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TECHNICAL ADVISOR'S REPORT TO THE FOOD, DRUG, AND COSMETIC PACKAGING MATERIALS COMMITTEE* FDA and EU Revisions to Technical Guidance Documents June 28, 2002 Lester Borodinsky, Ph.D. Ladies and Gentlemen: It is a great pleasure for me to be with you once again in the role of the Committee's Technical Advisor. This report will describe one of the current technical issues we are dealing with in establishing satisfactory regulatory positions for plastic food-contact materials. Specifically, this report will provide observations on recent changes that have been made in guidance documents issued recently by both the United States Food and Drug Administration (FDA) and the European Union (EU) for establishing the regulatory status of food-contact materials. As many of you know, the official laws and regulations implemented by FDA and the EU for food-contact materials do not (and cannot) include minute detail with regard to the specific types of data, and how to acquire them, for demonstrating the safe use of food-contact substances. Instead, the regulatory authorities have provided guidance documents intended to supplement the laws and regulations so that those individuals needing such information can properly acquire and present the information to the authorities. Thus, guidance documents not only provide detail for the readers, but also provide a vehicle for the government reviewers to shape the data needed. FDA Guidance Documents As you will recall from our previous reports, FDA issued draft guidance documents regarding the chemistry and toxicology needs for Food Contact Notifications (FCN)1 entitled "Preparation of Premarket Notifications for Food Contact Substances: Chemistry Recommendations" and "Preparation of Premarket Notifications for Food Contact Substances: Toxicology Recommendations," respectively, in September 1999.2 FDA has now finalized these guidance documents; changes in the finalized version of the guidelines from the most recent drafts of these two documents, as well as other notable aspects of these documents, are discussed below. In addition, FDA finalized its rules formally implementing the FCN process on May 21, 2002 (67 Fed. Reg. 35724), along with a finalized companion administrative procedures guideline entitled "Guidance for Industry: Preparation of Premarket Notifications: Administrative," May 2002. 3 Chemistry Recommendations Three years ago (June 1999), we provided a detailed summary of the draft Chemistry Recommendations, and the following year (June 2000) an FCN update report which focused on technical issues emerging from the then-newly implemented FCN program, including chemistry related issues. One of the changes that FDA now has brought about in finalizing its Chemistry guidelines is one of consolidation - the guidance document that FDA has recently issued, now entitled "Guidance for Industry: Preparation of Food Contact Notifications and Food Additive Petitions for Food Contact Substances: Chemistry Recommendations" (April 2002), officially covers both FCNs and Food Additive Petitions (FAP). Up until now, FDA's last revision of its guidance relating specifically to FAPs was in June 1995 and the chemistry guidance documents issued since have uniquely addressed FCNs. As the guidance for both is the same and, in fact, the FCN draft guidelines are a general revision of the Chemistry Recommendations for FAPs last issued in 1995, this consolidation is both logical and welcomed - there is now no appearance of a difference between the requirements for either FCNs or FAPs. With regard to the previous versions of the Chemistry Recommendations, while a framework of petition requirements has been in place since 1959,4 the regulations governing FAPs in 21 C.F.R. Part 171 do not provide practical guidance on the quality and the nature of the data required for petitions. Because questions began almost immediately regarding the kinds of data and other information which would satisfy FDA's needs for evaluating food additive petitions, FDA first set forth its guidelines in this area in "FDA Guidelines for Chemistry and Technology Requirements of Food Additive Petitions," issued in August, 1966.5 These Guidelines were divided into three sections: (I) "Protocol for Direct Additives," (II) "Protocol for Indirect Additives," and (III) "Protocol for Radiation and Radiation Sources." Questions continued to arise after the issuance of the 1966 Guidelines, and FDA also had acquired a greater appreciation of the subtleties involved with evaluating components of food packaging materials. As a result, the Guidelines were revised to address indirect food additives alone and issued in March 1976 as "FDA Guidelines for Chemistry and Technology Requirements of Indirect Food Additive Petitions."6 The Agency's next issuance of guidelines involved two "amendments" rather than the revision of the Guidelines per se. Specifically, in May, 1981 FDA issued "Validation Guidelines," which outlined the general criteria for validation of analyses presented in indirect food additive petitions, and in June, 1981 FDA issued its seminal "Procedures for Estimating Exposure to Indirect Food Additives," FDA's first public "paper" describing the exposure estimating approach it "invented," which employs consumption factors and food-type distribution factors. The Agency next revised its guidelines after the completion of exploratory research on the nature of food simulating solvents and testing temperatures and times conducted on its behalf by contract laboratories. Along with these new items of knowledge, the two amending guidelines were included in the Agency's "Recommendations for Chemistry Data for Indirect Food Additive Petitions" in September, 1988. 7 The guidelines were next revised in June, 1995, again titled FDA's "Recommendations for Chemistry Data for Indirect Food Additive Petitions." The introductory portion of the 1995 "Recommendations" indicated four items the Agency considered to be the highlights of the revised edition: (1) migration testing protocols for high temperature applications were included; (2) the use of Miglyol 812™ as an alternative fatty-food simulant was discussed; (3) in the spirit of international harmonization, FDA recommended testing with 10% ethanol (instead of 8% ethanol) to simulate aqueous, acidic, and low-alcohol foods, and indicated acceptance of testing at 40°C (instead of 49°C) to model long-term storage at ambient temperatures; and (4) the Chemistry criteria relating to reviews under the Threshold of Regulation were addressed. In addition to these, however, there were other changes that were noteworthy; all of these modifications were addressed in the December 1995 Technical Advisor's Report. Finally, with the establishment of the FCN program, revised draft guidelines were issued twice in 1999 (March and September) and in May 2000, and finalized in April 2002. The latest version of the Chemistry Recommendations is changed very little from earlier installments of the Chemistry guidelines. Section I (Introduction) is entirely new; and it appears to be a good descriptive background regarding food contact substances, touching on the definition of a food contact substance as it appears in the Federal Food, Drug, and Cosmetic Act, as amended. Section II (Chemistry Data) also has a new introduction, focusing on uses resulting in exposures <0.5 part per billion (ppb) and the data requirements of such applications in an FCN and under the Threshold of Regulation policy (as set forth in Section 170.39). A noteworthy point of clarification is in Appendix II (Selected Migration Testing Protocols), Item 1.C. (i.e., Condition of Use C ("Hot filled or pasteurized above 150°F") 8 testing conditions). The test conditions are not changed, but a note at the end of this subsection now clarifies that testing using Condition of Use C test conditions covers Conditions of Use C through G ("Frozen storage (no thermal treatment in the container)") and not C through H ("Frozen or refrigerated storage: Ready-prepared foods intended to be reheated in container at time of use"). This is not a change in interpretation, but a matter of clarification, as FDA has for some time been issuing clearances for Conditions of Use C through G when testing is performed using the recommended conditions for Condition of Use C. In addition, Appendix II, Item 2 has been modified. This subsection contains FDA's guidance on the procedure to employ to obtain a clearance for adjuvants for all polyolefins or, in fact, for all polymers. As has been the case for some time now, FDA continues to indicate that low-density polyethylene (LDPE) may be used in migration testing for a new adjuvant to cover use of the adjuvant in all polymers (including all polyolefins), but now contains additional advice on selection of appropriate polyolefins for testing the migration of a new adjuvant, as follows:
As you may recall, this Committee (via a letter we drafted on behalf of an ad hoc FDA Standards Task Group of the Food, Drug, and Cosmetic Packaging Materials Committee) provided comments on July 27, 2000 to FDA regarding properties that can be used to characterize olefin polymers used to fabricate migration test samples with regard to low density polyethylene (LDPE), linear low density polyethylene (LLDPE), high density polyethylene (HDPE), and polypropylene. As you can see, FDA chose not to recommend specific properties and, instead, recommends that parties interested in performing migration testing for polymer adjuvants should select polymers of appropriate grades and indicate the molecular weight distribution, melt flow index, and degree of crystallinity. Nonetheless, FDA's files contain our suggestions and it is possible that FDA may rely, in a practical way, on the suggestions we made in July 2000, in reviewing FCNs and FAPs. The new consumption factors (CF) for polyethylene terephthalate (PET) (CF = 0.16) and recycled PET (CF = 0.05) are now included in Appendix IV, Table I (Consumption Factors). In addition, the CFs for "types" of polystyrene are further broken out than previously - in the 1999 draft, impact (CF = 0.04) and non-impact (CF = 0.06) were broken out from the overall polystyrene consumption factor of 0.1; now, these two are the same as before, but non-impact is further subdivided into general purpose (CF = 0.02) and foam (CF = 0.04). Toxicology Recommendations As with the Chemistry Recommendations, three years ago (June 1999), we provided a detailed summary of the draft Toxicology Recommendations and the following year (June 2000), an FCN update report which focused on technical issues emerging from the then-newly implemented FCN program, including toxicology related issues. Once again, one of the changes that FDA has brought about in finalizing its Toxicology guidelines is one of consolidation - the guidance document that FDA has recently issued, now entitled "Guidance for Industry: Preparation of Food Contact Notifications and Food Additive Petitions for Food Contact Substances: Toxicology Recommendations" (April 2002), now officially covers both FCNs and FAPs. This consolidation, too, is both logical and welcomed. With regard to the history of the Toxicology guidelines, it is a shorter history than the Chemistry guidelines. As noted above, Part 171 of the Food Additive Regulations sets forth the types of data needed in a petition to permit the Agency to establish the safe use of a food additive, but the Sections in Part 171 do not provide practical guidance on the quality and the nature of the toxicology data required for petitions. Although questions began almost immediately regarding the kinds of toxicology data and other information which would satisfy FDA's needs for evaluating food additive petitions, FDA issued its first set of guidelines in 1982 for support of Direct Food Additive Petitions in a document entitled "Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food," usually referred to as the "Redbook."9 FDA issued a draft revision of this document, having the same title but commonly referred to as "Redbook II," in 1993; FDA has not yet issued a final version of Redbook II. While these documents are useful for guidance in the performance of a given test that is needed, they are not intended to cover food-contact substances and do not, consequently, provide guidance on which tests are needed to assure the safety of such substances. FDA has issued guidance "sheets" over the years that provide a sketch of the dietary exposure "cross-over" points that require more or less rigorous toxicology testing. However, with the issuance of the "Draft Toxicology Information Prepared for the March 12, 1999 Stakeholders Meeting on Premarket Notification for Food-Contact Substances," FDA for the first time issued its Toxicology guidelines for food-contact substances. These guidelines were revised as "Preparation of Premarket Notifications for Food Contact Substances: Toxicology Recommendations," in September 1999, and now finalized as "Guidance for Industry: Preparation of Food Contact Notifications for Food Contact Substances: Toxicology Recommendations" in April 2002. The finalized Toxicology Recommendations are fundamentally unchanged, although there has been quite a bit of reorganization of the placement of the information in the guideline from the 1999 version - this is not surprising, as the 1999 version was FDA's first attempt at a set of guidelines like this for food-contact materials. The following is a summary of the changes (other than editorial changes). The discussion in Section II (Exposure Estimates) makes it clear that toxicology data are not needed at a dietary level of 0.5 ppb or lower, not only for the use of a new food-contact substance, but also for an incremental increase in exposure of 0.5 ppb for a substance for which there are existing clearances, i.e., in effect, FDA has concluded that an incremental change of 0.5 ppb is effectively no change. In Section IV (Safety Testing Recommendations), FDA still indicates a preference for the mouse lymphoma tk± assay (as compared to in vitro chromosomal damage assays) - this is not a change, but noteworthy nonetheless. There is now a separate portion of the section that states explicitly that the exposure levels establishing toxicity test requirements for biocides are one-fifth of those for other types of food-contact substances. FDA is now more explicit, in Section V (Organization of the Safety Information), in the recommended organization of safety information, as follows: Section I - Comprehensive Toxicology Profile In Section VII (Comprehensive Toxicology Profile), with regard to risk assessments for carcinogenic constituents, FDA has removed the previous reference that indicated that the risk needed to be below 10-8. This reflects FDA's longstanding practice of determining the acceptable risk level on a case-by-case basis. Section VIII (FDA's Views of the Relevance of Various Types of Safety Studies in Notifications) now makes it clear that only studies relevant to the safety assessment of a substance in food need to be discussed, i.e., data from studies using routes of administration other than oral are not of value unless effects at distill sites are observed. In addition, there is now a (little) bit more guidance regarding the significance of the results of genetic toxicity tests, as follows: "Factors that should be considered in determining whether results of genetic toxicity studies indicate a potential safety concern for an FCS include: 1. Other available safety data such as bioassays; EU Guidance Documents The European Union (EU) Directives are administered by the European Commission (EC); the Directives generally are applied by the EC's consulting body, the Scientific Committee for Food (SCF), in the review of Technical Dossiers to clear new substances. The migration testing parameters for clearing new substances in the EU are provided in the European Commission's Directive 82/711/EEC, which was amended for the second time (the most recent amendment) on July 29, 1997, in the Official Journal of the European Communities.10 Directive 82/711 establishes "the basic rules for testing migration of constituents of plastics materials and articles intended to come into contact with foodstuffs;" the Second Amendment to this Directive is a total revision of the Directive, although most of the testing parameters were unchanged from the previous version. Additional guidance is provided in the EU's Practical Guide, which was amended recently on 1 March 2002, as well as in the EU's Note for Guidance, which also was amended recently on 1 March 2002. Notable changes in the March 2002 versions of these guidelines are discussed below. Practical Guide The Practical Guide has been modified, primarily in format, since the previous revisions focused primarily on providing a more complete background on the various Directives relating to food-contact substances. One of these background items is Section 2 of Chapter II, a section entitled "Other Matters." Item 2 in the Section covers the "Threshold of Regulation and 'No Migration Concept'," and focuses on FDA's Threshold of Regulation. Unfortunately, the Practical Guide makes the incorrect assumption that FDA's new "notification" program is merely an extension, and simplification, of FDA's Threshold of Regulation policy. Specifically, the discussion indicates that, where the dietary exposure is less than 0.5 ppb, formal clearance by FDA is no longer needed, but one merely needs to notify FDA with a reduced technical dossier. Of course, this is not the case. FDA's FCN process is a replacement for the food additive petition system (except for the rare occasion where the replacement is not acceptable to FDA) so that dietary exposures up to 1 part per million (ppm) would fit the program (and, for some instances, greater than 1 ppm). Equally as important, the filing with FDA is not a "reduced" filing; in fact, our experience is that FCNs are required by FDA to be more comprehensive than would have been acceptable to FDA for petitions (including for exposures below 0.5 ppb). Unfortunately, readers of this section of the Practical Guide are bound to get the impression that FDA is now allowing a "short cut," an impression that would be far from the truth. In addition, the Practical Guide now has a separate portion of the document devoted to mathematical modeling of migration based on the principles of diffusion (Chapter II, Section 5, Annex 1). While the model's general form is the same as has been considered scientifically sound for a number of years (including being acceptable to FDA for many years), we notice that an equation that can be used to calculate a diffusion coefficient generally is new. In fact, it appears to be a refinement of the general model published in 1996 by Baner et al.11 However, based on our review of the references for the diffusion modeling discussion in the Practical Guide, many (if not most) of the references for this discussion have yet to be published (being referred to as "in press"). This appears to us to be a very recent development, as FDA's recently finalized guidelines (discussed above) refer to the "old" 1996 Baner et al. paper - one might have thought that FDA would have referenced the "latest" version if it was, in fact, widely accepted. For all of the above reasons, we are reserving judgment until we have had the opportunity to review the actual publications on the subject. Note for Guidance With regard to the Note for Guidance, the significant revisions appear to be in Chapter III, which covers the Explanatory Guidance for the preparation of a written presentation for clearing new polymer starting substances or additives. In this revised Chapter, the new sections are printed in bold type to alert the reader to the additional information requirements. It appears to us that the most significant of these new requirements is item 6.3, which indicates the need to include "information on the migration of oligomers and reaction products from polymers produced from new monomers or which are produced by means of polymerisation aids that influence the molecular structure of molecular weight of the polymer. In the first instance there is a need for information on the identity and level of substances that migrate as a consequence of the use of a new monomer." With regard to requiring migration data on oligomers, this appears to be a move to "converge" with FDA, as it has long been a requirement to include migration data on oligomers to clear a "new" polymer (FCN or FAP). What is not clear from the Note for Guidance is the objective of presenting such data in a Technical Dossier requesting EU clearance of a new monomer - the Note for Guidance does not indicate how to assess the safety of the oligomers. One may presume that the level of migration of oligomers would be deemed safe if it does not exceed a migration level of 60 ppm, as the Monomers Directive mandates a global migration limit of 60 ppm for food-contact materials and articles. However, it is not certain whether this presumption is correct. Concluding Remarks We recognize that revising guidance documents is a laborious task; we commend the individuals responsible for their efforts in producing them. These guidelines continue to be indispensable to the industry for instruction in the performance of the necessary testing to establish the regulatory status of food-contact substances. It is important, however, for the users of the documents to review them carefully so as to be able to advise the authorities if factual errors are introduced or other potential errant directions appear to be taken. Prepared by Dr. Lester Borodinsky, Keller and Heckman LLP, for the June 27-28, 2002 meeting of The Society of the Plastics Industry, Inc.'s (SPI) Food, Drug, and Cosmetic Packaging Materials Committee, Baltimore, Maryland, Baltimore Marriott Waterfront Hotel. 1 The guidance documents relating to FCNs, or to Food Additive Petitions (FAP), relate to the data needed to acquire clearances for components of food-contact articles that are not yet cleared. These guidelines are not relevant to determine compliance of food-contact materials that are already cleared for their intended uses. 2 These two draft documents were revisions of the initial draft documents issued by FDA in March, 1999. In addition, FDA issued "revision 1.1" to the September 1999 Chemistry Recommendations document in May 2000. 3 The final administrative guidance document is a revision of the most recent draft issued by FDA in July 2000. 4 Section 121.54 (recodified in 1977 as Section 171.1) was promulgated on March 28, 1959 in substantially the same form we see it today. 5 The first published migration testing guidelines were actually prepared by SPI in a bulletin entitled "Food Additives Amendment: Migration from Plastics Packaging," issued in September, 1959. FDA publicly praised SPI for the bulletin and undoubtedly included some of its concepts in the 1966 Guidelines. 6 The Guidelines for direct food additives remained unchanged until 1983, when the Agency issued "FDA Guidelines for Chemistry and Technological Data Requirements for Direct Food Additives and GRAS Food Ingredients." 7 FDA subsequently issued two editorial revisions to the 1988 "Recommendations" in July, 1990 (referred to as "Version 1.1") and in March, 1993 ("Version 1.2"). 8 FDA's Conditions of Use are set forth under Section 176.170(c), Table 2. 9 Before issuing the Redbook, toxicologists generally relied upon accepted practices for the day, such as those noted in "Experimental Methods in Determining Chronic Toxicity," Barnes, J., and Denz, F., Pharmacol. Rev., 1954, 6, 191-242, and "Measurement of Chronic Toxicity," Benitz, K.F., in: Methods in Toxicology, Paget, G.E., ed., F.A. Davis Company, Philadelphia, 82-131, 1970. 10 Unlike the FDA system, the EU migration testing Directive is applicable to both acquiring the data to establish the clearance for a new food-contact material as well as performing compliance tests on food-contact articles composed of materials that are already permitted. 11 A. Baner, J. Brandisch, R. Franz, and O.G. Piringer, "The Applications of a Predictive Migration Model for Evaluating the Compliance of Plastic Materials with European Food Regulations," Food Additives and Contaminants, 1996, 13(5), 587-601. Back to TopMore About SPI: Vision and Mission . Membership . Business Units . Regional Offices . News and Publications . Calendar of Events . Terms and Conditions of Use |
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