GOOD LABORATORY PRACTI CE COMPLIANCE INSPECTIONS j OF LABORATORIES CONDUCTING HEALTH EFFECTS STUDIES INSPECTOR'S MANUAL UNITED STATES ENVIRONMENTAL PROTECTION AGENCY OFFICE OF PESTICIDES AND TOXIC SUBSTANCES OFFICE OF COMPLIANCE MONITORING WASHINGTON, D.C. APRIL 1985 ------- CONTENTS I. Background A. Introduction 1 B. Good Laboratory Practice (GLP) Regulations ...3 C. Laboratory Inspection Programs - an Overview... 3 D. Data Audit Programs - an Overview... .......4 E. Similar Programs at Other Agencies: 1. Food and Drug Administration (FDA) 5 2. National Toxicology Program (• NTP) . ... ..6 3. Organization tor Economic Cooperation and Development (OECD) .7 F. Acknowledgement ....9 II. Procedures for Laboratory Inspections A. Preinspection Activities: . 1. Headquar ter ' s Functions 10 2. Personnel Assignments.... 13 3. Dealing with Confidential Business In format ion . 13 4-. Records Review ....14 5.. Briefing Package.... .,...15 6. Previsit Conferences..- 16 B. On-site Inspection Procedures: 1. Entry into Facility 17 2. Opening Conference 17 3. On-site Monitoring 19 a. Administration: (1) Laboratory Organization ..20 (2) Management Support.. ...20 (3) Support Services 20 (4) Quality Assurance Unit...... ;20 (5) Master Schedule 21 (6) Standard Operating Procedures 22 (7 ) Archives 2 2 (8) Administration-Check List... ..23 b. Animal Care: (1) Personnel 25 (2) Facilities 25 (3) Strains of Animals 26 (4) Shipment and Receipt .26 (5) Quarantine Procedures 26 (6) Inspection of Animal Rooms....' 28 (7) Sanitation.' ' 29 (8) Water 30 (9) Feed 31 (10) Animal Care-Check List 32 ------- -i i- c. Chemistry: (1) Personnel n (2) Management ..37 (3) Facilities and Equipment 38 (4) Receipt, Storage, Distribution ...40 (5) Analysis of Test Chemical ...42 (6) Chemical/Vehicle Mixing Operation 43 (7) Chemical/Vehicle Analysis 44 (8) End of Study . 45 (9) Chemistry-Check List V. ...45 d. Toxicology: (1) Personnel 49 (2) Management 50 (3) Facilities and Equipment 52 (4) Dose Preparation ' 55 ( 5 ) An imals 59 (6) Clinical Signs Observation 60 (7) Unscheduled Deaths 61 (8) Sentinel Animals 61 (9) Toxicological Monitoring ..'..61 e. Pathology: (1) Personnel.' .68 (2) Facilities'and Equipment. .'. 70 (3) Protocols and Recordkeeping 73 (4) Pathology-Check List 77 f. Special Studies: (1) Clinical Chemistry Monitoring 79 (2) Pharmacokinetics Monitoring 82 4. Executive Session 84 5. Closing Conference 84 C. Report Preparation 85 D. Appendix I: Sequence and Time-line projections for Inspectional Activities 87 Appenxix II: Format for Laboratory GLP Inspection/ Data Audit Report 89 Appendix III: Interagency Agreement Between EPA and FDA 95 Appendix IV: Notes on EPA/FDA Interagency Agreement 104 Appendix V: Work Assignments During Inspections and Audits 113 ------- -1- LABORATORY INSPECTIONS AND DATA AUDIT I. BACKGROUND A. Introduction Health effects test data, ecological effects data, and other types of data required under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), as amended, and the Toxic Substances Control Act (TSCA), form the basis for the Agency's regulatory decisions on pesticides and toxic chemicals. FIFRA requires that registrants of pesticide products demonstrate that their products meet the safety and efficacy requirements of the Act and that their use does not cause "unreasonable adverse effects upon the environment." TSCA gives the Administrator the authority to require manufacturers and processors to test chemical substances or mixtures .in order to acquire data sufficient to determine if the substances present an "unreasonable risk of injury to health or the environment." EPA, therefore, has the authority to require extensive testing to ensure that products under its regulatory jurisdiction are safe and effective. The responsibility for these tests, including their adequacy and validity, rests with the registrant in the area of FIFRA, and the manufacturer or processor in the case of TSCA. Test results may have to be submitted either before the product or chemical is distributed or after distribution has begun. Testing requirements are established through Registration Guidelines required by §3 of FIFRA or by rule making under §4 or §5(e) of TSCA. Such testing may include physical and ------- -2- chemical studies (environmental, residue, and general chemistry) and studies to assess hazards to humans, domestic animals, fish and wildlife. Test data may also be submitted under negotiated testing agreements in lieu of. TSCA §4 test rules and these include an agreement to adhere to TSCA GLPs. Important decisions on the safety and efficacy of pesticides and other chemicals must be based on adequate and reliable data. In order to produce such data, studies need to be conducted according to scientifically sound protocols with detailed attention to quality control and with qualified personnel. The reliability of the data submitted is essential if EPA is to regulate chemicals in such a way as to protect the environment and public health. The Food and Drug Administration has similar program responsibilities under the Federal Food, Drug .and Cosmetics Act, and other legislation. Until 1975, both Agencies accepted with little question the accuracy and reliability of data submitted for regulatory decision making. However, in 1974 and 1975, problems surfaced in laboratories generating data for FDA and EPA. Preliminary investigations projected that approximately 40% of the data being submitted by the drug industry was inadequate. As a result of these discoveries, EPA and FDA established a program to ensure that future data would be generated only under the highest quality standards. This program involves two aspects, the inspection of laboratories and the auditing of studies to ensure compliance with these standards. These two aspects of the program are discussed in this manual. ------- -3- B. Good Laboratory Practice (GLP) Regulations The Laboratory Data Integrity Program within EPA has as its base a system of laboratory testing and laboratory management principles known collectively as Good Laboratory Practice (GLP) Regulations. These regulations are designed to ensure that laboratories conducting health effects testing that are to be reported to the EPA in support of any petition for regulation under the applicable sections of TSCA or FIFRA, have the facilities, personnel, expertise, equipment and management commitment to provide adequate and reliable data. EPA's GLP regulations became effective on -O&eem&eH?-29, 1983 (48 FR 53922) for TSCA and on May 2, 1984 (48 FR 53946) for FIFRA. FDA's GLP- regulations (40 CFR 58) became effective in 1978. By interagency agreements FDA will work together with EPA to conduct GLP Laboratory compliance inspections and data audits. C. Laboratory Inspection Programs - An Overview Laboratory inspections are performed while a study is in progress to ensure that the testing facilities are adequate and meet all the study requirements. They also provide the opportunity to discuss and review the program with key technical personnel and observe techniques in the laboratory. In general, these inspections help determine whether the testing laboratories are conducting the testing in a manner designed to ensure the quality and integrity of the data. Specifically these site visits assure: ------- -4- 0 that the specific protocols and amendments- are followed, ° that Standard Operating Procedures (SOPs) are in place, and adhered to, 0 that the recordkeeping is accurate and in compliance with GLP regulations, 0 that safety and quality assurance procedures are in conformance with requirements. D. Data Audit Programs - An Overview While the GLP inspection is concerned with laboratory facilities and procedures for in-process studies, the data audit is used to compare raw data to final reports submitted to the Agency. An audit (health effects or ecological effects) deals with ongoing or completed studies: ° To determine whether raw data are consistent with information submitted to the Agency; 0 To obtain information not provided in the final report; and 0 To determine whether practices were employed that impair the validity of the study. ------- -5- E. Similar Programs at Other Agencies 1. Food and Drug Administration (FDA)a Acts of U.S. Congress require that industry submit data to the FDA for the purpose of ensuring the safety of human and animal drugs, human biological drugs, medical devices and diagnostic products, food additives, color additives, and electronic products. In order to meet its consumer protection responsibility FDA stipulates that extensive animal and other types of testing be carried out by the manufacturers. The FDA's functions in monitoring these non-clinical laboratory studies require that the studies be conducted according to scientifically sound protocols; that detailed attention be paid to quality control so. that the integrity of the studies is ensured; and, that the test.ing facilities strictly comply with GLP regulations. The FDA's inspection procedures are of two types: a. Surveillance Inspections Surveillance inspections are those undertaken as periodic, routine determinations of a laboratory's compliance with Good Laboratory Practices (GLP) Regulations. b. Directed Inspections (1) Follow-up to a routine surveillance inspection which has been classified OAI or VAI on the basis of noncompliance with GLP Regulations and/or findings of significant a Source: Food and Drug Administration: Compliance Progran Guidance Manual, 7348.808, 9-01-80. ------- -6- or major discrepancies between the reports and original data and records of a nonclinical laboratory study. (2) Findings of questionable data or material which raise suspicions by headquarters personnel during a review of a report of a study submitted in support of an application for a research or marketing permit for a product. (3) The need to audit the data of an important study submitted in support of an application for a research or marketing permit. (4) The need to verify the audit performed by a sponsor or third party of the data and records of a study. (5) The need to review or inspect entities or studies brought to FDA's attention by other sources (i.e., news .media or other operating firms/labs) 2. National Toxicology Program (NTP)k The NTP sponsors and manages the _in_ vitro and in vivo toxicity testing of environmental agents in several laboratories. A major component of NTP's operations is devoted to the monitoring of these bioassays to ensure the quality and integrity of the bioassays and the safety of the personnel assigned to the program. Monitoring is intended to ensure that the tests are adequately conducted according to a specific protocol and that the data as reported are valid. Source: "Monitoring Guidelines for the Conduct of Carcinogen Bioassays". NTP Technical. Report Series, No. 218, (DHHS Publication No. (NIH) 81-1774). ------- -7- The NTP's monitoring procedures are of two types: a. Off-site monitoring requires an assessment of the program from written reports, computerized data, and telephone conversations with the personnel assigned to the studies at the contracting laboratory. Such audits of the data may be used to follow the performance of an assigned task and to verity the adherence to protocols. They cannot be substituted for frequent on-site monitoring, and they should precede and follow on-site monitoring visits. b. On-si.te monitoring is essential to assess various aspects of the program that cannot be accomplished by off-site means. Regular visits to the laboratory are made to inspect facilities, discuss and review specific protocols, standard opera-ting pr ocedur es , ..and the entire program with the key technical personnel, observe techniques, and inspect recordkeeping, training programs, and safety and quality assurance procedures.. 3. Organization for Economic Cooperation and Development (QECD)c A number of OECD Member countries have recently passed legislation to control chemical substances. This legislation usually requires the manufacturer to perform laboratory studies and to submit the results of these studies to c Source: OECD Publication - C(81) 30 (Final), 1st June 1981. ------- -8- a governmental authority for assessment of the potential hazard to human health and the environment. Government and industry are increasingly concerned with the quality of studies upon which hazard assessments are based. As a consequence, several OECD Member countries have established criteria for the performance of these studies. To avoid different schemes of implementation that could impede international trade in chemicals, OECD Member countries have recognized the unique opportunity for international harmonization of test methods and good laboratory practices. This led to the development of a document concerning the "Principles of Good Laboratory Practice (GLP)" utilizing common managerial and scientific practices and experience from various national and international sources. The purpose of these Principles of GLP is to promote the development of quality test data. Comparable quality of test data forms the basis for the mutual acceptance of test data among countries. The scope of OECD's program is to apply the Principles of GLP to testing of chemicals to obtain data on their properties and/or their safety with respect to human health or the environment. Studies covered by GLP also include work conducted in field studies. Those data would be developed for the purpose of meeting regulatory requirements. As its counterpart in the US, OECD's GLP is concerned with the organizational process and the conditions under which laboratory studies are planned, performed, monitored, recorded, and reported. It encompasses such areas are test ------- -9- laboratory organization and personnel, quality assurance program, facilities and equipment, test system, test article management, standard operating procedures, study plans, reporting procedures and archiving. F. Acknowledgement Guidelines provided in this manual are derived from publications and procedures of several agencies, including earlier drafts of the EPA Laboratory Inspection Manual. The editor has attempted to include in these inspectional guidelines the best and most relevant procedures from other programs so that some uniformity between agencies might be achieved. While each agency has established inspectional procedures that meet its goals and mandates, the core purposes always remain the same. ------- -lo- ll. PROCEDURES FOR LABORATORY INSPECTIONS A. Preinspection Activities 1. Headquarters' Functions The .Laboratory Data Integrity Program (LDIP) of the Office of Compliance Monitoring (OCM) will initiate, coordinate, and track the scheduling of GLP inspections and data audits for the Office of Pesticide Programs (OPP), and the Office of Toxic Substances (OTS). Tentative list of laboratories for GLP inspection/data audit will be generated using the integrated, computerized data file in LDIP and will be submitted to OPP and OTS for review. Additional information from OPP and OTS will be integrated with the tentative schedule and an essentially firm first (next) quarter schedule will be established. A second quarter schedule will be sketched in by month.and tentative third and fourth quarter information will be generated. a. Sequence and time line projections for inspection activities The attached chart (Appendix 1) schematically presents the scheduling cycle. The interaction of OPP, OTS, FDA, Regions and OCM/LDIP is outlined in the chart and described in the following paragraphs. b. Selection of laboratories for GLP inspection A "tentative inspection schedule" is generated by the LDIP scheduling and tracking system. This is a listing of the laboratories in the system arranged chronologically by estimated next GLP inspection date (determined by adding a year 1 to the last inspection date for all laboratories except those ------- -11- which conduct only long-term studies, when a two-year increment will be used). This schedule will be generated for only those laboratories with active studies underway, and those we have reason to believe will be starting new studies for EPA. LDIP scheduling staff examine the list and establish a tentative one year schedule using "the following fac tors: (1) Date of the last inspection (as sorted by the computer). Here is where the 1- or 2-year cycle comes in. (2) The importance of an EPA inspection report vs. one from FDA or NTP. Whether FDA's inspection was performed at EPA's request. (3) Prioritization based on prior inspectional history: priority assigned to those laboratories with a history of problems (either intermittent problems in several different study components or repetitive problems in one study component or facilities area). Inspections at laboratories with a history of no problems of consequence may be given a lower priority. (4) An unacceptable number of laboratories located in one Region are scheduled. Ordinarily no more than two inspections per region per month should be attempted. (5) Specific request for inspection received from OPP or OTS. ------- -12- c. Assignment The laboratories selected will be segregated into (a) EPA assignments and (b) FDA assignments. The assignment list will then be submitted for review and comments to OTS's Health and Environmental Study Audit Program (HESAP), to OPP's National Laboratory Audit Program (NLAP), and to FDA. Using their response an assignment list will be developed designating which inspections/audits should be led by FDA', which by the Regions, and which by NEIC/Headquarters staff. A finalized list of laboratory insepctions to^be led by the Regions will be provided to the Regions and a schedule with confirmed inspection dates generated. The FDA list will be available for consideration during the FDA assignment meeting so that any supplementary chalnges .can be made to best accommodate the coordination of FDA assignments with those of EPA. d. Investigation Requests Inquiries will be made of the testing laboratory and/or sponsor as to the location of the facility performing different aspects of the studies, e.g., animal holding and treatment, preparative and analytical chemistry, histology, clinical pathology, etc. The regions will then be notified via Investigation Requests the laboratory to be visited, dates, study reports to be audited, participants in the GLP inspection/audit, and background information necessary for the inspection of the facility. ------- -13- e. Notification of Inspection Notification of inspection will be sent to the laboratory a week to 10 days prior to the date of inspection. Request will also be made in the notification letter for raw data, and SOPs, and for key personnel to be available for d iscussions. 2. Personnel Assignments If an inspection involves only EPA personnel, the regional inspector is usually the team leader and has overall responsibility for the -inspection, including planning, conduct, and report preparation. Accompanying scientists support the team leader by reviewing data when necessary, asking technical questions, and providing technical input for the inspection report. In a joint FDA/EPA inspection the team leader is the FDA investigator, and EPA provides support. 3. ' Dealing with Confidential Business Information In all studies to be audited "the inspection must deal with claims of Confidential Business Information (CBI). The facility owner or agent in charge has the right to claim any part or all of the information to be audited as CBI. Considerations involving the handling of CBI include: a. Access to CBI is controlled and limited to authorized persons. ------- -14- b. The TSCA Inspection Confidentiality Notice must be presented to facility officials. (TSCA Manual: Chapter Three, Section 1) c. Data claimed as confidential may not be entered into the field notebook. (TSCA Manual: Chapter Three, Section 4c) d. Special precautions must be taken to protect CBI. e. Claims of confidentiality may be made by facility officials up to 7 days after the audit. (TSCA Manual: Chapter Three, Section 5) 4. .Records Review Reviewing the Agency's files on a facility to be inspected will provide important background information on the study and on the facility's operations and compliance history. These records will be provided when available before the audit. When available, the following documents and types of information should be reviewed. a. General facility information, including type, size, and location of the facility to be inspected. This information is helpful in planning time and resource allocations. b. Previous inspection records and reports on enforcement proceedings that resulted from other inspections. Note any violations observed in previous inspections. ------- -15- c. Reports prepared by the facility that were obtained during previous inspections. Review these reports and npte any discrepancies previously observed in the facility records. d. Milestone status. Review these and note any deviations that may affect the scheduled dates of laboratory inspections and/or data audits. e. List of studies either in progress or recently completed. 5. Briefing Package A briefing.package including the following items will be made available to the inspection team: a. The date and time of the proposed"visit b. Travel and accommodation arrangements c. The purpose of the visit d. The proposed agenda e. The names, disciplines, positions and/or responsibilities, of key laboratory personnel f. A map indicating location, address, and phone numbers of the laboratory g. A floor plan, if available, of all facilities participating in the program ------- -16- h. Company organization charts and the curricula vitae (CV's) of key personnel i. Program organizational charts within the. company. 6. Previsit Conferences Several informal telephone conferences will be held among participants in the inspection to discuss specific details. A final conference will be scheduled for the inspection team to be held on the day previous to the inspection date to address the following. a. Define visit objective b. Identify problem areas c. Delineate any specific areas to be covered by each member d. Discuss the critical items in the briefing package Once preliminaries are over the inspection team personnel will conduct their activities, accompanied by appropriate test facility personnel thus permitting rapid coverage of most specialty areas and detailed coverage as needed. ------- -17- B. On-site Inspection Procedures 1. Entry into Facility The following steps must be taken to gain entry and protect inspection from challenge on legal grounds: a. Obtaining consent to enter. b. Arrival during normal working hours. c. Presentation of official credentials. If entry is denied, or if consent is withdrawn during the audit, consult the denial of entry procedures. The above procedures are discussed in detail in TSCA manual: Chapter 3, Section 2, and in FIFRA Manual, Chapter 3, Section 2. 2. Opening Conference After entry has been established, an opening conference with facility officials should be conducted, covering .the following areas: a. Inspector presents the Notice of Inspection, and as needed TSCA Inspection Confidentiality Notice and Declaration of Confidential Business Information, all appropriately completed. b. Inspector outlines the inspection objectives: An outline of inspection objectives informs facility officials of the purpose and scope of the inspection and helps avoid misunderstandings. Explanation of records required, and ------- -18- information which may be collected and copied as necessary during', the inspection will.include: ° Test protocol, 0 Quality assurance unit records (as allowed by GLPs), ° Amendments to protocol, 0 Personnel lists for study, 0 Raw data books (and receipts), 0 Sample chemical records, ° Animal colony records, ° Observation records for test, ° Chemistry lab records, ° Necropsy, post-mortem records, 0 Histopathological records, slides, specimen samples, and 0 Interim reports, draft reports, data summaries c. General Information. General information on the company and personnel required for the audit should be obtained. The name and address of the chief executive officer and resumes of the staff who conducted the studies are two examples. d. Obtain a copy of the Master Schedule. This will help you direct the GLP inspection with special attention to ongoing studies. (See also, II, B, 3.a. (5) Master Schedule). ------- -19- 3. On-Site Monitoring The purpose of the site visit is to evaluate whether the testing laboratory is conducting its oncogensis and toxicology studies in compliance with the EPA-GLP regulations The list of questions in the following paragraphs is designed: (a) to provide an outline that can be used to collect important update information on personnel, facilities, protocols, and record'' keeping as they relate to EPA's specifications, and (b) to pinpoint specific problems and potential problem areas. It is essential, therefore, that all items in the list of questions be thoroughly studied. It should be emphasized that the Inspector should use his discretion to identify those areas in a particular facility that will need special attention.- A careful check of these areas will be made, and if everything seems in compliance then he would proceed to the next step. But if problem areas or trouble spots are encountered then the inspector would investigate deeper. The questions raised in the following paragraphs are a comprehensive guideline of specific details. Not every item needs to be answered. It only prompts the Inspector to the numerous and various steps in an area. The specific study protocol, and, especially the SOPs would be source of checks for a specific study. Be careful to avoid discussions on the protocol if there are differences of opinion. Your analysis of protocol faults.are properly discussed only with the Product Manager. Do not interfere. If some gross problem is seen by you have the ------- -20- lead inspector reach the Product Manager by phone for a discussion of the problem. You are not authorized to change a protocol. As the most complex inspections are those involving long-term animal studies the procedures below are designed for such studies. For shorter-term studies select those questions and procedures that fit the inspectional program at hand. a. Administration (1) Laboratory organization. ° Is the program as organized by the institution adequate to ensure quality work performance? (2) Management support. ° Does management adequately support the Study Director and the Program? (3) Support services. 0 _ Are the support services required for the studies efficiently provided to the Study Director? Are they under his/her direct control? If not, how are these coordinated? (4) Quality Assurance Unit (a) Is there a Quality Assurance .(QA) unit that functions independantly of the Testing Program, and reports directly to the Corporate Management? (b) Who heads this unit? What are his qualifications for this position? Examine his curriculum vitae. * (c) Whom does the Head of QA report to? ------- -21- (d) What is the personnel make-up of this unit? What are their qualifications? (e) Do any of the QA personnel also function in any capacity in the Testing Program? (f) If possible watch how a QA inspection is performed for a particular task. Do they use the SOP's to check that the steps are followed as documented? (5) Master Schedule (a) Does the Management (QA unit) maintain a Master Schedule for all testing activities at the facility? (b) Examine the Master Schedule. Request the QA unit to provide the following information to be included in the Inspection Report, (Note; This should be stamped CONFIDENTIAL): ° Identification of studies performed at the facility that are sponsored by the EPA; if this list had been obtained previously an update will be sufficient. ° Identification of studies sponsored by other sources, and which may be submitted to the EPA for review. ° Code name or number for the chemical(s) on test (chemical name is optional). ° Types of studies performed for each chemical. ° Start date of each study, termination date, and date report due at EPA. The purpose of this activity is two-fold: First, the Master Schedule tells the Inspector if the laboratory has possibly overcommitted itself on tests and contracts with resulting degradation of performance. Second, the EPA segment of ------- -22- the Master Schedule permits the EPA to schedule future inspection at the facility in a period of maximum interest and diverse activities. (6) Standard Operating Procedures The importance of SOPs and the following of SOPs during a study cannot be overemphasized. These are the principal organized documents to be checked during an inspection. (a) Are there SOPs tor all testing functions? (b) Who writes them? (c) Who reviews them? (d) How often are they revised and updated? (e) Are they available in the laboratory? ( 7 ) Ar-ch ives (a) How are raw data handled and stored? (b) Where are the archives located? In or out of the testing facility? (c) Are documents, tissues, blocks, slides, etc. stored in the same archival area or different? (d) Is the organization of the archives adequate without being crowded and cluttered? (e) Are pallets used for boxes? (f) Are the environmental conditions of the archival area adequate? (g) What precautionary measures are installed against f ir e? (h) Is the archival area secure with limited access? ------- -23- (i) What are the procedures for removing material and returning these to the archives? (8) Administration-Check list. (a) Have there been any changes in professional staff? (Obtain CV's of new personnel.) (b) Is the master schedule for all studies up to date? Is the facility overcommitted? (c) Is the Study Director knowledgeable about the status of the following: ° Animals? 0 Chemicals? ° Scheduling? ° Recordkeeping? 6 Reportinq? (d) Has the Study Director received and understood the following protocols for the chemical: ° Safety and toxicity? ° Chemical analysis, if performed by the testing laboratory? 0 Dose preparation? ° Storage? 0 Animal studies? ° Special studies? ° Revisions of various protocols? (e) Has the laboratory received all "Safety and Toxicity" packages related to an individual chemical on test? (f) Are protocols available to appropriate staff? ------- -24- (g) Are there SOPs for all relevant areas of testing? (h) Are all precautions (as necessary) in place before receipt of the chemical (e.g., handling, storage or disposal requirements)? (i) How many types of accidents have been reported? What remedial action was taken? (j) Have any personnel developed medical problems? (k) Are personnel given regular medical check-ups? Who maintains these records? (1) Where are the raw data archived? (m) Who is the custodian of the archives? (n) What is the condition of the archival area- environmental, organization, precaution against fire, security? ------- -25- b. Animal Care (1) Per sonnel (a) Is there a veterinarian responsible for the institution's animal care program? (b) What are his/her qualifications for this responsibility? 0 What advanced degree or training does the veterinarian have? 0 Is the veterinarian certified? If so, by what organi zat ion? (c) Is he/she a full-time employee, part-time employee, or consultant? (d) What is his/her participation in this program? (e) Are the animal care technicians certified by AAA LA C? 0 If SO, huw many at e cet<-1 £ieu as: - Assistant laboratory animal technicians? - Laboratory animal technicians? - Laboratory animal technologists? - How many hold college degrees? ° If not, is there an ongoing training program to prepare animal care personnel for animal technician certification? ( 2) Fac ili ties (a) Is the facility AAALAC accredited? ° If so, what is the date of accreditation? ° What is the date of last site visit? ------- -26- ° If not, has accreditation been applied for? (b) Does the laboratory have SOPs for care of animals in a long term carcinogenicity or toxicity study? (c) Does the combination of facilities and management provide an environment that minimizes the entrance of pathogenic organisms into the animal cages and the exit of test substances from the cages? (d) Does the facility have a diagnostic laboratory? (e) What, routine health screening procedures are used to minimize the introduction of pathogens into the facility? (3) Strains of Animals (a) Are any strains of animals being used in the study other than those designated in the protocol? (b) Are animals from different sources housed in the same facility? (c) Will the disease status of the animals affect the results? (4) Shipment/receipt of animals (a) Have any problems been encountered with animal shipments? (b) Are the animals healthy? If not explain. (c) Are receipt records adequate? (5) Quarantine procedures (a) Are quarantine facilities available? ------- -27- (b) Inspect animal quarantine area and examine quarantine records and procedures. If possible, discuss procedures with the animal technicians assigned to this area. 0 Are quarantine animals receiving the same type of feed they will receive when tested? 0 Are quarantine animals using the same water system they will use when tested? ° How many animals are being killed from each shipment for parasite and disease examination before animals are placed on acute, repeated dose, subchronic, and chronic tests? 0 Who performs these disease examinations? 0 Are technicians familiar with clinical signs? ° What are the quarantine procedures? How are they recorded? 0 How often does a veterinarian examine the animals? How is the examination recorded? 0 How are sick animals reported? How are records kept? ° Who approves release from quarantine? ° Are animals inspected twice daily? 7 days per week? What is the weekend/holiday schedule? ° Are there crossovers between the clean and dirty sides of the facility? If so, how are these crossovers min imi zed? ° How is the dirty/clean concept enforced? ° Is more than one chemical being tested in the same room? If so, what are these other chemicals? ------- -28- (6) Inspection of Animal Rooms Inspect animal room(s) designated for the studies and examine records to ensure that the room(s) is properly, prepared. Inspect records, noting temperature and humidity controls and monitoring procedures for the animal rooms', and review emergency power systems and alerting mechanisms. (a) Are drains in animal rooms plugged? (b) How many air changes are there per hour in the animal rooms? (c) Are quantitative measurements and recording of air flow being performed as required? What action is taken when measurements are outside these limits? (.d) What is the light cycle? How is it checked? (e) How.is room temperature .monitored and recorded? (f) What is the prescribed animal room temperature and range? The high and low temperature? (g) What is the prescribed animal room humidity and range? The high and low humidity? (h) What temperature and humidity limits are allowed, and what happens when the temperature or humidity is outside these limits? (i) How often are the animal rooms being wet mopped? (j) How often are the rooms cleaned? How are they cleaned? How are records kept? (k) What cleaning compounds are used? Who manufactures them? Are they EPA registered and approved? ------- -29- (1) What is the source of emergency power? O How frequently is it tested? 0 Is it tested under load? O Where is a log kept? Check the log. O What areas does emergency power handle? O Is it of the automatic changeover type? (m) Is the emergency notification procedure adequate? (n) How frequently are the cages, filter sheets, feeders, and racks being changed? Refer to protocol. (o) Do racks, cages, filters, and water systems meet requ i rements? (p) What is the cage configuration on the racks? Refer to protocol. (q) How frequently- are cages rotated on racks? Refer to protocol. (7) Sanitation (a) How are cages cleaned? (b) How often are racks washed? How? (c) What chemicals are used to wash equipment? (d) What temperature does the cage washer reach? How is it monitored? Are records kept? Is water recycled? (e) What kind of bedding is used? (f) Do rat and mice cages receive adequate amounts of bedding per cage? How is this amount being dispensed? (g) Is there any evidence of vermin or loose animals in the animal rooms, cage wash area, storage areas, study support facilities, or outside environment? ------- -30- (h) What sanitization methods are being used for sanitization of equipment used in the program, including cages, racks, feeders, watering devices, rooms, walls, halls, and building? (i) Does one cycle of the rinse water reach 180°F? If not, what was the"highest temperature? (j) Is the clean storage area adequate? (8) Water (a) What is the source of the water for the animals? (Well, city supply, etc.)? (b) What treatments are given the water by the laboratory? (Acidification, chlorination, filtration, deionization, distillation, etc.) (c) How are these treatments monitored.-' - Are records available? (d) Are water bottles washed before refilling? How? (e) How often are water bo.ttles and stoppers washed? (f) How are sipper tubes cleaned? (g) How are automatic waterers checked to make sure they are functioning properly? (h) Does the water provided for animal use meet the USEPA drinking water standards? Are the water-analysis reports included in the test Final Reports to the sponsor? (i) What is the date of the last water analyses report? What is the frequency of water analysis? ------- -31- (9) Feed Inspect food storage area and note food source, lot number, and manufacturing date. Check feed rotation and review feed receipt procedures. (a) Is the storage area for feed and bedding clean? (b) What brand of feed is used? Does this agree with the protocol? Who is the supplier? (c) How is food examined on arrival, and what are the reasons for rejection of feed? (d) What is the oldest date of manufacture in current inventory? (Food should ordinarily be used within 90 days of manufacture.) (e) How is the food stored? Is it refrigerated? Examine storage area for insects, rodent feces, clutter, etc. Are first-in/first-out procedures followed?) (f) How is food stored after the bag is opened? (g) What type of records are kept on feed? (Examine (h) How are feeders loaded, and where is loading (i) Are feeders emptied and washed before refilling? (j) What type of feed container is used? (k) Does the facility have the ability to autoclave feed and/or bedding if required? (1) Are the following reference materials available? ° The Guide for the Care and Use of Laboratory Animals, DHEW Publication No. (NIH) 78-23, Revised 1978 them.) done? ------- -32- ° A Guide to Infectious Disease of Mice and Rats, NAS, 1971 Publication ISBN 0-309-01914-1 (m) Is the feed to be analyzed at intervals? If so, is it done according to protocol and is the analytical report included in the test Final Report? (10) Animal Care-Check list The following check list enumerates the specific questions related to the various areas of animal care that need clarification. It is emphasized that this is only guidance; the inspector should use these to formulate his own approach in dealing with a specific laboratory. (a) Shipping and receiving ° Have any problems been encountered with animal shipments? ° Are animal receipt records adequate? ° Are there problems with the feed supply? (Record the oldest feed in the current inventory.) (b) Facilities ° Are the facilities adequate for testing needs? 0 Have there been any changes in assigned facilities during the course of the study? If so, why? Are the new facilities adequate for the testing needs? ° Do the testing areas have limited access? 0 How consistent is airflow and air direction? 0 Have any HVAC equipment malfunctions been reported? ------- -33- 0 Is personnel protective equipment required. Is it appropriate? 0 What are the. hiqhest and lowest temperatures recorded? ° What are the highest and lowest humidity recorded? ° What are the weekend/off hour emergency procedures. 0 Have any emergencies occurred during the study? If so, explain. (c) Maintenance 0 Is there any evidence of vermin in the fac ility? 0 Are room sanitation procedures adequate? ° How are animal rooms and support corridors cleaned? How frequently? ° What clean-up techniques are employed? ° Do members of the maintenance staff comply with the personnel protective requirements of the animal care staff? ° Are maintenance logs up-to-date? 0 Has emergency power been tested recently? How frequently is this done? Is there a log for these tests? 0 What are the procedures for room decommissioning after the testing phase? 0 How is equipment serviced (e.g. HAVAC, case washer, rack washer, etc.)? ------- -34- 0 Are members of the maintenance staff familiar with the study needs and requirements? (d) Testing and Animal Handling 0 Are protocols available in the laboratory for responsible technicians? 0 Are SOP's available in the laboratory for responsible technicians? 0 How are animal logs and records handled? Electronic? Notebooks? Are daily logs initialled and dated? ° Verify -frequency of daily observations for moribundity/mortality. 0 What times of day during the week are observations made? ° What are the weekend and holidav schedules for observations? day? How often is weighing done? What time of Who observes clinical signs? Do technicians understand clinical signs terminology? ° Who checks the accuracy of clinical observations? How often? Sign-off? ° Who determines food consumption? ° Who determines water consumption? ° Are daily records kept on the number of dead animals? ------- -35- ° How frequently are cages/racks changed? Individual housing? Group housing? 0 Who determines sacrifice of moribund animals? (e) Dose administration 0 Dosed feed: Are dedicated feeders used for each chemical? Do animals appear to waste excessive food? Are feeders filled in ventilated hoods? 0 Gavage: Are records of deaths due to gavage accident kept as an indication of technicians' performance? Is gavage performed under hoods with appropriate personal protection? ° Skin painting. Are animals housed as groups or as ind ividuals? What is the hair clipping procedure? How frequently is hair clipped? What is the site and area (cm ) of application? - How are descriptions of observations made? Are individual animal diagrams used? Are lesions measured? How frequently are observations made and recorded? Is regression recorded? ------- -36- (f) Cage emptying/washing ° Is adequate local exhaust ventilation provided in this area? ° How are wastes handled? ° Examine the loading dock (for waste shipment) or on-site incinerator area (if present). 0 Are washing and sanitizing equipment properly operated? ° Are temperature logs in place for these equipment? ° Are control cages washed before cages are used for dosed animals? ° When feeders/water bottles are washed, are the control containers washed before the dose containers.? ° How are treated cages marked? Is it easy to determine which cages were used for each chemical? ------- -37- c. Chemistry (1) Personnel (a) What are the backgrounds of the responsible chemist and chemical support staff? ° What is their experience in analytical chemistry or in performing analyses similar to those required in the program? ° What experience do they have in analyzing and handling potentially carcinogenic material? (b) What are the backgrounds of the supervisor and technicians responsible for dose preparation? ° What experience do they have in preparing dosage mixtures for chronic studies? ° What is their experience in handling chemicals and carcinogenic materials? (c) Is there a SOP for briefing technicians (i.e., a training program) on the proper handling of specific chemicals? (2) Management (a) What is the relationship of the analytical chemistry department to the testing laboratory? ° Is the analytical chemistry department providing a service to the testing laboratory, or is it an integral part of the program? ° If the chemistry department is separate from the testing laboratory, is it meeting the requirements of the testing facility? Is it in compliance with GLP regulations? ------- -38- (b) Is the responsible chemist knowledgeable of all the chemistry requirements of the testing? (c) Has the responsible chemist discussed the scheduling of sample submissions (.dosage mixtures, bulk chemical, corn oil) with the Study Director, and is the schedule being met? (d) Who is responsible for preparing reports on the analyses performed for the testing laboratory? ° Are they reviewed for accuracy? ° Who receives copies of these reports? (e) What quality assurance procedures are followed by the analytical chemistry laboratory? ° Are SOP's available for laboratory activities? (f) Has the chemist reviewed the procedures used for. dosage preparation activities? (g) Does the supervisor for dosage preparation activities know all the chemical/vehicle requirements of the study? (h) Have emergency procedures addressing such situations as chemical exposure or spills been established? (3) Facilities and Equipment (a) Analytical facility ° What analytical instrumentation is available for use in these studies? ° What is the maintenance schedule and quality assurance procedure used for each piece of equipment? ------- -39- 0 Are the analytical laboratories- designed and utilized in a safe and efficient manner? 0 Can the facility handle potentially carcinogenic materials? ° Is there adequate cold storage (at 5° and -20°C or lower) for bulk chemical reference standards? (See also Toxicology) ° How are wastes generated in the analytical facility disposed of? (b) Dosage preparation facility ° What equipment is available for use in the program? What are the number and sizes of blenders for dosed-feed studies? What type of balances are used? What equipment are used for preparing gavage mixtures? Skin painting mixtures? - What is the maintenance schedule and quality assurance procedure used for each piece of equipment? 0 Is the dosage preparation area designed and utilized in a safe and efficient manner? Can the facility handle potentially carcinogenic materials? ° Is there adequate storage (both at ambient and 5°C temperatures) for both bulk chemical and chemical/vehicle mixes and dosed diets? ------- -40- 0 How are wastes generated in the dosage preparation area disposed of? 0 How are dosage mix samples taken and transferred to analytical chemistry for analysis? ° How are the dosage mixes transferred from the mixing vessel to the storage container? ° How are the dosage mixes stored and labeled? If the dosage mixes are stored, what quality assurance procedures are used to ensure that dose levels, etc., are not mixed up during distribution for dosing?- ° How are dosage mixes distributed to the animal rooms? (c) Inhalation facility 0 What capabilities exist for generation of gases? Of aerosols? ° What instrumentation is available to monitor chamber concentrations? ° Is there adequate storage space for large numbers of gas cylinders or other containers of bulk chemicals? ° See also 11.B.3.d.(3).(d) . (4) Receipt, Storage, and Distribution of Bulk Test Chemicals (a) Receipt ° Is there an SOP for receipt of bulk chemicals and transfer to the storage area? ° Was the chemical received in good condition? ° Was it properly packaged and labeled? ------- -41- 0 Was a return receipt requested? 0 Were the chemical reference standards for bulk chemical analyses pulled and stored at -20°C? (b) Storage 0 Was the material transferred directly from receipt to storage or was it repackaged? 0 If repackaged, why and how was the repackaging done? 0 Do storage conditions meet those recommended by the analytical laboratory or manufacturer? ° If multiple batches are received over the course of a study, are they used on a first-in/first-out distribution system? ° Is" special handling required and, if so, is the bulk broken down into working batches for easier handling? ° Are chemical reference standards stored at -20 °C? (c) -Distribution ° Is material signed for when transferred for mixing operations? 0 Is there an inventory system to keep track of amounts being used so that, if necessary, more can be ordered and received before current batch runs out? Has consideration been given to storing a 90-day supply for emergency situations? ° Is material transferred from storage to mixing operations safely? ------- -42- 0 When material is returned, is it sealed and stored properly? ° Are special handling conditions- being followed by all personnel? (5) Analysis of Test Chemical Analysis of the test chemical may not be a requirement for acute toxicity testing, 14-day repeated-dose and other short term studies. But they are performed periodically (at regular intervals) during subchronic and chronic tests to check the stability and purity of the test substance during the course of the studies. When it is performed the following items should be checked: (a) Is the chemist provided with background information on chemicals, including an analysis report? (b) Is the bulk material analyzed on a regular basis? What intervals are specified in the protocol? Are these being followed? Are the results consistent? (c) Is the analysis protocol developed by the Sponsor laboratory being followed? If not, why? If so, what approved modifications, if any, were necessary? (d) Are the results reported to the Study Director? To Sponsor? (e) What QA procedures are used by the analytical laboratory for 0 Calibration of instruments, 0 Running standard curves, ------- -43- 0 Use of internal standards, ° Record keeping? (6) Chemical/Vehicle Mixing Operation (a) Is the mixing technician briefed on the safe handling and toxicity of the materials being used? (b) Is protective clothing and respiratory protective equipment worn when dosage mixtures are prepared? (c) Was a mixing protocol provided by the Sponsor and, if so, is it being used? (d) Are the vehicles (feed, corn oil, acetone, etc.) properly stored and handled? (e) Do the mixing operations yield an acceptable dosage mixture (i.e., homogeneous feed mixes, clear corn.oil gavage solutions, etc.)? (f) How are samples taken and transferred to chemistry laboratory for analysis? Are samples of vehicles, taken from the same lot used in the mixing operation, sent as blank samples? (g) How is the dosage mixture transferred from the mixing vessel to the storage container? (h) Are the dosage mixtures properly stored and labeled? (i) If dosage mixtures are stored, what quality assurance (QA) is there to ensure dose levels, etc., are not mixed up during distribution for dosing? (j) How are dose levels prepared? ° Are the formulation instruction sheets written, detailed, and complete? ------- -44- 0 Are the different levels weighed and mixed separately, or is the high dose mixed and then diluted for subsequent lower doses? (k) What is the QA on the instruments (i.e., balances, pipets, etc.) used, in the mixing process? (1) If corn oil is used as vehicle, is it stored below 5°C? Is it food grade? Is it analyzed periodically for peroxide level? (m) How are excess dosage mixtures and waste handled? (n) In feeding studies how are feeders filled and "topped off"? (o) Are dosage mixtures taken from the animal room during test tor analysis? If so what is the frequency of such analyses? (p) See also 11.B.3.d.(4) . (7) Chemical/Vehicle Analysis (a) Are dosage mixtures analyzed promptly? Where? If in the Sponsor's analytical facility is there an adequate chain of custody procedure? (b) Who performs the analysis? 0 It testing laboratory performs the analysis do they follow the method provided by the manufacturer? ------- -4 5- If not, why? If so, what modifications, if any, were necessary? (c) What is the time frame between mixing and analysis? Do they occur before the animals are dosed? (d) What is the QA on the analysis instruments used tor dosage analysis? (e) How are the data monitored? How is the Study Director informed it results are out of tolerance? What steps are taken to notify the proper personnel? What corrective actions are taken, and within what time trame? (f) How are the data recorded, verified, and maintained? Are results within specified limits? (8) End of Study (a) Was a final, bulk test chemical reanalysis performed at the conclusion of a chronic study? (b) Are all chemistry data generated during the study available for the final report? (c) What is the status of surplus test material? (9) Chemistry-Check List The following check list enumerates the specific ¦questions related to various areas of chemistry aspects of the study. These questions are provided as a guidance. The inspector should use these to formulate his own approach in dealing with a specific laboratory. (a) Was the chemical received in good condition? If not, how was it handled? Was damage reported? (b) Was the chemical properly packaged and labeled? ------- -46- (c) Was chemical transferred directly from receipt to storage or was it repackaged? If repackaged, was it done by an approved method? (d) Where are analytical operations carried out?' Was the responsible chemist provided with .the background information on the chemical? (e) How is the active ingredient in the test material identified and quantitated? Is there an SOP? (f) Is there a mixing schedule for dose preparations and required analyses in place for the chemical? (g) Has there been any particular problem with chemis try? (h) Were chemical reference standards for bulk chemical analysis pulled and stored at -2U°C? (i) Are all chemicals stored according to prescribed cond i tions? (j) Is the individual chemical disbursement log up-to- date? Where are records maintained? (k) Are labeling requirements being met (including the use of any radiolabeled material)? (1) Do technicians appear well informed about Standard Operating Procedures and specific requirements? (m) What is the general appearance of the analytical areas? (n) How effective does the exhaust ventilation appear? (o) Is biotest material transferred under controlled condi tions? ------- -47- (p) Do any special studies or routes of administration pose procedural problems? (q) Are staff members aware of spill cleanup proced ur es? (r) Who performs the mixing procedure - testing laboratory, sponsor or other? (s) Are standard mixing protocols being used? (t) Are hoods, blenders, etc., adequately cleaned between preparations of different doses? (u) Do mixing operations yield acceptable dosage mixtures (i.e,, homogeneous food mixes, clear corn oil, gavage solutions , etc.)? (v) Are dosage mix'tures properly labelled and stored? Do they follow the storage and handling procedures outlined- in the SOPs? (w) How are dose levels prepared? Are the different levels weighed and mixed separately, or is the high dose mixed and then diluted for subsequent lower doses? (x) Is the transfer of dosed feed minimizing aerosol contaminat ion? (y) Where are the feed hoppers filled? How? (z) Are the dosage mixtures being analyzed promptly? What is the time frame between mixing and analysis? (aa) Are analyses performed before the animals are dosed? If not, how soon after? (bb) How is the chemical surplus handled/shipped? (cc) Is all material accounted for? ------- -48- (dd) Are special decontamination procedures required in specific work areas? ------- -49- d. Toxicology (1) Per sonnel Ar e the key people qualified for the testing program? (a) Is the toxicologist O ex per ienced wi th the animal species used in the studies? 0 exper ienced with the type of study called for? o exper ienced with tox ic chemicals/carcinogens? o exper ienced with the method of administration (teedi ng , gavage , dosed water, skin pai nting, inhalation) of the test chemical? Certified? If so, by what organization? How many hours per week does the toxicologist devote to the study? What advanced degree or training does the toxicologist have? How many years has the toxicologist been at the laboratory? (b) Is the clinical chemist ° experienced in hematology? ° experienced with automated microanalysis techniques for various markers in blood, and urinalysis? ° experienced in clinical enzymology? (c) Are personnel available in special disciplines as required : ------- -50- 0 immunology? 0 pharmacokinetics? 0 biochemistry? 0 residue analysis in biological samples? (d) Are experienced personnel available for dose pr epar at ion? (2) Management (a) Study Director ° Is the Study Director knowledgeable in all respects about the status ot the following: protocols? chemicals? recordkeeping? reporting? scheduling? ° Who is the designated back-up for the Study Dir ec tor? 0 Is the master schedule for the studies up-to- date? ° Are reports verified for completeness and accuracy? (by whom?) ° Is there an adeguate staff to conduct the studies? (b) Training ° Are there training programs for the following personnel or activities? ------- -51- technicians? group leaders? data evaluators? gavage techniques? necropsy techniques? skin painting (when applicable)? inhalation equipment (when applicable)? clinical observations? clinical chemistry? dose preparation? histology? ° Are there records to check the following? Verification of proficiency, speed, accur acy. Periodic refresher training. Who does training? Qualifications? (c) Safety Is there a safety committee that reviews toxicology activities? 0 Who serves on this committee? 0 To whom does it report? 0 How often does it meet? (d) Emergency Have emergency procedures been established for the following: O O Electrical failures? Heating/cooling failure? ------- -52- 0 Airtlow disruption? 0 Chemical spill? 0 Shortage of personnel? ° food or water rejection by animals? ° Has an up-to-date emergency notitication procedure been posted inside and outside of the study rooms? (3) Facilities and Equipment (a) Is the facility properly designed for toxicology studies? ° Does the facility design allow for controlled access, and are SOP's in existence as to how the facility is used to ensure controlled access? ° Has the flow of the followinq been considered: personnel.-' Equipment? - Laundry? Bulk chemicals? Dose preparations? Contaminated material? Incoming animals? Animal carcass? Other waste? (b) Is general housekeeping adequate for the following areas Of fices? HalIs? Change rooms? ------- -53- 0 Personnel hygiene stations? 0 Laboratories? 0 Animal rooms? ° Storage areas? ° Dose preparation laboratories? 0 Cage/washing facilities? ° Disposal/pick up sites? (c) Are there adequate storage areas for: ° Bulk test chemicals (Room temperature, +5°C, -20 0 C)? ° Dose preparations (+50C and room temperature)? ° General supplies? 0 Feed and bedding? 0 Clean cages and.racks? 0 Analytical tissue samples/sera (-20°C)? 0 Animals for necropsy (+5°C)? ° Animal carcasses (-20°C)? (d) It the facilities are equipped for inhalation toxicology, determine the following: 0 What type of chamber equipment is available? 0 How many chambers are available? ° What size are the chambers? ° What types of generation procedures are ava ilable? ° Can the chamber concentration be monitored intermittently or continuously? ------- -54- ° Is the generation system isolated from the chamber room? 0 Is emergency power automatic? What is handled by emergency power? 0 Are animals housed in the chamber or removed when it is being cleaned? ° What techniques are used to determine particle size and particle concentration? Is size determined by number or mass? ° Does each chamber have temperature and humidity controls? ° Is the pressure/vacuum in the chamber negative to the room? (e) Maintenance tor the testing program. Are there SOP's and record verification for following maintenance act iv i ties? 0 Decontamination procedures for lab equipment/ e tc.? ° Schedules for maintenance of equipment/ filters, alarm systems, and emergency power? 0 Flow of maintenance personnel? ° Temperature check records? ° Humidity check records? (f) The following items are to be monitored for each chemical assigned to a laboratory: ° Has the Study Director received and understood the following protocols for each chemical: ------- Safety and toxicity? Chemical analysis? Dose preparation? Storage? Animal studies? Special studies? Revisions of various protocols? ° Are the records adequate for each chemical assigned to the laboratory? (See also Chemistry: II.B.3.C.) Do they include: Log-in receipt? Inventory system for bulk? Access controlled storage for bulk? Bulk- storage, as. specified? Storage of analytical samples? Dose storage? Confirmation of chemical identity? Referee samples and reports? - Procedure for transfer of chemical, doses , from the preparation room to storage, analytical laboratory inoculation center? (4) Dose Preparation (a) Dosed-feed 0 Who is responsible for calculations? ° Are calculations recorded for each dose pr epar at ion? ° Who supervises dose preparation? etc. and ------- -56- ° Are written mixing procedures and dose levels available for each chemical? ° Are dose levels weighed and mixed separately? ° Have records been verified for: Lot numbers of bulk chemical, feed, corn oil, etc.? irecord book)? Who is technically responsible (who signs Calcula tio ns? Date of dose preparations? Dates doses used? Analytical samples taken, labeling, s tor age? 0 How are mixers cleaned? o Are there labels on dosed feed o Ar e balances calibrated? How o Are chemical and dose spec i f ic dosed pr eparations? O Are doses analyzed before use? 0 Is there an up-to-date schedule for dosed-feed preparation? (b) Gavage/skin painting 0 Who is responsible for calculations? ° Are calculations recorded for each dose? 0 Who supervises? 0 Are the dose levels for each chemical available in the laboratory? ------- -57- ° Are SOP's available in the laboratory for each chemical preparation? ° Is each dose prepared separately or by diluting the highest concentration? ° Are records kept for the vehicle (corn oil, etc.), the supplier, and the lot number? How old is the supply, the chemical analysis, and the record of storage conditions? ° Is an SOP available for each chemical for cleanup ot equipment? ° How are doses transferred from the preparation room to storage and to the animal room? ° Is the type of container adequate? Is the cap liner or stopper .soluble in the chemical? 0 Are. any ot the chemicals light sensitive?- 0 Are the storage .conditions of the gavage/skin painting preparations those prescribed by the manufacturer? Is the storage method safe? Is there limited access? 0 What is the length of storage for dose preparations? 0 Are color-coded labels used? Is the key posted? (c) Dosed-water Who is responsible for calculations? Are calculations recorded for each dose? Who supervises? Are written mixing procedures and dose levels available in the preparation room? ------- -58- ° Is water analysis — pH adjustment, hardness, source, and additional treatment information -- available and a part of permanent records? ° Are there dedicated water bottles, rubber stoppers, and sipper tubes per chemical? Per dose? ° Does the dose chemical deposit on bottles or discolor bottles (glass or plastic)? ° Are storage conditions adequate? How long.is the chemical stored? 0 was analysis done before the chemical was used? 0 Has the schedule for preparation been verified? Has it been updated? ° How is disposal of excess chemicals performed? (d) Inhalation 0 What is the generation procedure? ° Is the concentration determined before animals are exposed? How? ° What is the schedule for a chamber concentration monitoring of each chemical? Is monitoring intermittent or continuous? ° Is there layering (nonhomogenity) of material in the chamber? 0 Is the generation system isolated from the chamber room? ° For gas exposure, are all cylinders secured at all times? ------- -59- ° For aerosols, is particle sizing performed? How frequently? 0 Is emergency power automatic? ° Have records for calculations and analysis, new lots, etc., been verified? ° Are there SOP's for clean up of generator vessels? (5) An imals (a) Is there a log-in procedure for receipt of animals? Does it specify: 0 Number/sex/strain/species? 0 Birthdates? What is the range? ° Condition of animals on receipt? ° Source? (supplier and location, since some suppliers have several locations) (b) Is there a quarantine period? ° How long is it? ° Where are animals quarantined? 0 What observations are made? ° Does a Doctor of Veterinary Medicine certify che fitness of animals for test? (c) Has randomization of animals been verified? ° When? 0 What procedure was used? (Assignment by weight, random numbers) ° How are animals assigned to groups? ° Are cages/racks rotated? How? How often? ------- -60- (d) How are animals identified? (e) Animal care: Are there special problems related to specific chemicals? (f) How are animals observed? ° Have twice-daily observations been verified? 0 What times of the day during the week are observations made? observations? What are tne weekena/noliday schedules for ° How often is weighing done; what time of day are animals weighed; what experience do personnel have? Is weighing combined with some other test? If so, what? ° Are cages/racks rotated? ° What is. the condition of filters? (6) Clinical Signs Observations (a) When are animals observed? Is observation done in conjunction with other functions? (b) Who makes clinical observations? Who palpates for tumors? (c) Who supervises these functions? (a) Are findings spot checked for verification by a veterinarian? How often? (e) Do the staff making clinical observations understand terminology? (f) Are clinical signs recorded? (g) Are records inspected for verification? ------- -61- (7) Unscheduled Deaths (a) How are decisions on moribund sacrifices made? (t>) What is the ratio of moribund sacrifice vs. found dead? (c) How-many of the "found dead" animals are discarded because of complete autolysis ot tissues? (d) Is there a log for unscheduled deaths? For necropsies? (e) How are carcasses stored until necropsy? (f) What is the time period from death to necropsy? (g) How is disposal of carcasses handled? (8) Sentinel Animals (a) Does the laboratory include sentinel animals during cnronic study to evaluate nealtn status periodically? (b) Where are sentinels housed in relation to test an imals? (c) How frequently are sentinel animals bled for serological evaluation? (d) How are sentinel animals bled for serology? (e) How are the sera handled? (f) Who performs the serological tests? (g) What are the findings? ( 9 ) Tox icolog ical Monitoring (a) Dosed-Feed ° Is food consumption dose related? ° Are dedicated feeders used for each chemical? ------- -62- ° How are samples selected for analysis? Who makes the selection? ° How is excess food disposed of? ° Is the mixing schedule posted? 0 What are the topping-off procedures for dosed feed? 0 What are the dosed feed storage conditions and length of storage time? ° Is the same lot of feed used for controls and dosed feed preparation? (b) Dosed-Water 0 Are water bottles replaced instead of refilled? ° Is water consumption dose related? ° What are the storage conditions (temperature, light, etc.) for dosed water? 0 What is the condition of bottles, sippers, and stoppers? 0 Are the bottles labeled as to chemical, dose, and date of preparation? ° How is disposal of extra dosed water carried out? 0 When bottles are washed, are those for controls washed first? Is the wash water discarded when bottles for other chemicals are to be cleaned? ° Are there dedicated bottles, sipper tubes, and stoppers? ------- -63- personnel? si ze? is used? (c) Gavage 0 What are the training procedures for 0 What procedure is used by the laboratory? 0 What syringe size is used relative to dose 0 Are Luer-Lok syringes used? What cannula size 0 What is the administration sequence for control/test doses? 0 Is the individual or group weight used as a basis for dose size? 0 What time of day is dosing done? 0 What vehicle/solvent is used? -What is the lot number and source? Is this information accurately recorded? 0 What is the temperature of the doses? (Are they room temperature or iced?) 0 Is chemical stability related to exposure to light? 0 Are doses homogeneous? 0 Is a hood used for gavaging? Is proper ventilation provided? 0 Is volume recorded? (Is it the same for all tests?) 0 Is the accuracy of delivery determined? 0 What is the schedule for changing needles or cannulas? ------- -64- 0 Are records of accidental inoculation and deaths per technician kept as an indication of performance? 0 Are necropsies of all unscheduled deaths performed to determine the cause? ° Are different concentrations of chemical kept in different size bottles? Separate bottles for mice and rats - are bottles color coded? (d) Skin-painting ° Are animals housed as groups or individuals? ° What are the clipping procedures? How is clipping done? How frequently? ° What is site of application? ° How are descriptions of observations made? Are observations recorded on individual animal diagrams? How are lesions measured? How is regression recorded? 0 What is the frequency for recording lesions? 0 What is the present potential for irritation? ° Is the accuracy of the dose checked per iodically? ° What is the dosing procedure -- glass rod or rubber tip for application, use.of automatic syringes, stirring dev ices? ° What is the volume administered? ° What is the vehicle? ------- -6 5- ° What is the suitability of the'chemical for skin painting? 0 Is \there build-up of material? What is the procedure tor cleaning of skin? 0 Are the techniques of all technicians compar able? 0 Is skin painting being done with the skin as the organ site, or is it used tor system'ic exposure? 0 Are systemic effects visible? Are they documented? 0 Is application carried out under a hood? (e) Inhalation 0 Chamber operation What is the type or exposure (gas, aerosol, vapor, particulates)? If gas, are gas cylinders properly secured at all times? If aerosol or particulates, is particle sizing performed to insure that a majority of particles are in the respirable size range? How frequently are samples taken and raeasur ed? What types of contaminants (chemicals and particulates) are added by the generating system? Are the generating systems checked for leaks on a regular basis? Are generating systems "isolated" from the chamber room? ------- -66- Can temperature and humidity be individually monitored, controlled, and recorded for each chamber? Is monitoring continuous or intermittent? Are chambers maintained at a negative pressure with respect to the chamber room during all exposures? - Is monitoring continuous for each chamber? Are chambers tested for layering (nonhomogeneity) with each test material? Is chamber cleaning done daily after the exposure period, and is cleaning confirmed by sampling before opening chambers? How are concentrations in chambers determined? How otten? Is tjie sampling sys tem • automa t ic? Are there manual backup sampling systems? When are calibrations of analytical instruments made to determine chamber concentrations? Do personnel wear full protective equipment while working in chamber rooms during the exposure per iod? What- precaut ions are taken with highly flammable or explosive materials? Are there alarm systems? What kind? How often are they checked? Is there automatic emergency power to the chambers? Is it adequate to continue the exposure operation? Is it tested regularly? ------- -67- How often is equipment serviced? By whom? How long is the up-and-down time per day? What is the equilibration time per chemical? 0 Animal care and observation Is the chamber volume adequate for maximum loading for the study? Is food and/or bedding removed from the chamber during the exposure period? - Are animals caged individually? Is automatic watering used? If so, is it checked daily for proper functioning? Are cages rotated within the chamber? How of ten? Are catch pans used during exposure? If so, were measurements made showing that uniform concentrations can be maintained? Are animals in the chambers between exposure periods? If so, are chambers open or sealed with respect to chamber rooms? Are morbidity/mortality checks done twice daily during exposure and nonexposure periods? Where are animals housed during the chamber cleaning period? ------- -68- e. Pathology (1) Personnel (a) Pathlogist(s) ° Is there a full time pa tholog ist( s) at the labora tory? ° How many hours per week does the pathologist devote to the study? ° What advanced degree or training does the pathologist have? ° How many years, of post-doctoral experience does the pathologist have? ° How many years of post-doctoral experience in rodent pathology does the pathologist have? Does this include tumor and aged rodent experience? 0 Is the pathologist certified? If so, by what organi zation? ° How many years has the pathologist been at the labora tory? (b) Prosectors ° How many prosectors are available to work on the project? 0 Do any of the prosectors serve in other capabilities (animal caretaker, histotechnician, etc.)? If so, specify the task and respond to the following questions: - How many weeks does each prosector spend in these activities? ------- -69- How many hours per week are spent with formal lecture, formal training, on-the-job training? How many prosectors have been at the laboratory for 1 to 3 years? More than 3 years? How many prosectors have had less than 1 year of experience performing necropsies on laboratory rodents? 1 to 3 years? More than 3 years? (c) Histology Technicians 0 How many technicians are available to.work on the project? capaci ties? Do any of the technicians serve in other ° Is the histoloqy supervisor certified by the American Society of Clinical Pathologists (ASCP)? ° How many of the technicians are certified by ASCP? 0 Is there a training program for technicians at the laboratory? If so, how long does it last? Who supervises the training? ° How many technicians have less than 1 year experience? 1 to 3 years? More than 3 years? ° How many of the technicians have worked at the laboratory for less than 1 year? 1 to 3 years? More than 3 years? ------- -70- (d) Clinical Laboratory 0 What degree does the direct supervisor of the clinical laboratory hold? ° Is the supervisor certified? If so, by whom? ° How many certified medical technologists are employed in the laboratory? ° How many technicians employed in the laboratory have less than 1 year experience? 1 to 3 years? More than 3 years? (2) Facilities and Equipment (a) Necropsy Room 0 Is the necropsy room adequate? 0 Is the room .used for any other purpose? (If so, what?) 0 How many individual work stations are there? ° Are the stations ventilated? 0 Is there a vented hood for general purposes? 0 What type of lighting is used? 0 Is the lighting adequate for close work? 0 Is there a balance in the necropsy room? What type is it? How frequently is it calibrated? 0 Is there a calibration log book? 0 How many sinks are there in the room? Are they conveniently located? ° Are the following pieces of equipment available in the necropsy room: - Refrigerator? ------- -71- Cutting boards? (Specify number) Dissecting microscopes? Gross photography equipment? 0 Are the numbers and quality of dissecting instruments adequate? ° Are the following types of personal equipment available for the prosectors? Gloves? Masks? (Specify type) Safety glasses? Caps? Smocks, lab coats, etc.? ° Is the equipment properly maintained and cleaned? (b) Histology Laboratory ° Is there adequate laboratory space? 0 Is there adequate "bench space? 0 Is ventilation adequate in the following areas? Trimming? Processing? Embedding? Staining? ° Is the lighting adequate for close work in the work areas? ------- -72- labora tory? How many processors are present in the What type of processors are present? How many embedding centers are present? Are they vented? ° What methods of embedding are used? 0 Is staining done manually or automatically? (If automated, specify the number, type of equipment.) ° How many and what type of microtomes are pr esent? 0 Is a cryostat present? (If so, what type?) ° How many and what types of knife sharpeners are present? ° How many and what -types of balances are present? ° Are there safety cabinets for storage of flammable chemicals? ° Is there a room for storage of wet "tissues ana blocks? 0 Is the room used for any other purpose? (If so, specify.) How large is the room? Is access to the room controlled? Is the temperature and humidity in the room controlled? (c) Clinical Laboratory ° How many square feet in the laboratory are devoted to hematology? ------- -73- ° How many square feet are devoted to clinical chemistry? 0 What types of automated equipment are used for hematological tests? ° What types of automated clinical chemistry analyzers are available? (3) Protocols and Recordkeeping (a) How long are animals quarantined before they are put on test? (b) On what proportion of the quarantined animals are the following types of observations made: ° Clinical? 0 Gross necropsy? ° Microbiological? (c) Who evaluates the data obtained from quarantined animals to determine if they are suitable for testing? (d) Who makes the day-to-day clinical observations on test animals? Where are the observations recorded? (e) Necropsy ° To complete the parts of this section, it will be necessary for a qualified pathologist to check completed Individual Animal Data Records (IADRs) used for documenting necropsy findings. He also should observe complete necropsies by as many of the prosectors as time permits. Is a list of SOP's readily available in the necropsy room? ------- -74- Is there a necropsy log? Is a pathologist present for all scheduled necropsies (sub-chronic and chronic)? Is a pathologist present for all unscheduled necropsies? If not, who supervises and conducts necropsies? If an animal dies on a weekend, is it stored until the following week or necropsied immediately? How are dead animals stored? Are pathologists available on weekends? 0 Observe one or more of the prosectors doing a complete necropsy. not, specify'.') Is the necropsy procedure adequate? (If Does the procedure deviate trom EPA guidelines? (If so, specify.) How long are tissues fixed? Is there sufficient fixative (there should be 3 to 5 times as much fixative as tissue)? Are the animal identification parts (tags, ears, feet, clips) removed and preserved with the tissues? Where are tissues stored during fixation? Are labels legible? Can tissues readily be retrieved? ° Ask to see certain specific IADRs. Were the forms easily located? Are the forms legible? ------- -7 5- Are the forms complete? Do descriptions of lesions include the location, size, shape, and color when appropriate? Are all gross and clinical observations accounted for by histopathologic diagnoses? Who checks IADR's for accuracy? ° Pick some samples and check if the identity of the animal during in-life study is carried through into wet tissues, blocks, slides and all records. (f) Histology ° Is a list of SOP's readily available in the histology laboratory? ° Is there a histology log? ° Are all handlers of the tissues identified? ° Does an individual technician perform all steps (from trimming through coverslipping) on a given animal's tissues, or do different technicians complete the separate steps? ° Who trims the tissues? Is a pathologist available if necessary? ° Are additional gross observations made during tissue trimming? ° How are tissues identified to insure proper labeling of blocks and slides? 0 How are blocks identified? ° Are slides permanently labeled by etching or other nonremovable mark? ------- -7 6- 0 Are blocks- sealed with paraffin after sect ioni ng? 0 Are stock solutions dated and initialed? ° Are positive controls prepared when special stains are requested? ° Are all slides checked against the necropsy record to insure that all submitted tissues have been sectioned? ° Ask to see certain specific slides, blocks, and tissues. Was the material easily located? Are the. sections free from artifact? Are all tissues specified in the necropsy report accounted for on the slides? Is tnere a master inventory for stored slides? What procedure is required to obtain release of- slides? (g) Histopathologic Evaluation ° What materials are made available to the pathologist along with the slides? ° Are the slides read in a particular sequence? 0 Are the slides read without knowledge of the group to which they belong? ° How does the pathologist record his/her diagnosis? 0 Is there an in-house quality assurance (QA) program? If so, ------- Who makes the original evaluation? Who reviews the slides for QA? What is reviewed? (4) Pathology-Check List The following check list enumerates the specific questions related to the various areas ot histopathology. These questions are provided as a guidance. The inspector shall use these to formulate his own approach in dealing with a specific laboratory. (a) Necropsy. ° Who decides when abnormal animals are to be k illed?' seem reasonable? than 24 hours? Does the number of moribund animals killed Are unschedule necropsies performed in less Are-animals necropsied on weekends? Where are dead animals stored until necropsy What is done with moribund animals on the weeke nd? 0 Is protective equipment/clothing worn? 0 Where/how are necropsy tissues stored? (Are there any contamination problems?) Were animal identifying markers preserved? ° Do the prosectors have adequate work areas? ------- -78- ° How are animal records handled and transferr ed? ° Does the necropsy staff have any problems that relate to working conditions? ° Is a list of SOP's present in the necropsy room? 0 Is ventilation adequate? (Are formalin fumes or other odors obvious)? is dye present in the formalin bottles or jars? (b) Histopathology the laboratory? 0 How many histology technicians are working in ° Are SOPs readily accessible? ° What protective equipment is in use? ° How are solvents stored and handled? ° How is HVAC performing? (Are there strong odors?) 0 Is there any evidence of food or tobacco products in the area? 0 How are waste solvents handled? ° How is area cleaned up? By whom? ° Are necropsy samples decontaminated before being transferred to histology? (If required.) 0 How many slides, blocks, and tissues from the bioassay are currently in storage at the laboratory? Where are they located? ------- -79- f. -Special Studies (1) Clinical Chemistry Monitoring (a) Personnel ° What are the qualifications of the clinical chemistry supervisor? 0 What is his/her training and experience in clinical chemistry? 0 How do the personnel maintain their proficiency? (Training .and observation) ° Are safety precautions taken in handling the tissues of dosed animals? (b) Animal handling ° What is the method of bleeding? 0 What volume of blood is taken? ° Is the physiological state of the animal at the time of bleeding recorded? ° Have records been verified? (c) Specimen handling ° Are the specimens properly identified and labeled? ° What is the serum or plasma separation method? 0 What are the storage conditions for specimens? 0 How long are specimens stored before they are tested? ° What are the preparation procedures for specimen analysis? ------- -80- (d) Testing and- analysis 0 What is the scheduling of testing and analysis? ° Is instrumentation adequate? Has the service record been verified? Is the preventive maintenance scheduled? ° What is the method of analysis, the accuracy of the determination, and the sensitivity of the test? How precise is the method? ° What are the SOP's for preparing and storing reagents? Has labeling and dating on reagents been verified? ° How many samples are analyzed at a time? ° How are the data captured? ° Is any statistical analysis Carried out? ° In regard to•diagnostic evaluation, is there- any correlation of clinical chemistry results with clinical signs and histopathologic findings? Is the correlation with historical values checked? ° What is the procedure for tracking and retesting values that are outside set limits? (e) Are quality control measures adequate? Have the following items been verified: ° Proficiency of testing record (CAP, AAB)? ° Program standards analysis? 0 Standard specimen (in and above normal range). Interbatch? Intrabatch? Day-to-day? ° Acceptability of data related to historical standards? ------- -81- (f) Are records tor the tollowing adequate: 0 Specimen/animal identification? ° Method of analysis? 0 Identification and dating of entries? 0 Location of records? 0 Accessibility of involved personnel? ------- -82- (2) Pharmacokinetics Monitoring (a) Regarding purity of the test compound, 0 Is the compound 98% or more pure? 0 Are there toxic impurities? (Impurities must not have any toxicity or inducing capacity greater, on a molar basis, than that of parent compound.) (b) For verifying the accuracy of dose measurements, ° Is the acutal dose determined? ° Is the ef.fect of the size of the dose on absorption determined? ° Is the effect of the number of doses on absorption determined? 0 Is the effect of the injection site determined?. (No more than 10% ot dose should be in the injection site at the time that the tissues are assayed.) ° Is the amount of material at the injection site determined? (c) Are facilities, equipment, and expertise adequate for measuring the concentration of the compound administered? 0 With radioactive compounds, the capability to separate parent compound from metabolites must be available. Does such capability exist? 0 Is the laboratory measuring relative amounts at 3 to 4 selection time points? (d) Has the relative importance of excretory routes been taken into account? Are the following being determined: ------- -83- 0 Urine? ° Feces? 0 Nature of excreted compound? 0 Relative amounts of parent compound and metaboli tes? 0 Is the parent compound in feces? Are parent compounds and metabolites in the bile? (e) Do personnel have analytical chemical capability and expertise in the following: ° Isolation and identification of metabolites? 0 Concentration of metabolites in selected tissues at selected time points? ° Determination of the relative amount of metabolites excreted? (f) Have the following data in reports been verified: 0 Small animal data in triplicate tests? ° Individual animal data? 0 Mean for three animals and standard deviation of mean? 0 Percent recovery of material? 0 Computed half-lives, volume of distribution, and clearance rate/organ? (g) Have other special areas received adequate moni tor i ng? ------- -84- 4. Executive Session At the end of the on-site inspectional activities the participants will meet in executive session. Each discipline inspected will be discussed, and a summary statement prepared ot the salient findings. 5. Closing Conference A final meeting with facility officials will be scheduled,- and a discipline-by-discipline summary of the ¦findings will.be provided. Such a meeting will also provide an opportunity to gather additional information, discuss guestions, and complete administrative duties. The inspector should complete the Receipt for Samples form listing all material removed from the laboratory as exhibits to substantiate his and the Team's findings. A copy of the receipt should be given to the laboratory at the closing conference. ------- -85- C. Report Preparation A complete report detailing the findings during a GLP inspection shall be prepared and filed with the Field Activities Section of the LDIP. It is. important to note that when two or more chemicals are on test in a given facility one collective report covering GLP inspections for all the chemicals is not acceptable. The report shall be chemical-specific. There may be redundancies and repetitions but it is imperative that the report tor each chemical be a stand-alone document. In general the report should follow the attached format containing the following five elements: 1. Signature page Signed and dated by the inspector(s). 2. Summary statement Brief abstract (not exceeding 200 words) of all salient findings should be made. 3. Narrative report The narrative portion of the report should be concise, factual summary of observations and activities, organized in a logical manner by discipline, and supported by specific references to accompanying evidence. In addition, the following information should be noted and described in detail in the inspection report: ° Unauthorized deviations from protocols and SOPs. ° Improper substitutions of test systems, procedures or laboratory personnel. ------- -86- 0 Unacceptable training programs and records 0 Potential violation of test standards 0 Suspicious statements, findings, erasures, etc. 4. Supporting documentation Copies of raw data, receipts, calibration records, logs, etc. in support of findings and conclusions should be included. 5. Exit interview-statement Copy of notes used for presentation at the exit interview during the closing conference should be included. ------- 87 APPENDIX I SEQUENCE AND TIME LINE PROJECTIONS FOR INSPECTIONAL ACTIVITIES ------- APPEN'Mv I CLP INSPECTION/DATA AUDIT, TRACKING SEQUENCE AND TIME-LINE PROJECTIONS FOR NEUTRAL SCHEME SELECTIONS IORATORY FOR CLP INSPEC- JN/DATA AUDIT DURING AH iUING QUARTER IDENTIFIED DM5 ' [ DAY -150 LABORATORIES SEGREGATED INTO: (A) FDA ASSIGNMENTS (B) EPA ASSIGNMENTS AND (C) INACTIVE CO-ORDINATE TRAVEL, ACCOMMODATION, ETC. WITH TEAM MEMBERS LEAD DAY -30 N r QMS DAT -135 STUDY REPORTS SENT TO REGIONS INVESTIGATION REQUESTS SENT TO REGIONS FAS DAY -35 FAS DAY -45 \ f N ' STUDY REPORTS SENT TO AUDITORS OPP/OTS [ DAY -30~ INSPECTION REPORT AND REGULATORY REVIEW TO CASE SUPPORT FOR REVIEW OPP/OTS REGULATORY REVIEW DUE AT DMS DMS DAY 60 OPP/OTS | DAY 75 OPP AHD OTS PROVIDED WITH LAD SELECTIONS, MID REQUESTS HADE FOR CHEMICALS LIST/STUDY REPORTS FOR AUDIT. A PRELIMINARY LIST DE3UVED FROM POMS GIVEN TO OPP FOR PRIORITIZATION. DllS DAY -120 RESPONSE FROM OPP AND OTS (PANEL MEETING) FDA ASSIGNMENT MEETING: FDA FURNISHED WITH STUDY REPORTS FOR AUDIT FAS 0AY-90 FAS | DAY -75 \ t DISCUSSIONS AMONG LDIP, OPP, OTS, NEIC, REGIONS, CONTRAC- TORS TO FIRM-UP DATES, LEAD INSPECTOR AND OTHER RESOURCES PAS DAY -50 > r RESPONSE RECEIVED FROM REGIONS FAS I DAY -55 REGIONS NOTIFIED OF LAO SELECTIONS (TSCA/FIFRA TASKS IDENTIFIED) AND TENTATIVE INSPECTION/ AUDIT DATE REQUESTED DCM I DAY -75 DHS NOTIFIED OF LADS/ DATES/CHOI ICALS/STUDIES/ PARTICIPANTS/LEAD FAS DAY-45 O 00 NOTIFICATION OF INSPECTION SQJT TO LABORATORY PRC-VISIT CONFERENCE OF TEAM MEMBERS START INSPECTION/ DATA AUDIT FAS | DAY -14 LEAD | DAY -1 TEAM | DAY 0 CONCLUDE INSPECTION/ DATA AUDIT TEAM | DAY 5 INSPECTION/AUDIT INCOM- PLETE; SUMMARY REPORTS SUBMITTED TO FAS LEAD DAY 1 2 INSPECTION/AUDIT COMPLETE FINAL SITE-VISIT REPORT COLLATED AND SUBMITTED TO: (A) OPP/OTS FOR REVIEW (D) LABORATORY (C) SPONSOR FAS | DAY 45 SUMMARY SITS- VISIT REPORTS COLLATKO FAS j PAY 2C FINAL SITE-VISIT REPORTS FROM TEAM MEMBERS TO FAS SUMMIRY SIT.-:- VISIT REPORTS TO L\B LEADER | DAY 35 FAS I DAY 30 CSB RESPONSE RECEIVED CLOSE FILES AT DMS —> AT LDIP » CSB | OAY 110 CSB | DAY 112 SITE-VISIT REPORT AVAILABLE UNDER FOI DMS | DAY 115 DMS » DATA MANAGEMENT SECTION FAS » FIELD ACTIVITIES SFCTION CSU « CASE SUPPORT BRANCH ------- 99 APPENDIX II FORMAT FOR LABORATORY GLP INSPECTION/DATA AUDIT REPORT ------- 93 APPENDIX II page j_ of LABORATORY GLP INSPECTION/DATA AUDIT REPORT I. FACILITY: ADDRESS: CONTACT PERSON: TITLE: PHONE NUMBER: II. DATE OF INSPECTION/DATA AUDIT: III. CHEMICALS/STUDIES AUDITED: Sponsor Chemical Study EPA Accession No. SITE VISIT TEAM: Inspector: Name, Of f ice Signature Date Auditors: Name, Office Signature Date Name, Office Signature Date Name, Office Signature Date ------- 91 Page 2 of GLP INSPECTION/DATA AUDIT REPORT V. ABSTRACT OF FINDINGS ------- 92 Page 3 of GLP INSPECTION/DATA AUDIT REPORT VI. GLP FINDINGS A. TEST FACILITY MANAGEMENT STRUCTURE 1. Corporate structure: 2. Laboratory organization: B. PERSONNEL,. CVs, TRAINING 1. Animal Care: 2. Chemistry: 3. Toxicology: 4. Clinical chemistry; 5. Histology: 6. Pathology: 7. QA Unit: 8. Other disciplines: C. MASTER SCHEDULE Lab Commitments D. SOPs 1. Animal Care: 2. Chemistry: 3. Toxicology: ------- 93 4. Clinical chemistry 5. Histology 6. Pathology: 7 . QA Un i t: 8. Other disciplines: E. FACILITIES, EQUIPMENT & TEST PROCEDURES 1. Animal Care: 2. Chemistry: 3. Toxicology: 4. Clinical chemistry 5. Histology 6. Pathology: 7. QA Unit: 8. Other disciplines: F. RECORDS & REPORTING 1. Animal Care: 2. Chemistry: 3. Toxicology: 4. Clinical chemistry 5. Histology 6. Pathology: 7 . QA Un i t: 8. Other disciplines: ------- 94- G. ARCHIVES H. LIST OF EXHIBITS I. EXIT INTERVIEW STATEMENT ------- 95 APPENDIX III INTERAGENCY AGREEMENT BETWEEN EPA AND FDA ------- 96 APPENDIX III INTERAGENCY AGREEMENT BETWEEN THE U.S. ENVIRONMENTAL PROTECTION AGENCY OFFICE OF PESTICIDES AND TOXIC SUBSTANCES AND THE U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION 1. PURPOSE - This agreement provides for cooperation between .the Food and Drug Administration (FDA) and the Environmenta 1 Protection Agency (.EPA) to determine whether hea 1 th-re 1 ated toxicity testing was properly performed, whether the final reports fully and accurately reflect the test procedures and are supported by the raw data and whether the testing carried out was in compliance with Good Laboratory Practices regulations. 2. SCOPE OF WORK - The Environmental Protection Agency (EPA) is responsible'for setting tolerances for pesticide residues in or on raw agricultural commodities and processed food under the Federal Food, Drug, and Cosmetic Act (FFDCA) (21 U.S.C. 346 and 348) and for registering pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) (7 U.S.C. 136 et sec). In addition, EPA has the mandated task under the Toxic Substances Control Act (TSCA) (15 U.S.C. 2601) to assure that no chemical will present an unreasonable risk of injury to health or the environment. EPA regulatory decisions on such matters are based ------- in part on the data submitted pursuant to (a) TSCA Section 4 Test Rule or Negotiated Testing Agreement, (b) TSCA Section 5 Signi- ficant New Use Rule or Section 5(e) Order, (c) FIFRA Sections 3, 5, 8, 18, and 24(c) as well as (d) FFDCA Sections 408 and 409. It is essential that such testing provide an objective and reliable basis for decision making. An EPA determination that testing was deficient or a final report is inadequate may lead to regulatory action; accordingly, such determinations must be well founded and fully documented. Final report integrity is assured by both data audits designed to show that final reports are fully supported by the raw data developed at the te'stinq lab'or-ato.ry .and by the Good Laboratory Practice (G L P) .inspections designed to show that the data were gathered in a proper and auditable fashion. All laboratories conducting studies on substances regulated by the EPA are to-be monitored for compliance with GLP regulations as published at 40 CFR 160 (FIFRA) and 40 CFR 792 (TSCA) and 21 CFR 58 (FDA). This agreement provides for FDA and EPA cooperation in monitoring testing 1aboratories1 adherence to GLP regulations as well as in auditing of health-related toxico1ogica1 test reports and related laboratory records. This cooperation and assistance will enable EPA to reach the objectives described above. Audits and inspections will be carried out on site. Laboratories inspected may be facilities of joint interest to ------- -3- both FDA and EPA or they may be facilities carrying out studies applicable only to the EPA. This agreement is limited to coverage of laboratories within the United States. 3. EXCHANGE OF INFORMATION - Each agency will exchange 1nformat1o and coordinate act 1ons concerning active Investigations, regulator correspondence and legal or administrative action being considered against any laboratory covered under this agreement. 4. FDA's RESPONSIBILITIES a. Personnel - This agreement will result 1n FDA's provi- ding EPA with the equivalent' of six (6) .sup ported, person-years of effort of which three (3) are operational investigative person- years. b. Aud i t s - On-site visits may include a detailed data audit of one or more studies to determine whether the final laboratory report submitted to EPA is accurately reflective of the raw data, whether the testing was performed 1n a manner that did not involve errors or practices that may have adversely affected the validity of the study and whether the testing was performed in accordance with the protocol submitted to EPA. ------- -4- c. GLP Compliance Monitoring - All GLP monitoring carried out at testing laboratories as part of an FDA/EPA inspection and/or audit will be according to GLP regulations. d. Reports - For all EPA-requested GLP inspections of . health-effects testing laboratories, a copy of FDA-483, "Notice of Inspectional Observations", will be submitted to EPA immediately upon completion of the- insDection. A full report of the inspection will be submitted to EPA. For all directed inspections requested by EPA as well as audits of final reports where the audit report is required prior to EPA making a regu'latory decision, the full inspection- or' audit report will be submitted to EPA within 30 days of completion of the inspection or audit. e. Responding to Scientific and Enforcement Review - In some cases regulatory and scientific follow-up by EPA may require the- FDA investigator who performed the audit to respond to questions and comments which EPA scientific reviewers may have concerning the audit report. In addition, in some cases, enforcement action by EPA may require the FDA investigator to participate in civil or criminal proceedings concerning the audit he or she performed. ------- -5- 5. EPA'S RESPONSIBILITIES a. List of Laboratories for Inspection - EPA will provide FDA with a quarterly listing of health effects testing laboratories to be inspected for GLP surveillance and/or data audit. This listing is to be provided to FDA at least 30 days in advance of a given quarter and will include the name(s) of the faci1ity(ies ) to be inspected and proposed dates on which EPA scientific personnel who will participate in a particular inspection- or audit will be available. b. Data Audits - EPA will provide FDA with a listing of data audits to b.e carried out in the next quarter. Prior to a scheduled EPA audit EPA wi n provide FDA .with copi.es of the- toxicology final reports of the study to be audited, together with EPA's scientific reviews and any special instructions which might be appropriate to the audit of a particular study. These documents shall be provided directly to the FDA Bioresearch Monitoring Staff prior to the inspection. EPA will provide FDA with copies of reports of any prior GLP inspections conducted by EPA to familiarize FDA inspectors with previously encountered GLP compliance problems, if any. c. Delegation of Authority - As necessary EPA will provide to FDA personnel a letter containing appropriate delegation of authority to review data subject to EPA jurisdiction. This letter will then be furnished to the management of the laboratory at the beginning of the visit. ------- -6- d. GLP' Inspections - EPA will inspect health - effects testing laboratories which do not conduct studies of interest to the FDA. Directed inspections of health-effects laboratories may be requested by the EPA to the FDA. e. Special Requests - EPA may refer to the FDA special directed (for-cause) laboratory inspections or data audits which may impact on a major regulatory decision. The nature of these decisions may require that these special activities" be started in two to five days following notice to the FDA. If the FDA is unable to meet this special request the activity will be carried out by.the EPA. f. Notification of Sponsor - Contracts may exist between laboratory and sponsor prohibiting disclosure of raw data by the laboratory without the permission of the sponsor. In order to ensure that raw data are available to EPA and FDA personnel conducting a data audit, EPA's Compliance Monitoring Staff may notify the sponsor of the study of the intent to audit one or two working days preceding the scheduled visit. g. Scientific Support ana Team Leaders - EPA, wherever possible, will designate a staff scientist to participate in the ¦laboratory inspection or study audit conducted by the FDA. EPA staff scientists-accompanying an FDA investigator team leader will be advisory to the FDA inspector who will be responsible for the conduct of the GLP inspection or study audit as well as for preparation of the report. ------- -7- h. Evaluati on of Reports - EPA will determine whether discre- pancies listed in reports submitted by FDA investigators impact on the validity of the studies. Any administrative or regulatory actions resulting from EPA audit reports will be the responsi- bility of EPA and will be consistent with TSCA or FIFRA regulations. 6. CONFIDENTIALITY - Each agency will maintain the confidentiality of all data received as a result of implementing this agreement. Any Freedom of Information Act requests received by F.DA for information resulting from laboratory inspections or data audits requested by the EPA will be referred to EPA for processing. All documents provided to FDA by EPA for the conduct of the audits will be returned to EPA along with the inspection or audit report. 7. DURATION OF AGREEMENT -This agreement, will become effective on the date of the last signature and shall continue in effect until September 30, 1985 un1ess modified by mutual written consent of both parties or terminated by either party upon a ninety (90) day advance written notice to the other. 8. PROJECT OFFICERS a. For EPA: Dr. Dexter S. Goldman Compliance Monitoring Staff (EN-342) Environmental Protection Agency 401 M Street, S.W. Washington, DC 20460 ------- -8- b. For FDA: Dr. Paul Lepore (HFC-30) Bioresearch Monitoring Staff Food and Drug Administration 5600 Fi shers Lane Rockville, MD 20857 9. FUNDING No transfer of funds is necessary under this agreement. FDA will provide support costs for the 6 person-years of service allocated to this agreement. 10. AUTHOR ITY - Authority for the Agreement is 31 USC 686 (The Economy Act), 7 USC 1361 and 15 USC 2625. Approved and accepted for the Approved and accepted for the Environmental Protection Agency Food and D'rug Administration John A. Moore Assistant Administrator for Pesticides and Toxic Substances wJoseph P. Hile JAssociate Commissioner for /Regulatory Affairs Date : ZX 3y Date 7 Appropriation: Account Number: Document Control Number: Object Class: Task Order No: ------- 104- APPENDIX IV NOTES ON EPA/FDA INTERAGENCY AGREEMENT ------- appendix rv 7 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY / WASHINGTON. D.C. 20460 DEC I 9 1984 OFFICE OF PESTICIDES ANO TOXIC SUBSTANCES MEMORANDUM SUBJECT: Notes on the EPA/FDA Interagency Agreement FROM: A. E. Conroy II, Director n /) ^ Office of Compliance Monitoring TO: Addressees ft " ^ I / V For several years the EPA has had an Interagency Agreement with the FDA. This agreement enabled the EPA to benefit from FDA's experience with surveillance monitoring of health effects laboratories for compliance with Good Laboratory Practice (GLP) regulations. The EPA has recently published its own GLP regulations for both TSCA (4 0CFR 7 9 2 ) and' F IF R A (40CFR 160)'. The publication of these regulations,-to.g ether with the. administrative changes within' OPTS nade it advisable to rewrite this Interagency Agreement with the FDA.- As this document was rewritten we found it necessary •to redefine our relationship with the FDA and to redistribute our responsibilities in line with the regulations published by both a genci es. I am pleased to provide you with a copy of this recently signed Interagency Agreement. I would like to take this opportunity to provide further explanation of the division of responsibilities between OCM and FDA in the areas of GLP compliance monitoring and data audits. Within OCM the Laboratory Data Integrity Program (LDIP) is respon- sible for all field and support activities relating to EPA's GLP compliance monitoring and data audits. ------- 135 -2- 1. GLP COMPLIANCE MONITORING A. Laboratories of interest to the EPA alone These would be typically ecotox testing laboratories, sponsor analytical chemistry 1aboratories, fish and wildlife effects 1 a boratories , etc. OCM will schedule GLP monitoring inspections of these laboratories. Such inspections are decen- tralized to-the Regions; assistance of Headquarters staff will be available. B. Laboratories of interest to the FDA alone Th/ese will continue to be monitored by the FDA. If at some time in the future such a laboratory engages in testing coming to the EPA then EPA will inform the FDA of its interest and the two agencies will exchange information. C. Laboratories of interest to both FDA and EPA The basic agreement is that if the FDA has this laboratory under routine biennial surveillance then it will continue in this mode. The EPA will inform the FDA of its need to conduct a GLP monitoring inspection of the facility and the studies that should be included in the inspection. The FDA will schedule . this inspection as part of its- routine operation and report the resul'ts to. the EPA. The EPA may el-ect to include- up to two EPA scientists in t-h i s inspectio-n and will inform the FDA of this in advance. OCM will provide the necessary letter of identification needed by the FDA Investigatov to enter the faci- lity on behalf of the EPA. The role of the EPA scientists is explained in the Interagency Agreement. D. Common versus separate facilities It should be clear that it is the testing area that is of joint interest to the two Agencies, not the corporate entity itself. It is quite possible that in a given complex testing facility tests of interest to or under the surveillance of the two Agencies will be in totally different physical areas. OCM and FDA will discuss and decide which Agency or Agencies will carry out the inspection of the different areas. Again, the two Agencies will share information resulting from inspections. E. Special inspections out of schedule Special needs will arise when the EPA decides that an extra- ordinary or priority inspection of a testing facility is required. OCfi, at the request of OPP or OTS, will discuss this need and the time frame for completing the inspection with the FDA and the FDA will indicate if it-will lead this priority inspection or defer this to an EPA team. In any event, each.Agency will promptly inform the other of the results of this priority inspection. ------- -3- F. Follow-up repeat inspections If a follow-up inspection is required to assure the Agency that problems detected in a routine inspection have been dealt with, the follow-up inspection will be conducted by the Agency that carried out the origina-l inspection. 2. SCOPE AND CONTENT OF A GLP COMPLIANCE INSPECTION A. General A GLP compliance inspection is designed to inform the Agency of the current compliance status of a testing facility. The content and intensity of the inspection may be influenced by the past history of the facility. A GLP inspection may be concerned with any or all of the following subject areas: Adherence to the protocol Adequacy of the personnel assigned Th-e physical facilities, its security and emergency .operatingplans Che-mi stry and dose preparation Animal care and toxicology' Training of non-professionals, for example, animal room and necropsy technicians Gross- and micro-pathology Quality assurance personnel and procedures Ar ch i v es Instrument records Electron fc data gathering B. In-life study audits Key to our monitoring of the compliance status of a facility are audits of studies during the in-life testing phase. Based on listings supplied in advance by LDIP, the GLP inspection team will decide which phase or phases of which ongoing tests will be audited while that test is still going on. These study audits provide -the assurance to the Agency that the test is in progress, is under scrutiny by the facility's QA unit and all activities are in compliance with GLP regulations. The inspectional report will contain a careful reporting of all aspects of study audits done during a compliance inspection. ------- 108 -4- C. Training for GLP inspections OCM will-begin training sessions for field inspectors early in 1985; announcements will be sent to all regions in advance. Guidelines for GLP inspections by EPA personnel will be the subject of a field manual currently in preparation. 3. DATA AUDITS A. General Data audits are the process of validating the final report of a submitted study by means of a full examination of the original data. To accomplish this validation a team of 2 to 6 scientists is selected and spends up to a week at the facility auditing the original data. All phases of a study are scrutinized with the exception of histopatho 1ogy. If histopathology data validation is required then a different mechanism, using a contract Quality Assurance laboratory, is generally used. B-. Role of the FDA and the EPA in data audits a. * FDA The FDA will, on request from the'EPA, conduct an audit of a final report as part of a GLP compliance, monitoring inspection of the laboratory. One ortwo EPA scientists will accompany the FDA field investigator for this purpose. As studies are identified as candidates for audit OCM will discuss these audit assignments with the FDA. The FDA will reconcile the need for the audit with the surve'illance schedule and inform OCM of the audit schedule. Studies that the FDA cannot fit into their schedule will be referred back to OCM. b. EPA Based on its selection mechanisms OCM will schedule audits of finished studies. Audits are centralized to Headquarters. Those audits which are not accepted by the FDA will be scheduled by OCM for an EPA audit team. Scheduling will take into account the priority of the audit, availability of resources, optimal number of studies to be audited at the same location and other factors of importance to the scheduling process. ------- -5- C. Audit team personnel a . FDA wi th EPA. support Such a team will usually consist of an FDA investigator from the region plus one or two specialists from the EPA. This team will usually have limited goals in terms of the numbers of studies to be audited, the areas of the study aduited, and the depth the audit. b. EPA audit team The size of the EPA audit team will take into account several factors including the number of studies to be audited at the facility, the complexity of study or studies and resources available. The minimum team for a chronic (2-year) .study will be an inspector, a chemist, a toxicolgist, a pathologist and an animal care specialist. Usually the inspector will fill one of the specialty roles. EPA Regions will be informed of the audit in ad.vance and invited to participate either by sending an inspector or by sending less experienced inspectional staff who can learn and participate at the same time. The- audit team for e.cotox audits, analytical chemvstry audits, teratology auaits, etc. will be made up as necessary and will include regional personnel whenever possible. D. Audit procedures The procedures for an audit by EPA personnel will be the subject of a field manual currently in preparation. A training course for auditors will be part of the training course for GLP inspectors, probably in early 1985. 4. RELATIONSHIP BETWEEN AUDITS AND GLP INSPECTIONS It should be understood that a GLP compliance inspection and a data audit are not the same entities, have different goals, different procedures and may have different enforcement strategi es. While a GLP compliance inspection or surveillance inspection may include in-life study audits and audits of final reports, a full data audit does not include a GLP inspection. It is inevitable that discussions of SOPs and some aspects of GLP compliance will come up during the audit of a final report but the audit team is not to make a GLP compliance inspection part of its goals without Special and extraordinary permission. The audit team may recommend, ------- -6- as part of the final audit report, that a GLP compliance inspection be carried out with special emphasis on certain areas or procedures at the facility. OCM will then act as necessary on the recommendation and, as necessary, bring the FDA into the procedure. 5". SUMMARY The information conveyed in these notes is to answer questions about goals and procedures that have- come from both Headquarters and Regions. If there are further questions on this matter please feel free to contact Dexter Goldman di rectiy at 382- 7853. I will send notices later this year about a week-long training session in Washington. This training session will concentrate on health effects theory and testing practice and the direct application of inspections and audits to health effects testing. Enc1osu re Addressees : ------- -7- John McCann (TS-768C) Carl Morris (TS-778) John Mackenzie, Region IX Paul lepore (FDA) Ha r ley F. Lai rig, Dire-ctor Air and Management Oivision, Region I A. Charles Lincoln, Chief Office of Pesticides and Toxic Substances, Region I Barbara Metzger, Director Environmental Services Division, Region II Dan Kraft, Chief Toxic Substances Inspections Section, Region II Stephen R. Wassersug, Director Pesticides and Toxic Substances, Region III La r ry M-i 1 1 e r , Ch i e f TSCA an'd F IF R A_ Enforcement Section, Region III. Thomas Devine, Director Air Management (Division, Region IV Roy P.. Clark, Chief Pesticides and Toxic Substances Branch, Region IV William H. Sanders III, Director Environmental Services Division, Region V Mitchell J. Wrich, Chief Toxic Materials Branch, Region V A1 lyn Davi s , Di rector Air and Waste Management, Region VI Norman Dyer, Chief Pesticides and Toxics Branch, Regio VI David A. Wagoner, Director Air and Waste Management Division, Region VII ------- -8- Leo Alderman, Head Toxics and Pesticides Section, Region VII Robert L. Duprey, Director Air and Waste Management Division, Region VIII Robert W. Harding, Chief Field Operations Section, Region VIII Harry Seraydarian, Director Toxics and Waste Management Division, Region IX Nancy Frost, Head Pesticides and Toxi.cs Section, Region IX Gary I. O'Neal, Director Air and Waste Management Division, Region X Diana Banta, Chief Pesticides and Toxic Substances Branch, Region X Thomas P. Gallagher, Director • National Enforcement Investigations Center Theodore.0. Meiggs, -Assistant Director . National Enforcement Investigations Center' ------- 113 APPENDIX V WORK ASSIGNMENTS DURING INSPECTIONS AND AUDITS ------- APPEHMX V A 2ZZ UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D C. 20460 NOV 2 I 1984 \ \ \ OFFICE OF PESTICIDES ANO TOXIC SUBSTANCES MEMORANDUM SUBJECT: Work Assignments During Inspections and Audits FROM: A. E. Conroy II, Director Compliance Monitoring Staff TO: Addressees ¦ J In answer to questions from Inspectors and Field Investigators I would like tore iterate the areas of responsibilities of both Inspectors, Investigators and EPA advi sors. 1. The credentialed EPA Inspector or FDA Field Investigator (team .Leader) is in.'charge .of'the' inspection/audit, 2. Assignments for all personnel participating in a field activity are the responsibility of the Team Leader. This is most satisfactorily worked out in a pre-inspect ion conference in which the schedule of operations and assign- ments are agreed to cooperatively. 3. If contact with FDA or EPA is needed during a field activity such contact is made only by the Team Leader. FDA Team Leaders will contact FDA through their usual chain of command; for EPA Team Leaders contact will be with Laboratory Data Integrity Program (LDIP) personnel only at 8-382-7853. 4. The Team Leader is responsible for the preparation of the report of the activities. Each participant in the field activity will prepare a written and signed report, complete with exhibits as needed and provide this to the Team Leader within 20 days of return from the field activity. The Team Leader will complete all the individual..reports to make the final report and submit this through channels (FDA) to LDIP or directly (EPA) to LDIP management. The final report is normally due to LDIP management 30 days after return from the field activity. ------- _ ? _ t. • 5. Each report by each participant will be chemi cal -speci f i c , not facility specific. The reason for this requirement is the manner in which activities are ultimately reported to sponsors and the manner in which these reports are reviewed within EPA. Each chemical-specific report will contain the fol1owi ng element s : (a) Summary (b) Introduction identifying the study inspected and the segments of the study covered in this report. (c) Report of inspection and findings iryeluding all GLP or audit activities carried out. All copied documents used as illustrations or presented to show problems will be listed as Exhibits and included in the indivi- dual reports. It is equally important to list fully all activities in which no problems were found as it is to list activities in which actual problems are documented. This will show, among others, the overall thoroughness of the field activity. (d) Avoid making statements or conclusions that are definitive lest this compromise enforcement activities later. Be "careful to qualify conclusions, "In the opinion of the inspector/auditor,..."-or similar* 6. An audit or inspection is not an evaluation of the report or protocol and is not a hazard evaluation report; this is done by others within EPA and is not the responsibilty of LDIP. When the activity report is received by LDIP management it will be read and checked for completeness before being forwarded to OPP or OTS for regulatory review. If any portion of the report contains language considered inappropriate for the report it will be returned to the Team Leader for action. 7. If there are any questions relative to these activities please contact Dexter Goldman (8-382-7853) directly. There will be a full discussion of this both in the field manuals for GLP inspections and data audits now in preparation as well as in a training course planned for early 1985. Addressees: John McCann (OPP Panel Representative] (T S - 7 6 8 C ) Carl Morris (OTS Panel Representative) (TS-778) Paul Lepore \FDA) Jake Mackenzie, Region IX Theodore Meiggs, Assistant Director, NEIC ------- 1 J.O Region I: A. Charles Lincoln,. Chief Office of Pesticides and Toxic Substances Region II: Barbara Metzer, Director Environmental Services Division Region III: Stephen R. Wasse-rsug, Director Pesticides and Toxic Substances Division Region IV: Roy P. Clark, Chief Pesticides and Toxic Substances Branch Region V: William H. Sanders, 11 I ;.Director Environmental Services Division Region VI: Allyn Davis, Director Air and Waste Management Division Region VII: David A. Wagoner, Director Air and Waste Management Division Region VIII: Robert L. Duprey, Director Air and Waste Manaaement Division Region IX: Harry. S. Seraydarian, Director Toxic and Waste Management Division Region X: Gary I. O'Neal, Director Air and Waste Management Division ------- |