X
Hazardous
Air Pollutants
under the
Clean Air Act
X
X
X
X
Chemicals
Ethylene glycol
Formaldehyde
n-Heptane
n-Hexane
Isopropanol
Isopropyl acetate
Isopropyl ether
Methanol
Methylene
chloride
Petroleum
naphtha
Phenol
n-Propanol
Pyridine
Tetrahydrofuran
Toluene
Priority
Pollutants
under the Clean
Water Act
X
X
X
Hazardous
Air Pollutants
under the
Clean Air Act
X
X
X
X
X
X
X
Source: adapted from Development Document for Proposed Effluent Guidelines and Standards for the Pharmaceutical
Manufacturing Point Source Category, 1995 and US Environment Laws, 1994.
Table 10: Solvents Used in Fermentation Processes
Chemicals
Acetone
Acctonitrilc
Ammonia (aqueous)
n-Amyl acetate
Amyl alcohol
n-Butyl acetate
n-Butyl alcohol
Chloroform
N,N-
Diethylformamidc
Ethanol
Ethyl acetate
Formaldehyde
Priority
Pollutants Under
the Clean Water
Act
X
Hazardous
Air Pollutants
under the
Clean Air Act
X
X
X
X
Chemicals
n-Heptane
n-Hexane
Isopropanol
Isopropyl acetate
Methanol
Methyl cellulose
Methylene
chloride
Methyl
isobutane ketone
(MiBK)
Petroleum
naphtha
Phenol
Toluene
Triethvlamine
Priority
Pollutants Under
the Clean Water
Act
X
X
X
Hazardous
Air Pollutants
under the
Clean Air Act
X
X
X
X
X
X
X
Source: adapted from Development Document for Proposed Effluent Guidelines and Standards for the Pharmaceutical
Manufacturing Point Source Category, 1995 and US Environment Laws, 1994.
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IH.B.2. Air Emissions and Control Systems
Both gaseous organic and inorganic compounds, as well as particulates, may
be emitted during pharmaceutical manufacturing and formulation. Some of
the volatile organic compounds (VOC) and inorganic gases that are emitted
are classified as hazardous air pollutants (HAPs) under the Clean Air Act.
The type and amount of emissions generated are dependent on the operations
conducted by the facility, as well as how the product is manufactured or
formulated. "Each (pharmaceutical) plant is unique, differing from other
plants in size, types of products manufactured, amounts and types of VOC
used, and air pollution control problems encountered" (EPA, 1979).
Bulk Manufacturing
As previously described, the industry manufactures most bulk pharmaceutical
substances and intermediates in campaigns via batch processes. Following the
completion of one campaign, another bulk substance or intermediate is
typically made using the same equipment (e.g., reactors, filters, dryers). The
reactants and solvents used in manufacturing the next bulk substance or
intermediate may vary greatly from the ones previously used. While some
reactions may require the use of halogenated solvents, the next reaction may
use another solvent or no solvent at all.
This wide variations in bulk manufacturing makes predicting typical or annual
average emissions difficult. This is because the emission generated are
predicated on what bulk substance or intermediate is manufactured and over
what length of time, and which equipment and raw materials are used. Some
bulk substances and intermediates are made frequently, while others may be
made only once every two to three years over a one to two week period. This
has often prevented the calculation of typical emission rates for each
operation. However, an approximate ranking of emission sources has been
established by EPA and is presented below in order of decreasing magnitude.
The first four sources generally will account for the majority of emissions
from a bulk manufacturing plant.
Dryers
Reactors
Distillation units
Storage and transfer of materials
Filtration
Extraction
Centrifugation
Crystallization
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Dryers are one of the largest sources of VOC emissions in bulk
manufacturing. In addition to the loss of solvent during drying, manual
loading and unloading of dryers can release solvent vapors into ambient air,
especially when tray dryers are used. VOCs are also generated from reaction
and separation steps via reactor vents and manways. Centrifuges may be a
source of VOC emissions, especially in top loading types, where solids are
manually scooped out.
Typical controls for these emission sources, excluding storage and transfer
operations, include condensers, scrubbers, carbon absorbers and, on occasion,
incinerators. "Storage and transfer emissions can be controlled by vapor
return lines, vent condensers, conservation vents, vent scrubbers, pressure
tanks and carbon absorbers. Floating roofs may be feasible controls for large
vertical storage tanks" (EPA, 1979).
Formulation
Both particulates and VOCs may be formed during mixing, compounding,
formulation, and packaging steps. Because these compounds may pose a
danger to workers, through direct inhalation, they are a principal concern.
Depending on the process and the batch record requirements, the particulates
(e.g., tablet dusts) may be recycled back into the formulation process.
However, sometimes the particulates are collected for destruction or disposal.
As in bulk manufacturing, the type and quantity of compounds emitted
depends on the operation. For example, formulation facilities may or may not
emit VOCs. Some formulation operations do not require the use of solvents,
some may only use solvents for cleaning, and some may use solvents in
granulation and coating operations. In some facilities, organic compounds,
such as ethanol or isopropyl alcohol, might be used in the formulation of the
product and VOCs may be emitted during mixing, formulation, and/or
packaging.
Air Pollution Control Equipment
More than one type of air control equipment may be used at any one time in
any one facility. A description of the various equipment used by the industry
is provided below.
Condensers. Condensers are widely used in the pharmaceutical industry to
recover solvents from process operations (a process condenser) and as air
pollution control devices to remove VOCs from vented gases. Process
condensers differ from condensers used as air pollution control devices as the
primary purpose of a process condenser is to recover material as an integral
part of a unit operation. The process condenser is the first condenser located
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after the process equipment and supports a vapor-to-liquid phase change for
the vapors produced in the process equipment. Examples of process
condensers include distillation condensers, reflux condensers, process
condensers in line before the vacuum source, and process condensers used in
stripping or flashing operations. The primary purpose of a condenser used
as an air pollution control device is to remove VOCs prior to venting.
Condensation is the process of converting a gas or vapor to liquid. In this
method, gas streams from vents containing VOCs are cooled to below their
saturation temperatures, converting the gas into a VOC liquid. This removes
some VOCs from the gas, but some remains. The amount of VOCs remaining
in the gas depends on the temperature and vapor-liquid equilibrium of the
VOC. Lowering the temperature of the condenser generally lowers the
content of VOC in the gas stream.
"In the most common type, surface condensers, the coolant does not directly
contact condensable vapors, rather heat is transferred across a surface (usually
a tube wall) separating vapor and coolant. In this way the coolant is not
contaminated with condensed VOC and may be directly reused. The type of
coolant used depends on the degree of cooling needed for a particular
situation" (EPA, 1979). Coolants in common use are water, chilled water,
brine, and glycol.
Scrubbers. Scrubbers or gas absorbers are used to remove one or more
constituents from a gas stream by treatment with a liquid. "Absorption is
important in the pharmaceutical industry because many VOCs and other
chemicals being used are soluble in water or aqueous solutions. Therefore,
water, caustic or acidic scrubbers can be applied to a variety of air pollution
problems" (USEPA 1979).
When using a scrubber as an air pollution control device, the solubility of the
constituents in the gas stream in the absorbing liquid must be determined.
"The rate of transfer of the soluble constituents from the gas to the liquid
phase is determined by diflusional processes occurring on each side of the gas
liquid interface" (Theodore and Bonicore, 1989).
The main types of scrubbers used are packed tower, plate or tray tower,
venturi scrubber, and spray tower. Each type of scrubber is designed to
provide intimate contact between the scrubbing liquid and the gaseous
constituents so that mass transfer between phases is promoted. The degree
of control achieved is dependent on the residence time of the gas and liquids,
the interfacial area, and the physical and thermodynamic properties of the
VOC species involved.
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Combustion or Incineration. Another method used for controlling VOC
emissions is combustion or incineration. "In general, factors that influence
the efficiency of combustion are: (1) temperature, (2) degree of mixing, (3)
residence time in the combustion chamber, and (4) type of VOC combusted.
Since more waste streams contain dilute VOC concentrations, they require
that supplemental fuel maintain the necessary combustion temperatures"
(EPA, 1979). Although combustion systems can achieve high removal
efficiencies, these systems are typically more expensive to install, operate, and
maintain, and have secondary emissions associated with their operation.
Additionally, a scrubber may be required to control inorganic gases produced
as by-products of combustion.
"Equipment used to control waste gases by combustion can be divided into
three categories: direct combustion or flaring (not often used by the
pharmaceutical industry), thermal oxidation, and catalytic oxidation. A direct
combustor or flare is a device in which air and all the combustible waste gases
react at the burner. In contrast, in thermal oxidation, the combustible waste
gases pass over or around a burner flame into a residence chamber where
oxidation of the waste gases is completed. Catalytic oxidation is very similar
to thermal oxidation. The main difference is that after passing through the
flame area, the gases pass over a catalyst bed which promotes oxidation at a
lower temperature than does thermal oxidation" (Theodore and Buonicore,
1989). Efficiency rates of catalytic oxidizers in destroying VOCs can reach
close to 98% (Buonicore and Davis, 1992).
Adsorption. Adsorption is another method for removing VOCs from gas
streams. This method filters out the volatiles by passing them through a
packed column of activated carbon, silicates, aluminas, aluminosilicates, or
any other surface which is porous and has a microcrystalline structure. As the
gas stream passes through the column, the VOCs adsorb to the surface of the
media. The adsorption material in the column eventually becomes saturated,
and must be either regenerated or disposed. Most sorbents may be
regenerated repeatedly by passing hot gas or steam through the bed. VOCs
will desorb into the gas or steam. The high VOC concentration in the gas or
steam can then be removed through condensation. Adsorption can be about
98% efficient in removing VOCs in the waste gas stream (Crume and Portzer,
1992).
ffl.B.3. Wastewater
Pharmaceutical manufacturers use water for process operations, as well as for
other non-process purposes. However, the use and discharge practices and
the characteristics of the wastewater will vary depending on the operations
conducted at the facility. Additionally, in some cases, water may be formed
as part of a chemical reaction.
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Process water includes any water that, during manufacturing or processing,
comes into direct contact with or results from the use of any raw material or
production of an intermediate, finished product, byproduct, or waste. Process
wastewater includes water that was used or formed during the reaction, water
used to clean process equipment and floors, and pump seal water. Non-
process wastewater includes noncontact cooling water (e.g., used in heat
exchangers), noncontact ancillary water (e.g., boiler blowdown, bottle
washing), sanitary wastewater, and wastewater from other sources (e.g.,
storm water runoff).
Based on the responses from 244 facilities to a 1990 308 Questionnaire, EPA
estimated the average daily wastewater generation by the pharmaceutical
manufacturing industry to be 266 million gallons. Additionally, EPA learned
that more than half of the responding facilities have implemented water
conservation measures. Such measures include: careful monitoring of water
use, installation of automatic monitoring and alarm systems or in-plant
discharges, implementation of alternative production processes, reuse of non-
contact water as process makeup water and treatment of contact cooling
water to allow reuse.
Pharmaceutical manufacturers generate process wastewater containing a
variety of conventional parameters (e.g., BOD, TSS, and pH) and other
chemical constituents. The top ten chemicals discharged by the
pharmaceutical industry are provided in Table 11. Of these compounds, two
are "priority pollutants"3. The top four compounds are oxygenated organic
solvents (e.g., methanol, ethanol, acetone, and isopropanol).
Priority pollutants are the pollutants listed in 40 CFR part 403, Appendix A.
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Table 11: Chemicals Discharged in Wastewater by the Pharmaceutical
Manufacturing Industry
Constituent Name
Methanol
Ethanol
Acetone
Isopropanol
Acetic acid
Methylene chloride
Formic acid
Ammonium hydroxide
N(N-Dimethylacetamide
Toluene
Quantity
Discharged (Ibs/yr)
15,388,273
6,802,384
4,573,766
4,565,370
4,328,691
3,590,640
2,136,059
1,365,741
1,046,333
783,364
Percent of Total
Loading
28
12
8.4
8.4
7.9
6.6
3.9
2.5
1.9
1.4
# of Facilities Reporting
Constituents
82
97
55
85
44
47
9
32
7
43
Source: adapted from Development Document for Proposed Effluent Guidelines and Standards for the Pharmaceutical
Manufacturing Point Source Category, 1995 and US Environment Laws, 1994.
Most process wastewater receives some treatment, either in-plant at the
process unit prior to commingling with other facility wastewater or prior to
discharge to a permitted outfall. Table 12 provides a trend analysis prepared
by EPA of wastewater treatment technologies used by the pharmaceutical
industry. EPA found that "since 1986, the use of neutralization, equalization,
activated sludge, primary clarification, multimedia filtration, steam stripping,
secondary clarification, granular activated carbon, and oxidation have all
increased, while the use of aerated lagoons, chlorination, waste stabilization
ponds, and trickling filters have decreased slightly" (USEPA 1995).
More than half of the surveyed facilities provide pH adjustment or
neutralization to adjust the pH prior to discharge. Additionally, because
wastewater treatment can be sensitive to spikes of high flow or high
constituent concentration, many treatment systems include equalization.
Advanced biological treatment is used to treat biochemical oxygen demand
(BOD5), chemical oxygen demand (COD), total suspended solids (TSS), as
well as various organic constituents. Biological systems can be divided into
two basic types: aerobic (treatment takes place in the presence of oxygen) and
anaerobic (treatment takes places in the absence of oxygen). Very few
pharmaceutical facilities (only two) use anaerobic treatment. However, more
than 30 percent use aerobic systems such as activated sludge, aerated lagoons,
trickling filter, and rotating biological contactors (RBC).
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Table 12: Wastewater Treatment Technology Trends
Treatment Technology
Neutralization
Equalization
Activated sludge
Settleable solids removal
Primary sedimentation
Aerated lagoon
Primary clarification
Chlorination
Polishing ponds
Waste stabilization pond
Trickling filter
Multimedia filtration
Stream stripping
Evaporation
Secondary clarification
Granular activated carbon
Oxidation
Dissolved air flotation
pH adjustment
Phase separation
Percentage of Facilities Using
Technology Prior to 1986
26.0
20.1
16.9
13.3
12.0
7.5
3.9
3.6
3.2
2.9
2.9
2.3
1.9
1.9
1.6
1.3
1.0
1.0
NA
NA
Percentage of Facilities Using
Technology in 1989/1990
44.3
28.6
20.5
NA
NA
4.9
9.8
2.5
NA
2.5
2.0
6.1
5.7
NA
20.9
3.3
2.0
NA
50.0
12.3
Note: Total percentage is not 100 because facilities may use multiple treatment technologies.
NA - Not available.
Source: adapted from Development Document for Proposed Effluent Guidelines and Standards for the
Pharmaceutical Manufacturing Point Source Category, 1995 and US Environment Laws, 1994.
Although the pharmaceutical industry has routinely utilized recovery systems
to recover and reuse solvents, only four facilities were identified by EPA as
using stream stripping to remove gases and/or organic chemicals from
wastewater streams. Sixty one facilities were identified that use distillation
either to recover a specific solvent from a process stream or to treat one or
more process waste streams. However, according to PhRMA, it is likely that
these facilities use this method to recover a specific solvent from a specific
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process stream rather than to treat wastewater from numerous operations
since the treatment technology is not applicable to the wide range of waste
characteristics common in the pharmaceutical industry.
in.B.4. Solid Wastes
Both nonhazardous and hazardous wastes are generated during all three
stages of pharmaceutical manufacturing. These wastes can include off-spec
or obsolete raw materials or products, spent solvents, reaction residues, used
filter media, still bottoms, used chemical reagents, dusts from filtration or air
pollution control equipment, raw material packaging wastes, laboratory
wastes, spills, as well as wastes generated during packaging of the formulated
product.
Filter cakes and spent raw materials (plants, roots, animal tissues etc.) from
fermentation and natural product extraction are two of the largest sources of
residual wastes in the pharmaceutical industry. Other wastes include reaction
residues and filtrates from chemical synthesis processes. These wastes may be
stripped of any solvents which remain in them, and then disposed as either
hazardous or nonhazardous wastes. Typically, solid wastes are shipped off-
site for disposal or incineration.
A number of practices are implemented by the industry to reduce waste
generation and material losses. Typical practices include process
optimization, production scheduling, materials tracking and inventory control,
special material handling and storage procedures, preventive maintenance
programs, and waste stream segregation.
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IILC. Management of TRI Chemicals in the Production Process
The Pollution Prevention Act of 1990 (PPA) requires facilities to report
information about the management of Toxics Release Inventory (TRI)
chemicals in waste and efforts made to eliminate or reduce those quantities.
These data have been collected annually in Section 8 of the TRI reporting
Form R beginning with the 1991 reporting year. The data summarized below
cover the years 1994 through 1997 and are meant to provide a basic
understanding of the quantities of waste handled by the industry, the methods
typically used to manage this waste, and recent trends in these methods. TRI
waste management data can be used to assess trends in source reduction
within individual industries and facilities, and for specific TRI chemicals. This
information could then be used as a tool in identifying opportunities for
pollution prevention compliance assistance activities.
While the quantities reported for 1994 and 1995 are estimates of quantities
already managed, the quantities reported for 1996 and 1997 are projections
only. The PPA requires these projections to encourage facilities to consider
future waste generation and source reduction of those quantities as well as
movement up the waste management hierarchy. Future-year estimates are not
commitments that facilities reporting under TRI are required to meet.
Table 13 shows that the TRI reporting pharmaceutical facilities managed
about 382 million pounds of production related wastes (total quantity of TRI
chemicals in the waste from routine production operations in Column B) in
1995. From the yearly data presented in Column B, the total quantity of
production related wastes increased between 1994 and 1995. This is probably
in part because the number of chemicals on the TRI list almost doubled
between those years. The quantity of wastes generated was also projected to
increase in 1996 and 1997. The effect of production increases on the amount
of wastes generated has not been evaluated.
Values in Column C are intended to reveal the percentage of TRI chemicals
that are either transferred off-site or released to the environment. Column C
is calculated by dividing the total TRI transfers and releases (reported in
Sections 5 and 6 of the TRI Form R) by the total quantity of production-
related waste (reported in Section 8 of Form R). Column C shows a decrease
in the portion either transferred off-site or released to the environment from
50 percent in 1994 to 46 percent in 1995. The waste released to the
environment or transferred off-site for disposal decreased slightly in 1995 to
about 10 percent of total wastes generated, as shown in Column J. This
decreasing trend is projected to continue through 1997.
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The overall proportions of wastes managed off-site (Columns D, E, and F)
and onsite (Columns G, H, and I) change very little from year to year. About
50 percent of the industry's TRI wastes were managed on-site through
recycling, energy recovery, or treatment as shown in columns D, E, and F,
respectively. Almost all of these on-site managed wastes were recycled or
treated on-site. Only about two percent were used in energy recovery. Waste
that is transferred off-site can be divided into portions that are recycled off-
site, recovered for energy off-site, or treated off-site as shown in columns G,
H, and I, respectively. The remaining portion of the production related
wastes, 10 percent, shown in column J, is either released to the environment
through direct discharges to air, land, water, and underground injection, or it
is disposed off-site.
Table 13: Source Reduction and Recycling Activity for the
Pharmaceuticals Industry as Reported within TRI
A
Year
1994
1995
1996
1997
B
Quantity of
Production-
Related
Waste
(lO'lbs.)"
324
382
404
414
C
% Released
and
Transferred1"
50%
46%
NA
NA
On-Site
D
%
Recycled
13.9%
16.8%
18.7%
20.4%
E
% Energy
Recovery
2.0%
1.6%
1.6%
1.6%
F
% Treated
33.5%
34.3%
37.1%
35.9%
Off-Site
G
%
Recycled
5.3%
4.7%
5.1%
5.5%
H
% Energy
Recovery
21.7%
21.6%
18.8%
18.4%
I
% Treated
13.3%
11.7%
10.4%
9.9%
J
%
Released
and
Disposed"
Off-site
10.8%
9.7%
8.4%
8.3%
Source: Toxics Release Inventory Database, 1995.
3 Within this industry sector, non-production related waste < 1% of production related wastes for 1995.
Total TRI transfers and releases as reported in Section 5 and 6 of Form R as a percentage of production related wastes.
c Percentage of production related waste released to the environment and transferred off-site for disposal.
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IV. CHEMICAL RELEASE AND TRANSFER PROFILE
This section is designed to provide background information on the pollutant
releases that are reported by this industry. The best source of comparative
pollutant release information is the Toxic Release Inventory (TRI). Pursuant
to the Emergency Planning and Community Right-to-Know Act, TRI includes
self-reported facility release and transfer data for over 600 toxic chemicals.
Facilities within SIC Codes 20 through 39 (manufacturing industries) that
have more than 10 employees, and that are above weight-based reporting
thresholds are required to report TRI on-site releases and off-site transfers.
The information presented within the sector notebooks is derived from the
most recently available (1995) TRI reporting year (which includes over 600
chemicals), and focuses primarily on the on-site releases reported by each
sector. Because TRI requires consistent reporting regardless of sector, it is
an excellent tool for drawing comparisons across industries. TRI data provide
the type, amount and media receptor of each chemical released or transferred.
Although this sector notebook does not present historical information
regarding TRI chemical releases over time, please note that in general, toxic
chemical releases have been declining. In fact, according to the 1995 Toxic
Release Inventory Public Data Release, reported onsite releases of toxic
chemicals to the environment decreased by 5 percent (85.4 million pounds)
between 1994 and 1995 (not including chemicals added and removed from the
TRI chemical list during this period). Reported releases dropped by 46
percent between 1988 and 1995. Reported transfers of TRI chemicals to off-
site locations increased by 0.4 percent (11.6 million pounds) between 1994
and 1995. More detailed information can be obtained from EPA's annual
Toxics Release Inventory Public Data Release book (which is available
through the EPCRA Hotline at 800-535-0202), or directly from the Toxic
Release Inventory System database (for user support call 202-260-1531).
Wherever possible, the sector notebooks present TRI data as the primary
indicator of chemical release within each industrial category. TRI data
provide the type, amount and media receptor of each chemical released or
transferred. When other sources of pollutant release data have been obtained,
these data have been included to augment the TRI information.
TRI Data Limitations
Certain limitations exist regarding TRI data. Release and transfer reporting
are limited to the approximately 600 chemicals on the TRI list. Therefore, a
large portion of the emissions from industrial facilities are not captured by
TRI. Within some sectors, (e.g. dry cleaning, printing and transportation
equipment cleaning) the majority of facilities are not subject to TRI reporting
because they are not considered manufacturing industries, or because they are
below TRI reporting thresholds. For these sectors, release information from
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other sources has been included. In addition, many facilities report more than
one SIC code reflecting the multiple operations carried out onsite. Therefore,
reported releases and transfers may or may not all be associated with the
industrial operations described in this notebook.
The reader should also be aware that TRI "pounds released" data presented
within the notebooks is not equivalent to a "risk" ranking for each industry.
Weighting each pound of release equally does not factor in the relative
toxicity of each chemical that is released. The Agency is in the process of
developing an approach to assign toxicological weights to each chemical
released so that one can differentiate between pollutants with significant
differences in toxicity. As a preliminary indicator of the environmental impact
of the industry's most commonly released chemicals, the notebook briefly
summarizes the toxicological properties of the top five chemicals (by weight)
reported by each industry.
Definitions Associated with Section IV Data Tables
General Definitions
SIC Code — the Standard Industrial Classification (SIC) is a statistical
classification standard used for all establishment-based Federal economic
statistics. The SIC codes facilitate comparisons between facility and industry
data.
TRI Facilities — are manufacturing facilities that have 10 or more full-time
employees and are above established chemical throughput thresholds.
Manufacturing facilities are defined as facilities in Standard Industrial
Classification primary codes 20-39. Facilities must submit estimates for all
chemicals that are on the TRI list and are above throughput thresholds.
Data Table Column Heading Definitions
The following definitions are based upon standard definitions developed by
EPA's Toxic Release Inventory Program. The categories below represent the
possible pollutant destinations that can be reported.
RELEASES ~ are an on-site discharge of a toxic chemical to the
environment. This includes emissions to the air, discharges to bodies of
water, releases at the facility to land, as well as contained disposal into
underground injection wells.
Releases to Air (Point and Fugitive Air Emissions) — Include all air
emissions from industry activity. Point emissions occur through confined air
streams as found in stacks, vents, ducts, or pipes. Fugitive emissions include
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equipment leaks, evaporative losses from surface impoundments and spills,
and releases from building ventilation systems.
Releases to Water (Surface Water Discharges) — encompass any releases
going directly to streams, rivers, lakes, oceans, or other bodies of water.
Releases due to runoff, including storm water runoff, are also reportable to
TRI.
Releases to Land ~ occur within the boundaries of the reporting facility.
Releases to land include disposal of toxic chemicals in landfills, land
treatment/application farming, surface impoundments, and other land disposal
methods (such as spills, leaks, or waste piles).
Underground Injection — is a contained release of a fluid into a subsurface
well for the purpose of waste disposal. Wastes containing TRI chemicals are
injected into either Class I wells or Class V wells. Class I wells are used to
inject liquid hazardous wastes or dispose of industrial and municipal
wastewaters beneath the lowermost underground source of drinking water.
Class V wells are generally used to inject non-hazardous fluid into or above
an underground source of drinking water. TRI reporting does not currently
distinguish between these two types of wells, although there are important
differences in environmental impact between these two methods of injection.
TRANSFERS— is a transfer of toxic chemicals in wastes to a facility that is
geographically or physically separate from the facility reporting under TRI.
Chemicals reported to TRI as transferred are sent to off-site facilities for the
purpose of recycling, energy recovery, treatment, or disposal. The quantities
reported represent a movement of the chemical away from the reporting
facility. Except for off-site transfers for disposal, the reported quantities do
not necessarily represent entry of the chemical into the environment.
Transfers to POTWs — are wastewater transferred through pipes or sewers
to a publicly owned treatments works (POTW). Treatment or removal of a
chemical from the wastewater depend on the nature of the chemical, as well
as the treatment methods present at the POTW. Not all TRI chemicals can
be treated or removed by a POTW. Some chemicals, such as metals, may be
removed, but are not destroyed and may be disposed of in landfills or
discharged to receiving waters.
Transfers to Recycling -- are sent off-site for the purposes of regenerating
or recovery by a variety of recycling methods, including solvent recovery,
metals recovery, and acid regeneration. Once these chemicals have been
recycled, they may be returned to the originating facility or sold commercially.
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Transfers to Energy Recovery — are wastes combusted off-site in industrial
furnaces for energy recovery. Treatment of a chemical by incineration is not
considered to be energy recovery.
Transfers to Treatment — are wastes moved off-site to be treated through
a variety of methods, including neutralization, incineration, biological
destruction, or physical separation. In some cases, the chemicals are not
destroyed but prepared for further waste management.
Transfers to Disposal — are wastes taken to another facility for disposal
generally as a release to land or as an injection underground.
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IV.A. EPA Toxic Release Inventory for the Pharmaceutical Industry
This section summarizes TRI data of pharmaceutical facilities reporting SIC
codes 2833 and 2834 as the primary SIC code for the facility. Of the 916
pharmaceutical establishments reported by the 7992 Census of
Manufacturers, 200 reported to TRI in 1995.
According to 1995 TRI data, the reporting facilities released (discharged to
the air, water, or land without treatment) and transferred (shipped off-site) a
total of 177 million pounds of pollutants, made up of 104 different chemicals.
This represents about 3 percent of the 5.7 billion pounds of TRI chemicals
released and transferred by all manufacturers that year. In comparison, the
chemical industry (SIC 28) as a whole produced 1.7 billion pounds that year,
accounting for about 30 percent of all releases and transfers.
Of the pharmaceutical industry's TRI releases. 57 percent go to the air, 25
percent to underground injection, 17 percent to surface waters, and 1 percent
to the land. This release profile differs from other TRI industries which
average approximately 59 percent to air, 30 percent to water, and 10 percent
to land. Table 14 lists the pharmaceutical industry's TRI reported chemical
releases.
Of the pharmaceutical industry's transfers, about 55 percent are transferred
for energy recovery off-site, 19 percent for treatment off-site, 13 percent are
transferred to POTWs, 12 percent for recycling off-site, and about 1 percent
for disposal off-site. Table 15 lists the pharmaceutical industry's TRI reported
toxic chemical transfers.
Of the top ten most frequently reported toxic chemicals on the TRI list, the
prevalence of volatile chemicals explains the air intensive toxic chemical
loading of the pharmaceutical industry. Seven of the ten most commonly
reported toxic chemicals are highly volatile. Six of the ten are volatile organic
compounds (methanol, dichloromethane, toluene, ethylene glycol, N,N-
Dimethylformamide, and acetonitrile). These are primarily solvents used to
extract active ingredients and for cleaning equipment. The primary means of
release to the environment are from fugitive air and point air sources. Large
quantities of methanol, N,N-Dimethylformatnide, and acetonitrile, however,
are released via underground injection. Other commonly reported chemicals
released and transferred are acids (hydrochloric, sulfuric, and phosphoric)
which can be used for pH control or as catalysts.
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The TRI database contains a detailed compilation of self-reported, facility-
specific chemical releases. The top reporting facilities for the pharmaceutical
industry are listed below in Tables 16. Facilities that have reported only the
SIC codes covered under this notebook as a primary SIC code appear on the
first list. Table 17 contains additional facilities that have reported the SIC
code covered within this report, and one or more SIC codes that are not
within the scope of this notebook. Therefore, the second list includes facilities
that conduct multiple operations ~ some that are under the scope of this
notebook, and some that are not. Currently, the facility-level data do not
allow pollutant releases to be broken apart by industrial process.
Table 16: Top 10 TRI Releasing Pharmaceutical Manufacturing Facilities8
Rank
1
2
3
4
5
6
7
8
9
10
Facility
Pharmacia & Upjohn Co., Portage, Michigan
Warner-Lambert Co., Holland, Michigan
Eli Lilly & Co. - Tippecanoe Labs, Shadeland, Indiana
Upjohn Mfg., Co., Barceloneta, Puerto Rico
Pfizer Inc., Groton, Connecticut.
Eli Lilly & Co - Clinton Laboratories, Clinton, Indiana
Abbott Chemicals, Inc., Barceloneta, Puerto Rico
Pfizer Inc., Southport, North Carolina
Schering-Plough Products, Inc., Las Piedras, Puerto Rico
Biokyowa Inc., Cape Girardeau, Missouri
Total TRI Releases in
Pounds
8,307,190
2,594,111
2,504,810
2,001,450
1,761,385
1,282,605
1,193,707
1,164,350
756,089
669,869
Source: US EPA 1995 Toxics Release Inventory Database.
* Being included on this list does not mean that the release is associated with non-compliance with environmental laws.
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Table 17: Top 10 TRI Releasing Facilities Reporting Pharmaceutical Manufacturing SIC
Codes to TRP
Rank
1
2
3
4
5
6
7
8
9
10
SIC Codes
Reported in TRI
2834
2819,2834,2842,
2865, 2869, 2873,
2879
2834
2834
2834
2833
2834, 2869, 2969
2833, 2834
2819,2821,2824,
2834, 2865, 2869,
2879, 2979
2833, 2834
Facility
Pharmacia & Upjohn Co., Portage, Michigan
Monsanto Co., Luling, Louisiana
Warner-Lambert Co., Holland, Michigan
Eli Lilly & Co. - Tippecanoe Labs, Shadeland,
Indiana
Upjohn Mfg., Co., Barceloneta, Puerto Rico
Pfizer Inc., Groton, Connecticut.
Ethyl Corp., Orangeburg, South Carolina
Eli Lilly & Co - Clinton Laboratories, Clinton,
Indiana
Dow Chemical Co., Midland, Michigan
Abbott Chemicals, Inc., Barceloneta, Puerto Rico
Total TRI Releases in
Pounds
8,307,190
5,698,031
2,594,111
2,504,810
2,001,450
1,761,385
1,284,456
1,282,605
1,228,629
1,193,707
Source: US EPA Toxics Release Inventory Database, 1995.
Being included on this list does not mean that the release is associated with non-compliance with environmental laws.
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IV.B. Summary of Selected Chemicals Released
The following is a synopsis of current scientific toxicity and fate information
for the top chemicals (by weight) that facilities within both SIC 2833 and
2834 self-reported as released to the environment based upon 1994 TRI data.
Because this section is based upon self-reported release data, it does not
attempt to provide information on management practices employed by the
sector to reduce the release of these chemicals. Information regarding
pollutant release reductions over time may be available from EPA's TRI and
33/50 programs, or directly from the industrial trade associations that are
listed in Section Vm of this document. Since these descriptions are cursory,
please consult the sources referenced below for a more detailed description
of both the chemicals described in this section, and the chemicals that appear
on the full list of TRI chemicals appearing in Section IV. A.
The brief descriptions provided below were taken from the Hazardous
Substances Data Bank (HSDB) and the Integrated Risk Information System
(IRIS). The discussions of toxicity describe the range of possible adverse
health effects that have been found to be associated with exposure to these
chemicals. These adverse effects may or may not occur at the levels released
to the environment. Individuals interested in a more detailed picture of the
chemical concentrations associated with these adverse effects should consult
a toxicologist or the toxicity literature for the chemical to obtain more
information. The effects listed below must be taken in context of these
exposure assumptions that are more fully explained within the full chemical
profiles in HSDB. For more information on TOXNET" , contact the
TOXNET help line at 1-800-231-3766.
Methanol (CAS: 67-56-1)
Toxicity. Methanol is readily absorbed by the gastrointestinal tract and the
respiratory tract, and is toxic to humans in moderate to high doses. In the
body, methanol is converted into formaldehyde and formic acid. Methanol is
excreted as formic acid. Observed toxic effects at high dose levels generally
include central nervous system damage and blindness. Long-term exposure
* TOXNET is a computer system run by the National Library of Medicine that includes a number of toxicological
databases managed by EPA, National Cancer Institute, and the National Institute for Occupational Safety and Health.
For more information on TOXNET, contact the TOXNET help line at 800-231 -3766. Databases included in TOXNET
arc: CCRIS (Chemical Carcinpgenesis Research Information System), DART (Developmental and Reproductive
Toxicity Database), DBBR. (Directory of Biotechnology Information Resources), EMICBACK (Environmental Mutagen
Information Center Backfile), GENE-TOX (Genetic Toxicology), HSDB (Hazardous Substances Data Bank), IRIS
(Integrated Risk Information System), RTECS (Registry of Toxic Effects of Chemical Substances), and TRI (Toxic
Chemical Release Inventory). HSDB contains chemical-specific information on manufacturing and use, chemical and
physical properties, safety and handling, toxicity and biomedical effects, pharmacology, environmental fate and exposure
potential, exposure standards and regulations, monitoring and analysis methods, and additional references.
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to high levels of methanol via inhalation cause liver and blood damage in
animals.
Ecologically, methanol is expected to have low toxicity to aquatic organisms.
Concentrations lethal to half the organisms of a test population are expected
to exceed one mg methanol per liter water. Methanol is not likely to persist
in water or to bioaccumulate in aquatic organisms.
Carcinogenicity. There is currently no evidence to suggest that methanol is
carcinogenic.
Environmental Fate. Liquid methanol is likely to evaporate when left
exposed. Methanol reacts in air to produce formaldehyde which contributes
to the formation of air pollutants. In the atmosphere it can react with other
atmospheric chemicals or be washed out by rain. Methanol is readily
degraded by microorganisms in soils and surface waters.
Physical Properties. Methanol is a colorless, highly flammable liquid.
Methanol is miscible in water and has a boiling point of 147 degrees F.
Methylene Chloride (Dichloromethane) (CAS: 75-09-2)
Toxicity. Short-term exposure to methylene chloride (MC) is associated with
central nervous system effects, including headaches, giddiness, stupor,
irritability, and numbness, and tingling in the limbs. More severe neurological
effects are reported from longer-term exposure, apparently due to increased
carbon monoxide in the blood from the break down of MC. Contact with MC
causes irritation of the eyes, skin, and respiratory tract.
Occupational exposure to MC has also been linked to increased incidence of
spontaneous abortions in women. Acute damages to the eyes and upper
respiratory tract, unconsciousness, and death were reported in workers
exposed to high concentrations of MC. Phosgene (a degradation product of
MC) poisoning has been reported to occur in several cases where MC was
used in the presence of an open fire.
Populations at special risk from exposure to MC include obese people (due
to accumulation of MC in fat), and people with impaired cardiovascular
systems.
Carcinogenity. MC is a probable human carcinogen via both inhalation and
oral exposure, based on limited evidence in humans, and sufficient evidence
in animals.
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Environmental Fate. When spilled on land, MC is rapidly lost from the soil
surface through volatilization. The remainder leaches through the subsoil into
the groundwater.
Biodegradation is possible in natural waters but will probably be very slow
compared with evaporation. Little is known about bioconcentration in aquatic
organisms or adsorption to sediments but these are not likely to be significant
processes. Hydrolysis is not an important process under normal
environmental conditions.
MC released into the atmosphere degrades via contact with other gases with
a half-life of several months. A small fraction of the chemical diffuses to the
stratosphere where it rapidly degrades through exposure to ultraviolet
radiation and contact with chlorine ions. Being a moderately soluble
chemical, MC is expected to partially return to earth in rain.
Physical Properties. Methylene chloride is a colorless liquid. It is soluble to
2 percent in water and has a boiling point of 104 degrees F.
Ammonia0 (CAS:.7664-4J-7)
Toxicity. Anhydrous ammonia is irritating to the skin, eyes, nose, throat, and
upper respiratory system.
Ecologically, ammonia is a source of nitrogen (an essential element for aquatic
plant growth), and may therefore contribute to eutrophication of standing or
slow-moving surface water, particularly in nitrogen-limited waters such as the
Chesapeake Bay. In addition, aqueous ammonia is moderately toxic to aquatic
organisms.
Carcinogenicity. There is currently no evidence to suggest that ammonia is
carcinogenic.
Environmental Fate. Ammonia combines with sulfate ions in the
atmosphere and is washed out by rainfall, resulting in rapid return of ammonia
to the soil and surface waters.
Ammonia is a central compound in the environmental cycling of nitrogen.
Ammonia in lakes, rivers, and streams is converted to nitrate.
a The reporting standards for ammonia were changed in 1995. Ammonium sulfate is deleted from the list and threshold
and release determinations for aqueous ammonia are limited to 10 percent of the total ammonia present in solution. This
change will reduce the amount of ammonia reported to TRI. Complete details of the revisions can be found in 40 CFR
Part 372.
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Physical Properties. Ammonia is a colorless gas at atmospheric pressure,
but is shipped as a liquefied compressed gas. It is soluble to about 34 percent
in water and has a boiling point of-28 degrees F. Ammonia It is corrosive and
has a pungent odor.
Toluene (CAS: 108-88-3)
Toxicity. Inhalation or ingestion of toluene can cause headaches, confusion,
weakness, and memory loss. Toluene may also affect the way the kidneys and
liver function.
Reactions of toluene (see environmental fate) in the atmosphere contribute to
the formation of ozone in the lower atmosphere. Ozone can affect the
respiratory system, especially in sensitive individuals such as asthma or allergy
sufferers.
Some studies have shown that unborn animals were harmed when high levels
of toluene were inhaled by their mothers, although the same effects were not
seen when the mothers were fed large quantities of toluene. Note that these
results may reflect similar difficulties in humans.
Carcinogenicity. There is currently no evidence to suggest that toluene is
carcinogenic.
Environmental Fate. A portion of releases of toluene to land and water will
evaporate. Toluene may also be degraded by microorganisms. Once
volatilized, toluene in the lower atmosphere will react with other atmospheric
components contributing to the formation of ground-level ozone and other air
pollutants.
Physical Properties. Toluene liquid with a sweet, pungent odor. It is soluble
to 0.07 percent in water and has a boiling point of 232 degrees F.
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IV.C. Other Data Sources
The toxic chemical release data obtained from TRI captures many of the
facilities in the pharmaceutical industry. It also allows for a comparison
across years and industry sectors. Reported chemicals are limited however to
the approximately 600 reported chemicals. Most of the hydrocarbon
emissions from pharmaceutical facilities are not captured by TRI. The EPA
Office of Air Quality Planning and Standards has compiled air pollutant
emission factors for determining the total air emissions of priority pollutants
(e.g., total hydrocarbons, SO2, NQ, CO, particulates, etc.) from many
chemical manufacturing sources.
The EPA Office of Air's Aerometric Information Retrieval System (AIRS)
contains a wide range of information related to stationary sources of air
pollution, including the emissions of a number of air pollutants which may be
of concern within a particular industry. With the exception of volatile organic
compounds (VOCs), there is little overlap with the TRI chemicals reported
above. Table 18 summarizes annual releases of carbon monoxide (CO),
nitrogen dioxide (NO^, particulate matter of 10 microns or less (PM10), total
particulate (PT), sulfur dioxide (SO2), and volatile organic compounds
(VOCs).
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Pharmaceutical Industry
Releases and Transfers Profile
Table 18: Air Pollutant Releases by Industry Sector (tons/year)
Industry Sector
Metal Mining
Nonmetal Mining
Lumber and Wood
Production
Furniture and Fixtures
Pulp and Paper
Printing
Inorganic Chemicals
Organic Chemicals
Petroleum Refining
Rubber and Misc. Plastics
Stone, Clay and Concrete
Iron and Steel
Nonferrous Metals
Fabricated Metals
Electronics and Computers
Motor Vehicles, Bodies,
Parts and Accessories
Dry Cleaning
Ground Transportation
Metal Casting
Pharmaceuticals
Plastic Resins and
Manmade Fibers
Textiles
Power Generation
Shipbuilding and Repair
CO
4,670
25,922
122,061
2,754
566,883
8,755
153,294
112,410
734,630
2,200
105,059
1,386,461
214,243
4,925
356
15,109
102
128,625
116,538
6,586
16,388
8,177
366,208
105
NO2
39,849
22,881
38,042
1,872
358,675
3,542
106,522
187,400
355,852
9,955
340,639
153,607
31,136
11,104
1,501
27,355
184
550,551
11,911
19,088
41,771
34,523
5,986,757
862
PM10
63,541
40,199
20,456
2,502
35,030
405
6,703
14,596
27,497
2,618
192,962
83,938
10,403
1,019
224
1,048
3
2,569
10,995
1,576
2,218
2,028
140,760
638
PT
173,566
128,661
64,650
4,827
111,210
1,198
34,664
' 16,053
36,141
5,182
662,233
87,939
24,654
2,790
385
3,699
27
5,489
20,973
4,425
7,546
9,479
464,542
943
S02
17,690
18,000
9,401
1,538
493,313
1,684
194,153
176,115
619,775
21,720
308,534
232,347
253,538
3,169
741
20,378
155
8,417
6,513
21,311
67,546
43,050
13,827,511
3,051
voc
915
4,002
55,983
67,604
127,809
103,018
65,427
180,350
313,982
132,945
34,337
83,882
11,058
86,472
4,866
96,338
7,441
104,824
19,031
37,214
74,138
27,768
57,384
3,967
Source: U.S. EPA Office of Air and Radiation, AIRS Database, 1997.
Sector Notebook Project
73
September 1997
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Pharmaceutical Industry
Releases and Transfers Profile
IV.D. Comparison of Toxic Release Inventory Among Selected Industries
The following information is presented as a comparison of pollutant release
and transfer data across industrial categories. It is provided to give a general
sense as to the relative scale of releases and transfers within each sector
profiled under this project. Please note that the following figure and table do
not contain releases and transfers for industrial categories that are not
included in this project, and thus cannot be used to draw conclusions
regarding the total release and transfer amounts that are reported to TRI.
Similar information is available within the annual TRI Public Data Release
Book.
Figure 12 is a graphical representation of a summary of the 1995 TRI data for
the pharmaceutical industry and the other sectors profiled in separate
notebooks. The bar graph presents the total TRI releases and total transfers
on the vertical axis. The graph is based on the data in Table 19 and is meant
to facilitate comparisons among the relative amounts of releases, transfers,
and releases per facility both within and among these sectors. The reader
should note, however, that differences in the proportion of facilities captured
by TRI exist among industry sectors. This can be a factor of poor SIC
matching and relative differences in the number of facilities reporting to TRI
from the various sectors. In the case of the pharmaceutical industry, the 1995
TRI data presented here covers 200 facilities. Only those facilities listing
primary SIC codes falling within SIC 2833 and 2834 were used.
Comparisons of the reported pounds released or transferred per facility in
Table 19 demonstrate that the pharmaceutical industry is above average in its
pollutant releases and transfers per facility when compared to other TRI
industries. Of the twenty manufacturing SIC codes listed in the TRI database,
the mean amount of pollutant release per facility (including pharmaceutical
facilities) was approximately 101,000 pounds. The TRI releases of the
average pharmaceutical facility (SIC 2833 and 2834) were 150,000 pounds,
making the industry 1.5 times higher in per facility releases than for other
industries. For transfers, the mean of pharmaceutical facilities was about 4.6
times as much as that of all TRI manufacturing facilities (161,000 pounds
transferred off-site per facility compared to 736,000 pounds per
pharmaceutical facility). This comparison is difficult to interpret due to the
divergent nature of the industries listed in Table 19 and the differences in the
raw materials and processes used to manufacture the specific industry's
products. The batch nature and large volumes of raw materials used to
produce the relatively small amounts of high purity pharmaceutical products
may account for the higher rate released and transferred by the pharmaceutical
industry.
Sector Notebook Project
74
September 1997
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Pharmaceutical Industry
Releases and Transfers Profile
Figure 12: Summary of TRI Releases and Transfers by Industry
600
CM
CO
CM
SIC Range
D Total Releases
I Total Transfers
Source: US EPA 1995 Toxics Release Inventory Database.
SIC
Range
22
24
25
2611-2631
2711-2789
2812-2819
2821,
2823, 2824
Industry Sector
Textiles
Lumber and Wood
Products
Furniture and Fixtures
Pulp and Paper
Printing
Inorganic Chemical
Manufacturing
Plastic Resins and
Manmade Fibers
SIC
Range
2833,
2834
2861-
2869
2911
30
32
•331
332, 336
Industry Sector
Pharmaceuticals
Organic Chem. Mfg.
Petroleum Refining
Rubber and Misc. Plastics
Stone, Clay, and Concrete
Iron and Steel
Metal Casting
SIC
Range
333,334
34
36
371
3731 ,
Industry Sector
Nonferrous Metals
Fabricated Metals
Electronic Equip, and
Comp.
Motor Vehicles, Bodies,
Parts, and Accessories •
Shipbuilding
Sector Notebook Project
75
September 1997
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Pharmaceutical Industry
Releases and Transfers Profile
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ource: US EPA Toxics E
Sector Notebook Project
September 1997
-------
Pharmaceutical Industry
Pollution Prevention Opportunities
V. POLLUTION PREVENTION OPPORTUNITIES
The best way to reduce pollution is to prevent it in the first place. Some
companies have creatively implemented pollution prevention techniques that
improve efficiency and increase profits while at the same time minimizing
environmental impacts. This can be done in many ways, such as reducing
material inputs, re-engineering processes to reuse by-products, improving
management practices, and employing substitution of toxic chemicals. Some
smaller facilities are able to actually get below regulatory thresholds just by
reducing pollutant releases through aggressive pollution prevention policies.
The Pollution Prevention Act of 1990 established a national policy of
managing waste through source reduction, which means preventing the
generation of waste. The Pollution Prevention Act also established as national
policy a hierarchy of waste management options for situations in which source
reduction cannot be implemented feasibly. In the waste management
hierarchy, if source reduction is not feasible the next alternative is recycling
of wastes, followed by energy recovery, and waste treatment as a last
alternative.
In order to encourage these approaches, this section provides both general
and company-specific descriptions of pollution prevention activities that have
been implemented within the pharmaceutical industry. While the list is not
exhaustive, it does provide core information that can be used as the starting
point for facilities interested in beginning their own pollution prevention
projects. When possible, this section provides information from real activities
that can be, or are being, implemented by this sector - including a discussion
of associated costs, time frames, and expected rates of return. This section
provides summary information from activities that may be, or are being
implemented by this sector. Please note that the activities described in this
section do not necessarily apply to all facilities that fall within this sector.
Facility-specific conditions must be carefully considered when pollution
prevention options are evaluated, and the full impacts of the change must be
examined to determine how each option affects air, land and water pollutant
releases.
The bulk manufacturing processes of the pharmaceutical industry are
characterized by a low ratio of finished product to raw material. Therefore,
large quantities of residual waste are generated, especially in fermentation and
natural product extraction. Chemical synthesis processes generate wastes
containing hazardous spent solvents and reactants, combined with residual
wastes such as reaction residues. Equipment cleaning water and residue, often
containing hazardous chemicals, also are a major waste stream (U.S. EPA,
1991).
Sector Notebook Project
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Pharmaceutical Industry
Pollution Prevention Opportunities
Source reduction is one method by which the industry aims to reduce these
wastes. However, source reduction methods such as process modifications
and material substitutions may not be as easily implemented in the
pharmaceutical industry as in other manufacturing sectors. This is because
any significant change to the production process of an existing product, may
need approval from the Food and Drug Administration (FDA). If a company
wishes to change the method of making a drug or active ingredient that goes
into it, the FDA requires the company to prove that the 'new' drug is of the
same or better quality as the old drug and that any reformulation will not
adversely affect the identity, strength, quality, purity, or bioavailability of the
drug. The process of gathering information to support the change and
awaiting FDA review and approval can be lengthy, time-consuming and
expensive.
As a result, many pharmaceutical companies are looking at ways to minimize
waste in future production processes at the research and development stage.
Incorporating pollution prevention at the start of a new drug development
process is much more economical, efficient, and environmentally sound (see
Section VI. D. for further details). The factors affecting the pharmaceutical
industry's pollution prevention efforts were documented by PhRMA members
in a 1997 document entitled Pharmaceutical Industry Waste Minimization
Initiatives.
Many pharmaceutical companies have already implemented pollution
prevention programs in their manufacturing facilities. Although pollution
prevention may not always be a substitute for control technologies, it is often
viable and is an increasingly popular method for meeting environmental
compliance requirements. Some examples of innovative waste reduction
programs that incorporate source reduction as well as recycling and reuse are
presented in the case studies that appear in this section.
Sector Notebook Project
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September 1997
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Pharmaceutical Industry
Pollution Prevention Opportunities
V.A. Material Substitutions
Substituting raw materials to lessen the volume and/or toxicity of waste
generated is a type of source reduction (U.S. EPA, 1991). One of the most
common opportunities for material substitutions in the Pharmaceuticals
industry is found in the tablet coating process. Until recently, many tablet
coating operations involved the use of methylene chloride and other
chlorinated solvents. By switching to aqueous-based coating films, many
firms have reduced the hazardous waste content in their air and effluent waste
streams, as well as the cost of purchasing chemicals. Aqueous-based cleaning
solutions are also being used more frequently for equipment cleaning instead
of solvent-based solutions (U.S. EPA, 1991).
Sector Notebook Project
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September 1997
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Pharmaceutical Industry
Pollution Prevention Opportunities
POLLUTION PREVENTION CASE STUDIES
Material Substitution
• Schering-Plough Pharmaceuticals will market a new inhaler for the treatment of
asthma, which is free of chlorofluorocarbons (CFCs). The CFC-free inhaler was
developed by 3M Pharmaceuticals. CFCs are used as a propellant in metered-dose
inhalers (MDI). In a new MDI, which was approved by the FDA in August, 1996,
CFCs have been replaced by hydrofluoroalkane-134a (HFA-134a). Unlike CFCs,
HFA-134a does not deplete the ozone. The product will be marketed under the
brand name Proventil® HFA.
• Schering-Plough Laboratories is switching to a coated natural kraft (CNK)
paperboard for its packaging. CNK is stronger and less expensive than the
previous packaging material, as well as recyclable and compostable. The
paperboard is not bleached with chlorine, but is coated with white clay coating.
Instead of mineral-based varnishes and inks, water and soy-based materials are
used. In New Jersey alone, the company is expected to save $225,000 per year
and could save up to $1.2 million if the program expands to other divisions.
• At its West Point, PA, facility, Merck removed 1,1,1 -Trichloroethane (TCA) from
its production bperations. TCA was used in stripping labels off bottles and other
cleaning operations, printing, and manufacturing. A citrus-based solvent was
substituted for cleaning packaging equipment. For cleaning manufacturing
equipment, a petroleum-based solvent was substituted, the waste from which is
used for energy recovery in an off-site facility.
• At the same facility, Merck substituted phenol for thimerosal, a mercury-based
compound. Thimerosal had been used as a biocide to inactivate bacteria during the
initial stages of fermentation in the production of a vaccine. Substituting phenol, a
less-hazardous, FDA-approved biocide enabled Merck to achieve an 85 percent
reduction in mercury-based waste. In addition, the substitution resulted in
increased product yields, improved microbial kinetics, and cost savings for raw
materials.
• At its Cherokee plant in Riverside, PA, Merck developed an innovative new
manufacturing chemistry which substitutes toluene for dichloromethane. The
change has resulted in a 98 percent reduction in releases and transfers of
dichloromethane. In addition, because toluene is less volatile and more easily
recovered, the controls and recovery equipment on the new process are able to
control toluene releases such that they have increased only slightly.
Sector Notebook Project
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Pharmaceutical Industry
Pollution Prevention Opportunities
Material Substitution (cont)
• Riker Laboratories in Northbridge, CA recently replaced several different organic
solvent coating materials used on medicine tablets with a water-based coating
material. Differences in the new coating material required that new spray
equipment be installed. However, the company saves $15,000 per year not
purchasing these organic solvents and determined that $180,000 in pollution
control equipment was no longer needed. They estimate that the investment will
pay for itself in less than one year. The substitution prevents 24 tons per year in
organic solvent emissions, reduced exposure risks to workers, and has made it
easier for the company to comply with strict California air emission standards.
• In producing the anti-viral drug 6-aminopenicillanic acid, Bristol-Myers Squibb
used to extract the intermediate, penicillin V from an aqueous fermentation broth.
The broth was filtered and the intermediate then was extracted in several centrifuge
steps using the toxic solvent methyl isobutyl ketone (MiBK). The extraction was a
major source of fugitive emissions. The broth now is filtered through a membrane
and the intermediate is extracted using n-butyl acetate, a non-toxic chemical, in
closed centrifuges, reducing fugitive emissions. The overall capital investment for
this project came to almost $10 million. However, the annual operating cost
reductions, coupled with a 10 percent increase in throughput, generate $4.9 million
in additional cash flow. Based on this, the project will generate a return on
investment of 28 percent and a payback period of 2.7 years. In addition the project
reduced hazardous waste by 20,000 pounds and eliminated over one million pounds
of MiBK releases to the air and water.
• Glaxo-Wellcome, Inc. developed an innovative aqueous coating method that
eliminated the use of methylene chloride, isopropyl alcohol, methanol, and ethanol
in their Zantac tablet coating operations performed at their Zebulon, North Carolina
facility. Glaxo-Wellcome overcame a number of obstacles before using the
aqueous-based coating material on the Zantac production line. First, the
pharmaceutical active readily degraded at the extreme heat and moisture
encountered during aqueous coating. Also, the pharmaceutical active migrates
through the aqueous coating causing discolorization and degradation of the tablet
coating film. To implement the use of the substitute materials, Glaxo-Wellcome
had to make extensive changes to the coater spray assemblies, revamped the coater
air handling system with larger fans and heating coils, and installed a dehumidifying
system. The capital investment for this equipment was $1.5 million. However, the
company annually saves $286,800 in organic solvent purchases and $322,900 in
disposal costs of the more than 479 tons of hazardous waste generated by the old
system every year. The estimated payback period for the modifications is three
years. In addition, the new system cut VOC emissions to the air from almost
15,000 pounds per year to zero.
Sector Notebook Project
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September 1997
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Pharmaceutical Industry
Pollution Prevention Opportunities
Material Substitution (cont)
• The Pharmacia and Upjohn, Inc. Sterile Manufacturing area in Kalamazoo has
received FDA approval for a Thimerosal-free formulation of one of its products.
This new formulation will eliminate the use of Thimerosal, a mercury based
preservative, in the manufacture of the drug Atgam. Atgam will be manufactured
without any preservative using new closed column chromatography and Restrictive
Access Barrier technology. Atgam is used to prevent organ transplant rejection
and in the treatment of aplastic anemia.
• The Eli Lilly Cleaning Technology Center in late 1996 initiated a formal screening
program to identify potential aqueous based cleaners as replacements for the
various organic and chlorinated solvents currently used in bulk pharmaceutical
manufacturing equipment cleanings. In one product line, 8,700 liters of acetone per
cleaning was replaced with an alkaline aqueous based cleaner for an estimated
annual reduction of 17,400 liters of acetone. An acid aqueous based cleaner
replaced methanol in another product line, resulting in methanol reductions of
25,800 liters per year. In cleaning operations associated with another product, an
alkaline aqueous based cleaner replaced 117,000 liters of methanol and 600 liters of
ethylene dichloride per cleaning. This resulted in an estimated annual reduction of
368,000 liters of methanol and 1,200 liters of ethylene dichloride.
Sector Notebook Project
82
September 1997
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Pharmaceutical Industry
Pollution Prevention Opportunities
V.B. Process Modifications
Process modifications are alterations to or modernization of existing processes
to reduce waste generation. Process modifications can involve re-designing
chemical transfer systems to reduce spillage and other material losses. For
example, in batch operations, each loading and unloading of the reactors and
other equipment increases the risk of chemical spills and solvent vapor
releases. Batch operations often require more frequent reactor clean outs
using significant volumes of cleaning solution and solvents. With continuous
operations, the reactor is loaded once and solvents and reactants are fed into
the reactor continually, thereby reducing the risk of pollutant releases (US
EPA, 1991).
Thus switching from batch to continuous operations for certain products may
potentially reduce large volumes of wastes. Switching to a continuous or
partially continuous process may be possible for a facility that is the primary
producer of a product which is in constant demand. For example, Hoffmann
La Roche's facility in Nutley, NJ is one of the primary producers of Vitamin
E in the country. Consequently, much of their vitamin production equipment
is dedicated and run as semi-continuous operations.
Process changes that optimize reactions and raw material use can reduce
waste and releases to the environment (US EPA, 1995). Modifications as
simple as careful monitoring of reaction parameters (temperatures, pH, etc.)
can dramatically improve manufacturing efficiency. Production in many of the
large pharmaceutical companies is computerized and highly automated.
Computers equipped with computer aided design (CAD) programs visually
simulate the production process on the screen. The automated system allows
production managers to turn on the batch process and control temperatures,
pressure, and other process parameters, from the keyboard. While, the system
runs, production personnel are free to do other things such as check
equipment or take product samples. Such careful automated monitoring may
insure against the formation of fouling waste at the bottom of reactor vessels,
thereby reducing the need for additional cleaning, as well as lessening the risk
of damaged batches of product which have to be disposed (US EPA, 1991).
Sector Notebook Project
83
September 1997
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harmaceutical Industry
Pollution Prevention Qpportunitie
POLLUTION PREVENTION CASE STUDIES
Process Modifications
• As part of their "Environment 2000" program, Bristol-Myers Squibb has started to
look at Product Life Cycle (PLC) management as a way to implement pollution
prevention. PLC involves investigating the environmental impacts of a product at
every stage of production: R&D, manufacturing, and packaging. Pollution
prevention options are now being investigated at the very beginning of drug
development. This eliminates the possibility of lengthy Supplementary Drug
Approval applications with FDA. Using PLC management, Bristol-Myers Squibb
discovered the use of a filtration membrane for their 6-aminopenicillanic acid
production (see Section V.A. Case Studies).
• At its East Hanover, NJ facility, Sandoz Pharmaceutical Co. changed processes in
its reactors, to reduce solvent usage. An inert atmosphere above the reaction
mixture is used during synthesis to protect the reaction from exposure to oxygen.
In the previous process, nitrogen flowed continuously over the mixture, carrying
away with it a certain amount of solvent vapors. The nitrogen gas blanketing
process uses a non-flowing nitrogen layer that only bleeds out a very small amount
of nitrogen and solvent.
• In their main drug development lab in Tippecanoe, IN, Eli Lilly and Company has
implemented a pollution prevention program. Beginning in the R&D phase, the
company assesses the environmental impacts of every new product and determines
where wastes can be minimized. As a result, Eli Lilly developed a new process
which eliminated the use of methylene chloride, aluminum wastes, use of an
odoriferous raw material, and all distillation steps from production of a drug under
development for the treatment of osteoporosis.
• One of Hoffmann La Roche's major manufacturing processes uses glycol ether as
an extractive solvent, much of which had to be disposed of as wastewater. After
the product is recovered, the glycol ether is distilled and reused. The overhead.
from the distillation is primarily water with some glycol ether which is disposed as
wastewater. The process was redesigned to increase per pass recycle of the glycol
ether in the distillation column by 12%. As a result, use of the chemical was
reduced by about 60% and solvent releases decreased by 300,000 pounds per year
and the batch cycle time was reduced by four hours. Annual savings are $250,000.
Sector Notebook Project
84
September 1997
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Pharmaceutical Industry
Pollution Prevention Opportunities
Process Modifications (cont)
• At one of its facilities, Hoffman La Roche was using 110,000 gallons of methanol per
year for cleaning equipment during product changeovers. Methanol was being used
for all cleaning and rinsing stages. To reduce methanol usage and the associated
waste disposal costs, a new method was developed whereby a two-stage water-based
cleaning is done before a final methanol rinse. This reduced the amount of methanol
used to about 30,000 gallons per year and saves about $49,000 per year.
• In one of its manufacturing processes, Hoffman La Roche extracted a synthesized
pharmaceutical intermediate from toluene into water, and then from water into
chloroform. Because toluene was soluble in the extraction, it contaminated the
chloroform and created a waste stream of the mixed solvents. The company eliminated
the waste stream by steam-distilling the toluene from the water so that the toluene
never came in contact with the chloroform. Chloroform use decreased by 76 percent
which was sufficient to remove this material from the list of chemicals the facility was
required to include in its Toxic Release Inventory report. The project saved $22,000
per year.
• At its West Point, PA facility, Merck Co. made a simple change in the sequence of
process steps used to manufacture a vaccine, which resulted in a substantial reduction
of mercury-based wastes. Thimerisol, a mercury-based chemical, was used as a
preservative during an intermediate process step. Thus any waste stream produced
during the rest of the process was contaminated with mercury. A process change was
initiated to add thimerosal at the end of the process. By climating mercury in waste
streams generated prior to the addition of thimerisol, mercury contaminated wastes
generated during manufacturing were dramatically reduced.
• At its Flint River plant in Albany, Georgia, Merck used steam jets to produce a
vacuum in the process vessel during the production of an antibiotic. This results in
dichloromethane being mixed with steam and subsequently evaporating into the air.
The steam jets were replaced with liquid ring vacuum pumps which reduced air
emissions. Dichloromethane emissions were further reduced by maintaining the
vacuum pump seal fluid at subzero temperatures which condenses the
dichloromethane vapor so it can be recycled and reused.
• Pharmacia and Upjohn's wastewater treatment process was modified to significantly
reduce waste disposed by its Underground Injection Control operation. A
modification suggested by an employee eliminated about 1 million pounds of solid
waste. This modification involved substituting a bag filter for a precoat vacuum filter.
The precoat vacuum filter used a diatomaceous filter medium, which generated large
volumes of solid waste. The bag filter creates much less waste per volume of liquid
filtered. The used filter bags are incinerated on site, thereby greatly reducing landfill
wastes.
Sector Notebook Project
85
September 1997
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Pharmaceutical Industry
Pollution Prevention Opportunities
Process Modifications (cont)
• In converting to a new process for bioconversion of a steroid intermediate, Pharmacia
and Upjohn, Inc. has eliminated approximately 90,000 pounds of dimethylformamide
waste and approximately 190,000 pounds of filter aid waste per year. In addition,
solvent handling was reduced from about 6 million pounds to about 600,000 pounds
and aqueous waste was reduced more than 4 million pounds per year.
Sector Notebook Project
86
September 1997
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V.C. Good Operating Practices
One of the easiest and most economical ways to achieve source reduction is
to implement good operating practices. Pharmaceutical companies already
follow a list of Good Manufacturing Practices (GMP) guidelines outlined by
the FDA. In some cases these involve good operating practices that will
reduce raw materials use and waste generation. As a result, many companies
have developed environmental policies for all of their facilities, both in the
U.S. and abroad. Typically, policies may be written for employee training,
employee health and safety, hazardous chemical spill cleanup procedures,
equipment maintenance procedures, leak detection, and emergency response
procedures.
Management commitment. Good operating practices start with on-site
commitment and understanding of the need and methods for pollution
prevention, from top management levels to the plant floor. Without facility-
wide efforts to reduce pollution, source reduction may not be successful (US
EPA, 1991).
Employee training. An employee training program is essential to the success
of a source reduction program. Employees should be trained in safe handling
of equipment, chemicals, and wastes. They should also be informed of any
potentially harmful health effects of the hazardous chemicals they handle. As
well as being trained in proper operation of equipment and chemical handling,
employees should be trained in spill cleanup and methods for detecting
chemical releases (US EPA, 1991).
Maintenance programs. Maintenance programs should target both
preventive and corrective maintenance of equipment. This means that
equipment should be regularly checked and cleaned to insure its proper
functioning, and damaged equipment should be repaired quickly. Routine
cleaning, minor adjustments, testing and replacement of parts, should be a part
of the maintenance program. Additionally, good record keeping of equipment
checks, repairs, cleaning, and equipment failure will help to reduce the
likelihood of future equipment breakdowns and any associated pollution
releases (US EPA, 1991).
Inventory control. The wide range of chemicals used in the pharmaceutical
industry makes it essential to instigate an efficient inventory tracking system,
such as a "first-in, first-out" policy and chemicals must be properly labeled
with their name, date of purchase, and date of expiration. This helps to insure
that older, un-used chemicals do not have to be needlessly discarded (US
EPA, 1991). In addition, having one person responsible for the distribution of
chemicals and supplies insures a more efficient tracking system (US EPA,
1995). Inventory tracking is a valuable and easy method for reducing wastes.
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Spill prevention and storage. Spill and leak prevention are critical to
pollution prevention. Tightly secured storage tanks are a key to avoiding
spills. Containers should have good valves with tight stopping devices to
avoid the spilling or dripping of hazardous chemicals. Storage containers
should have legible signs indicating the contents of the container, health
hazard warnings (where necessary), and spill cleanup procedures in case of
emergencies. Large drums can be raised above the ground to avoid corrosion.
An organized storage area facilitates fast and easy removal of chemicals, as
well as reduction and cleanup of spills (U.S. EPA, 1991).
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POLLUTION PREVENTION CASE STUDIES
Good Operating Practices
• At its Kenilworth, NJ facility, Schering-Plough Pharmaceuticals has a central
warehouse with a computerized inventory system. Raw materials come into the
warehouse in large volumes. Materials are weighed according to batch
requirements, labeled, and then sent to different process areas throughout the
facility. This eliminates excess raw material wastes and ensures that only the
amounts needed are used.
• Sandoz Pharmaceuticals has also developed a system to improve scheduling of
batch operations in their facilities worldwide and domestically. Accurate
scheduling reduces the chances of excess wastes and costs, which occur when a
batch changeover takes place.
• At its Nutley, NJ plant, Hoffmann La Roche was able to identify and repair more
than 900 sources of fugitive emissions. In addition, the company installed ultra-low
temperature condensers to remove solvents from vent streams. The captured
solvents are recycled or treated off-site.
• The Pharmacia and Upjohn, Inc. Puerto Rico Technical Operations group was the
first offshore location to implement the company's pollution prevention program.
The local pollution prevention team helps the plant set pollution prevention goals.
The team reports progress toward meeting goals annually. As a result, the Butyl
Alcohol recovery efficiency at the facility has been increased to 95% and Acetone
to 96%. The facility has been tracking waste indices (Tons of waste generated vs.
Kilograms of product produced) and results for several wastes show reductions
over a four-year period. The pollution prevention program has been fully
implemented at all Pharmacia and Upjohn U.S. sites. Under the program individual
business units set goals and report on progress annually. More than 300 pollution
prevention projects, many of them in the research and development areas, have
been recorded since the program started in 1990.
• The Chemical and Fermentation operation at Pharmacia and Upjohn, Inc. in
Kalamazoo has begun using interlocked valve systems on jacketed coolers. The
new valve systems help prevent the inadvertent discharge of methanol, used as
refrigerant, to surface waters. They also have begun using new drip-less pipe
couplers to reduce solvent losses and spills from hose connections.
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V.D. Recycling, Recovery, and Reuse
"Recovery and recycling include direct reuse of waste material, recovering
used materials for a separate use, and removing impurities from waste to
obtain relatively pure substances" (EPA 1991). Although "strict quality
control requirements of the pharmaceutical industry often restrict reuse
opportunities, some do exist" (EPA 1991) and are considered valuable by the
industry since they reduce the volume of raw materials used and the amount
of waste generated and disposed.
Except for in-process recycling, EPA does not consider recycling, recovery,
and reuse to be source reduction techniques. However, in-process recycling,
which includes the reuse or recirculation of a chemical within a process and
may include recovery or reclamation, is considered a source reduction
technique. The pharmaceutical industry often uses this form of recycling
which is dedicated to and physically integrated with the pharmaceutical
manufacturing process by means of piping or another form of conveyance.
Recycling and recovery provides the pharmaceutical industry a great
opportunity to reduce the volume and toxicity of spent solvents. As
described in Section 3, solvents are used for a wide range of applications,
from synthesis, extraction, and purification of active ingredients to cleaning
process equipment. The types of solvent recovery employed include
distillation, evaporation, decantation, centrifugation, and filtration. However,
limitations exist with both on and off-site recycling and recovery since several
types of solvents (including water), reactants, and other contaminants may be
present. These materials must be extracted to allow the solvent to be reused"
either in a pharmaceutical process or in another process. Additionally, special
techniques and equipment must be used to break azeotropes formed during
the chemical reactions.
In addition to solvents, some residual wastes may also be recovered and
reused. For example, filter cakes from fermentation processes are usually
disposed of in landfills. An alternative being used in some facilities is to
collect the waste filter cakes, recover any valuable by-products, and then sell
the cakes to be used as fertilizers or soil additives. To be used as a fertilizer,
the nitrogen, phosphorus, and potassium content must be greater than 5%,
which sometimes can be achieved by reducing the moisture content in the
filter cake (US EPA, 1991).
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POLLUTION PREVENTION CASE STUDIES
Recycling, Recovery, and Reuse
• Nycomed Inc. manufactures bulk pharmaceutical products by batch processing. In
processing a product for medical diagnostic imaging, the company installed closed
loop distillation units to recover all of its methanol washes and methanol-containing
wastewater. The methanol recovery system can distill approximately 2,000 gallons
per day of 70 percent methanol to more than 99.5 percent methanol, which can be
reused in the same process. Nycomed Inc. eliminated water discharges of
methanol, reduced hazardous waste, and saved approximately 680,000 pounds of
methanol in the first half of 1992, saving $54,438 in the same period.
• The Pharmacia and Upjohn, Inc. Chemical and Fermentation operation in
Kalamazoo reuses more than 195 million pounds of solvent annually.
Approximately 80% of the site's total solvent requirement and 90% of the site's
chlorinated solvent requirement is met by reused solvent. The reused solvent
demand is met through a combination of in process solvent reuse (150 million
pounds) and distillation (45 million pounds). There are now six centralized
distillation units. On site solvent reuse and recovery in chemical processes helped
the company exceed its 33/50 Program goals. The achievement was
commemorated by a National Performance Review Environmental Champion
Award given to the company by Vice President Al Gore in 1995.
• Pharmacia and Upjohn, Inc. Chemical Process Research and Development
developed a proprietary distillation process for splitting Tetrahydrofiiran from a
mixture of alcohol, water, and other wastes. Without the new process,
Tetrahydrofliran forms azeotropic mixtures with alcohol which cannot be distilled.
This process now recovers approximately 1 million pounds of THF per year.
• Pharmacia and Upjohn, Inc. is evaluating the possibilities of reusing waste solvent
condensate produced from their cryogenic air pollution control equipment. They
have identified one methylene chloride rich stream to recover as a trial. An
estimated 2.5 million pounds of this waste solvent is generated annually. Recovery
by an off-site recycler or on site reclamation are being further evaluated.
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V.E. Pollution Prevention Research
Because of comprehensive regulations from both the FDA and the EPA,
pharmaceutical companies are continuously researching new and innovative
ways to reduce their wastes. Many companies are starting to look at pollution
prevention options early in development and are collaborating with
universities and other research institutions to develop new technologies that
will help reduce or eliminate wastes. Some of these technologies, still in the
research and testing stages, are discussed below.
Solvent Minimization
One potential research area which has been identified is in supercritical
solvents. Supercritical fluids are known to be very effective solvents and can
function as an alternative to traditional chlorinated and other toxic solvents
used in pharmaceutical separations. These solvents are in a supercritical state,
meaning that they are at a very high temperature and/or pressure. A
relatively small change in the temperature and/or pressure in supercritical state
can lead to large changes in the solubility of chemicals in the solvent. This
increase in solubility is ideal for separations because the overall volume of
solvent needed is reduced (NJIT, 1991).
Separation Improvements
Separation of active ingredients from solvents is one of the most important
processes in the pharmaceutical industry. Research has been conducted to
find separation methods which generate fewer by-products and less waste.
One technology with such a potential is inorganic membrane reactors. "They
are in effect reactors with built-in separators which may have potential for
reaction sequences with much better reactor utilization and product
concentrations" (NJIT, 1991). Inorganic membranes enable a continuous
removal of product and a controlled addition of reactant. This increases the
potential for higher yields and greater selectivity by chemicals, which could
reduce the volume of solvents required, thereby reducing costs and wastes.
Also, because the reaction and separation are combined in a single step, the
emissions associated with the traditional transfer step between reaction and
separation are eliminated (NJIT, 1991).
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Federal Statutes and Regulations
VI. SUMMARY OF APPLICABLE FEDERAL STATUTES AND REGULATIONS
This section discusses the Federal regulations that may apply to this sector.
The purpose of this section is to highlight and briefly describe the applicable
Federal requirements, and to provide citations for more detailed information.
The three following sections are included:
Section VI. A contains a general overview of major statutes
Section VLB contains a list of regulations specific to this industry
Section VI. C contains a list of pending and proposed regulations
Section VI.D contains a general overview of other federal statutes applicable
to the industry
Section VIE. contains a general overview of state regulations affecting the
industry.
The descriptions within Section VI are intended solely for general
information. Depending upon the nature or scope of the activities at a
particular facility, these summaries may or may not necessarily describe all
applicable environmental requirements. Moreover, they do not constitute
formal interpretations or clarifications of the statutes and regulations. For
further information readers should consult the Code of Federal Regulations
and state or local regulatory agencies. EPA Hotline contacts are also
provided for each major statute.
VI.A. General Description of Major Statutes
Resource Conservation And Recovery Act (RCRA)
RCRA of 1976, which amended the Solid Waste Disposal Act, addresses solid
(Subtitle D) and hazardous (Subtitle C) waste management activities. The
Hazardous and Solid Waste Amendments (HSWA) of 1984 strengthened
RCRA's waste management provisions and added Subtitle I, which governs
underground storage tanks (USTs).
Regulations promulgated pursuant to Subtitle C of RCRA (40 CFR Parts
26.0-299) establish a "cradle-to-grave" system governing hazardous waste
from the point of generation to disposal. RCRA hazardous wastes include the
specific materials listed in the regulations (commercial chemical products,
designated with the code "P" or "U"; hazardous wastes from specific
industries/sources, designated with the code "K"; or hazardous wastes from
non-specific sources, designated with the code "F") or materials which exhibit
a hazardous waste characteristic (ignitability, corrosivity, reactivity, or toxicity
and designated with the code "D").
Regulated entities that generate hazardous waste are subject to waste
accumulation, manifesting, and record keeping standards. Facilities must
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obtain a permit either from EPA or from a State agency which EPA has
authorized to implement the permitting program if they store hazardous
wastes for more than 90 days before treatment or disposal. Facilities may
treat hazardous waste stored in less-than-ninety-day tanks or containers
without a permit. Subtitle C permits contain general facility standards such
as contingency plans, emergency procedures, record keeping and reporting
requirements, financial assurance mechanisms, and unit-specific standards.
RCRA also contains provisions (40 CFR Part 264 Subpart S and §264.10) for
conducting corrective actions which govern the cleanup of releases of
hazardous waste or constituents from solid waste management units at
RCRA-regulated facilities.
Although RCRA is a Federal statute, many States implement the RCRA
program. Currently, EPA has delegated its authority to implement various
provisions of RCRA to 47 of the 50 States and to two U.S. territories.
Delegation has not been given to Alaska, Hawaii, or Iowa.
Most RCRA requirements are not industry specific but apply to any company
that generates, transports, treats, stores, or disposes of hazardous waste.
Here are some important RCRA regulatory requirements:
Identification of Solid and Hazardous Wastes (40 CFR Part 261)
lays out the procedure every generator should follow to determine
whether the material in question created is considered a hazardous
waste, solid waste, or is exempted from regulation.
Standards for Generators of Hazardous Waste (40 CFR Part 262)
establishes the responsibilities of hazardous waste generators including
obtaining an EPA ID number, preparing a manifest, ensuring proper
packaging and labeling, meeting standards for waste accumulation
units, and record keeping and reporting requirements. Generators can
accumulate hazardous waste for up to 90 days (or 180 days depending
on the amount of waste generated) without obtaining a permit.
Land Disposal Restrictions (LDRs) (40 CFR Part 268) are
regulations prohibiting the disposal of hazardous waste on land
without prior treatment. Under the LDRs program, materials must
meet LDR treatment standards prior to placement in a RCRA land
disposal unit (landfill, land treatment unit, waste pile, or surface
impoundment). Generators of waste subject to the LDRs must provide
notification of such to the designated TSD facility to ensure proper
treatment prior to disposal.
Used Oil Management Standards (40 CFR Part 279) impose
management requirements affecting the storage, transportation,
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burning, processing, and re-refining of the used oil. For parties that
merely generate used oil, regulations establish storage standards. For
a party considered a used oil processor, re-refiner, burner, or marketer
(one who generates and sells off-specification used oil), additional
tracking and paperwork requirements must be satisfied.
RCRA contains unit-specific standards for all units used to store,
treat, or dispose of hazardous waste, including Tanks and
Containers. Tanks and containers used to store hazardous waste
with a high volatile organic concentration must meet emission
standards under RCRA. Regulations (40 CFR Part 264-265, Subpart
CC) require generators to test the waste to determine the
concentration of the waste, to satisfy tank and container emissions
standards, and to inspect and monitor regulated units. These
regulations apply to all facilities that store such waste, including large
quantity generators accumulating waste prior to shipment off-site.
Underground Storage Tanks (USTs) containing petroleum and
hazardous substances are regulated under Subtitle I of RCRA.
Subtitle I regulations (40 CFR Part 280) contain tank design and
release detection requirements, as well as financial responsibility and
corrective action standards for USTs. The UST program also
includes upgrade requirements for existing tanks that must be met by
December 22, 1998. .
Boilers and Industrial Furnaces (BIFs) that use or burn fuel
containing hazardous waste must comply with strict design and
operating standards. BIF regulations (40 CFR Part 266, Subpart H)
address unit design, provide performance standards, require emissions
monitoring, and restrict the type of waste that may be burned.
EPA's RCRA/Superfund/UST Hotline, at (800) 424-9346, responds to
questions and distributes guidance regarding all RCRA regulations. The
RCRA Hotline operates weekdays from 9:00 a.m. to 6:00 p.m., ET, excluding
Federal holidays.
Comprehensive Environmental Response, Compensation, And Liability Act (CERCLA)
CERCLA, a 1980 law commonly known as Superfund, authorizes EPA to
respond to releases, or threatened releases, of hazardous substances that may
endanger public health, welfare, or the environment. CERCLA also enables
EPA to force parties responsible for environmental contamination to clean it
up or to reimburse the Superfund for response costs incurred by EPA. The
Superfund Amendments and Reauthorization Act (SARA) of 1986 revised
various sections of CERCLA, extended the taxing authority for Superfund,
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and created a free-standing law, SARA Title III, also known as the
Emergency Planning and Community Right-to-Know Act (EPCRA).
The CERCLA hazardous substance release reporting regulations (40 CFR
Part 302) direct the person in charge of a facility to report to the National
Response Center (NRC) any environmental release of a hazardous substance
which equals or exceeds a reportable quantity. Reportable quantities are
defined and listed in 40 CFR §302.4. A release report may trigger a response
by EPA, or by one or more Federal or State emergency response authorities.
EPA implements hazardous substance responses according to procedures
outlined in the National Oil and Hazardous Substances Pollution Contingency
Plan (NCP) (40 CFR Part 300). The NCP includes provisions for permanent
cleanups, known as remedial actions, and other cleanups referred to as
"removals." EPA generally takes remedial actions only at sites on the
National Priorities List (NPL), which currently includes approximately 1300
sites. Both EPA and states can act at other sites; however, EPA provides
responsible parties the opportunity to conduct removal and remedial actions
and encourages community involvement throughout the Superfund response
process.
EPA's RCRA/Superfund and EPCRA Hotline, at (800) 424-9346, answers
questions and references guidance pertaining to the Superfund program.
The CERCLA Hotline operates weekdays from 9:00 a.m. to 6:00 p.m., ET,
excluding Federal holidays.
Emergency Planning And Community Right-To-Know Act (EPCRA)
The Superfund Amendments and Reauthorization Act (SARA) of 1986
created EPCRA, also known as SARA Title m, a statute designed to improve
community access to information about chemical hazards and to facilitate the
development of chemical emergency response plans by State and local
governments. EPCRA required the establishment of State emergency
response commissions (SERCs), responsible for coordinating certain
emergency response activities and for appointing local emergency planning
committees (LEPCs).
EPCRA and the EPCRA regulations (40 CFR Parts 350-372) establish four
types of reporting obligations for facilities which store or manage specified
chemicals:
EPCRA §302 requires facilities to notify the SERC and LEPC of the
presence of any "extremely hazardous substance" (the list of such
substances is in 40 CFR Part 355, Appendices A and B) if it has such
substance in excess of the substance's threshold planning quantity, and
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directs the facility to appoint an emergency response coordinator.
EPCRA §304 requires the facility to notify the SERC and the LEPC
in the event of a release equaling or exceeding the reportable quantity
of a CERCLA hazardous substance or an EPCRA extremely
hazardous substance.
EPCRA §311 and §312 require a facility at which a hazardous
chemical, as defined by the Occupational Safety and Health Act, is
present in an amount exceeding a specified threshold to submit to the
SERC, LEPC and local fire department material safety data sheets
(MSDSs) or lists of MSDS's and hazardous chemical inventory forms
(also known as Tier I and II forms). This information helps the local
government respond in the event of a spill or release of the chemical.
EPCRA §313 requires manufacturing facilities included in SIC codes
20 through 39, which have ten or more employees, and which
manufacture, process, or use specified chemicals in amounts greater
than threshold quantities, to submit an annual toxic chemical release
report. This report, commonly known as the Form R, covers releases
and transfers of toxic chemicals to various facilities and environmental
media, and allows EPA to compile the national Toxic Release
Inventory (TRI) database.
All information submitted pursuant to EPCRA regulations is publicly
accessible, unless protected by a trade secret claim.
EPA'sRCRA, Superfund and EPCRA Hotline, at (800) 424-9346, answers
questions and distributes guidance regarding the emergency planning and
community right-to-know regulations. The EPCRA Hotline operates
weekdays from 9:00 a.m. to 6:00 p.m., ET, excluding Federal holidays.
Clean Water Act (CWA)
The primary objective of the Federal Water Pollution Control Act, commonly
referred to as the CWA, is to restore and maintain the chemical, physical, and
biological integrity of the nation's surface waters. Pollutants regulated under
the CWA include "priority" pollutants and various toxic pollutants;
"conventional" pollutants, such as biochemical oxygen demand (BOD), total
suspended solids (TSS), fecal coliform, oil and grease, and pH; and "non-
conventional" pollutants which are pollutants not identified as either
conventional or priority.
The CWA regulates both direct and indirect discharges. The National
Pollutant Discharge Elimination System (NPDES) program (CWA §402)
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controls direct discharges into navigable waters. Direct discharges or "point
source" discharges are from sources such as pipes and sewers. NPDES
permits, issued by either EPA or an authorized State (EPA has authorized 42
States to administer the NPDES program), contain industry-specific,
technology-based and/or water quality-based limits, and establish pollutant
monitoring requirements. A facility that intends to discharge into the nation's
waters must obtain a permit prior to initiating its discharge. A permit
applicant must provide quantitative analytical data identifying the types of
pollutants present in the facility's effluent. The permit will then set forth the
conditions and effluent limitations under which a facility may make a
discharge.
A NPDES permit may also include discharge limits based on Federal or State
water quality criteria or standards that were designed to protect designated
uses of surface waters, such as supporting aquatic life or recreation. These
standards, unlike the technological standards, generally do not take into
account technological feasibility or costs. Water quality criteria and standards
vary from state to state, and site to site, depending on the use classification
of the receiving body of water. Most states follow EPA guidelines, which
propose aquatic life and human health criteria for many of the 126 priority
pollutants.
Storm Water Discharges
In 1987 the CWA was amended to require EPA to establish a program to
address storm water discharges. In response, EPA promulgated the NPDES
storm water permit application regulations. These regulations require that
facilities with the following storm water discharges apply for an NPDES
permit: (1) a discharge associated with industrial activity; (2) a discharge
from a large or medium municipal storm sewer system; or (3) a discharge
which EPA or the State determines to contribute to a violation of a water
quality standard or is a significant contributor of pollutants to waters of the
United States.
The term "storm water discharge associated with industrial activity" means a
storm water discharge from one of 11 categories of industrial activity defined
at 40 CFR 122.26. Six of the categories are defined by SIC codes while the
other five are identified through narrative descriptions of the regulated
industrial activity. If the primary SIC code of the facility is one of those
identified in the regulations, the facility is subject to the storm water permit
application requirements. If any activity at a facility is covered by one of the
five narrative categories, storm water discharges from those areas where the
activities occur are subject to storm water discharge permit application
requirements.
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Those facilities/activities that are subject to storm water discharge permit
application requirements are identified below. To determine whether a
particular facility falls within one of these categories, the regulation should be
consulted.
Category i: Facilities subject to storm water effluent guidelines, new
source performance standards, or toxic pollutant effluent standards.
Category ii: Facilities classified as SIC 24-lumber and wood
products (except wood kitchen cabinets); SIC 26-paper and allied
products (except paperboard containers and products); SIC 28-
chemicals and allied products (except drugs and paints); SIC 291-
petroleum refining; and SIC 311-leather tanning and finishing, 32
(except 323)-stone, clay, glass, and concrete, 33-primary metals,
3441-fabricated structural metal, and 3 73-ship and boat building and
repairing.
Category iii: Facilities classified as SIC 10-metal mining; SIC 12-
coal mining; SIC 13-oil and gas extraction; and SIC 14-nonmetallic
mineral mining.
Category iv:
facilities.
Hazardous waste treatment, storage, or disposal
Category v: Landfills, land application sites, and open dumps that
receive or have received industrial wastes.
Category vi: Facilities classified as SIC 5015-used motor vehicle
parts; and SIC 5093-automotive scrap and waste material recycling
facilities.
Category vii: Steam electric power generating facilities.
Category viii: Facilities classified as SIC 40-railroad transportation;
SIC 41-local passenger transportation; SIC 42-trucking and
warehousing (except public warehousing and storage); SIC 43-U.S.
Postal Service; SIC 44-water transportation; SIC 45-transportation by
air; and SIC 5171-petroleum bulk storage stations and terminals.
Category ix: Sewage treatment works.
Category x: Construction activities except operations that result in
the disturbance of less than five acres of total land area.
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Category xi: Facilities classified as SIC 20-food and kindred
products; SIC 21-tobacco products; SIC 22-textile mill products; SIC
23-apparel related products; SIC 2434-wood kitchen cabinets
manufacturing; SIC 25-furniture and fixtures; SIC 265-paperboard
containers and boxes; SIC 267-converted paper and paperboard
products; SIC 27-printing, publishing, and allied industries; SIC 283-
drugs; SIC 285-paints, varnishes, lacquer, enamels, and allied
products; SIC 30-rubber and plastics; SIC 31-leather and leather
products (except leather and tanning and finishing); SIC 3 23-glass
products; SIC 34-fabricated metal products (except fabricated
structural metal); SIC 35-industrial and commercial machinery and
computer equipment; SIC 36-electronic and other electrical
equipment and components; SIC 37-transportation equipment (except
ship and boat building and repairing); SIC 38-measuring, analyzing,
and controlling instruments; SIC 39-miscellaneous manufacturing
industries; and SIC 4221-4225-public warehousing and storage.
Pretreatment Program
Another type of discharge that is regulated by the CWA is one that goes to a
publicly-owned treatment works (POTWs). The national pretreatment
program (CWA §307(b)) controls the indirect discharge of pollutants to
POTWs by "industrial users." Facilities regulated under §307(b) must meet
certain pretreatment standards. The goal of the pretreatment program is to
protect municipal wastewater treatment plants from damage that may occur
when hazardous, toxic, or other wastes are discharged into a sewer system
and to protect the quality of sludge generated by these plants. Discharges to
a POTW are regulated primarily by the POTW itself, rather than the State or
EPA.
EPA has developed technology-based standards for industrial users of
POTWs. Different standards apply to existing and new sources within each
category. "Categorical" pretreatment standards applicable to an industry on
a nationwide basis are developed by EPA. In addition, another kind of
pretreatment standard, "local limits," are developed by the POTW in order to
assist the POTW in achieving the effluent limitations in its NPDES permit.
Regardless of whether a State is authorized to implement either the NPDES
or the pretreatment program, if it develops its own program, it may enforce
requirements more stringent than Federal standards.
Spill Prevention. Control and Countermeasure Plans
The 1990 Oil Pollution Act requires that facilities that could reasonably be
expected to discharge oil in harmful quantities prepare and implement more
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rigorous Spill Prevention Control and Countermeasure (SPCC) Plan required
under the CWA (40 CFR §112.7). There are also criminal and civil penalties
for deliberate or negligent spills of oil. Regulations covering response to oil
discharges and contingency plans (40 CFR Part 300), and Facility Response
Plans to oil discharges (40 CFR §112.20) and for PCB transformers and PCB-
containing items were revised and finalized in 1995.
EPA's Office of Water, at (202) 260-5700, will direct callers with questions
about the CWA to the appropriate EPA office. EPA also maintains a
bibliographic database of Office of Water publications -which can be
accessed through the Ground Water and Drinking Water resource center, at
(202) 260-7786.
Safe Drinking Water Act (SD WA)
The SDWA mandates that EPA establish regulations to protect human health
from contaminants in drinking water. The law authorizes EPA to develop
national drinking water standards and to create a joint Federal-State system
to ensure compliance with these standards. The SDWA also directs EPA to
protect underground sources of drinking water through the control of
underground injection of liquid wastes.
EPA has developed primary and secondary drinking water standards under its
SDWA authority. EPA and authorized states enforce the primary drinking
water standards, which are, contaminant-specific concentration limits that
apply to certain public drinking water supplies. Primary drinking water
standards consist of maximum contaminant level goals (MCLGs), which are
non-enforceable health-based goals, and maximum contaminant levels
(MCLs), which are enforceable limits set as close to MCLGs as possible,
considering cost and feasibility of attainment.
The SDWA Underground Injection Control (UIC) program (40 CFR Parts
144-148) is a permit program which protects underground sources of drinking
water by regulating five classes of injection wells. UIC permits include
design, operating, inspection, and monitoring requirements. Wells used to
inject hazardous wastes must also comply with RCRA corrective action
standards in order to have RCRA permit by rule status, and must meet
applicable RCRA land disposal restrictions standards. The UIC permit
program is primarily state-enforced, since EPA has authorized all but a few
states to administer the program.
The SDWA also provides for a Federally-implemented Sole Source Aquifer
program, which prohibits Federal funds from being expended on projects that
may contaminate the sole or principal source of drinking water for a given
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area, and for a State-implemented Wellhead Protection program, designed to
protect drinking water wells and drinking water recharge areas.
EPA's Safe Drinking Water Hotline, at (800) 426-4791, answers questions
and distributes guidance pertaining to SDWA standards. The Hotline
operates from 9:00a.m. through 5:30 p.m., ET, excluding Federal holidays.
Toxic Stibstances Control Act (TSCA)
TSCA granted EPA authority to create a regulatory framework to collect data
on chemicals in order to evaluate, assess, mitigate, and control risks which
may be posed by their manufacture, processing, and use. TSCA provides a
variety of control methods to prevent chemicals from posing unreasonable
risk.
TSCA standards may apply at any point during a chemical's life cycle. Under
TSCA §5, EPA has established an inventory of chemical substances. If a
chemical is not already on the inventory, and has not been excluded by TSCA,
a premanufacture notice (PMN) must be submitted to EPA prior to
manufacture or import. The PMN must identify the chemical and provide
available information on health and environmental effects. If available data
are not sufficient to evaluate the chemicals effects, EPA can impose
restrictions pending the development of information on its health and
environmental effects. EPA can also restrict significant new uses of chemicals
based upon factors such as the projected volume and use of the chemical.
Under TSCA §6, EPA can ban the manufacture or distribution in commerce,
limit the use, require labeling, or place other restrictions on chemicals that
pose unreasonable risks. Among the chemicals EPA regulates under §6
authority are asbestos, chlorofluorocarbons (CFCs), and polychlorinated
biphenyls (PCBs).
EPA's TSCA Assistance Information Service, at (202) 554-1404, answers
questions and distributes guidance pertaining to Toxic Substances Control
Act standards. The Service operates from 8:30 a.m. through 4:30 p.m., ET,
excluding Federal holidays.
Clean Air Act (CAA)
The CAA and its amendments, including the Clean Air Act Amendments
(CAAA) of 1990, are designed to "protect and enhance the nation's air
resources so as to promote the public health and welfare and the productive
capacity of the population." The CAA consists of six sections, known as
Titles, which direct EPA to establish national standards for ambient air quality
and for EPA and the States to implement, maintain, and enforce these
standards through a variety of mechanisms. Under the CAAA, many facilities
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will be required to obtain permits for the first time. State and local
governments oversee, manage, and enforce many of the requirements of the
CAAA. CAA regulations appear at 40 CFR Parts 50-99.
Pursuant to Title I of the CAA, EPA has established national ambient air
quality standards (NAAQSs) to limit levels of "criteria pollutants," including
carbon monoxide, lead, nitrogen dioxide, particulate matter, volatile organic
compounds (VOCs), ozone, and sulfur dioxide. Geographic areas that meet
NAAQSs for a given pollutant are classified as attainment areas; those that do
not meet NAAQSs are classified as non-attainment areas. Under § 110 of the
CAA, each State must develop a State Implementation Plan (SIP) to identify
sources of air pollution and to determine what reductions are required to meet
Federal air quality standards. Revised NAAQSs for particulates and ozone
were proposed in 1996 and may go into effect as early as late 1997.
Title I also authorizes EPA to establish New Source Performance Standards
(NSPSs), which are nationally uniform emission standards for new stationary
sources falling within particular industrial categories. NSPSs are based on the
pollution control technology available to that category of industrial source.
Under Title I, EPA establishes and enforces National Emission Standards for
Hazardous Air Pollutants (NESHAPs), nationally uniform standards oriented
towards controlling particular hazardous air pollutants (HAPs). Title I,
section 112(c) of the CAA further directed EPA to develop a list of sources
that emit any of 189 HAPs, and to develop regulations for these categories of
sources. To date, EPA has listed 174 categories and developed a schedule for
the establishment of emission standards. The emission standards will be
developed for both new and existing sources based on "maximum achievable
control technology (MACT)." The MACT is defined as the control
technology achieving the maximum degree of reduction in the emission of the
HAPs, taking into account cost and other factors.
Title II of the CAA pertains to mobile sources, such as cars, trucks, buses,
and planes. Reformulated gasoline, automobile pollution control devices, and
vapor recovery nozzles on gas pumps are a few of the mechanisms EPA'uses
to regulate mobile air emission sources.
Title IV of the CAA establishes a sulfur dioxide emissions program designed
to reduce the formation of acid rain. Reduction of sulfur dioxide releases will
be obtained by granting to certain sources limited emissions allowances,
which, beginning in 1995, will be set below previous levels of sulfur dioxide
releases.
Title V of the CAA of 1990 created a permit program for all "major sources"
(and certain other sources) regulated under the CAA. One purpose of the
operating permit is to include in a single document all air emissions
requirements that apply to a given facility. States are developing the permit
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programs in accordance with guidance and regulations from EPA. Once a
State program is approved by EPA, permits will be issued and monitored by
that State.
Title VI of the CAA is intended to protect stratospheric ozone by phasing out
the manufacture of ozone-depleting chemicals and restrict their use and
distribution. Production of Class I substances, including 15 lands of
chlorofluorocarbons (CFCs) and chloroform, were phased out (except for
essential uses) in 1996.
EPA's Clean Air Technology Center, at (919) 541-0800, provides general
assistance and information on CAA standards. The Stratospheric Ozone
Information Hotline, at (800) 296-1996, provides general information about
regulations promulgated under Title VI of the CAA, and EPA's EPCRA
Hotline, at (800) 535-0202, answers questions about accidental release
prevention under CAA §112(r). In addition, the Clean Air Technology
Center's website includes recent CAA rules, EPA guidance documents, and
updates of EPA activities (www.epa.gov/ttn then select Directory and then
CATC).
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VLB. Industry Specific Requirements
The pharmaceutical industry is affected by several major federal
environmental statutes. In addition, the industry is subject to numerous laws
and regulations from state and local governments designed to protect and
improve the nation's health, safety, and environment. A summary of the
major federal regulations affecting the pharmaceutical industry follows.
Clean Air Act (CAA)
The original CAA authorized EPA to set limits on pharmaceutical plant
emissions. Some of these new source performance standards (NSPS) apply
to pharmaceutical manufacturers including those for flares (40 CFR Part 60
Subpart A), and storage of volatile organic liquids (40 CFR Part 60 Subpart
Kb). The Clean Air Act Amendments of 1990 set control standards by
industrial sources for 41 pollutants to be met by 1995 and for 148 other
pollutants to be reached by 2003. Under the air toxics provisions of the
CAAA, more sources are covered including small businesses. The Hazardous
Organic National Emissions Standard for Hazardous Air Pollutants, also
known as HON, covers hundreds of chemicals and thousands of process units.
The pharmaceutical industry is affected by standards for equipment leaks (40
CFR Part 63 Subpart H), equipment leaks from pharmaceutical processes
using carbon tetrachloride or methylene chloride (40 CFR Part 63 Subpart I),
and standards for emissions from halogenated solvent cleaning (40 CFR Part
63 Subpart T). The HON also includes innovative provisions such as
emissions trading, that offer industry flexibility in complying with the rule's
emissions goals.
Specific industries are regulated under other National Emission Standards for
Hazardous Air Pollutants (NESHAP). These standards are being developed
for the pharmaceutical industry (see Section VI. C). Title V of the CAA
introduces a new permit system that will require all major sources to obtain
operating permits to cover all applicable control requirements. States were
required to develop and implement the program in 1993 and the first permits
were issued in 1994. In December 1994, Schering-Plough Pharmaceutical's
facility in Kenilworth, New Jersey, was the first in the nation to receive a
facility-wide permit under this Title V program.
Clean Water Act (CWA)
The Clean Water Act, first passed in 1972 and amended in 1977 and 1987,
gives EPA the authority to regulate effluents from sewage treatment works,
chemical plants, and other industrial sources into waters. The act sets "best
available" technology standards for treatment of wastes for both direct and
indirect (to a Publicly Owned Treatment Works (POTW)) discharges. In
1983, EPA proposed effluent guidelines for the pharmaceutical manufacturing
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point source category. These guidelines are currently undergoing revisions
(see Section VI. C). The implementation of the guidelines is left to the states
who issue National Pollutant Discharge Elimination System (NPDES) permits
for each facility.
The pharmaceutical manufacturing effluent guidelines for point source
category (40 CFR Part 439) is divided into process specific effluent guidelines
as follows:
Fermentation - 40 CFR Part 439 Subpart A,
Natural product extraction - 40 CFR Part 439 Subpart B,
Chemical synthesis - 40 CFR Part 439 Subpart C,
Mixing, compounding, formulation - 40 CFR Part 439 Subpart D, and
Research - 40 CFR Part 439 Subpart E.
Each Subpart consists of effluent limitations representing the amount of
effluent reduction possible by using either best practicable control
technologies (BPT), best conventional pollution technologies (BCT), or best
available technologies (BAT). BPTs are used for discharges from existing
point sources to control conventional and non-conventional pollutants as well
as some priority pollutants. BCTs are used for discharges from point sources
to control conventional pollutants. Finally, B ATs are used to control priority
pollutants and non-conventional pollutants when directly discharged into the
nation's waters. Standards are provided for cyanide, biologic oxygen demand
(BOD), chemical oxygen demand (COD), total suspended solids (TSS) and
pH. Guidelines for BCT and BAT for the research category, new source
performance standards (NSPS), and pre-treatment standards for new and
existing sources, are being revised and are in the final rule stage (see Section
VI. C).
The Storm Water Rule (40 CFR §122.26) requires pharmaceutical facilities
discharging storm water associated with industrial activities (40 CFR §122.26
(b)(14)(xi)) to apply for storm water permits.
Safe Drinking Water Act Underground Injection Control Program
The federal Underground Injection Control (UIC) program was established
under the provisions of the SDWA of 1974. This federal program prescribes
minimum requirements for effective state UIC programs. Since ground water
is a major source of drinking water in the United States, the UIC program
requirements were designed to prevent contamination of Underground
Sources of Drinking Water (USDW) resulting from the operation of injection
wells. A USDW is defined as an "aquifer or its portion which supplies any
public water system or contains a sufficient quantity of ground water to
supply a public water system, or contains less than 10,000 milligrams per liter
total dissolved solids and is not an exempted aquifer."
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Since the passage of the Safe Drinking Water Act, state and federal regulatory
agencies have modified existing programs or developed new strategies to
protect ground water by establishing regulations to control the permitting,
construction, operation, monitoring, and closure of injection wells. In
Michigan, where all five of the pharmaceutical industry's injection wells are
located, the state has not sought authority to implement the federal UIC
program but does regulate use of injection wells through state law. The EPA
is the responsible regulatory agency for implementing the UIC program in the
state.
The five wells used by the pharmaceutical companies in Michigan are termed
hazardous Class I injection wells since they inject hazardous waste into
formations below the USDW. The process of selecting a site for a Class I
disposal well involves evaluating many conditions with the most important
being the determination that the underground formations possess the natural
ability to contain and isolate the injected waste. A detailed study is conducted
to determine the suitability of the underground formation for disposal. The
receiving formation must be far below any usable ground waters and be
separated from them by confining layers of rock, which prevent fluid
migration into the ground water. The injection zone in the receiving
formation must be of sufficient size and have sufficient pore space to accept
and maintain the injected wastes.
Class I injection wells are regulated in 40 CFR Part 146, Subpart G. Subpart
G requires facilities with injection wells to submit operating reports and to
submit plans for testing and monitoring the wastes, hydrogeologic conditions,
condition of the well materials, mechanical integrity of the well, and ambient
conditions in adjacent aquifers. Subpart G also sets criteria for siting Class
I hazardous waste injection wells, construction requirements, corrective
action procedures, operating requirements, and closure plans.
Resource Conservation and Recovery Act (RCRA)
The Resource Conservation and Recovery Act (RCRA) was enacted in 1976
to address problems related to hazardous and solid waste management.
RCRA gives EPA the authority to establish a list of solid and hazardous
wastes and to establish standards and regulations for the treatment, storage,
and disposal of these wastes. Regulations in Subtitle C of RCRA address the
identification, generation, transportation, treatment, storage, and disposal of
hazardous wastes. These regulations are found in 40 CFR Part 124 and CFR
Parts 260-279. Under RCRA, persons who generate waste must determine
whether the waste is defined as solid waste or hazardous waste. Solid wastes
are considered hazardous wastes if they are listed by EPA as hazardous or if
they exhibit characteristics of a hazardous waste: toxicity, ignitability,
corrosivity, or reactivity.
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Products, intermediates, and off-specification products potentially generated
at pharmaceutical facilities that are considered hazardous wastes are listed in
40CFRPart261.33(f). Some of the handling and treatment requirements for
RCRA hazardous waste generators are covered under 40 CFR Part 262 and
include the following: determining what constitutes a RCRA hazardous waste
(Subpart A); manifesting (Subpart B); packaging, labeling, and accumulation
time limits (Subpart C); and record keeping and reporting (Subpart D).
Many pharmaceutical facilities store some hazardous wastes at the facility for
more than 90 days, and are therefore, a storage facility under RCRA. Storage
facilities are required to have a RCRA treatment, storage, and disposal facility
(TSDF) permit (40 CFR Part 262.34). Some pharmaceutical facilities are
considered TSDF facilities and are subject to the following regulations
covered under 40 CFR Part 264: contingency plans and emergency
procedures (40 CFR Part 264 Subpart D); manifesting, record keeping, and
reporting (40 CFR Part 264 Subpart E); use and management of containers
(40 CFR Part 264 Subpart I); tank systems (40 CFR Part 264 Subpart J);
surface impoundments (40 CFR Part 264 Subpart K); land treatment (40 CFR
Part 264 Subpart M); corrective action of hazardous waste releases (40 CFR
Part 264 Subpart S); air emissions standards for process vents of processes
that process or generate hazardous wastes (40 CFR Part 264 Subpart AA);
emissions standards for leaks in hazardous waste handling equipment (40 CFR
Part 264 Subpart BB); and emissions standards for containers, tanks, and
surface impoundments that contain hazardous wastes (40 CFR Part 264
Subpart CC).
A number of RCRA wastes have been prohibited from land disposal unless
treated to meet specific standards under the RCRA Land Disposal Restriction
(LDR) program. The wastes covered by the RCRA LDRs are listed in 40
CFR Part 268 Subpart C and include a number of wastes commonly generated
at pharmaceutical facilities. Standards for the treatment and storage of
restricted wastes are described in Subparts D and E, respectively.
Many pharmaceutical manufacturing facilities are also subject to the
underground storage tank (UST) program (40 CFR Part 280). The UST
regulations apply to facilities that store either petroleum products or
hazardous substances (except hazardous waste) identified under the
Comprehensive Environmental Response, Compensation, and Liability Act.
UST regulations address design standards, leak detection, operating practices,
response to releases, financial responsibility for releases, and closure
standards.
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Comprehensive Environmental Response Compensation and Liability Act (CERCLA)
The Comprehensive Environmental Response Compensation and Liability Act
of 1980 (CERCLA) and the Superfund Amendments and Reauthorization Act
of 1986 (SARA) provide the basic legal framework for the federal
"Superfund" program to clean up abandoned hazardous waste sites (40 CFR
Part 305). The 1986 SARA legislation extended these taxes for five years and
adopted a new broad-based corporate environmental tax, applicable to the
allied chemicals (SIC 28) industry, which includes the Pharmaceuticals
industry. In 1990, Congress passed a simple reauthorization that did not
substantially change the law but extended the program authority until 1994
and the taxing authority until the end of 1995. A comprehensive
reauthorization was considered in 1994, but not passed. Since the expiration
of the taxing authority on December 31, 1995, taxes for Superfund have been
temporarily suspended. The taxes can only be reinstated by reauthorization
of Superfund or an omnibus reconciliation act which could specifically
reauthorize taxing authority. The allied chemical industry pays about $300
million a year in Superfund chemical feedstock taxes. Superfund's liability
standard is such that Potentially Responsible Parties (PRPs) may pay the
entire cost of clean-up at sites, even though they may be responsible for only
a fraction of the waste.
Title HI of the 1986 SARA amendments (also known as Emergency Response
and Community Right-to-Know Act, EPCRA) requires all manufacturing
facilities, including pharmaceutical facilities, to report annual information to
the public about stored toxic substances as well as release of these substances
into the environment (42 U.S.C. 9601). This is known as the Toxic Release
Inventory (TRI). EPCRA also establishes requirements for federal, state, and
local governments regarding emergency planning. In 1994, over 300 more
chemicals were added to the list of chemicals for which reporting is required.
Toxic Substances Control Act (TSCA)
The pharmaceutical industry is specifically excluded from some of the
requirements of TSCA. Any drugs manufactured, processed, and distributed
in commerce are excluded by definition from the Inventory Reporting
Regulations (40 CFR Part 710.4(c)) and the Pre-Manufacturing Notice
requirements (40 CFR 720.30(a)) of TSCA.
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VI.C. Pending and Proposed Regulatory Requirements
Clean Air Act (CAA)
Under the Clean Air Act, National Emissions Standards for Hazardous Air
Pollutants (NESHAPS) are being developed for the pharmaceutical
manufacturing industry.
Clean Water Act (CWA)
As part of the Clean Water Act revision process, the effluent guidelines for
the pharmaceutical industry (40 CFR 439) are currently being revised and
reviewed. A major part of the review considers the inclusion of limitations
for toxic and non-conventional volatile organic pollutants. Additionally, the
1983 New Source Performance Standards (NSPS) for conventional pollutants
will also be reevaluated.
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VI.D. Other Federal Regulations Affecting the Pharmaceutical Industry
Food and Drug Administration (FDA)
The Food and Drug Administration (FDA) is part of the Department of
Health and Human Services. FDA has the statutory authority to regulate a
wide range of products such as prescription and over-the-counter drugs,
foods, biologies (e.g., blood plasma, vaccines), medical devices (e.g., needles'
heart valves), veterinary drugs, cosmetics and consumer goods that emit
radiation. This authority has been granted to FDA by Congress under various
laws including the Federal Food, Drug and Cosmetic Act and the Public
Health Service Act.
There are five Centers within FDA that deal with FDA-regulated articles:
Center for Drug Evaluation and Research (CDER), Center for Biologies
Evaluation and Research (CBER), Center for Veterinary Medicine (CVM),
Center for Devices and Radiological Health (CDRH), and Center for Food
Safety and Applied Nutrition (CFSAN). The Centers review scientific
information provided by persons wishing to place FDA-regulated articles into
interstate commerce in order to determine whether regulatory requirements
are met. FDA has offices throughout the U.S. where testing of FDA-
regulated articles is performed and where investigators are based.
Investigators go to U.S. and foreign manufacturing facilities and other types
of facilities involved in FDA-regulated activities to verify that they are in
compliance with FDA regulations.
FDA's general approach to regulating various articles is similar, however, due
to the diverse nature of these products, there are regulatory requirements
tailored to each type of FDA-regulated article. Below is a summary of
information relating to the type of products regulated by CDER. Additional
information on other FDA-regulated articles may be located in 21 CFR or by
contacting FDA directly.
The manufacturing facilities that produce drugs for human use are regulated
by CDER. The methods, facilities, and controls used for the manufacture,
processing, and packing of a drug are reviewed by FDA to determine whether
they are adequate to ensure and preserve the drug's identity, strength, quality
and purity. These characteristics are critical to ensure the safety and efficacy
of a drug for human use. CDER conducts a scientific review of
manufacturing methods and process controls for the drug substance and drug
product. Field investigators conduct on-site reviews to verify the accuracy
of the information submitted to CDER and to determine facility compliance
with FDA's Good Manufacturing Practices (GMPs).
FDA's review of a pharmaceutical facility does not include auditing
compliance with regulations pertaining to the protection of the environment.
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However, in accordance with the National Environmental Policy Act of 1969
(NEPA),' which requires all Federal agencies to assess the environmental
impacts 'of their actions, CDER has integrated the consideration of the
environmental impacts of approving drug product applications into its
regulatory process (21 CFR Part 25). When an environmental review under
NEPA is required, the review focuses on the environmental impacts of
consumer use and disposal of the drug and is based on information submitted
by the manufacturers, or on a manufacturer's certification that an application
falls within an established category of applications excluded from the
requirement to submit information.
After the original approval from CDER, an applicant may wish or need to
make changes in the method of manufacture, testing, etc. described in their
application. An applicant is required to notify FDA about each change in each
condition established in an approved application (e.g., ingredients, solvents,
processes) beyond the variations already provided for in the application (21
CFR §314.70(a)). Depending on the type of change, the applicant notifies
FDA about it in (1) a supplement requiring FDA approval before the change
is made (§314.70(b)), (2) a supplement for changes that may be made before
FDA approval (§314.70(c)), or (3) an annual report (§314.70(d)). Changes
requiring FDA approval before they are made may include changes in the
synthesis of the drug product or changes in solvents; the addition or deletion
of an ingredient; and changes in the method of manufacture or in-process
control of the drug product manufacturing process. The regulations specify
the method of reporting certain changes. CDER also provides additional
guidance on the method of reporting changes and documentation needed to
support changes in guidance for industry (e.g., "Guidance for Industry,
Immediate Release Solid Oral Dosage Forms, Scale-Up and Post Approval
Changes: Chemistry Manufacturing and Controls, In Vitro Dissolution
Testing and In Vivo Bioequivalence Documentation," November 1995).
The changes in a manufacturing process that a manufacturer may wish to
undertake to prevent or reduce pollution would most likely be reported in a
supplement requiring FDA approval before the change could be made (e.g.,
§§314.70(b)(l)(iv) and 314.70(b)(2)(v)). Changes such as these often require
the manufacturer, before submitting the supplemental application to the FDA,
to generate data that demonstrate the proposed change does not adversely
affect the identity, strength, quality or purity of the drug. An applicant may
ask FDA to expedite its review if a delay in making the change would impose
an extraordinary hardship on the applicant (§314.70(b)). For changes relating
to pollution prevention, "expedited review" is typically reserved for those
changes mandated by the Federal, State or local environmental protection
agencies, which must be accomplished within a specified time frame. The
granting of an expedited review does not change the type of documentation
that needs to be submitted to CDER to support the change.
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Summary of FDA Regulations Applicable to the Pharmaceutical Industry
Statutory Authority
The Federal Food Drug and Cosmetic Act, principally Sections 201, 301, 501,
502, 503, 505, 506, 507, 512, 701, 704.
CDER Regulations
21 CFR Parts 3 00-499
Manufacturing Information Submittal
Manufacturing Information Submitted to CDER in Investigational New Drug
Applications (INDs), New Drug Applications (NDAs), Antibiotic
Applications, Abbreviated New Drug Applications (ANDAs), and
Abbreviated Antibiotic Drug Applications (AADAs)
INDs: §312.23(a)(7)(i)
Other applications: §§314.50(d)(l)(i) and 314.50(d)(l)(ii)(a)
Reporting Changes in Manufacturing Methods and Controls to CDER
IND Information amendments: §312.31
Supplements and other changes to an approved application: §314.70
Good Manufacturing Practices (GMPs)
Current Good Manufacturing Practice in Manufacturing, Processing, Packing,
or Holding of Drugs; General, Part 210
Current Good Manufacturing Practice for Finished Pharmaceuticals: Part 211
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VI.E. Other Statutes and Regulations Affecting the Pharmaceutical Industry
State Statutes and Regulations
Most states have long-established broad-based environmental regulatory
programs. Many of these regulatory schemes were enacted to implement
federal programs and have been granted local primacy by the USEPA.
Generally, the state programs are allowed to be more restrictive than federal
requirements and, in some cases, they are.
Some states with high concentrations of pharmaceutical manufacturing
facilities, have their own regulations pertaining specifically to the industry.
For example, both New York and New Jersey have Reasonably Achievable
Control Technology (RACT) requirements for process specific volatile
organic compound (VOC) emissions. Other states may have similar
requirements under their own State Implementation Plans (SIPs).
International Standards
The U.S. Pharmaceutical industry is largely an international industry in which
many companies have manufacturing facilities and sales and distribution
operations in countries other than the U.S. In addition to U.S. federal statutes
and regulations there are international laws, regulations, treaties, conventions
and initiatives which are drivers of the environmental programs of
pharmaceutical companies. The Basel Convention, ISO 14000 standards, the
environmental requirements of NAFTA, and the evolving European Union
Directives and Regulations are a few examples of important international
environmental standards and programs which affect this industry.
Drug Enforcement Administration Regulations
Pharmaceutical manufacturing operations may also be regulated under the
Controlled Substances Act. This Act regulates the manufacture, distribution,
and dispensing of controlled substances and is enforced by the Drug
Enforcement Administration (DBA). Examples of pharmaceutical products
regulated under this Act include Demerol, Percodan, Ritalin, Valium, and
Darvon. A list of controlled substances can be found in 1308 of 21 CFR.
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The statute provides "closed" system for virtually every person who
legitimately handles controlled substances, other than the ultimate user. As
a means of controlling the distribution of regulated products, DBA sets quotas
limiting the quantities which may be manufactured or produced to that
amount which is necessary to meet the legitimate needs of the United States.
The regulations set specific requirements for how such compounds are
handled and stored at a manufacturing facility. In addition, when disposed of,
these substances must be destroyed in the presence of DBA personnel in
accordance with the regulations found in 21 CFR, Section 1307.21.
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Compliance and Enforcement History
VH. COMPLIANCE AND ENFORCEMENT HISTORY
Background
Until recently, EPA has focused much of its attention on measuring
compliance with specific environmental statutes. This approach allows the
Agency to track compliance with the Clean Air Act, the Resource
Conservation and Recovery Act, the Clean Water Act, and other
environmental statutes. Within the last several years, the Agency has begun
to supplement single-media compliance indicators with facility-specific,
multimedia indicators of compliance. In doing so, EPA is in a better position
to track compliance with all statutes at the facility level, and within specific
industrial sectors.
A major step in building the capacity to compile multimedia data for industrial
sectors was the creation of EPA's Integrated Data for Enforcement Analysis
(IDEA) system. IDEA has the capacity to "read into" the Agency's single-
media databases, extract compliance records, and match the records to
individual facilities. The IDEA system can match Air, Water, Waste,
Toxics/Pesticides/EPCRA, TRI, and Enforcement Docket records for a given
facility, and generate a list of historical permit, inspection, and enforcement
activity. IDEA also has the capability to analyze data by geographic area and
corporate holder. As the capacity to generate multimedia compliance data
improves, EPA will make available more in-depth compliance and
enforcement information. Additionally, sector-specific measures of success for
compliance assistance efforts are under development.
Compliance and Enforcement Profile Description
Using inspection, violation, and enforcement data from the IDEA system, this
section provides information regarding the historical compliance and
enforcement activity of this sector. In order to mirror the facility universe
reported in the Toxic Chemical Profile, the data reported within this section
consists of records only from the TRI reporting universe. With this decision,
the selection criteria are consistent across sectors with certain exceptions.
For the sectors that do not normally report to the TRI program, data have
been provided from EPA's Facility Indexing System (FINDS) which tracks
facilities in all media databases. Please note, in this section, EPA does not
attempt to define the actual number of facilities that fall within each sector.
Instead, the section portrays the records of a subset of facilities within the
sector that are well defined within EPA databases.
As a check on the relative size of the full sector universe, most notebooks
contain an estimated number of facilities within the sector according to the
Bureau of Census (See Section II). With sectors dominated by small
businesses, such as metal finishers and printers, the reporting universe within
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the EPA databases may be small in comparison to Census data. However, the
group selected for inclusion in this data analysis section should be consistent
with this sector's general makeup.
Following this introduction is a list defining each data column presented
within this section. These values represent a retrospective summary of
inspections and enforcement actions, and solely reflect EPA, State, and local
compliance assurance activities that have been entered into EPA databases.
To identify any changes in trends, the EPA ran two data queries, one for the
five calendar years (April 1, 1992 to March 31, 1997) and the other for the
most recent twelve-month period (April 1, 1996 to March 31, 1997). The
five-year analysis gives an average level of activity for that period for
comparison to the more recent activity.
Because most inspections focus on single-media requirements, the data
queries presented in this section are taken from single media databases. These
databases do not provide data on whether inspections are state/local or EPA-
led. However, the table breaking down the universe of violations does give
the reader a crude measurement of the EPA's and states' efforts within each
media program. The presented data illustrate the variations across EPA
Regions for certain sectors/ This variation may be attributable to state/local
data entry variations, specific geographic concentrations, proximity to
population centers, sensitive ecosystems, highly toxic chemicals used in
production, or historical noncompliance. Hence, the exhibited data do not
rank regional performance or necessarily reflect which regions may have the
most compliance problems.
Compliance and Enforcement Data Definitions
General Definitions
Facility Indexing System (FINDS) ~ this system assigns a common facility
number to EPA single-media permit records. The FENDS identification
number allows EPA to compile and review all permit, compliance,
enforcement and pollutant release data for any given regulated facility.
Integrated Data for Enforcement Analysis (IDEA) -- is a data integration
system that can retrieve information from the major EPA program office
databases. IDEA uses the FINDS identification number to link separate data
records from EPA's databases. This allows retrieval of records from across
a EPA Regions include the following states: I (CT, MA, ME, RI, NH, VT); II (NJ, NY, PR, VI); III (DC, DE, MD, PA,
VA, WV); IV (AL, FL, GA, KY, MS, NC, SC, TN); V (EL, IN, MI, MN, OH, WI); VI (AR, LA, NM, OK, TX); VII
(IA, KS, MO, ME); VIII (CO, MT, ND, SD, UT, WY); IX (AZ, CA, HI, NV, Pacific Trust Territories); X (AK, ID, OR,
WA).
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media or statutes for any given facility, thus creating a "master list" of
records for that facility. Some of the data systems accessible through IDEA
are: AIRS (Air Facility Indexing and Retrieval System, Office of Air and
Radiation), PCS (Permit Compliance System, Office of Water), RCRIS
(Resource Conservation and Recovery Information System, Office of Solid
Waste), NCDB (National Compliance Data Base, Office of Prevention,
Pesticides, and Toxic Substances), CERCLIS (Comprehensive Environmental
and Liability Information System, Superfund), and TRIS (Toxic Release
Inventory System). IDEA also contains information from outside sources
such as Dun and Bradstreet and the Occupational Safety and Health
Administration (OSHA). Most data queries displayed in notebook sections
IV and VII were conducted using IDEA.
Data Table Column Heading Definitions
Facilities in Search ~ are based on the universe of TRI reporters within the
listed SIC code range. For industries not covered under TRI reporting
requirements (metal mining, nonmetallic mineral mining, electric power
generation, ground transportation, water transportation, and dry cleaning), or
industries in which only a very small fraction of facilities report to TRI (e.g.,
printing), the notebook uses the FINDS universe for executing data queries.
The SIC code range selected for each search is defined by each notebook's
selected SIC code coverage described in Section II.
Facilities Inspected — indicates the level of EPA and state agency
inspections for the facilities in this data search. These values show what
percentage of the facility universe is inspected in a one-year or five-year
period.
Number of Inspections - measures the total number of inspections
conducted in this sector. An inspection event is counted each time it is
entered into a single media database.
Average Time Between Inspections - provides an average length of time,
expressed in months, between compliance inspections at a facility within the
defined universe.
Facilities with One or More Enforcement Actions ~ expresses the number
of facilities that were the subject of at least one enforcement action within the
defined time period. This category is broken down further into federal and
state actions. Data are obtained for administrative, civil/judicial, and criminal
enforcement actions. Administrative actions include Notices of Violation
(NOVs). A facility with multiple enforcement actions is only counted once
in this column, e.g., a facility with 3 enforcement actions counts as 1 facility.
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Total Enforcement Actions -- describes the total number of enforcement
actions identified for an industrial sector across all environmental statutes. A
facility with multiple enforcement actions is counted multiple times, e.g., a
facility with 3 enforcement actions counts as 3.
State Lead Actions ~ shows what percentage of the total enforcement
actions are taken by state and local environmental agencies. Varying levels
of use by states of EPA data systems may limit the volume of actions
recorded as state enforcement activity. Some states ortensively report
enforcement activities into EPA data systems, while other states may use their
own data systems.
Federal Lead Actions ~ shows what percentage of the total enforcement
actions are taken by the United States Environmental Protection Agency.
This value includes referrals from state agencies. Many of these actions result
from coordinated or joint state/federal efforts.
Enforcement to Inspection Rate - is a ratio of enforcement actions to
inspections, and is presented for comparative purposes only. This ratio is a
rough indicator of the relationship between inspections and enforcement. It
relates the number of enforcement actions and the number of inspections that
occurred within the one-year or five-year period. This ratio includes the
inspections and enforcement actions reported under the Clean Water Act
(CWA), the Clean Air Act (CAA) and the Resource Conservation and
Recovery Act (RCRA). Inspections and actions from the TSCA/FIFRA/
EPCRA database are not factored into this ratio because most of the actions
taken under these programs are not the result of facility inspections. Also,
this ratio does not account for enforcement actions arising from non-
inspection compliance monitoring activities (e.g., self-reported water
discharges) that can result in enforcement action within the CAA, CWA, and
RCRA.
Facilities with One or More Violations Identified ~ indicates the
percentage of inspected facilities having a violation identified in one of the
following data categories: In Violation or Significant Violation Status
(CAA);ReportableNoncompliance, Current Year Noncompliance, Significant
Noncompliance (CWA); Noncompliance and Significant Noncompliance
(FIFRA, TSCA, and EPCRA); Unresolved Violation and Unresolved High
Priority Violation (RCRA). The values presented for this column reflect the
extent of noncompliance within the measured time frame, but do not
distinguish between the severity of the noncompliance. Violation status may
be a precursor to an enforcement action, but does not necessarily indicate that
an enforcement action will occur.
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Media Breakdown of Enforcement Actions and Inspections - four
columns identify the proportion of total inspections and enforcement actions
within EPA Air, Water, Waste, and FIFRA/TSCA/EPCRA databases. Each
column is a percentage of either the "Total Inspections," or the "Total
Actions" column.
VILA. Pharmaceutical Industry Compliance History
Table 20 provides an overview of the reported compliance and enforcement
data for the pharmaceutical industry over the past five years (April 1992 to
April 1997). These data are also broken out by EPA Region thereby
permitting geographical comparisons. A few points evident from the data are
listed below.
• Region n has more than twice the number of pharmaceutical facilities
than any other Region and more than half of all inspections nationally
were carried out in this Region. The high rate of inspections in
relation to the number of facilities is reflected in the Region's
relatively low average time between inspections (6 months)
• Regions VI had only five pharmaceutical facilities (identified by the
IDEA system) and a relatively high average time between inspections.
However, in the past five years four enforcement actions were
brought against facilities in the Region, giving it one of the highest
enforcement to inspection rates.
• Region X had only one pharmaceutical facility identified by the IDEA
system. In the past five years this facility was inspected twice and had
two enforcement action brought against it.
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VH.B. Comparison of Enforcement Activity Between Selected Industries
Tables 21 and 22 allow the compliance history of the pharmaceutical industry
to be compared with the other industries covered by the industry sector
notebooks. Comparisons between Tables 21 and 22 permit the identification
of trends in compliance and enforcement records of the industry by comparing
data covering the last five years to that of the past year. Some points evident
from the data are listed below.
• The pharmaceutical industry had one of the highest inspection rates
as indicated by its relatively low average time between inspections (8
months) compared to other industries.
• Compared to other sectors, the pharmaceutical industry had a
relatively high enforcement to inspection rate (0.07) and a relatively
high percent of facilities inspected with violations (105 percent).
Tables 23 and 24 provide a more in-depth comparison between the
pharmaceutical industry and other sectors by breaking out the compliance and
enforcement data by environmental statute. As in Tables 21 and 22, the data
cover the last five years (Table 23) and the previous year (Table 24) to
facilitate the identification of recent trends. A few points evident from the
data are listed below.
• Over the past five years, about 80 percent of the industry's
inspections were for CAA and RCRA. Over the past year CAA and
RCRA inspections accounted for almost 90 percent of inspections.
This trend is primarily due to an increase in CAA inspections and a
decrease in CWA and FIFRA/TSCA/EPCRA/Other inspections.
• The percentage of CAA enforcement actions increased from 49
percent over the past five years to 71 percent in the past year. At the
same time the percentage of CWA enforcement actions decreased
from 25 percent to 14 percent.
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Sector Notebook Project
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Pharmaceutical Industry
Compliance and Enforcement Histoi
VII.C. Review of Major Legal Actions
This section provides summary information about major cases that have
affected this sector, and Supplementary Environmental Projects (SEPs).
SEPs are compliance agreements that reduce a facility's stipulated penalty in
return for an environmental project that exceeds the value of the reduction.
Often, these projects fund pollution prevention activities that can significantly
reduce the future pollutant loadings of a facility.
VII.C.1. Review of Major Cases
As indicated in EPA's Enforcement Accomplishments Report, FY1995 and
FY1996 publications, 5 significant enforcement actions were resolved between
1994 and 1996 for the pharmaceutical industry.
In the Matter of Ciba-Geigy, Inc.: On November 7, 1994, Region II issued
an administrative consent order to Ciba-Geigy, Inc., assessing a penalty of
$130,000 for violations of EPCRA at its Toms River, New Jersey, facility.
The order was based upon an inspection of Ciba-Geigy's facility that resulted
in a sixteen count complaint alleging that Ciba-Geigy failed to report that it
used certain of the following: copper compounds; glycol ethers; chromium
compounds; cobalt compounds; C.I. Disperse Yellow 3; diethanolamine and
ethylene glycol during the calendar years 1988 through 1991.
Ciba-Geigy Superfund Site: On October 18, 1995, Region II issued an
administrative order on consent under Sections 104, 107, and 122 of
CERCLA to the Ciba-Geigy Corporation. The order requires Ciba-Geigy to
perform, under EPA oversight, a feasibility study for Operable Unit Two to
develop and evaluate remedial alternatives for approximately twenty-one
potential source areas of groundwater contamination on the site. The
estimated cost of the work that Ciba-Geigy will perform is $20 million. In
addition, Ciba-Geigy will also pay all of EPA's unreimbursed past response
costs, $797,000, plus all of EPA's future response costs, including oversight
costs.
The site is on the National Priorities List and located in Toms River, Ocean
County, New Jersey. Groundwater at the site is contaminated with organic
and inorganic compounds, and emanates from surface and subsurface former
disposal areas on the site. Pursuant to a settlement with EPA in 1994, Ciba-
Geigy is currently remediating the groundwater contamination. EPA recently
completed a baseline public health risk assessment or source area surface
soils, as well as a remedial investigation to examine the nature and extent of
the contamination in the source areas at the site. In performing the feasibility
study for the source areas, Ciba-Geigy has agreed to adopt EPA's risk
assessment and remedial investigation report.
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Takeda Chemical Products USA, Inc. (NC): On August 31, 1995, Region
IV entered into a consent agreement/consent order (CACO) resolving claims
against Takeda Chemical Products USA, Inc., for violations of RCRA at its
vitamin manufacturing plant in Wilmington, North Carolina. As part of a
solvent extraction process, Takeda generated a by-product referred to as
DAS-fuel, which Takeda intended to burn for energy recovery. Prior to
receiving any permits to burn the DAS-fuel, Takeda generated DAS-fuel and
stored it on-site for a period in excess of 90 days without a permit or interim
status, and later shipped it off-site. EPA determined that the DAS-fuel
(essentially spent toluene mixed with DAS water and polymers) was F005
hazardous waste. As a result, on September 24, 1994, Region IV issued a
complaint for illegal storage of hazardous waste, failure to make a hazardous
waste determination, and failure to manifest the DAS-fuel shipped off-site.
The CACO requires Takeda to pay a civil penalty of $99,000, but allows
Takeda to bring DAS-fuel back on-site for reprocessing, provided Takeda
manages any waste it produces as a result as a hazardous waste.
Abbott Laboratories: A consent agreement and final order was signed in
September 1995, concerning Abbott Laboratories Corporation's violations of
RCRA standards applicable to the burning of hazardous waste in boilers and
industrial furnaces (BIF) at its North Chicago, Illinois facility. Negotiations
with Abbott Laboratories after issuance of the complaint in February 1994
resulted in a penalty of $182,654. Abbott also agreed to conduct a
supplemental environmental project (SEP) that will allow Abbott to recover
and recycle the methylene chloride produced in its manufacturing processes
and will reduce fugitive methylene chloride emissions. The SEP involves
three separate, albeit similar, operations, replacing "wet" vacuum pump
systems with "dry" pumps and high efficiency condensers. The projected cost
of the SEP is $480,000.
Vn.C.2. Supplementary Environmental Projects (SEPs)
Supplemental environmental projects (SEPs) are enforcement options that
require the non-compliant facility to complete specific projects. Information
on SEP cases can be accessed via the internet at EPA's Enviro$en$e website:
http ://es.inel.gov/sep.
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Pharmaceutical Industry Activities and Initiatives
Vm. COMPLIANCE ACTIVITIES AND INITIATIVES
This section highlights the activities undertaken by this industry sector and
public agencies to voluntarily improve the sector's environmental
performance. These activities include those independently initiated by
industrial trade associations. In this section, the notebook also contains a
listing and description of national and regional trade.associations.
VIII.A. Sector-related Programs and Activities
The Pharmaceutical Research and Manufacturers of America (PhRMA) and
EPA are considering developing compliance and regulations guides,
concerning the interactions of EPA and FDA regulations for the
pharmaceutical industry.
VIH.B. EPA Voluntary Programs
33/50 Program
The 33/50 Program is a ground breaking program that has focused on
reducing pollution from seventeen high-priority chemicals through voluntary
partnerships with industry. The program's name stems from its goals: a 33%
reduction in toxic releases and transfers by 1992, and a 50% reduction by
1995, against a baseline of 1.5 billion pounds of releases and transfers in
1988. The results have been impressive: 1,300 companies have joined the
33/50 Program (representing over 6,000 facilities) and have reached the
national targets a year ahead of schedule. The 33% goal was reached in 1991,
and the 50% goal - a reduction of 745 million pounds of toxic wastes — was
reached in 1994. The 33/50 Program can provide case studies on many of the
corporate accomplishments in reducing waste.
Table 25 lists those companies participating in the 33/50 program that
reported the SIC codes 2833 and 2834 to TRI. Some of the companies
shown also listed facilities that are not producing Pharmaceuticals. The
number of facilities within each company that are participating in the 33/50
program and that report pharmaceutical SIC codes is shown. Where available
and quantifiable against 1988 releases and transfers, each company's 33/50
goals for 1995 and the actual total releases and transfers and percent
reduction between 1988 and 1994 are presented. At the time of publication
of this document (August 1997) 1995 33/50 Program TRI data were not
available.
Table 20 shows that 34 companies comprised of 160 facilities reporting SIC
2833 and 2834 are participated in the 33/50 program. For those companies
shown with more than one pharmaceutical manufacturing facility, all facilities
may not be participating in 33/50. The 33/50 goals shown for companies with
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Pharmaceutical Industry
Activities and Initiatives
multiple pharmaceutical facilities, however, are company-wide, potentially
aggregating more than one facility and facilities not carrying out
pharmaceutical operations. In addition to company-wide goals, individual
facilities within a company may have their own 33/50 goals or may be
specifically listed as not participating in the 33/50 program. Since the actual
percent reductions shown in the last column apply to all of the companies'
pharmaceutical manufacturing facilities and only pharmaceutical
manufacturing facilities, direct comparisons to those company goals
incorporating non-pharmaceutical facilities or excluding certain facilities may
not be possible. For information on specific facilities participating in 33/50,
contact David Sarokin (202-260-6907) at the 33/50 Program Office.
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Table 25: Pharmaceutical Industry Participation in the 33/50 Program
Parent Company
(Headquarters Location)
3M Minnesota Mining &
Mfg.. Company -
St. Paul, MN
Abbott Laboratories -
North Chicago, IL
American Home Products
Corporation -
Madison ,NJ
Anabolic Incorporated -
Irvine, CA
Baxter International Inc. -
Deerfield, IL
Boehringer Ingelheim Corp. -
Ridgefield, CT
Bristol-Myers Squibb Co. -
New York, NY
Burroughs Wellcome Co. -
Durham, NC
Ciba-Geigy Company -
Tarrytown, NY
Coating Place Incorporated -
Verona, WI
Dow Chemical Company -
Midland, M
Eastman Kodak Company -
Rochester, NY
Eli Lilly and Company -
[ndianapolis, IN
Fisons Company -
Rochester, NY
Ganes Chemicals Inc. -
Carlstadt, NJ
Hoechst Celanese Company -
Corpus Christi, TX
r-foffmann-La Roche Inc. -
Nutley, NJ
Johnson & Johnson -
*Jew Brunswick, NJ
Mallinckrodt Group Inc. -
Saint Louis, MO
Merck & Company Inc. -
Whitehouse Station, NJ
Company-Owned
Pharmaceutical
Facilities Reporting
33/50 Chemicals
2
6
19
1
8
2
15
2
14
1
1
1
7
1
2
1
5
2
1
7
Company-wide
% Reduction
Goal1 (1988-
1995)
70
20
50
75
80
50
50
26
50
***
50
50
50
***
***
50
62
65
50
50
1988TRI
Releases and
Transfers of
33/50 Chemicals
(pounds)
885,011
3,017,869
1,828,970
39, 602
921,282
198,500
4, 876, 002
469, 075
2,613,266
149, 000
115,000
87, 350
5, 749, 879
3,395
67,018
0
2, 154,667
258, 090
0
5, 863, 293
1994TRI
Releases and
Transfers of
33/50 Chemicals
(pounds)
194,850
2, 869, 793
930, 992
0
33,312
247, 166
2, 305, 269
193,171
1, 179,471
0
109, 100
15,766
1, 194,760
2,229
19,586
0
1,230,361
234, 444
500
927, 225
Actual %
Reduction for
Pharmaceutical
Facilities (1988 -
1994)
78
5.0
49
100
96
-24.5
53
59
55
100
5
82
79
34
71
~
43
9
-
84
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Table 25: Pharmaceutical Industry Participation in the 33/50 Program
Monsanto Company -
Saint Louis, MO
Par Pharmaceutical Inc. -
Spring Valley, NY
Pcrrigo Company -
Allcgan, MI
Pfizer Incorporated -
New York, NY
Sandoz Corporation
New York, NY
Schering-Plough Corp, -
Madison, NJ
Smithklinc Bcccham
Americas -
Philadelphia, PA
Solvay America Inc. -
Houston, TX
Syntex USA Incorporated -
Palo Alto, CA
Tishcon Corporation -
Wcstbury.NY
United Organics Corp. -
Williamston.NC
Upjohn Company -
Kalamazoo, ME
Upsher-Smith Laboratories
Inc.-
Minncapolis, MN
Warner-Lambert Company -
Morris Plains, NJ
3
1
2
10
18
7
6
1
3
2
1
3
1
4
160
25
***
95
50
50
70
81
*
33
**
*
50
100
40
9,200
194,099
638, 235
2,492,314
572,915
3,181,202
2, 882, 573
0
1,093,051
3,900
0
7,128,339
94, 000
197,540
47, 784, 637
3,480
0
0
3, 250, 940
100,439
1,867,558
35, 469
36, 474
393, 493
113,000
5,950
5,654, 150
320, 000
242, 638
23,711,586
62
100
100
-30
82
41
99
—
64
-2797
—
21
-240
-22
50
Source: US EPA 33/50 Program Office, 1996. 1995 33/50 TRI data was not available at time of publication.
1 Company-wide Reduction Goals aggregate all company-owned facilities which may include facilities not producing Pharmaceuticals.
* » Reduction goal not quantifiable against 1988 TRI data.
** =• Use reduction goal only.
*** - No numeric reduction goal.
Environmental Leadership Program
The Environmental Leadership Program (ELP) is a national initiative
developed by EPA that focuses on improving environmental performance,
encouraging voluntary compliance, and building working relationships with
stakeholders. EPA initiated a one year pilot program in 1995 by selecting 12
projects at industrial facilities and federal installations that demonstrate the
principles of the ELP program. These principles include: environmental
management systems, multimedia compliance assurance, third-party
verification of compliance, public measures of accountability, pollution
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prevention, community involvement, and mentor programs. In return for
participating, pilot participants received public recognition and were given a
period of time to correct any violations discovered during these experimental
projects.
EPA is making plans to launch its full-scale Environmental Leadership
Program in 1997. The full-scale program will be facility-based with a 6-year
participation cycle. Facilities that meet certain requirements will be eligible
to participate, such as having a community outreach/employee involvement
programs and an environmental management system (EMS) in place for 2
years. (Contact: http://es.inel.gov/elp or Debby Thomas, ELP Deputy
Director, at 202-564-5041)
Project XL
Project XL was initiated in March 1995 as a part of President Clinton's
Reinventing Environmental Regulation initiative. The projects seek to
achieve cost effective environmental benefits by providing participants
regulatory flexibility on the condition that they produce greater environmental
benefits. EPA and program participants will negotiate and sign a Final Project
Agreement, detailing specific environmental objectives that the regulated
entity shall satisfy. EPA will provide regulatory flexibility as an incentive for
the participants' superior environmental performance. Participants are
encouraged to seek stakeholder support from local governments, businesses,
and environmental groups. EPA hopes to implement fifty pilot projects in
four categories, including industrial facilities, communities, and government
facilities regulated by EPA. Applications are being accepted on a rolling
basis.
In 1996, EPA accepted a proposal by Merck to deliver superior
environmental protection while allowing flexible operation at its
pharmaceutical manufacturing facility near Elkton, Virginia. Merck, along
with its stakeholders, developed a simplified air permit for the facility that will
cap total air emissions of criteria pollutants at less than recent actual levels
and allow the facility to make changes and additions to its manufacturing
processes as soon as they are needed without prior approval. The upfront
environmental benefit which will enable Merck to operate flexibly under the
emissions cap will come from converting the coal burning powerhouse to
natural gas. This conversion will reduce the site's actual air emissions by over
900 tons per year of criteria pollutants, and 50 tons per year of hazardous air
pollutants.
Under the proposal, EPA and the Virginia Department of Environmental
Quality (VADEQ) will adopt the Prevention of Significant Deterioration
(PSD) permit through different mechanisms under their respective
jurisdictions. EPA plans to promulgate a site-specific rule making in order to
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make adjustments to current applicable regulations to allow for the flexible
operation of the permit. The Virginia State Air Pollution Control Board will
promulgate a variance to make the PSD permit legally enforceable under state
laws. These proposed actions and the draft permit were subject to public
comment and it is expected that the permit will be issued to Merck during
1997.
For additional information regarding XL projects, including application
procedures and criteria, see the May 23, 1995 Federal Register Notice.
(Contact: Fax-on-Demand Hotline 202-260-8590, Web: http://www.epa.gov/
ProjectXL, or Christopher Knopes at EPA's Office of Policy, Planning and
Evaluation 202-260-9298)
Climate Wise Program
Climate Wise is helping US industries turn energy efficiency and pollution
prevention into a corporate asset. Supported by the technical assistance,
financing information and public recognition that Climate Wise offers,
participating companies are developing and launching comprehensive
industrial energy efficiency and pollution prevention action plans that save
money and protect the environment. The nearly 300 Climate Wise companies
expect to save more than $300 million and reduce greenhouse gas emissions
by 18 million metric tons of carbon dioxide equivalent by the year 2000.
Some of the actions companies are undertaking to achieve these results
include: process improvements, boiler and steam system optimization, air
compressor system improvements, fuel switching, and waste heat recovery
measures including cogeneration. Created as part of the President's Climate
Change Action Plan, Climate Wise is jointly operated by the Department of
Energy and EPA. Under the Plan many other programs were also launched
or upgraded including Green Lights, WasteWi$e and DoE's Motor Challenge
Program. Climate Wise provides an umbrella for these programs which
encourage company participation by providing information on the range of
partnership opportunities available. (Contact: Pamela Herman, EPA, 202-
260-4407 or Jan Vernet, DoE, 202-586-4755)
Energy Star Buildings Program
EPA's ENERGY STAR Buildings Program is a voluntary, profit-based program
designed to improve the energy-efficiency in commercial and industrial
buildings. Expanding the successful Green Lights Program, ENERGY STAR
Buildings was launched in 1995. This program relies on a 5-stage strategy
designed to maximize energy savings thereby lowering energy bills, improving
occupant comfort, and preventing pollution — all at the same time. If
implemented in every commercial and industrial building in the United States,
ENERGY STAR Buildings could cut the nation's energy bill by up to $25 billion
and prevent up to 35% of carbon dioxide emissions. (This is equivalent to
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taking 60 million cars of the road). ENERGY STAR Buildings participants
include corporations; small and medium sized businesses; local, federal and
state governments; non-profit groups; schools; universities; and health care
facilities. EPA provides technical and non-technical support including
software, workshops, manuals, communication tools, and an information
hotline. EPA's Office of Air and Radiation manages the operation of the
ENERGY STAR Buildings Program. (Contact: Green Light/Energy Star Hotline
at 1-888-STAR-YES or Maria Tikoff Vargas, EPA Program Director at 202-
233-9178 or visit the ENERGY STAR Buildings Program website at
http ://www. epa.gov/appdstar/buildings/)
Green Lights Program
EPA's Green Lights program was initiated in 1991 and has the goal of
preventing pollution by encouraging U.S. institutions to use energy-efficient
lighting technologies. The program saves money for businesses and
organizations and creates a cleaner environment by reducing pollutants
released into the atmosphere. The program has over 2,345 participants which
include major corporations, small and medium sized businesses, federal, state
and local governments, non-profit groups, schools, universities, and health
care facilities. Each participant is required to survey their facilities and
upgrade lighting wherever it is profitable. As of March 1997, participants had
lowered their electric bills by $289 million annually. EPA provides technical
assistance to the participants through a decision support software package,
workshops and manuals, and an information hotline. EPA's Office of Air and
Radiation is responsible for operating the Green Lights Program. (Contact:
Green Light/Energy Star Hotline at 1-888-STARYES or Maria Tikoff
Vargar, EPA Program Director, at 202-233-9178 the )
WasteWi$e Program
The WasteWiSe Program was started in 1994 by EPA's Office of Solid Waste
and Emergency Response. The program is aimed at reducing municipal solid
wastes by promoting waste prevention, recycling collection and the
manufacturing and purchase of recycled products. As of 1997, the program
had about 500 companies as members, one third of whom are Fortune 1000
corporations. Members agree to identify and implement actions to reduce
their solid wastes setting waste reduction goals and providing EPA with
yearly progress reports. To member companies, EPA, in turn, provides
technical assistance, publications, networking opportunities, and national and
regional recognition. (Contact: WasteWi$e Hotline at 1-800-372-9473 or
Joanne Oxley, EPA Program Manager, 703-308-0199)
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NICE3
The U.S. Department of Energy is administering a grant program called The
National Industrial Competitiveness through Energy, Environment, and
Economics (NICE3). By providing grants of up to 45 percent of the total
project cost, the program encourages industry to reduce industrial waste at
its source and become more energy-efficient and cost-competitive through
waste minimization efforts. Grants are used by industry to design, test, and
demonstrate new processes and/or equipment with the potential to reduce
pollution and increase energy efficiency. The program is open to all
industries; however, priority is given to proposals from participants in the
forest products, chemicals, petroleum refining, steel, aluminum, metal casting
and glass manufacturing sectors. (Contact: http//www. oit.doe.gov/access/
niceS, Chris Sifri, DOE, 303-275-4723 orEricHass, DOE, 303-275-4728)
Design for the Environment (DfE)
DfE is working with several industries to identify cost-effective pollution
prevention strategies that reduce risks to workers and the environment. DfE
helps businesses compare and evaluate the performance, cost, pollution
prevention benefits, and human health and environmental risks associated with
existing and alternative technologies. The goal of these projects is to
encourage businesses to consider and use cleaner products, processes, and
technologies. For more information about the DfE Program, call (202) 260-
1678. To obtain copies of DfE materials or for general information about
DfE, contact EPA's Pollution Prevention Information Clearinghouse at (202)
260-1023 or visit the DfE Website at http://es.inel.gov/dfe.
VIQ.C. Trade Association/Industry Sponsored Activity
Vm.C.l. Environmental Programs
The Pharmaceuticals Research and Manufacturers of America (PhRMA)
coordinates the research-based pharmaceutical industry's response to
industry-specific environmental issues, such as the pharmaceutical MACT.
PhRMA works through an environmental committee, a series of
subcommittees responsible for regulatory areas such as water and air, and ad
hoc work groups to address narrowly-focused issues.
The research-based pharmaceutical industry also relies on other broad-based
trade associations for issues that affect the larger business community.
Several of the PhRMA members are also members of the Chemical
Manufacturers Association (CMA) and therefore are part of CMA's
Responsible Care® Initiative.
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In addition, many pharmaceutical companies have been implementing their
own environmental programs and initiatives to reduce the environmental
impacts of their products and manufacturing processes. These programs are
both company-wide and at the facility level. More information on such
programs can be obtained by contacting individual companies and facilities.
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Vm.C.2. Summary of Trade Associations
Pharmaceutical Research and Manufacturers
of America (PhRMA)
1100 15th Street, NW
Washington, D.C. 20035
Phone: (202) 835-3400
Fax: (202) 835-3414
Budget:$20,000,000
Staff: 80
Members: 40 companies
Affiliates: 30 companies
The Pharmaceutical Research and Manufacturers of America (PhRMA) is a non-profit
organization which was established in 1958. Its main function is to assist research-
based pharmaceutical companies in discovery, development, and marketing of new
drugs for humans. Comprised of most of the largest pharmaceutical companies in the
United States, PhRMA members are primarily engaged in research and development
of new medicines. To be a member of PhRMA, a company must be heavily involved
in research and development (R&D) and must also manufacture and market finished
dosage-form drugs under their own brand name. PhRMA member companies invest
nearly $19 billion a year in discovering and developing new drugs. Additionally,
PhRMA members account for approximately 90% of total pharmaceutical sales in the
United States.
Generic Pharmaceutical Industry
Association
16201 Street, NW
Washington, D.C. 20006-4005
Phone: (202) 833-9070
Fax: (202) 833-9612
Budget: $1-2,000,000
Staff: 6
Members: 46 companies
The Generic Pharmaceutical Industry Association (GPIA) is a primary trade
association for manufacturers and distributors of generic drugs. Its main publication
is "GPIA News".
National Pharmaceutical Alliance
(NPA)
421 King Street, Suite 222,
Alexandria, VA 22314
Phone: (703) 836-8816
Fax: (703) 549-4749
Budget: $250-500,000
Members: 165 companies
The National Pharmaceutical Alliance (NPA) is an organization which represents the
interests of small pharmaceutical companies and allied industries. Members of NPA
develop bioequivalent versions of major branded products, create products of
alternative combinations, strengths, and/or dosage forms, and market products which
are not produced by larger companies and which would not be available to the public
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otherwise. NPA assists in meeting these goals for its member companies. NPA also
publishes a bi-monthly journal called "NPA & News, Washington Report."
American Pharmaceutical Association
(APhA)
2215 Constitution Ave. NW
Washington, DC 20037
Phone: (202) 628-4410
Fax:(202)783-2351
Budget: $12,000,000
Members: 44,000
The American Pharmaceutical Association (APhA) is a professional society that
includes pharmacists in all practice settings, educators, students, researchers, editors
and publishers of pharmaceutical literature, pharmaceutical chemists and scientists,
and food and drug officials. APhA promotes quality health care and comprehensive
pharmaceutical care through the appropriate use of pharmacy services. APhA works
to: represent the interests of the profession before governmental bodies; interprets and
disseminates information on developments in health care; and assure quality pharmacy
services and patient care. APhA fosters professional education and training of
pharmacists; supports the Academy of Pharmaceutical Research and Science, the
Academy of Pharmacy Practice and Management, and the Academy of Students of
Pharmacy. APhA also publishes a quarterly newsletter, Academy Reporter, and
monthly journals including, American Pharmacy (Journal of the American
Pharmaceutical Association) and Journal of Pharmaceutical Sciences.
United States Pharmacopeial
Convention (USP)
12601 Twinbrook Pky.
Rockville, MD 20852
Phone: (301)881-0666
Fax: (301) 816-8247
Budget: $20,000,000
Members: 395
The United States Pharmacopeial Convention (USP) is a recognized authority in
medicine, pharmacy, and allied sciences. USP revises and publishes legally
recognized compendia of drug standards including the National Formulary.
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National Association of Pharmaceutical Manufacturers (NAPM)
320 Old Country Road - Suite 205
Garden City, NY 11530
Phone: (516) 741-3699
Fax:(516)741-3696
Nonprescription Drug Manufacturers Association
1150 Connecticut Avenue, NW
Washington, DC 20036
Phone: (202) 429-9260
Fax: (202) 223-6835
National Wholesale Druggist's Association
1821 Michael Faraday Drive
Suite 400
Reston, VA 22090
Phone: (703) 787-0000 ext. 240
Fax: (703) 787-6930
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Contacts and References
EX. CONTACTS/ACKNOWLEDGMENTS/REFERENCES
For further information on selected topics within the pharmaceutical industry
a list of publications and contacts are provided below:
Contacts3
Name
Emily Chow
Joanne Berman
Frank Hund
Randy McDonald
Umesh Dholakia
Nancy Sager
Daniel Kearns
Charles E. Eirkson,
III
Mervin Parker
Buzz L. Hoffman
Tom White
Organization
EPA/OECA
EPA/OECA
EPA/OW
EPA/OA
EPA Region II
FDA- Center for Drug
Evaluation and
Research
FDA - Center for
Biologies Evaluation
and Research
FDA - Center for
Veterinary Medicine
FDA - Center for
Devices and
Radiological Health
FDA - Center for Food
Safety and Applied
Nutrition
PhRMA
Telephone
(202) 564-7071
(202) 564-7064
(202)260-7182
(919)541-5402
(212) 637-4023
(301)594-5629
(301)827-3031
(301)594-1683
(301)594-2186
(202)418-3005
(202) 835-3546
Subject
Chemical Industry Branch,
Regulatory requirements and
compliance assistance
Chemical Industry Branch,
Regulatory requirements and
compliance assistance
Regulatory Requirements (CWA)
Regulatory Requirements (CAA)
Regulatory Requirements (CAA)
Information on Human Drugs
Information on Biologies
Information on Veterinary
Medicine
Information on medical devices
and radiological health
Information on foods
CWA: Clean Water Act
OECA: Office of Enforcement and Compliance Assurance
OA: Office of Air
OW: Office of Water
FDA: Food and Drug Administration
PhRMA: Pharmaceutical Research and Manufacturers of America
a Many of the contacts listed above have provided valuable background information and comments during development
of this document. EPA appreciates this support and acknowledges that the individuals listed do not necessarily endorse
all statements made within this notebook.
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Contacts and References
REFERENCES
Section IT: Introduction to the Pharmaceutical Industry
Opportunities and Challenges for Pharmaceutical Innovation: PhRMA Industry Profile,
Pharmaceutical Research and Manufacturers of America, Washington, DC., 1996.
Standard Industrial Classification Manual, 1987, Executive Office of the President, Office of
Management and Budget, Washington, DC., 1987.
Approved Drug Products with Therapeutic Equivalence Evaluations. FDA, Sixteenth Edition, 1996.
United States 1992 Census of Manufacturers for Drugs, Industry Series, US Department of
Commerce, Bureau of the Census, Washington, DC., 1992, (MC92-I-28C).
United States Industrial Outlook 1994, US Department of Commerce, International Trade
Administration, Washington, DC., 1994, chapter 43.
Section OT; Industrial Process Description
Encyclopedia of Polymer Science and Engineering, Vol.6, John Wiley and Sons, Inc., New York,
1986, p.514-515.
Guidelines to Pollution Prevention: The Pharmaceutical Industry, US EPA, Washington, DC.,
October 1991, (EPA/625/7-91/017).
Development Document for Proposed Effluent Limitations Guidelines and Standards for the
Pharmaceutical Point Source Category, US EPA, Washington, DC., February, 1995,
(EPA/821-R-95-019).
Control of Volatile Organic Compound Emissions from Batch Processes, US EPA Guideline
Series, Research Triangle Park, NC., November, 1993, (EPA-453/R-93-017).
Guidance for Industry: Manufacture, Processing or Holding of Active Pharmaceutical Ingredients,
U.S. Food and Drug Administration, August 1996.
Kirk-Othmer Encyclopedia of Chemical Technology, Fourth Edition, John Wiley and Sons, New
York, 1994.
Remington: The Science of Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton,
Pennsylvania, 1995.
Riegel's Handbook of Industrial Chemistry, Chapter 25: The Pharmaceutical Industry, Jeffrey H.
Watthey, Van Nostrand Reinhold, New York, 1992.
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Contacts and References
Perry's Chemical Engineers' Handbook, Sixth Edition, McGraw-Hill Book Company, 1984.
Personal Communication, Schering-Plough Pharmaceuticals, Kenilworth, New Jersey, October
1996.
Air Pollution Engineering Manual - Chapter 16: Pharmaceutical Industry, Richard Grume and
Jeffrey Portzer, eds. Buonicore, A.J., and Davis, W.T., Air and Waste Management
Association, Van Nostrand Reinhold, New York, 1992.
Air Pollution Control Equipment, Volume II Gases, Louis Theodore, and Anthony J. Buonicore
CFC Press, 1998.
Section V; Pollution Prevention Opportunities
Pharmaceutical Industry Waste Minimization Initiatives (White Paper), Pharmaceutical Research
and Manufacturers of America, 1997.
Guidelines to Pollution Prevention: The Pharmaceutical Industry, US EPA, Washington, DC.,
October 1991, (EPA/625/7-91/017).
Profile of the Inorganic Chemical Industry, US EPA, Washington DC., September, 1995 (EPA,
310-R-95-004).
Pollution Prevention Research Opportunities in the Pharmaceutical Industry, New Jersey
Institute of Technology, Emissions Reduction Research Center, New Jersey, April 1991.
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APPENDIX A
INSTRUCTIONS FOR DOWNLOADING THIS NOTEBOOK
Electronic Access to this Notebook via the World Wide Web (WWW)
This Notebook is available on the Internet through the World Wide Web. The EnviroSenSe
Communications Network is a free, public, interagency-supported system operated by EPA's Office
of Enforcement and Compliance Assurance and the Office of Research and Development. The
Network allows regulators, the regulated community, technical experts, and the general public to
share information regarding: pollution prevention and innovative technologies; environmental
enforcement and compliance assistance; laws, executive orders, regulations, and policies; points of
contact for services and equipment; and other related topics. The Network welcomes receipt of
environmental messages, information, and data from any public or private person or organization.
ACCESS THROUGH THE ENVIROSENSE WORLD WIDE WEB
To access this Notebook through the EnviroSenSe World Wide Web, set your World Wide
Web Browser to the following address:
http://es.epa.gov/comply/sector/index.html
or use
WWW.epa.gOV/OeCa - then select the button labeled Industry and Gov't
Sectors and select the appropriate sector from the
menu. The Notebook will be listed.
Direct technical questions to the Feedback function at the bottom of the web page or to
Shhonn Taylor at (202) 564-2502
Appendix A
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