The American Industrial Hygiene Association Stewardship 2015 June 1, 2015

Transcription

1 The American Industrial Hygiene Association Stewardship 2015 June 1, 2015 Devon Wm. Hill Partner Keller and Heckman LLP 1001 G Street NW Suite 500 West Washington, DC hill@khlaw.com Washington, DC Brussels San Francisco Shanghai Holly H. Foley Scientist Keller and Heckman LLP 1001 G Street NW Suite 500 West Washington, DC foley@khlaw.com

2 Agenda Introduction to FDA packaging compliance requirements Case Studies Establishing the FDA status of packaging components Evaluating suitable purity 2 Copyright 2015

3 FDA Jurisdiction The Federal Food, Drug, and Cosmetic Act Food Drugs Devices Cosmetics 3 Copyright 2015

4 Center for Food Safety and Applied Nutrition CFSAN Regulates: Food (except meat and poultry) Food Additives Infant Formula Dietary Supplements Cosmetics Color Additives Three types of food additives: Direct: Food Ingredients Secondary direct: Added to food during processing but generally removed Indirect: Food packaging and other food contact materials 4 Copyright 2015

5 Office of Food Additive Safety Office of Food Additive Safety (OFAS) one of several offices within CFSAN Division of Food Contact Substance Notifications About 35 employees (Consumer Safety Officers, chemists, toxicologists) Receive over 100 FCNs a year 112 FCNs become effective in 2014, 83 in 2013 Other responsibilities include: pre-submission consultations (called PNCs), Threshold of Regulation submissions, food additive petitions, requests for information, publication of guidance documents 5 Copyright 2015

6 Key Point All food contact substances must be cleared or subject to an exemption from premarket review by FDA 6 Copyright 2015

7 Adulteration U.S. Food and Drug Administration (FDA) has authority to prevent adulteration of food Food packaging may adulterate food If it makes food unsafe; If it makes food unfit for consumption (for example, by imparting unacceptable taste or odor); or If packaging material qualifies as a food additive, but does not have premarket clearance by FDA 7 Copyright 2015

8 Regulation of Food Additives Food additives must have FDA pre-market clearance, since 1958 ( 409) YES Food Additive? NO Not all foodcontact materials are food additives and some food additives are exempt from premarket review Is an exemption applicable? No Must be precleared by FDA or automatically adulterated Yes No pre-clearance required No pre-clearance required 8 Copyright 2015

9 What is a Food Additive? Start with FDCA 201(s) any substance the intended use of which results, or may reasonably be expected to result in its becoming a component or otherwise affecting the characteristics of any food, unless... Specific exceptions from the food additive definition include substances that are Generally Recognized As Safe (GRAS) Prior sanctioned substances And several more that are not applicable 9 Copyright 2015

10 Evaluating FDA Status 1. Is the substance cleared already? - Food Additive Regulation - Threshold of Regulation - Food Contact Notification (FCN)? 2. Is an exemption available? 3. Is the substance suitably pure for the intended use? If it is not cleared and no exemptions apply, then a FCN (or possibly food additive petition (FAP)) must be filed. 10 Copyright 2015

11 Question 1: Is it cleared already? First look in FDA s food additive regulations for indirect additives (21 C.F.R. Parts ) Also check FDA s website for inventory of effective FCNs and TORs 11 Copyright 2015

12 Food Contact Notifications Replaces Food Additive Petition process (which led to listings in the CFR) Instead of 21 CFR listings, inventory of effective FCNs found at FDA s website FCNs are unique to the notifier only the notifier/manufacturer and its customers can rely on the FCN 12 Copyright 2015

13 Threshold of Regulation 1995 rule allows FDA to exempt a foodcontact material from regulation if: Either: Use results in dietary exposure of 0.5 ppb or less, or Cleared as direct food additive and exposure from food-contact use is less than 1% of Acceptable Daily Intake (ADI) And: Not a carcinogen and it does not have impurities that are potent carcinogens (TD50 < 6.25 mg/kg b.w./day) 21 C.F.R TOR listings are not proprietary A TOR exemption must be confirmed by FDA 13 Copyright 2015

14 Question 2: If no explicit clearance, is an exemption available? Certain exemptions from FDA pre-clearance authority stem from the food additive definition A substance which, when used as intended, is reasonably expected to become a component of food, except GRAS and prior sanctioned substances ( 201(s)) Exemptions: No Migration Prior Sanction GRAS 14 Copyright 2015

15 No Migration No migration exemption: A substance not reasonably expected to become a component of food is not a food additive Monsanto v. Kennedy, 613 F.2d 947 (D.C. Cir. 1979): FDA must find a substance migrates into food in more than insignificant amounts to consider it a food additive What does no mean? Depends on toxicity and potential exposure Default? 50 ppb (1969 Ramsey Proposal) Never formally adopted by FDA; concept used by industry to establish no-migration position 15 Copyright 2015

16 Functional Barrier When the foodcontact substance is separated by a barrier that separates the substance from the food Aluminum Cans Glass Substances behind a functional barrier are not food additives Judicially upheld in Natick Paperboard Corp. v. Weinberger, 525 F.2d 1103 (1st Cir. 1975) 16 Copyright 2015

17 Prior Sanction Letters issued by FDA or USDA prior to C.F.R. Part 181 A.J. Lehman s 1956 article Food Packaging Materials Private company letters Prior sanctions viewed narrowly limitations matter Apply to specific use of a substance delineating level(s), condition(s), and product(s) set forth by explicit pre-1958 FDA/USDA approval Caveat: New safety concerns may impact prior sanctions Narrowly interpreted 17 Copyright 2015

18 Generally Recognized as Safe (GRAS) Some GRAS listings included in FDA s regulations (21 C.F.R. Parts 182, 184, 186) Self-determination Based on low dietary exposure, determined by 100% migration calculations, migration testing, or other means Must consider cumulative exposure GRAS Notification Procedure 18 Copyright 2015

19 Housewares Exemption Housewares used as consumer articles or in commercial food-service establishments to prepare or serve food Examples: utensils, appliances, empty containers Pre-market clearance not necessary, but must be safe and companies should conduct a risk assessment 19 Copyright 2015

20 If No Existing Clearances or Exemptions Apply It will be necessary to file with FDA Likely an FCN will be needed, but possibly a TOR request or a Food Additive Petition (only in special cases) It also could be helpful to file an FCN for marketing reasons 20 Copyright 2015

21 Impurities in Otherwise Compliant Products 21 CFR 174.5: Good Manufacturing Practices requirements for food contact materials Suitable Purity FDA clearance, alone, not sufficient Article may not impart to food: byproducts or impurities that are injurious or deleterious to health Taste or odor so as to make food unfit for consumption Quantity of substance in application shall be no more than necessary to accomplish intended technical effect 21 Copyright 2015

22 Hot Topic: Growth of State Chemical Laws Increased number of states adopting laws affecting packaging and the trend is likely to continue upwards Focus on chemical specific bans and green chemistry laws (most, but not all, limited to children s products) Hazard rather than risk based Why? Increased concern over exposure to chemicals ( chemophobia ) Diminishing trust in governmental agencies and other authoritative bodies Perceived inaction by FDA and other agencies Tremendous burden for companies Difficult and expensive to monitor all different state laws Destroys the common market Drives retail and consumer de-selection 22 Copyright 2015

23 CASE STUDIES Establishing FDA Status and Evaluating Suitable Purity

24 Case Study No. 1 Scenario: Company wishes to produce a finished food-contact article, containing a base resin, a stabilizer, and two antioxidants. What is its status? Components: Chemical Name CASRN Use Level (%) Function Polypropylene (PP) Polymer Irganox * Antioxidant Tetradecanoic acid, lithium salt * Stabilizer Adjuvant X? 0.05* Antioxidant *Expressed by weight of finished polymer 24 Copyright 2015

25 Case Study No. 1: Polypropylene Base Polypropylene Resin: Complies with the compositional requirements of Section (a)(1)(i) Must also meet the specifications identified in Section (c), Item 1.1a Olefin polymers Density Melting Point or Softening point Maximum extractable fraction (% by wt of polymer) in N-hexane at specified temperatures Maximum soluble fraction (% by wt of polymer) in xylene at specified temperatures 1.1a Polypropylene described in paragraph (a)(1)(i) of this section MP: C 6.4% at reflux temperature 9.8% at 25 C 25 Copyright 2015

26 Compliance Testing Also called end-tests Differ from migration tests Based on gross extraction or solubility (e.g., total nonvolatile extractives) Used only for cleared substances to determine compliance with regulatory requirements Protocol described in regulations, e.g., 21 CFR Sensitivity often relatively crude (e.g., 50 ppm in food) 26 Copyright 2015

27 Case Study No. 1: Irganox 1076 Irganox 1076 (CASRN ) Cleared in Section as antioxidant in several polymer types Note: listing covers generic chemical name, not specific trade named substance; anyone can rely Permitted for use at levels not exceeding 0.25 wt% of olefin polymers complying with (c), item 1.1, 1.2, 1.3, 2.1, 2.2, 2.3, 3.1, 3.2, 3.3, or Here, PP resin complies with item 1.1 and antioxidant is used at 0.25% by weight. 27 Copyright 2015

28 Case Study No. 1: Tetradecanoic acid, lithium salt Tetradecanoic acid, Li salt (CASRN ) Listed in Section for use at levels not to exceed 0.15 wt% of PP and PP copolymers complying with (c), items 1.1a, 1.1b, 3.1a, 3.1b, 3.1c, 3.2a, and 3.2b. But, subject to food type and temperature restrictions Conditions of Use B-H for aqueous and acidic foods; C-G for fatty and alcoholic foods Note: these restrictions would apply to final food contact article 28 Copyright 2015

29 Case Study No. 1: Tetradecanoic acid, lithium salt If CFR clearance not sufficiently broad, check for alternate clearances (e.g., FCN) Cleared under FCN 474 as a stabilizer for PP polymers and copolymers complying with Section (c), items 1.1, 3.1, and 3.2 at levels not to exceed 0.1 wt%. The finished articles containing the stabilizer may contact any type of food under Conditions of Use A through H. Provided purchase stabilizer from notifier of FCN 474, ASAHI DENKA Co., Ltd., can rely on this FCN clearance. 29 Copyright 2015

30 Case Study No. 1: Adjuvant X No FDA clearance Perform migration calculations and/or studies Results will determine if no migration or GRAS position is possible, or if FCN is warranted Need to know application(s) of interest Appropriate limit of detection (LOD) 50 ppb for substances/uses with no special tox concerns 10 ppb or lower for high-consumption applications Substances with special toxicological concerns, such as carcinogenic constituents, must be considered case-bycase 30 Copyright 2015

31 Migration Calculation Example Assume: Film sealant layer 0.1 mil thick = inch 0.91 g/cm 3 density PP Layer contains 25% PP polymer PP contains 0.05% by weight of uncleared adjuvant Film contacts 10 g food/in 2 (standard assumption) 100% Migration calculation: in x 16.4 cm 3 /in 3 x 0.91 g film/cm 3 x 0.25 g PP/g film x g adjuvant/g PP 10 g food/in 2 = 1.9 x 10-8 g adjuvant/g food = 19 ppb adjuvant in food Conclusion: Adjuvant not a food additive, as not reasonably expected to migrate to food at a suitably low detection limit (here 50 ppb appropriate LOD); thus, premarket clearance not required 31 Copyright 2015

32 Migration Testing If calculated migration too high, consider migration testing simulating real use conditions Migration known to depend on time, temperature of extraction LOD depends on toxicity of potential migrant Results can be used for: No migration, no food additive analysis GRAS analysis FCN (or FAP) submissions 32 Copyright 2015

33 Migration Testing Follow FDA s Chemistry Recommendations Available on FDA s website Guidance for Industry: Preparation of Premarket Submissions for Food-Contact Substances: Chemistry Recommendations (April 2002; December 2007) Relevant parameters for study design: samples, food simulating solvents, volume-to-surface area ratio, time/temperature, analytical methodology, validation Use maximum level of uncleared substance and other reasonable worst-case parameters 33 Copyright 2015

34 Case Study No. 2 Impurities in Compliant Product: Toluene Issue: Solvent used with catalyst system for PP Company discovers 10 ppm residual toluene in resin Does this present a suitable purity/safety concern? Assumptions: 100% Migration to food of residual toluene 10 mil thick molded PP article PP polymer density of 0.91 g/cm 3 Ratio of food mass to surface area = 10 g/in 2 100% Migration Calculation: 0.01 in x 16.4 cm 3 /in 3 x 0.91 g/cm 3 x 10 ppm 10 g/in 2 = 0.15 ppm in contacted food 34 Copyright 2015

35 Case Study No. 2 Calculating Dietary Exposure Calculated migration = 0.15 ppm How much toluene in diet? Multiply migration by a consumption factor (CF) CF = fraction of daily diet contacted by a specific food contact material Default CFs provided in FDA Chemistry Recommendations Use FDA CF for PP of 0.04 Dietary exposure: 0.15 ppm x 0.04 CF = ppm (6 ppb) in diet 35 Copyright 2015

36 Case Study No. 2 Toxicology Considerations Consider available safety data NTP (1990) Toxicology and carcinogenesis studies of toluene (NTP TR 371): NOT a carcinogen Cal. Proposition 65 reproductive toxin Gestation studies (oral and inhalation) non-reversible adverse fetal effects Maximum Allowable Dose Level = 7000 µg/person/day EPA oral reference dose of 0.08 mg/kg bw/day, or 80 µg/kg bw/day 36 Copyright 2015

37 Case Study No. 2 Safety Assessment Assumptions: Average consumer eats 3 kg food/day Reference body weight = 60 kg Calculations: 6 ppb dietary intake x 3 kg food/p/d = 18 µg/p/d 18 µg/p/d 60 kg bw = 0.3 µg/kg bw/d Assessment: 18 µg/day < 7000 µg/day (Prop. 65 standard) 0.3 µg/kg bw/d < 80 µg/kg bw/d (EPA RfD oral) Conclusion: No health hazard Under GMP, should minimize toxic impurities to extent possible 37 Copyright 2015

38 Case Study No. 3 Impurities in Compliant Product: Benzene Issue: Catalyst system for PP results in benzene residue (1 ppm) Assumptions: 50% benzene is volatilized and 100% remaining residual benzene migrates to food 10 mil thick molded PP article PP polymer density of 0.91 g/cm 3 Ratio of food mass to surface area = 10 g/in 2 PP CF = Copyright 2015

39 Case Study No. 3 Carcinogenic Constituents FDA uses data from animal carcinogenicity studies + Quantitative Risk Assessment procedures Calculated upper-bound lifetime cancer risk must be < 1 in 1 million For benzene, FDA assessment points to virtually safe dose (VSD) of 0.5 ppb in diet 65 Fed. Reg (Jan. 21, 2000) We use target dietary concentration of 0.05 ppb (i.e., 1/10th of VSD) 39 Copyright 2015

40 Case Study No. 3 Impurities in Compliant Product: Benzene Benzene in food: 0.01 in x 16.4 cm 3 /in 3 x 0.91 g/cm 3 x 0.5 ppm 10 g/in 2 = ppm, or 7.5 ppb Benzene in diet: 7.5 ppb x 0.04 CF = 0.3 ppb in diet 0.3 ppb exceeds target of 0.05 ppb in diet TOO HIGH Migration studies simulating actual use conditions needed to assess true exposure in food/diet 40 Copyright 2015

41 Other Jurisdictions An overview of China, Japan, and Mercosur

42 Other Jurisdictions Globally, food packaging requirements continually evolving and can significantly differ from FDA framework China Food safety legislation being overhauled to better ensure safety Recently passed stringent food safety law; revising GB 9685 Standard for additives and many other Standards Premarket approval required for food contact substances Japan General safety standard + specific standards applicable to certain types of packaging materials Voluntary industry standards very important in practice Mercosur Member countries: Brazil, Argentina, Paraguay, Uruguay, Venezuela Positive List approach 42 Copyright 2015

43 Thank you Devon Wm. Hill Partner Keller and Heckman LLP 1001 G Street NW Suite 500 West Washington, DC hill@khlaw.com Washington, DC Brussels San Francisco Shanghai Holly H. Foley Scientist Keller and Heckman LLP 1001 G Street NW Suite 500 West Washington, DC foley@khlaw.com