General Counsel's Report To The Society of The Plastics Industry, Inc.'s Food, Drug, and Comestics Packaging Materials Committee

June 8-9, 2000
Jerome H. Heckman
Ralph A. Simmons

INTRODUCTION

Ladies and Gentlemen:

We are pleased to present this report on the status of matters in which we have been involved or which we have monitored on behalf of The Society of the Plastics Industry, Inc.'s (SPI's) Food, Drug, and Cosmetic Packaging Materials Committee (FDCPMC) since the December 1, 1999 meeting of the Committee.

TABLE OF CONTENTS

FDA Implementation of the Food-Contact Notification Program

Developments in Establishing Interchangeability Protocols for Resins Used in Drug Packaging

FDA Makes Progress with Styrene Risk Assessment

Precautionary Principle Supported and Opposed at Recent Session of the Codex Committee on General Principles

Regulatory Bodies Around the World Consider the Regulation of Products Containing Genetically Modified Organisms

Expanding the Materials Approved for Use in Holding Food During Irradiation Continues to Be of Importance

As we have been reporting to you, FDA officially initiated its Food-Contact Notification (FCN) program on January 18, 2000. Although FDA had provided information on the chemistry, toxicology, and anticipated administrative procedures associated with the program before the scheduled starting date, final guidance and pertinent amendments to the regulations have yet to be issued. Consequently, the procedures and parameters of the system are beginning to take shape on a case-by-case basis. We had been working closely with Dr. Mitchell Cheeseman on the implementation of the program, and now we are continuing our work with Dr. Francis Lin, who has assumed responsibility for the program’s day-to-day operation while Dr. Cheeseman is on a temporary detail to FDA’s Legislative Affairs Office for the next several months. Several notifications already have become effective; mostly pending food additive petitions that FDA allowed to be converted to notifications. These effective notifications are listed on the Agency’s website at the following address: http://vm.cfsan.fda.gov/~dms/opa-fcn.html.

As notifications begin to become effective, FDA’s position is not yet clear on the issue of listing products by tradename only in letters and on the website list of effective notifications. The current website list does include one tradename, but it also is accompanied by a chemical description.

FDA has provided preliminary indications that notifications will be accepted for formulated products composed entirely of substances that are already cleared for the intended use and for recycling processes. The Agency has suggested, however, that it will not feel bound to observe the 120-day deadline in reviewing these filings, apparently because they are not legally required and are submitted only for enhanced customer assurance.

As mentioned above, we are still awaiting revised administrative guidance (updating the version released last March) and the completion of direct final rulemaking for the notification program’s implementing regulations, including amendment of the regulations on environmental assessments. We understand that these documents are in process, and we hope they will be issued reasonably soon. We also are awaiting finalization of the draft guidance documents "Preparation of Premarket Notifications for Food Contact Substances: Chemistry Recommendations" and "Preparation of Premarket Notifications for Food Contact Substances: Toxicology Recommendations." On February 9, 2000, we submitted comments on behalf of the Committee with respect to the revised versions of these documents that were released late last year. In those comments, we recommended streamlining the format and organization of the Toxicology Data Package and Comprehensive Toxicology Profile, and also commented on the need for flexibility in the toxicology data requirements as appropriate for particular food-contact substances. We also urged FDA to provide guidance on how the newly required genotoxicity data will be interpreted and used or to reconsider requiring this data.

With regard to environmental assessments (EA) for notifications, conversations with Dr. Buzz Hoffman, head of the Environmental Review Team, indicate that, until general guidance is

issued, the environmental impact data needed for notifications must be determined on a case-by-case basis. Since the regulations that set forth categorical exclusions from the need for an EA have not been amended to apply to notifications, an EA is currently required for every notification. The amount of information required depends on various factors; however the information needed for a notification that would qualify for a categorical exclusion if it were a petition is not very significant. FDA has indicated that the EA for this type of notification needs to include only a description of the substance and its intended use, and some information on the predicted annual market volume for the first year of production. For notifications that would not qualify for a categorical exclusion, the submission of a full EA is required.

In September 1998, the Drug Packaging Subcommittee of this Committee requested guidance from FDA on whether the Agency was amenable to interpreting the existing United States Pharmacopeia (USP) monograph on containers for ophthalmic drugs as a basis for demonstrating equivalency between like polymers supplied by different manufacturers. FDA was not wholly receptive to this idea, so, after several discussions with Agency personnel in the Office of Pharmaceutical Science in the Center for Drug Evaluation and Research (CDER), we submitted to FDA in June 1999 a proposed set of suitability and compatibility tests that could be conducted (in addition to the tests in the existing USP monograph for ophthalmic drug containers) preceding a change in the resin supplied for ophthalmic drug packaging. We proposed that performing these tests would render a change in resin suppliers "insignificant," only requiring notification to FDA in an Annual Report. We are currently waiting for FDA to complete its review of this proposed interchangeability protocol.

In the interim, however, FDA published in the Federal Register a proposed regulation to amend 21 C.F.R. § 314.70 ("Supplements and other changes to an approved application")(64 Fed. Reg. 34608 (June 28, 1999)), and made available a final guidance document entitled "Changes to an Approved NDA or ANDA." Both the proposed rule and guidance document include heightened reporting requirements applicable to changes within packaging materials for sterile liquid dosage forms (while, at the same time, further relaxing the rules on changes in packaging for solid oral dosage forms, as we reported in a letter to the Committee). More specifically, the proposed rule and guidance document alter the reporting category for changes within the container/closure system for sterile liquid drugs by requiring a drug manufacturer to file a Supplemental New Drug Application for any such change, even if the change is made based upon a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium. On September 14, 1999 and March 20, 2000, we submitted to the Agency, on behalf of the Committee, our comments on the proposed rule and guidance document, respectively. In those comments, we requested that FDA amend the language in the proposed rule and guidance document to continue allowing companies to make changes in packaging materials for all types of drugs, including sterile liquid drugs, based

on a showing of equivalency to the approved system under a protocol approved in the application or published in an official compendium.

More recently, we have submitted collaborative data to the United States Pharmacopeia on behalf of the Committee, which are intended to support proposals to amend the Polyethylene Containers monograph in the USP (<661>) to include liquid drugs, and to create a Polypropylene Containers monograph for solid and liquid drugs. Once established, compliance with these monographs could be a basis for demonstrating equivalency between like resins produced by different manufacturers.

As you know, in the Fall of 1998, FDA decided to suspend action on all food additive petitions involving styrene monomers and polymers, including petitions involving both butadiene and styrene. This suspension was triggered, in part, by an extensive FDA review of all of the available toxicology data on styrene and a follow-up draft memorandum recommending that FDA decide whether styrene is a carcinogen.

In response to the memorandum, FDA commissioned an outside contractor to review 20 selected epidemiology studies on styrene. The contractor’s work will be considered by FDA’s Cancer Assessment Committee (CAC) in determining if styrene should be deemed a carcinogen. If so, the Quantitative Risk Assessment Committee (QRAC) will develop a unit risk value for styrene, which, in turn, will provide the basis for determining a "virtually safe dose."

In an effort aimed at allowing action on pending petitions to resume, while the CAC deliberated, FDA embarked on development of a unit risk for styrene based on the "worst case" animal study results available, assuming that styrene is a carcinogen. This unit risk determination was facilitated by submission by this Committee’s Polystyrene Work Group of a toxicology study on styrene conducted for The Styrene Information and Research Center, Inc., (SIRC) in August 1998. This study showed carcinogenic effects in mice, which FDA used as the basis for a "worst case" unit risk. This unit risk value converts to an estimated VSD of 1.2 ppb in the diet.

On the basis of this interim estimated VSD, FDA has been able to act favorably on some pending petitions and notifications. As no decision is expected from the CAC in the immediate future, this worst case value for the time being will be the standard against which petitions and FCNs on products containing residual styrene will be evaluated.

On April 25, 2000, we accompanied SIRC representatives to a meeting with FDA so that SIRC could present additional data on styrene. SIRC presented a summary of studies on the mechanism by which styrene appeared to cause lung tumors in mice in the earlier study on styrene toxicity upon which FDA based its "worst case" risk assessment. The additional SIRC studies indicate that the effect does not involve genotoxicity. In addition, mice appear to metabolize styrene in a way that is significantly different from human metabolism. SIRC expects to have additional work on the metabolism issue completed by September 2000. FDA is very interested in the studies that have been completed and in the additional work that is underway. FDA indicated that the availability of additional information in September fits with the estimated timetable for FDA’s evaluation of styrene. The meeting was well attended by FDA personnel, including several toxicologists, pathologists, and consumer safety officers involved in the Agency’s evaluation of styrene.

Recently, the Precautionary Principle has taken center stage in European discussions on the promotion of food safety. This principle, championed by environmental and consumer groups, remains relatively undefined despite its endorsement in the European Union (EU). In essence, the principle stands for the proposition that it is better to require a full set of toxicology data and a complete assessment of all possible risks before allowing new technology or products on the market. This principle has effectively been used to argue against scientific advances because it favors potential risks (if for no other reason than our inability to know anything with absolute certainty) over quantifiable benefits. In a sense, the precautionary principle is already an integral part of some food safety decisions made in the United States. For example, the Food Quality Protection Action of 1996 establishes data requirements so rigorous for new pesticides that companies are having a difficult time justifying the development of new products. The precautionary principle also can be seen behind the so-called voluntary high-production volume (HPV) chemical testing program that has been developed by the U.S. Environmental Protection Agency (EPA), and is at least partially involved in the push behind the investigation into so-called "endocrine modulators."

On March 2, 2000, the European Commission (EC) issued a communication on the Precautionary Principle to further its discussions on the management of food safety. The communication is intended to explain how the EC intends to apply the principle and to establish guidelines for its application. According to the EC, the precautionary principle is part of a structured approach to the analysis of risk, as well as being relevant to risk management. It is intended to cover instances in which scientific evidence is insufficient, inconclusive, or uncertain and preliminary scientific evaluation indicates that there are reasonable grounds for concern for adverse affects to human health or the environment that are not consistent with the level of protection chosen by the EC. The Commission also suggests that, where the precautionary principle is put in action, measures should be proportionate to the chosen level of protection, nondiscriminatory in their application, and consistent with similar measures already taken. The principle, according to the Commission, also suggests the obligation to produce scientific evidence necessary for a comprehensive risk assessment. Supposedly, these guidelines guard against use of the precautionary principle as a form of protectionism.

Dr. Edward Groth with the Consumers Union has taken an active position supporting the use of the precautionary principle with respect to food safety laws. He suggests in his paper, "Science, Precaution and Food Safety: How Can We Do Better?," that precaution is not an alternative to science, but rather is an integral part of rigorous scientific analysis that takes into account what is known, and not known, about a particular substance or situation. Further, Groth advocates that a precautionary approach be applied consistently to all food safety situations, even in those instances where there is extensive scientific information.

At the April 10-14, 2000 session of the Codex Alimentarius Committee on General Principles held in Paris, France, the United States delegation took somewhat ambivalent positions, to the consternation of industry, but ended by expressing concerns over the EC communication, and the lack of definition ascribed to the Principle and its implementation. In particular, the U.S. Delegation addressed the concern that the precautionary principle, being ill-defined, could be used as a cover to make decisions that set up barriers to the import of U.S. goods and services. Industry groups strongly objected to formalizing the Principle, while other delegations supported its recognition. At the end of the session, the Committee agreed that a drafting group would continue to develop the proposal and further clarify how it would be applied in situations where scientific evidence is insufficient to fully assess risk. In addition, the risk assessment document will be re-circulated for comments, and workshops on the issue also will be held before the next Committee meeting.

Much publicity has be given lately to the controversy surrounding the regulation and labeling of foods derived from genetically modified (GM) organisms. As yet, the controversy has not spread in a significant way to food-contact materials that may contain genetically-modified components, although concerns about such products have recently come up before some official bodies in Europe. In addition, some products other than GM foods themselves, such as enzymes used as aids in food processing, are potentially the subject of recent regulatory initiatives; thus, there is an indication that the scope of materials that may be affected by the controversy is broadening. Even if these products are not banned, some companies are concerned that their customers may require them to maintain a cumbersome series of guarantees and certifications that their products do not contain any GM material. Keller and Heckman has been closely following this issue to ensure that the Committee is fully apprised of any developments in this area that may affect its members. The following is a brief summary of the current situation involving GM materials in general.

Currently in the United States, companies enter into a voluntary consultation process with FDA to present safety data to the Agency before marketing a new genetically-modified food. There are no labeling requirements. At the beginning of the year, FDA held a series of public meetings on foods derived from biotechnology. As a result of those meetings, FDA announced on May 3, 2000 that it intends to propose regulations that would require that developers of GM food submit a notification to FDA at least 120 days before marketing the product so that the Agency could review the safety of the substance. The Agency also announced that it intends to draft guidances for those manufacturers who wish to voluntarily label their products. In addition to FDA’s own proposal, several bills have been introduced in Congress that would require mandatory labeling and some state legislatures are considering labeling bills as well.

More opposition to GM foods exists in Europe than in the United States. The Commission of the European Union (EU) recently published two pieces of legislation regarding the labeling of GM ingredients, and is in the process of drafting new directives that would assess liability for deliberate releases of GM products into the environment. Because of the intense controversy over GM materials, approvals of new crops has ground to a halt and the EU continues to promote the precautionary principle (discussed earlier in this report) as the proper standard for conducting risk assessments of GM materials.

Other countries around the world also have begun to establish labeling and/or premarket review requirements for GM foods. Japan and Brazil have instituted an ambiguous regulatory framework that requires that GM products be tested for safety. Russia has passed a GM labeling bill that exempts most additives and preservatives, and the regulatory authorities in Australia, New Zealand, and Canada are developing labeling guidelines. Several committees of the Codex Alimentarius Commission as well as the United Nations Convention on Biological Diversity (UNCBD) are also debating the issue of how to deal with GM foods, including the proper methods to use in assessing the risk posed by these materials, the labeling that should be required if any, and traceability requirements.

At best, the picture surrounding the future of GM products is muddy. Much will depend on what happens at the upcoming meetings of the Codex and the UNCBD. What we can be sure of is that the decisions are likely to be more about politics than science, so we will continue to ensure the Committee is aware of any developments.

Because of the recent approval for the use of irradiation with red meat and because of the growing interest in using irradiation to control pathogens that cause food-borne illnesses, there continues to be interest in expanding the number of materials currently cleared for use in holding food during irradiation. The materials specifically approved by FDA for this application are listed in Section 179.45 of the food additive regulations.

In response to a request by USDA, FDA has temporarily expanded the existing clearances for materials that are permitted for holding meat and poultry during irradiation. The regulation currently limits many materials to use with gamma radiation which is seldom used to irradiate meat and poultry, but the provisional clearance now permits the use of these same materials with electron beam and x radiation. Under the terms of the temporary clearance, the materials must still meet all of the other requirements of the regulation, and this clearance will expire one year from its effective date, on February 22, 2001. The provisional clearance will permit packagers to use materials listed in Section 179.45 with electronic beam and x radiation while FDA considers a petition filed by the National Center for Food Safety and Technology (NCFST) earlier this year. The NCFST petition requests that FDA permanently clear the use of e-beam and x-ray radiation for materials which are already permitted for use with gamma radiation. The NCFST petition is supported by a white paper released by the Center that demonstrates the safety of these materials.

In addition to expanding the existing clearances for use with other sources of irradiation, the speed at which FDA’s can review new materials for in holding food during irradiation is greatly improved by the implementation FCN process. Now, with the full implementation of the program, FDA is accepting notifications for establishing a suitable FDA status for materials used in these applications, which means that with proper data a material can be marketed for these applications after 120 days from filing. It is important to note, however, that, in our view, packaging suppliers do not have to obtain a formal sanction for these products in every case. It is still possible for a manufacturer or supplier to determine on its own that their packaging material has a suitable FDA status if components do not migrate to food after irradiation or if the material is already cleared for use in contact with food and the irradiation of the material will not result in any additional migration or any migration of components that were not seen before irradiation.

More About SPI:   Vision and Mission . Membership . Business Units . Regional Offices . News and Publications . Calendar of Events . Terms and Conditions of Use