Good Laboratory Practice Regulations of the US ... - ACS Publications

Chapter 9

Good Laboratory Practice Regulations of the U.S. Environmental Protection Agency Our Mission: Past, Present, and Future

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Francisca Liem and Mark J. Lehr Laboratory Data Integrity Branch, Office of Compliance, Environmental Protection Agency, Washington, DC 20460

To one degree or another scientists have always worked within a set of principles which they consider to be good laboratory practices. American chemical testing laboratories took particular notice when the United States Environmental Protection Agency (EPA) revised its national testing standards known as the Good Laboratory Practice (GLP) regulations (40 Code of Federal Regulations (CFR) sections 160 and 792) in 1989. These new regulations, intended to govern testing for pesticides registration and toxic chemical manufacturing, motivated a large segment of the scientific community to standardize the concept of "good laboratory practice."

The GLP regulations were initially enacted in 1979 to cover health effects of drug testing and food additives for the U.S. Food and Drug Administration. In 1984 the EPA adopted the regulations to include the effects of pesticides on human health and domestic animals for studies to support marketing permits for pesticides. The EPA GLPs also covered all testing on toxic substances. The GLP regulations were revised in the fall of 1989 (7), to include all other chemical testing required by EPA for pesticides and toxic substances, most notably, environmental and chemical fate and ecological effects testing. Several principles were either introduced or formalized by the GLP standards regulations which had not always been utilized by laboratories working under what they considered to be good laboratory practices. These new aspects include the concepts of a formal study director, a defined quality assurance unit (QAU), a written and approved study protocol, standard operating procedures (SOPs), and final report requirements. Since formalizing these standards, interest in the GLP regulations has grown throughout the United States and is now expanding beyond its boarders to countries around the world. Nations in Europe, Asia and the Pacific, Latin America, and North America are actively implementing quality assurance programs based on the GLP

U . S . government work. Published 1999 A m e r i c a n C h e m i c a l Society

In International Pesticide Product Registration Requirements; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.

71


72 regulations. The Organization of Economic Cooperation and Development (OECD), an intergovernmental organization consisting of twenty-four industrialized nations, recognized the need for a program aimed at ensuring valid, high quality test data. The OECD determined that globally accepted data must be based on a program comprised of GLP principles, including a mechanism for monitoring and assuring compliance with the adopted GLP principles. This harmonization and broad acceptance of the basic concepts of GLP was an important step toward mutual acceptance of data. An international group of experts on GLP standards was established and work began developing a set of guidelines to govern the conduct of laboratory studies world wide. This effort resulted in the development of the first OECD GLP principles which were established in 1981 (2). Today OECD continues to refine its quality assurance guidelines using GLP Standards as its cornerstone. OECD has prepared revised guidelines which were published in January 1998 (J). In the United States, EPA's GLP program is directed by the Laboratory Data Integrity Branch (LDIB). The LDIB is located within the Office of Enforcement and Compliance Assurance under the Agriculture and Ecosystems Division. LDIB's primary mission is to assure the quality and integrity of studies submitted to the agency in support of application for research and marketing permits for pesticide products. EPA accomplishes this mission by conducting laboratory inspections and data audits to assure compliance with the GLP regulations. The past thirteen years have shown remarkable improvements in the quality of the data submitted to the EPA as a result of the GLP regulations. Laboratory enhancements in the areas of quality assurance/quality control, record keeping, and accountability have lead to a heightened level of scientific quality which is recognized throughout the world. The GLP regulations are the driving force behind this movement and the EPA is committed to continuing this trend. The EPA has continued to improve its GLP inspection program by giving inspectors a greater role in determining the fate of inspection reports which has greatly streamlined our ability to refer and close cases. Additionally, EPA has managed to increase its efficiency in the field, thus allowing its inspectors to conduct more inspections with a smaller inspection staff. In fiscal year FY 97 the EPA performed 127 inspections which included 480 data audits of studies already submitted to the EPA. The EPA currently estimates that approximately 1,400 laboratories are performing studies in accordance with the GLP regulations. Of these facilities, nearly 550 are analytical chemistry laboratories, 309 are performing field testing, 264 are toxicology facilities, 69 are insecticide efficacy, and 19 are antimicrobial laboratories. To accurately characterize and target these facilities the EPA has made several improvements to its inspection targeting data base known as Laboratory Inspection and Study Audit, or LISA. Recent modifications made to LISA have greatly enhanced its capabilities. Last year EPA staff members performed inspections at 84 testing facilities which had never before been audited. These "new testing facilities"



73 accounted for 66% of the total inspections performed last year. Analytical chemistry laboratories were the most frequently inspected facilities in 1997 making up 52.0% of the total number of inspections. Field testing sites were second at 17.3%, and toxicology laboratories third at 16.5%. In 1997 antimicrobial, environmental effects and insecticide efficacy laboratories were the least inspected laboratories at 7.1%, 3.9%, and 3.1 % respectively. In addition to using LISA for scheduling inspections, EPA's LDIB also targets facilities based on requests made by the Office of Pesticide Programs (OPP). OPP utilizes LDIB inspectors to address questions that arise during the pesticide review process. By carefully monitoring compliance trends from year to year, EPA is able to focus its time and resources in areas of the regulated community with the poorest compliance rate. In FY 97, EPA found that analytical testing facilities, more specifically product chemistry labs, were the least GLP compliant sector. EPA inspectors found that only 18 out of 66 analytical facilities, or approximately 27%, were fully compliant with the GLP regulations. Sponsor-run laboratories performing product chemistry testing were the most violative of these facilities, and consequently, the mostfrequented,accounting for 44 of the 66 inspected chemistry laboratories. By contrast, percent compliance rates rangefrom55% for field testing facilities to 33% for antimicrobial laboratories. Reasons for noncompliance in product chemistry laboratories will vary greatlyfromone facility to the next; however, there are possible explanations for poor regulatory performance in this sector. Product chemistry laboratories are typically found in pesticide formulation/manufacturing plants which focus their efforts in areas of production and packaging. While issues concerning quality assurance/quality control are very important to these facilities, attention to regulatory requirements sometimes finds itself taking a backseat. Additionally, the GLP regulations allow for certain exemptions under physical and chemical characterization studies (40 CFR §160.135). Because of these exemptions, product chemistry facilities sometimes perceive the GLP regulatory requirements as not necessary or unimportant. In many cases, product chemistry work is contracted "outof-house" to facilities not equipped to handle GLP regulatory requirements. It should be restated, however, that analytical laboratories account for the largest segment of testing facilities performing GLP work in the United States. After an inspection has been completed, it is the responsibility of the inspector to write a legally defensible report in support of Agency enforcement efforts. Violative cases are referred to either the Office of Regulatory Enforcement (ORE) for regulatory concerns or to the Office of Pesticide Programs (OPP) for scientific issues. In some instances reports are referred to both ORE and OPP if regulatory and scientific concerns are raised by the inspection team. Table I shows a comparison, by discipline, of old vs. new facilities inspected during FY 97. In addition, the table compares the number of inspections to the number of facilities referred, and the compliance rate of old vs. new facilities. Also provided are the total percent compliance rates for each discipline.


74 Table I Compliance Rate FY 1997

Discipline

Number Inspected

cm MW Downloaded by NORTH CAROLINA STATE UNIV on September 26, 2012 | http://pubs.acs.org Publication Date: June 16, 1999 | doi: 10.1021/bk-1999-0724.ch009

Number in Compliance

Number Referred

xm

Toxicology

20

1

2 (10%)

Analytical Chemistry

12

54

1 (18%)

Antimicrobial Efficacy

3

6

Field Sites

6

Environmental Effects Insecticide Efficacy

18 (90%)

0 (100%)

26(48%)

11 (92%)

28 (52%)

1 (33%)

2(33%)

2 (67%)

4(67%)

16

1 (17%)

0(0%)

5(83%)

16(100%)

2

3

1(50%)

0(0%)

1(50%)

3 (100%)

0

4

0(0%)

4 (100%)

0(0%)

0(0%)

1 (100%)

39(59%) ^^•"-•••ϋ.ί'·:

Γαία/ number of inspections: 127 FY 1997 marked the second year the EPA has utilized its Inspection Observation Form, also known as the 038. The 038 provides the inspected facility with instant written observed regulatory findings made by the inspection team during the audit. The 038 also provides EPA management with real-time information which can be used to better address problem areas within the regulated community as they occur. Table II lists the inspectors' findings observed during FY 97 in each subpart and their occurrence by percent. Table II Inspector Findings Inspection Observation Forms (038) FY 1L997 Percent Findiflgs A - General Provisions

9

7%

Β - Organization and Personnel

54

43%

C - Facilities

10

8%

D - Equipment

17

13%

Ε - Testing Facility Operation

21

17%

F - Test, Control, and Reference Substance

23

18%

G - Protocols for the Conduct of a Study

46

36%

J - Records and Reports

4

3%


75 As the table shows, Subpart Β - Organization and Personnel, and Subpart G Protocol for and Conduct of a Study were the most violative areas of the GLP regulations during 1997. Listed below are the most common observations made by EPA inspectors from these two subparts.


Subpart Β - Organization and Personnel • • • • • • • • • •

Lack of Independent Quality Assurance Unit (QAU) Lack of Quality Assurance (QA) inspections Problems associated in the routing of QA reports Lack of QA records Lack of/incomplete QA records Lack of/incomplete master schedule Final report does not match the raw data Lack of a study director Unforeseen circumstances not documented/reported Lack of technical training and records Subpart G - Protocol for and Conduct of a Study

• • • • • • •

Lack of raw data Data missing Lack of a signed and/or approved protocol Protocol missing required GLP elements Lack of signed protocol changes Incorrect calculations Records in pencil, not initialed and/or dated

As previously mentioned, organizational and technological changes have enabled inspectors to work smarter and faster resulting in stronger cases. These positive changes manifested themselves on April 24, 1997, when six Federal Insecticide Fungicide Rodenticide Act (FIFRA) GLP enforcement initiatives were announced by the Office of Regulatory Enforcement (ORE) resulting in nearly $70,000 in fines. Among the facilities fined were three product chemistry laboratories, two toxicology laboratories, and two efficacy facilities. The resulting GLP violations included in the enforcement action are listed as follows: Subpart Β - Organization and Personnel • • • • • •

QAU failure to assure the final report accurately reflected raw data QAU failure to prepare and sign a statement in the final report, specifying inspection dates and findings reported to management and the study director QAU failure to submit written status reports to management QAU failure to maintain a copy of the master schedule QAU failure to maintain written records describing responsibilities/ procedures applicable to QAU Study director failure to assure all experimental data were accurately recorded and verified


76 Subpart J - Records and Reports • • •


• •

Failure to describe in final report all circumstances that may have affected the quality/integrity of the data Failure to include in the final report all required GLP elements Failure to retain all raw data, documentation, records, protocols, specimens and final report of the study Failure to archive master schedule, receipt of test substance, test substance accountability form with the study files Failure to archive written approved test substance dose preparation instruction with study files Subpart G - Protocol for and Conduct of a Study

• • • •

Failure to document changes to the protocol Failure to have an approved written protocol for the study Failure to record data directly, promptly, and legibly in ink Failure to initial and date data entries Subpart Ε - Testing Facilities Operation

•

Failure to follow Standard Operating Procedures (SOP) for test system care

FY 97 also brought changes to the types of inspections EPA routinely performs. In addition to conducting GLP regulatory inspections, the EPA began conducting audits of laboratories claiming non-GLP compliance for submitted studies supporting permits for pesticide products. EPA is concerned about the quality, integrity, and reproducibility of all studies submitted to the Agency for registration including studies claiming non-compliance. These inspections are performed under the purview of FIFRA Books and Records [40 CFR 169.2(k)] which requires all records supporting a registration to be retained as long as the registration is valid and the producer remains in business. Among the top priorities of the EPA is to ensure compliance with environmental laws and regulations and to help ensure that good science is used in EPA decision making. Historically, EPA inspectors have played a key role in this effort by conducting rigorous inspections and identifying violations for subsequent enforcement actions. This approach has served the EPA well in the past in helping laboratories achieve compliance and providing the necessary deterrence to the regulated community. However, as the number of regulatory requirements and number of regulated entities has increased, it has become clear we need a more effective means to maintain this strategy. Promoting new innovative approaches in EPA's GLP program is essential to maximize compliance and encourage data quality and integrity within the regulated community. EPA is also working with universities around the nation to establish a quality assurance standards based curriculum designed to stress data integrity and the fundamentals of GLPs. EPA recognizes that maintaining the upward trend in data quality rests in the hands of future scientists. During the next year, EPA's targeting staff will continue to extend the range of its



77 laboratory inspection data base, LISA. The EPA is dedicated to expanding our inspection universe by locating unidentified laboratories and reaching out to new regulated sectors. In addition, EPA has recently taken steps to make training manuals, SOPs, and GLP regulatory advisories more accessible by placing them on the Internet. In supporting our primary mission of protecting human health and the environment, EPA will continue to stress the importance of good science. While enforcement and technical assistance will continue to remain the primary tool EPA uses to achieve and measure compliance, we are seeking other tools to promote and ensure data quality and integrity. The Agency must continue to identify environmental and health risks, analyze the underlining causes of noncompliance, and apply appropriate solutions. Developing and using new procedures to carry out this approach will place increased demands on field personnel. Today EPA inspectors must have sound technical skills and be capable of accurately conveying regulatory requirements. EPA will continue to support programs that promote compliance assistance, as well as further communication and outreach. It has always been our goal at the EPA to push the limits of quality and innovation, and this philosophy will continue into FY 1998. The EPA is dedicated to working as a partner with industry to adequately carry out this new approach.

Literature Cited 1. "Good Laboratory Practice Standards Under the Federal Insecticide, Fungicide, and Rodenticide Act Final Rule", Code of Federal Regulations Title 40, Part 160; Federal Register 54:58 (August 17, 1989) pp 34067-34074. 2. The OECD Chemicals Programme, OECD Publications, No. 72009, 1989. 3. OECD Series on Principles of Good Laboratory Practice and Compliance Monitoring, Number 1, OECD Principles on Good Laboratory Practice, ENV/MC/CHEM(98)17, 1998.

Note: Opinions presented in this paper reflect that of the authors and should in no way be perceived as official EPA interpretation.


Good Laboratory Practice Regulations of the US ... - ACS Publications

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