Good Laboratory Practices - ACS Publications - American Chemical

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Chapter 2

Industry Perspective on Good Laboratory Practice Regulation of Chemical Studies

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John F. McCarthy National Agricultural Chemical Association, Washington, DC 20005 In spring 1985, NACA began addressing GLPs for chemistry studies, and formed a Subcommittee to prepare guidelines for use by member companies. The Subcommittee deliberated, consulted EPA and completed the final document in mid-1986. The guidelines, modeled after FDA, EPA and OECD GLP regulations for animal studies, address residue (laboratory and field), metabolism (plant and animal), and environmental chemistry studies done for FIFRA registration requirements. However, they are more general due to the breadth of chemistry studies involved. During the development of GLP regulations by EPA, NACA encourages "non-compliance" audits of companies to assist them in their GLP programs. This provides EPA and industry opportunity to understand differing stances prior to a compliance situation. These experiences should aid EPA i n developing regulations and prepare industry for regulatory compliance. Compliance should be phased in so that completed and ongoing studies are accepted even if regulations are not precisely met. Industry's ccmrdtmcnt to quality science i s fundamental. The practice of quality science is at the heart of our industry. It is essential that the scientific cxxrmunity, regulators and the public have confidence in what we do and how we do i t . In other words, there should be no doubts about the validity of our data and the competence and integrity of our scientists. We a l l want to be trusted - i t ' s a fundamental human need. Trust is something one earns. A basic principle of science is that experiments should be repeatable. That i s , one investigator should be able to repeat the work of another. If experiments can't be repeated, then the trustworthiness of the original investigator may come into question. However, we cannot count on duplication as the only method of verification. There are simply not enough resources to do that. In addition, i t would not be a wise use of resources to verify everything done by the industry by repeating the experiments. 0097-6156/88/0369-0007$06.00/0 © 1988 American Chemical Society Garner and Barge; Good Laboratory Practices ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

GOOD LABORATORY PRACTICES

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There has to be another way. That's where GLPs and laboratory audits cone i n t o play. The incident which occurred at a major toxicology t e s t i n g laboratory i n the middle 1970's shook up the industry and taught us a lesson. Not only d i d we learn that we must pay more attention to what others (contractors) do f o r us, but we also needed to develop more rigorous GLP procedures within the corporate laboratory. This incident l e d to the promulgation of regulations by the Food and Drug Administration (FDA) on Good Laboratory Practices f o r n o n - c l i n i c a l laboratory studies i n 1978. This was followed by EPA with GLP regulations f o r the same kinds of studies i n November 1983. I think i t ' s safe to say that back i n 1976 when the FDA regulations were f i r s t proposed, they weren't welcomed with open arms by the industry. The impact of these were p r i m a r i l y on the pharmaceutical industry. There was a l o t of verbal sparring. The proposal was attacked as unnecessary, p r o h i b i t i v e l y expensive, and conducive to a s t i f l i n g bureaucratic blanket on creative research and s c i e n t i f i c investigations. By the time the EPA regulations were proposed i n 1980, the environment had changed somewhat. Industry had learned the value of GLPs. This i s not to say there were not thoughtful and germane comments on the EPA proposal. I believe a l l o f t h i s experience has prepared us f o r the GLP regulations of chemistry studies. However, before I get i n t o the d e t a i l s of t h i s aspect, I would l i k e to give an overview o f some of NACA's a c t i v i t i e s with respect to GLPs. NACA A c t i v i t i e s Starting i n about 1978, the Research Directors Committee o f the Association began to address the subject. The membership of the committee was p o l l e d regarding t h e i r views on data retention. This was l a r g e l y stimulated by proposed EPA guidelines on t h i s matter. I won't attempt to summarize the r e s u l t s of that survey, but emerging from i t was a consensus d e f i n i t i o n on the term "raw data," and a consensus statement on retention of samples. The d e f i n i t i o n of "raw data" which the industry preferred was as follows: "The term 'raw data' means laboratory or f i e l d worksheets, records, notes, or memoranda that are the r e s u l t of observations, measurements or other a c t i v i t i e s which contribute s i g n i f i c a n t l y to the conclusions drawn from the t e s t i n g or evaluation of a p e s t i c i d e for purposes o f r e g i s t r a t i o n . " The words "contribute s i g n i f i c a n t l y " and " f o r purposes o f r e g i s t r a t i o n " were key, and represented an important change i n the d e f i n i t i o n v i s - a - v i s what was proposed by EPA. I t was f e l t that the i n c l u s i o n o f these words would be a more reasonable d e f i n i t i o n because i t reduced the scope of raw data retention to the very type which was needed f o r v a l i d a t i o n and which could be reasonably expected to be retained. With respect to retention, i t was the consensus o f the Committee that EPA's d e f i n i t i o n was reasonable. However, i t was apparent that there was a v a r i e t y of sample retention practices within the industry. Most companies d i d not make a s p e c i a l e f f o r t

Garner and Barge; Good Laboratory Practices ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

2. MCCARTHY

GLP Regulation of Chemical Studies

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to r e t a i n samples o f a l l specimens used i n a l l o f the t e s t i n g a t the time o f the survey. This has now changed. Emerging from t h i s exercise was the development o f o f f i c i a l NACA p o s i t i o n papers on "The R e l i a b i l i t y o f Test Data i n Pesticide Research" and "Good Laboratory Practices" i n 1979. Needless t o say, the p o l i c y on the former indicated that the industry supported the concept o f r e l i a b l e t e s t data i n p e s t i c i d e research. The issue was how does one deterndne r e l i a b i l i t y o r v a l i d i t y . The industry addressed the question t h i s way:

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"Tests o f v a l i d i t y should be based upon the appropriateness and q u a l i t y o f the t e s t design; the manner i n which the research i s executed; documentation and records t o support s c i e n t i f i c l o g i c and expertise exhibited i n the evaluations and conclusions reported." As you can see, t h i s touched upon some o f the p r i n c i p l e s o f GLPs, namely, documentation, records and expertise. With respect t o the Good Laboratory Practices p o s i t i o n paper, NACA indicated the need f o r consistency o f regulations among the various regulatory agencies. The paper went on t o recommend that the FDA GLPs be uniformly adopted by a l l regulatory agencies f o r regulation o f health e f f e c t s t e s t i n g . The Association also endorsed the concept that a l l GLP standards should be s p e c i f i e d e x c l u s i v e l y i n GLP regulations and not incorporated i n t o t e s t i n g guidelines. The emphasis o f these p o s i t i o n papers was p r i m a r i l y i n the toxicology area. However, i t became c l e a r as time passed that GLPs needed t o be addressed with respect t o other studies required f o r p e s t i c i d e r e g i s t r a t i o n , namely, the chemistry studies. This then brings me t o the current t o p i c o f t h i s symposium. NACA GLPs For Chemistry Studies In the spring o f 1985, the Research Directors Committee o f NACA formed an ad hoc Subcommittee on Good Iiaboratory Practices f o r Chemistry Studies. The Subcommittee was composed o f s p e c i a l i s t s from f i f t e e n member companies who were responsible e i t h e r f o r the management o f these studies o r the q u a l i t y assurance aspects o f these studies. I t i s important t o note that by 1985 a considerable number o f companies had already established a q u a l i t y assurance u n i t and were w e l l underway with t h e i r GLP programs f o r chemistry studies. The Subcommittee was charged with the development o f a document which addressed good laboratory practices standards f o r residue, metabolism and environmental chemistry studies which were conducted f o r r e g i s t r a t i o n . The document was t o be made a v a i l a b l e to member companies t o guide them i n the development o f t h e i r GLP programs. The document was a l s o t o serve as a basis f o r industry discussions with EPA. on the subject o f GLPs f o r chemistry studies done f o r p e s t i c i d e r e g i s t r a t i o n . A f i n a l document was produced i n mid-1986. The guidelines were modeled a f t e r FDA, EPA and OECD GLP regulations f o r animal studies. The document addressed residue (laboratory and f i e l d ) , metabolism (plant and animal), and environmental chemistry studies done f o r FIFRA r e g i s t r a t i o n requirements. This paper w i l l not go i n t o d e t a i l

Garner and Barge; Good Laboratory Practices ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

GOOD LABORATORY PRACTICES

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conrerning the document other than to point out i t dealt with the following subjects: I.

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II.

General Provisions A. Scope B. Definitions C. A p p l i c a b i l i t y t o Studies Performed Under Contracts D. Statement o f Compliance or Noncompliance E. Inspection o f a Testing F a c i l i t y F. E f f e c t s o f Noncompliance

Grants

and

Organization and Personnel A. Personnel B. Testing F a c i l i t y Management C. Study Director D. Quality Assurance Unit

III. F a c i l i t i e s A. General B. Animal Care F a c i l i t i e s C. Animal Supply F a c i l i t i e s D. F a c i l i t i e s f o r Handling Test and Control Substances E. F a c i l i t i e s f o r Data Storage and the C o l l e c t i o n , Shipping and Storage o f Samples F. Laboratory Operation Area G. F i e l d Operation Area IV.

Equipment A. Equipment Design B. Maintenance and C a l i b r a t i o n o f Equipment

V.

Testing F a c i l i t i e s Operation A. Standard Operating Procedures B. Reagents and Solutions C. Dietary Mixtures o f Substances

VI.

Test A. B. C.

VII.

Protocol f o r and Conduct o f a Study A. Protocol B. Conduct o f a Study

VIII. A. B. C.

and Control Substances Testing and Control Substance Characterization Test and Control Substance Handling Dietary Mixtures o f Substances

Records and Reports Reporting o f Study Results Storage and Retrieval o f Records and Data Retention o f Records

These subjects were treated i n a general way. The e n t i r e document turned out to be 25 single-spaced, typewritten pages. During the development o f the document, several consultations with

Garner and Barge; Good Laboratory Practices ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

2.

MCCARTHY

GLP Regulation of Chemical Studies

11

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EPA personnel were held to exchange views and seek suggestions and comments on the d i r e c t i o n being taken by the Subcommittee. In addition, a one-day workshop was held with company f i e l d personnel to develop the section dealing with the f i e l d aspects of residue trials. The preparation of t h i s document had two main b e n e f i t s . F i r s t , i t heightened the awareness i n the industry of GLPs f o r chemistry studies - what tliey are and how to organize to implement them - and i t provided a framework f o r ccmmenting on EPA's proposed GLP regulations. That i s , since the issues had been thought through and a consensus reached, evaluation of EPA's proposed guidelines should be f a c i l i t a t e d . Other benefits of the a c t i v i t i e s o f t h i s NACA Subcommittee were the members' shared experiences on dealing with GLPs and the exchange of information on EPA inspections. This leads me to the next subject. EPA and Non-Compliance Audits EPA started non-compliance GLP audits i n about March of 1985. Some companies have experienced up to three such audits since then. I n i t i a l l y there was some misunderstanding with respect to the regulatory aspects of these EPA v i s i t a t i o n s . Some inspectors were i n i t i a l l y under the impression that the EPA's 1983 GLP regulations for n o n - c l i n i c a l animal studies applied to the chemistry studies. This was l a t e r cleared up and i t became understood that these audits were of a non-compliance nature. They (the audits) were to provide guidance to industry on what a GLP program should consist of, and what the EPA would be looking for i n a compliance s i t u a t i o n . Feedback from our members indicates that they generally found these audits to be constructive. Many good suggestions were received from the EPA inspectors. Hopefully, EPA personnel a l s o learned from these experiences and took away u s e f u l suggestions from the companies. I believe the program provided EPA and industry an opportunity to understand d i f f e r i n g stances p r i o r to a compliance s i t u a t i o n . Hopefully, these have aided EPA i n developing regulat i o n s . I t seems apparent that these audits have prepared industry for regulatory compliance. There are some points which we believe EPA should bear i n mind as we move to a f u l l - s c a l e regulatory s i t u a t i o n . The f i r s t i s with respect t o t r a i n i n g o f auditors. There i s a need f o r consistency. There has been, during t h i s non-compliance phase, some evidence o f inconsistency. While t h i s i s understandable during t h i s learning phase, we believe i t ' s important to stress to EPA the need f o r consistency among auditors. None of us can l i v e with a moving target. The second point i s understanding the difference between a GLP audit, a data audit, and a technical audit. I t i s the industry p o s i t i o n that these are three separate e n t i t i e s . A l l o f these are legitimate EPA a c t i v i t i e s . We r e a l i z e i t ' s tempting f o r s c i e n t i s t s to delve i n t o the technical d e t a i l s of a p a r t i c u l a r study when conducting a GLP inspection. However, we believe t h i s i s the purview of other EPA a c t i v i t i e s and the GLP inspector should " s t i c k to the k n i t t i n g . " On the other hand, we r e a l i z e that one cannot be b l i n d to discrepancies between raw and reported data, and t e c h n i c a l

Garner and Barge; Good Laboratory Practices ACS Symposium Series; American Chemical Society: Washington, DC, 1988.

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GOOD LABORATORY PRACTICES

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q u a l i t y issues which may surface during the GLP inspection. Understandably, such observations w i l l be reported "up the l i n e , " but they should not be the main focus o f the GLP inspector. Those issues should be l e f t t o others t o follow-up. The t h i r d area i s sample retention. The industry i s having some d i f f i c u l t y with t h i s , p a r t i c u l a r l y with respect t o the retention of crop and t i s s u e samples which have been analyzed f o r residues. A "forever" retention c r i t e r i a creates enormous p r a c t i c a l problems. We would hope that the regulations w i l l provide some f l e x i b i l i t y i n t h i s area. A fixed time l i m i t seems reasonable. The NACA GLP guideline document d e a l t with sample retention as follows: "Test system samples which are r e l a t i v e l y f r a g i l e and d i f f e r markedly i n s t a b i l i t y and q u a l i t y during storage s h a l l be retained only as long as necessary t o insure the v a l i d i t y o f the study. There s h a l l be appropriate standard operating procedures f o r disposal o f t e s t system samples. Samples o f t e s t o r control substances, samples o f t e s t o r control substance d i e t mixtures, s p e c i a l l y prepared materials, and t e s t system samples s h a l l be retained only as long as considered v a l i d by the study d i r e c t o r . " Proposed EPA GLP Regulations S p e c i f i c comments on EPA's proposed regulations are not possible as they haven't issued as o f the w r i t i n g o f t h i s paper. NACA w i l l study these c a r e f u l l y and submit thoughtful and constructive comments. There are a couple o f points, however, which we would l i k e t o s t r e s s . The f i r s t i s , we suggest i t be e x p l i c i t l y stated that the regulations do not cover e f f i c a c y t r i a l s . We believe that these t r i a l s present unique differences v i s - a - v i s laboratory studies such that the subject be dealt with separately. In addition, we prefer the terminology Good F i e l d Practices (GFPs) rather than GLPs for efficacy t r i a l s . The second point i s that compliance should be phased i n so that completed o r on-going studies are acceptable even i f the regulations aren't p r e c i s e l y met. In addition, there should be some time period between the p u b l i c a t i o n o f the f i n a l r u l e and s t r i c t enforcement o f compliance with the regulation. While we recognize the industry has been w e l l aware that compliance with GLPs was coming, and have had experiences with GLP audits, the regulations may have some s u b t l e t i e s \;hich companies have not anticipated. I t would, therefore, take time t o "gear-up" t o assure that a l l aspects o f the regulations w i l l be addressed. Summary The industry i s committed t o GLPs. In p r i n c i p l e , we support GLP regulations f o r chemistry studies. Our views on the s p e c i f i c s must await the issuance o f the proposal by EPA. However, we believe the industry' i s prepared t o deal with these regulations as a r e s u l t o f NACA's a c t i v i t i e s i n developing an industry GLP guideline document, and the experiences gained through EPA's non-compliance audits during the l a s t two years. While EPA's audit program has been h e l p f u l , compliance with the new regulations should be phased i n . R E C E I V E D January 29, 1988

Garner and Barge; Good Laboratory Practices ACS Symposium Series; American Chemical Society: Washington, DC, 1988.