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 December 28, 1999 (202) 434-4110 The Society of the Plastics Industry, Inc. Food, Drug, and Cosmetic Packaging Materials Committee Dear Ladies and Gentlemen: In this letter we provide a summary of additional information on the Food and Drug Administration's (FDA) plans for implementing the new Food Contact Notification program, as provided by Dr. Mitchell Cheeseman of FDA, who spoke at the Committee's semiannual meeting in Charleston on December 2nd. We also report on the U.S. Department of Agriculture's (USDA) approval of use of irradiation on red meat; FDA's issuance of a final guidance document on changes, including packaging changes, to approved new drugs; an FDA workshop on their Container Closure Systems guidance document; recent developments concerning phthalates; and other matters of interest to the Committee. Table of Contents
Dr. Mitchell Cheeseman, a Consumer Safety Officer (CSO) and Team Leader in FDA's Office of Premarket Approval (OPA) of the Center for Food Safety and Applied Nutrition (CFSAN), spoke at the semiannual meeting of the Food, Drug, and Cosmetic Packaging Materials Committee in Charleston on December 2, 1999, on FDA's plans for implementing the new Food Contact Notification (FCN) program. Dr. Cheeseman discussed FDA's guidance on the chemistry and toxicology requirements for notifications and the anticipated administrative procedures. You may recall from our previous letters that FDA issued three draft guidance documents in March, 1999, on chemistry, toxicology, and administrative aspects of the FCN system. These documents were the subject of a public meeting convened by FDA, and we filed comments concerning the guidance on behalf of this Committee. FDA issued revised chemistry and toxicology guidance documents in November, and expects early in 2000 to publish a revised draft administrative guidance and amendments to the Agency's regulations as needed to implement the FCN system. The current versions of all three guidance documents are available on our internet site, www.khlaw.com, and as well as on FDA's internet site at http://vm.cfsan.fda.gov/~dms/opa-pmnc.html (chemistry), http://vm.cfsan.fda.gov/dms/opa-pmnt.html (toxicology), and http://vm.cfsan.fda.gov/dms/opa-pmna.html (administrative). The November revisions of the chemistry and toxicology guidances are open for public comment until February 14, 2000. In his presentation to the Committee, Dr. Cheeseman explained that the standard for FDA's safety determination will be the same for food-contact notifications as for food additive petitions, (i.e., reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use, see 21 C.F.R. § 170.3(i)). Furthermore, Dr. Cheeseman indicated that the data required to support a notification will be very similar to the data needed for a petition, although not identical in all respects. It is probable, although not yet decided finally by FDA, that notifications will require environmental assessments unless eligible for one of the current categorical exclusions (such as substances present at 5% or less of food-contact articles and remaining with the articles through use by consumers or substances for repeated-use articles). Some notable differences in the data requirements for notifications and petitions are in the toxicology studies needed for exposures between 0.5 parts per billion (ppb) and 50 ppb in the diet and in the new burden on submitters to calculate the cumulative estimated dietary intake (CEDI) to potential migrants. Under the notification system, two genotoxicity studies (of the types specified in the guidance document) will replace the former requirement of an acute toxicity (LD50) for exposures between 0.5 ppb and 50 ppb. Submitters of notifications also will need to estimate the CEDI from all sources of exposure, rather than just the EDI from the use that is the subject of the notification. Dr. Cheeseman indicated that FDA already is compiling its own estimates of CEDI's, beginning with the most widely used substances, and intends to make this information publicly available, probably through the FDA website. In the absence of an estimate by FDA for a particular substance, however, providing this information may be a difficult task for submitters. With respect to other differences between the petition and notification processes, Dr. Cheeseman noted that the most important difference is that a food-contact substance (FCS) which is the subject of a petition cannot be marketed until a regulation is published, whereas under the notification system, an FCS may be marketed legally 120 days after FDA receives the notification, provided the Agency does not object within that time frame. Further, the petition process requires an affirmative action on the part of the Agency before the substance may be marketed legally; however, the FCN process requires no action by FDA for a notification to become effective. Additionally, a regulation promulgated in response to a FAP may be relied upon by anyone, whereas a notification is proprietary to the manufacturer identified in the notification. Finally, data and information submitted with a FAP, other than trade secret or confidential commercial information, are available for public disclosure after the petition is filed. Under the notification process, however, FDA is prohibited by statute from disclosing any information until after the 120 day period. After 120 days, information related to a notification will be subject to public disclosure if it is not subject to the exemption for trade secret or other confidential commercial information (but it is not yet clear how FDA will define the parameters of this exemption under the notification system). In addressing the scope of substances eligible for notification, Dr. Cheeseman explained that Section 409(h)(6) of the Federal Food, Drug, and Cosmetic Act defines a food-contact substance as "any substance intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if such use is not intended to have a technical effect in food." Thus, the definition includes, in addition to indirect food additives, secondary direct food additives that do not have a technical effect in the finished food. Therefore, some secondary directs (Dr. Cheeseman cited as examples boiler water additives and ion exchange resins) will be eligible for the notification process. There are several situations where FDA believes a particular use should not be notified, at least not without consulting the Agency in advance. These include uses already permitted by regulation, even where the notification is seeking clarification; uses already exempted under the TOR process; and uses that FDA determines should be reviewed under the FAP process. In this last regard, there are two categories that FDA expects to be "presumptive petitions." First, since FDA has historically recommended the development of significant toxicity data to support the safe use of a substance at dietary concentrations greater than 3 mg/person/day, or, in the case of biocides, 0.6 mg/person/day, uses that increase the cumulative dietary concentration above these levels in most cases will require the filing of a food additive petition. Second, since the Delaney Clause1 is applicable to food-contact substances, FDA takes the position that it must have sufficient time to review any data that may relate to a determination under this proviso. Therefore, a petition will be required for those substances where a bioassay exists on the food-contact substance that is not clearly negative for carcinogenicity. Note that here we are discussing the possible carcinogenicity of the food-contact substance itself; potential carcinogenicity of constituents will continue to be addressed under the Constituents Policy and will not automatically create a presumptive need for a petition. Dr. Cheeseman spent considerable time discussing how the FCN program is expected to operate. Five copies of each notification should be submitted directly to the Notification Control Assistant (NCA), a recently created position at FDA. Following submission, a CSO will be assigned as the submitter's point of contact (as currently occurs with petitions). During the first 30 days following the submission, FDA will review the notification to determine if any major deficiencies exist. If none is found, FDA will issue a letter acknowledging the notification. The acknowledgment letter will state the date of receipt of the notification, the date that the notification may become effective, identify the food-contact substance and use, and identify the manufacturer for which the notification will become effective. If any deficiencies are found within the first thirty days, the Agency will contact the notifier, describe the deficiency and how it should be corrected, give the notifier a limited amount of time to correct the deficiency or withdraw the notification, and issue a letter declining to accept the notification if deficiencies are not corrected. If deficiencies are found in the last 90 days, FDA will follow a similar process in that it will issue a letter describing the deficiency and provide the notifier with a limited amount of time to correct the deficiency or withdraw the notification. However, if the deficiencies are not corrected or the notification is not withdrawn, the Agency will issue a letter objecting to the notification. Given the expected procedure by which FDA intends to handle notifications and any deficiencies in order to meet the 120-day review deadline, it will be critical that notifications be drafted in a careful manner. Thus, the guidance documents issued by FDA should be consulted and followed in the preparation of a notification, including use of the forms provided with the guidance documents. The submission form (Form 3480) has not been approved yet by the Office of Management and the Budget (OMB), and, therefore, cannot be required by FDA. It is a good guide, however, to organizing information for submission to FDA. Form 3480 is available on FDA's internet site at http://vm.cfsan.fda.gov/~acrobat/frm3480.pdf. With regard to objections, FDA expects to object only in circumstances where the use has not been shown to be safe or where any part of the 120 day review period of a notification falls within a fiscal year for which the program is not funded. Further, although absence of or deficiencies in the environmental information may be grounds for FDA declining to accept a notification, the Agency does not expect to object formally to a notification on this basis. If FDA objects to a notification, a letter will be issued to the submitter. Objection by the Agency is subject to immediate judicial review. Once a notification becomes effective, the Agency plans to issue a letter to the notifier, as long as issuing such letters does not present too great a burden on FDA's resources. Currently, FDA plans for the letters to contain language along the lines of the following: "Re: Food Contact Substance Notification PMN 0000. This is to inform you that as of [insert date 120 days after receipt of notification] your PMN became effective. It has been added to the list of effective notifications for food-contact substances which is also available on the Agency's internet site at http://www.fda.gov." We have suggested to FDA that it would be helpful to change the PMN terminology to an alternative, such as FCN, to avoid confusion that we already have experienced with premanufacturing notifications (PMNs) under the Environmental Protection Agency's (EPA) administration of the Toxic Substances Control Act (TSCA) program. It is not yet clear, however, whether FDA will be open to this change. Dr. Cheeseman stressed that the notification should include proposed language describing the substance and its intended use to help guide FDA in the descriptions made available to the public on its website. The language should be drafted carefully to ensure that it will be effective for the product manufactured by the submitter and use of the product by the submitter's customers. FDA's initial acknowledgment letter will provide the Agency's intended description of the food-contact substance and its uses, and should be reviewed carefully by the submitter. It is unclear at this point whether a company can have just a tradename listed. FDA will be publishing regulations to establish a procedure for revoking effective notifications. Currently, the Agency expects to inform a notifier once a tentative determination is made that the notification should be revoked, and provide a limited time frame for the notifier to respond to the Agency's concerns. If FDA determines that the use of the substance is not safe, a notice will be published in the Federal Register stating that the notification has been revoked. Finally, Dr. Cheeseman discussed the current state of affairs with respect to converting petitions or Threshold of Regulation requests to notifications. The petitioner should contact the CSO to determine whether the petition is eligible for conversion. FDA has reviewed most, if not all, pending filings, and has determined whether or not they may be converted. The CSO also should be able and willing to advise the petitioner on the approximate timing of FDA action on a petition or Threshold request. In our experience, the CSOs have been well-prepared and helpful, although the decision on whether to convert is up to the petitioner. We believe conversion is advantageous in most cases because the notification does not require FDA to draft and publish a regulation, a part of the current process that easily can take four months or more by itself.
The Food Safety and Inspection Service (FSIS) of the USDA published in the December 23rd Federal Register the final rule permitting the use of ionizing radiation for treating refrigerated or frozen uncooked meat, meat by-products, and certain other meat food products. See 64 Fed. Reg. 72150 (Dec. 23, 1999). Previously, irradiation has been allowed for poultry, but not for red meat. The regulation follows a proposed rule that was published February 24th. FSIS will require that labeling for packaged meat products irradiated in their entirety must bear the radura symbol, along with a statement such as "treated with radiation" or "treated by irradiation." Ingredient statements on finished food products containing irradiated meat also must reflect that irradiated meat is included in the product. USDA also announced on December 14th its intention to stop requiring separate USDA approval of additives, including irradiation, for meat and poultry products. FDA clearance of additives will automatically confer a suitable USDA status as well. In a related matter, during a recent U.S. Chamber of Commerce conference, "The Future of Food," industry members expressed concern over the slow governmental approval process for irradiated foods. These comments followed the letters to USDA Secretary Dan Glickman and HHS Secretary Donna Shalala sent by Senators Lugar and Harkin regarding expediting approval of irradiation for ready-to-eat food, on which we reported to you previously. The effect of these complaints on the approval process may likely be seen with respect to two petitions on food irradiation which are expected to be submitted to FDA in January by the National Center for Food Safety and Technology. The first petition will request that FDA establish the equivalence of X-ray, gamma, and electronic irradiation for use in processing foods. The second petition will ask FDA to approve six polymers (two types of ionomers, anhydridegrafted polyethylene, nylon 6,6, nylon 6,66, nylon 6I,6T, and EDOH) to be used in packaging for food that would be subjected to irradiation.
FDA has now published in final form its guidance document on changes, including packaging changes, to an approved New Drug Application (NDA) or Abbreviated New Drug Application (ANDA). The final guidance, dated November, 1999, follows a draft version, which was made available June, 1999. The draft guidance was released concurrently with a proposed rule to amend Section 314.70 of FDA's new drug regulations (21 C.F.R. § 314.70 "Supplements and other changes to an approved application") to implement provisions of the Food and Drug Administration Modernization Act of 1997 (FDAMA) with respect to manufacturing changes to approved new drugs. (See 64 Fed. Reg. 34608 (June 28, 1999). Section 314.70 sets forth the criteria for determining when a change, including a packaging change, to an approved new drug requires the filing of a supplemental new drug application (SNDA), when FDA prior approval is needed, and when notice in an annual report is sufficient. In September, 1999, we submitted comments on the draft guidance document on behalf of the Committee, focusing on the heightened reporting requirements applicable to changes within packaging materials for sterile liquid dosage forms. Specifically, we asserted that FDA did not provide any justification for requiring an SNDA to be filed for any change within the container/closure for a sterile liquid dosage form, 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 (for example, the United States Pharmacopeia (USP)). Unfortunately, the final guidance document continues to recommend the filing of a supplement for any change within a container and closure system for sterile liquid drugs. Since guidance documents such as this one are open to public comment and amendment by FDA at any time, the Committee could submit additional comments requesting FDA to reconsider this aspect of the guidance. Although FDA typically does not make changes in the absence of clear error (which we have not detected), as opposed to a matter of policy or interpretation, FDA has indicated that it may reissue the final guidance when the final rule to Section 314.70 is published. Further, as some you have expressed an interest in resubmitting comments, we plan to file additional comments on behalf of the Committee stating our objection to such an unduly burdensome requirement for changes to sterile liquid drugs. The final guidance is available on FDA's website at http://www.fda.gov/cder/guidance/2766fnl.htm.
On October 26, 1999, FDA and members of the pharmaceutical industry held a workshop to discuss the contents of FDA's guidance for industry entitled "Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation." This document provides recommendations for submitting information to FDA on materials used in packaging for drug and biologics. During the session, FDA provided a general summary of the recommendations found in the guideline, and further noted that an alternative approach to that described in the document may be used, provided that such approach satisfies the requirements of the applicable statute and/or regulations. FDA specifically discussed what information it recommends including in Type III Drug Master Files (DMFs). The Agency noted that some negative issues it frequently encounters with DMFs are a lack of updated information, lack of information on when the information within was submitted, and a lack of technical data. FDA further stated that it is often difficult for the Agency to locate specific information in the file and stressed the importance of a detailed table of contents. In this regard, it has always been our recommendation that a revised table of contents be submitted with every amendment. FDA also stressed the importance of annual updates, which should include all amendments submitted since the last update, as well as a complete list of companies/persons authorized to reference the DMF. FDA explained that it does not review DMFs until they are reviewed in conjunction with a specific drug application. Therefore, if there are any deficiencies in the file, the Agency will not be aware of them nor notify the holder until this time. It is important to note that all the information FDA needs to evaluate of the use of the packaging with a particular drug does not need to be contained in the DMF. Indeed, only the drug applicant would be in possession of certain types of information, such as stability data; this information should be included in the NDA or ANDA, not the DMF. Finally, FDA provided some discussion on post-approval changes, the proposed change to Section 314.70 and the guidance document on changes to an approved NDA or ANDA. FDA indicated that the final rule for Section 314.70 will be published early in 2000 and, as discussed above, further indicated that the Agency will concurrently release another version of the final guidance document. As we have reported in previous letters, FDA also is developing a guidance document focusing solely on post-approval changes to packaging materials, which is being referred to by FDA as the "PAC PAC" document. Although the "PAC PAC" guidance is not expected to be completed for quite some time, the Agency will hold a workshop on post-approval changes to packaging materials in Crystal City, Virginia, next Spring (late May/early June). We will provide the Committee with more detailed information on this workshop as it becomes available.
On October 18th, FDA held a workshop entitled "Plasticizers: Scientific Issues in Blood Collection, Storage, and Transfusion." The stated objective of the workshop was to provide an open forum for the discussion of scientific data pertaining to benefits and risks associated with the use of plasticizers in blood collection and storage bags and to examine the differences between the plasticizers in use as well as other available plasticizers and plastic formulations. The goals of the workshop were to: (1) review the effects of leachable plasticizers in the storage containers of cellular and acellular blood products; (2) review the toxicity of phthalate plasticizers; (3) discuss the availability of alternative plasticizers, as well as their toxicity and efficacy in stored blood products; (4) discuss the risk assessment process used in recent evaluations of the toxicity of phthalate plasticizers by blue ribbon panels; and (5) convene a panel to discuss new clinical issues in the use of plasticizers in blood product storage containers. These goals proved to be far too ambitious and only very basic information could be delivered in the 20 minutes allotted to each speaker. Of particular note was the report of a study by Dr. Virginia Karle, the Medical Director of the Neonatal Intensive Care Unit, Medical Center East, Birmingham, Alabama. In this study, which was performed at the Children's National Medical Center in Washington, D.C. and the Johns Hopkins School of Hygiene in Baltimore, Maryland, the level of exposure to plasticizers in critically ill infants was found to be 2 mg/kg rather than the 4.7-34.9 mg/kg postulated by various scientists. Dr. Karle stated that she observed no effects that could have been attributed to the plasticizers. Also of note was the report that a company marketing a substitute material containing no phthalate plasticizers dropped the product after very poor sales performance. The reason for the product failure was deemed to be high cost and lack of positive proof that the phthalate plasticizers represented a hazard. A second firm commented that it had developed a fluorocarbon polymer that was suitable, but that it was unable to sell any of the product because it was about three times as expensive as the phthalate-plasticized PVC materials. As in earlier plasticizer meetings, the industry scientists and the "consumer advocates" reviewed the same data and came to diametrically opposed interpretations. The industry representatives found that the data supported the continued safe use of plasticized PVC materials, while the "consumer advocates" found that the data indicated numerous toxic manifestations. FDA personnel stated that they would essentially remain in favor of the existing materials until such time as substitutes were proven to be equal or better. In the final analysis, there was no clear-cut resolution of any of the agenda items.
A recent ruling by California's Supreme Court has stymied industry's hopes for citing a pivotal lower court's decision which could have encouraged settlements in Proposition 65 cases. In American International Industries v. Superior Court, a class action suit was brought against manufacturers of hair coloring products for failing to place a warning on the labels that the products contain lead acetate, a substance listed as a potential toxin under Prop. 65. The appellate court held that the plaintiff's claims under Prop. 65 were barred because a final judgment on the merits had already been made in a previous case brought against the same company. This ruling was significant because it would have prevented a company from being sued repeatedly under Prop. 65 for the same cause of action. However, California's Supreme Court held that the appellate court's opinion should not be published in the Official Appellate Reports, thereby preventing the pivotal case from becoming legal precedent to parties other than those specifically involved in the case. The lower court also had ruled that the Federal Food, Drug, and Cosmetic Act (FFDCA) barred plaintiff's claims under two state law causes of action: violation of the Consumers Legal Remedies Act and fraud by concealment. Industry was particularly hopeful that this language could be cited as legal precedent since it would strengthen the argument that federal laws should preempt state laws on products covered under the FFDCA.
In a related matter, consumer groups are lobbying against the National Uniformity for Food Act, S. 1155, which, as we have reported in previous letters, would restrict states from imposing labeling laws that are more stringent than federal requirements, thereby preempting state laws such as Prop. 65 in some respects. The groups argue that the state food safety and labeling laws fill gaps in FDA regulations, and such preemption would endanger public health. Preemption of state laws, they argue, is appropriate only where federal law provides more protection than the state law. Industry groups counter that the bill is merely attempting to standardize legislation and that state legislation will remain effective where there is no federal regulation on the issue. The bill also provides for a mechanism by which states could petition for exemption in those cases where the exemption would serve to protect an important public interest that is otherwise unprotected in the absence of the exemption, would not cause a food to be in violation of federal law, and would not unduly burden interstate commerce.
A group of restauranteurs is suing the National Toxicology Program (NTP) and Department of Health and Human Services (HHS) for an injunction to prevent dioxin from being listed as a known human carcinogen in NTP's Ninth Report on carcinogens, which is due to be published soon. The previous listing classified dioxin as a suspected carcinogen. At issue is the criteria NTP used to support the reclassification. Specifically, the restauranteurs claim that NTP's reliance on toxicological and mechanistic data is in violation of NTP's 1995-96 revision of criteria. Rather, the group alleges, NTP's criteria mandate that only human epidemiological studies may be used to determine whether a substance is a known carcinogen. HHS, however, defends the use of toxicological and mechanistic data, claiming that the plaintiffs' interpretation of NTP criteria is incorrect. HHS further asserts that the explanatory paragraph of the 1996 revised criteria explicitly permits consideration of mechanistic data with respect to the "known" category, and, further, that a scientific conclusion regarding carcinogenicity in humans may be based on all relevant information. Meanwhile, representatives from various industry groups criticized the Report during a public meeting held last October. Specifically referencing the dioxin reclassification, a representative from the American Forest and Paper Association cited NTP's lack of reliance on human epidemiological studies in making the decision. NTP was further criticized for releasing background documents so late in the process that there is no time for modifications based on public comment. Public interest advocates, as well as NTP representatives, however, defended the current criteria used by NTP, and expressed their concern that formal responses to industry comments would unreasonably delay the process.
From time to time, we report on trends we observe with regard to regulatory enforcement actions. In this case, recent agreements between California regulators and four companies highlight the fact that visible companies are often those marked for regulatory attention. In an unprecedented action, the California Integrated Waste Management Board has targeted individual companies that are not in compliance with the state's Rigid Plastic Packaging Container Law. This action is based on state law which authorizes the Board to seek the compliance of individual manufactures if the overall plastic recycling rate dips below 25 percent. The Board reached agreements with 3M Co., Penzoil-Quaker State Co., Dietzgen Co., and Toro Co. concerning recycled-content packaging, exempting them from penalties in return for promises of compliance for next year. * * * As always, if you have any comments or if we can provide further information on any of the issues discussed above, please do not hesitate to contact me, Jerry Heckman or Deborah Ziffer. Cordially yours, Ralph A. Simmons 1 Under Section 409(c)(3)(A) of the Act, no food additive may be considered safe by FDA if the additive is found to "induce cancer when ingested by man or animal, or if it is found, after tests which are appropriate for the evaluation of safety of [the additive] to induce cancer in man or animal." Back to Top More 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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 © Copyright 2005 The Society of the Plastics Industry.
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