Chapter 10
Proposed Changes in FIFRA GLPS: Impact on the Agricultural Industry William J. Litchfield
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Agricultural Products, E.I. du Pont de Nemours and Company, Wilmington, DE 19880-0402
Significant changes are being proposed (1) by the U.S. Environmental Protection Agency to the Good Laboratory Practice Standards (40 CFR Part 160). At least nine of these changes were also proposed by the American Crop Protection Association's GLP Work Group, which presented a list of its recommendations (2) to EPA in April 1996. A review will be given of the proposed changes, their impact on the U.S. agricultural industry, and the prospects for additional modifications in the future.
Driven by a mandate to reduce paperwork, the U.S. Environmental Protection Agency (EPA) is now proposing changes to its Good Laboratory Practice Standards (GLP or GLPS) Regulations that will consolidate 40 CFR Part 160 (FIFRA) (3) and 40 CFR Part 792 (TSCA) (4). As part of this effort, EPA is also proposing amendments that are intended to "streamline and ease compliance" while maintaining data integrity. EPA's Office of Enforcement and Compliance Assurance (OECA) has indicated that such changes are coming for the past few years, and the Office has been open to suggestions offered by various organizations. To solicit public comment, a draft document containing these changes will be published in the Federal Register during 1998. The American Crop Protection Association (ACPA) has been active in this area since early 1994, when it organized a GLP Work Group and solicited comments on 40 CFR Part 160 from its eighty member companies. The GLP Work Group met frequently over the next two years to consider changes that could (1) improve the efficiency and cost effectiveness of FIFRA GLPS, (2) enhance international harmonization, and (3) adapt new technologies, while maintaining data integrity and public safety. Over fifty changes proposed by the GLP Work Group were presented to OECA in April 1996, and a few of these are
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© 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.
79 similar to ones now being proposed by EPA. The GLP Work Group endorses the consolidation of TSCA and FIFRA GLPS and encourages public comment on the following EPA proposed amendments.
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Proposed Changes and Impact In Subpart A under Definitions, EPA has proposed essentially four changes. Considering the first two of these as they appear in a draft to be published in the Federal Register, (1) the definitions of carrier and test system include "air", and (2) the definition for the Quality Assurance Unit excludes "individual(s) directly involved with the conduct of the study." Both of these changes are relatively innocuous and should have little impact on industry-wide programs to comply with GLPS. A third proposed change, however, affects the definition of raw data, so that it includes "any original data captured electronically or by some other medium". This might raise more questions than it solves regarding the long term storage and retrieval of data, so more clarification should be sought from EPA. A forth change, that simply adds an example "e.g., water, mineral oil, air" to the definition of the word "vehicle" has very little impact. In Subpart B, relating to the Quality Assurance Unit (QAU), EPA has proposed two changes. One is that the QAU must "maintain a copy of the Master Schedule ... indexed to permit expedient retrieval". The other states that the QAU must "maintain copies of all protocols until study completion". Both of these changes were also recommended by the ACPA GLP Work Group since practically every QAU now uses a computer spreadsheet to index studies and since protocols must be archived with the original study records. Asking for expedient retrieval is no additional burden on industry, and allowing each QAU to reduce its paper storage should eventually reduce cost. Of all the changes proposed by EPA, the one that could cause the most concern within industry is found within Subpart D on Equipment. It reads: "The integrity of data from computers, data processors and automated laboratory procedures involved in the collection, generation, or measurement of data shall be ensured through appropriate validation processes, maintenance procedures, disaster recovery and security measures." Incidentally, these words were also proposed by the ACPA GLP Work Group that felt that the statement was true and concisely written. Concerns, however, arise from the interpretation of "appropriate ... measures" and how far EPA will carry this within its GLP inspection program. Some multinational companies already spend millions of dollars on these items plus computer training, and the incremental cost of placing these items under GLP could be significant (in some cases exceeding $200,000 per year if all computer systems must be validated). Perhaps an alternative would be for EPA to consider other existing standards in
In International Pesticide Product Registration Requirements; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
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the computer industry or those defined within each company by their internal practices. Going back to less controversial items, there is only one proposed change to Subpart Ε on Testing Facilities Operation. ACPA had hoped to eliminate the need for labeling wash bottles. However, EPA modified the suggestion to read: "As an alternative to labeling wash bottles and transfer bottles with the expiration date, the testing facility may develop a welldocumented performance standard to ensure that the reagents or solutions have not deteriorated or are (not) outdated." As the change is now worded, this means that the laboratory must either label the wash bottles directly or develop a performance standard which at present is unclear. Changing the words from "a well-documented performance standard" to "a standard operating procedure" would help, but overall, there is not much benefit from this proposed change. There is some benefit from a proposed change in Subpart F that calls for test substance solubility to be determined either before the experimental start date or "concurrently according to written standard operating procedures ..." Usually, solubility testing is performed before application of a test substance. However, there are occasions when testing concurrently could shorten the study timeline and reduce costs without affecting data integrity. Proposed changes to Subpart F also contain a couple of cautionary items. For instance, one modification states: "With the study director's written approval, test substance storage containers need not be retained after use, provided that full documentation of the disposition of the containers is maintained as raw data for the study." The ACPA GLP Work Group recommended the first part of this sentence to relieve the burden of storing large numbers of containers. However, EPA added the remainder, and its description of "full documentation" is extensive. The list of items proposed for documentation is so large that it could produce more work than retaining the containers. The modification states: "1) (i) information of shipments pertaining to each container leaving the storage site (examples of such records are shipping request records, bills of lading, carrier bills, and monthly inventories of warehouse activity); (ii) test substance receipt records at each testing facility; (iii) complete use logs of material taken from containers; and (iv) a record of the final destination of the container, including the place and date of disposal or reclaiming, and any appropriate receipts.
In International Pesticide Product Registration Requirements; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
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2) an inventory record of empty containers before disposal, including sufficient information to uniquely identify containers, maintained in an up-to-date manner recording all arrivals of empty containers and their disposal. This record shall be maintained as raw data for this study. 3) location of facilities: where test substance is stored; where empty containers are stored prior to disposal; where records of use, shipment, and disposal of containers are maintained; and where the test substance is used in studies (i.e., testing facility)." The other item in Subpart F that creates concern, apart from an arbitrary 12 hour interval, reads: "Tank mixes prepared for application to soil or plants by typical agricultural practices within a 12 hour period between preparation and application, and solutions prepared for mammalian acute toxicology studies, metabolism studies, or mutagenicity studies, are exempt from requirements for concentration determinations." While this offers some relief in terms of the testing needed on test substances, it may not go far enough since tank mixes still need to be assessed for uniformity. In cases where uniformity testing is as rigorous as concentration testing, these proposed changes may not be much help. However, it could save effort in those cases where EPA and industry can accept a visual or qualitative assessment of uniformity. Both of the proposed changes in Subpart G are of some value to industry, since they can reduce paperwork and save effort. The first reads: "When a reference substance for a metabolite cannot be identified prior to the beginning of a study, it is not necessary to identify the substance in the protocol." Since one cannot identify what one does not know, many Study Directors in the past had to write protocol amendments once they knew the identity of such reference substances. Even more time consuming was the practice of writing reports on terminated studies that the following proposal would eliminate. It reads: "Discontinued studies or studies otherwise terminated before completion shall be finalized by writing a protocol amendment providing the reason(s) for termination "
In International Pesticide Product Registration Requirements; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
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82 Assuming a company terminates 20 studies per year, writing one or two page protocol amendments, rather than lengthy reports, could save tens of thousands of dollars in just labor costs for the Study Director and associated personnel. Lastly, EPA has proposed an addition in Subpart J on Reports and Records that moves it into the biotechnology realm. The change states: "For other test organisms (plants, bacteria), similarly detailed descriptions of the test system are required". The ACPA GLP Work Group agrees with the intent of this proposal but suggests that the wording be changed to: "For other test systems (plants, bacteria), similarly detailed descriptions are required." Conclusion The changes now being proposed by EPA represent the first opportunity to modify FIFRA GLPS since they went into effect in October 1989, and perhaps the only opportunity there will be in the next decade. While the reduction of paper, by combining FIFRA and TSCA GLPS, is the main driving force, EPA is interested in making other modest changes that could benefit the regulated industry as long as there is no negative impact to either data integrity or public safety. The ACPA GLP Work Group shares this interest with EPA and has taken this opportunity to provide comments and suggestions. When the proposed changes are published in the Federal Register later in 1998, we ask that you send your comments directly to the Public Response and Program, Resources Branch, Office of Pesticide Programs, Environmental Protection Agency, 401 M St., SW, Washington, DC 20460. Acknowledgments I would like to thank EPA's Office of Enforcement and Compliance Assurance for providing a draft of the proposed changes as it went to the U.S. Department of Agriculture and Congress for review. I would also like to acknowledge the following ACPA GLP Work Group Members: Ray Brinkmeyer, Dow-Elanco; Robert Brown, Agrevo; Selena Crenshaw, Griffin; Fran Dillion, Steward Ag; Tom Gale and Robert Wurz, Novartis; Clive Haider, Beyer; John Kobland, American Cyanimid; and Ray McAllister, ACPA. Literature Cited 1. Environmental Protection Agency Office of Enforcement and Compliance Assurance, 40 CFR Part XXX, RIN-2070-AC97, Good Laboratory Practice Standards, 1997, pp 1-54, draft document. 2. ACPA GLP Working Group Recommendations, 1966, pp 1-21, available from author. 3. Federal Register, The Federal Insecticide, Fungicide, and Rodenticide Act, 1988. 4. Federal Register, Toxic Substances and Control Act, 1983.
In International Pesticide Product Registration Requirements; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.
