미국 건강기능식품 원료 및 성분과 건강기능식품의 제조 , 포장 , 보관에 대한 우수제조기준 - ‘03.3.13 Proposed Rule( 입안예고 ) 중심 -

1. Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Ingredients and Dietary supplement 미국 건강기능식품 원료 및 성분과 건강기능식품의 제조, 포장, 보관에 대한 우수제조기준 - ‘03.3.13 Proposed Rule(입안예고) 중심 - 밝혀두기 : 이 자료는 미국 FDA의 http://www.cfsan.fda.gov/~dms/dscgmps3.html를 바탕으로 작성된 내용임.

2. 규제대상 • Everyone making dietary supplements 1,566 Total Companies 1,228 Manufacturers 110 Ingredient Suppliers 110 Repackers/Relabelers 110 Holders 94 Others -FDA estimates

3. 비용 According to FDA: Industry Compliance Cost $86 million Very Small $38,000/firm Small $61,000/firm Large $47,000/firm GMP기준을 준수하고자 하는 경우 산업체가 부담하여야 하는 비용

4. 어떤 점이 필요해서 • Protect consumers from adulterated product • Protect consumers from products that do not contain what is claimed on the label • Provide consistent industry-wide requirements • Ensure quality of product 소비자 보호, 품질향상, 안전성 확보 - adulterated food (부정불량식품) - misbranded food (허위,과대표시)

5. 왜 필요한가 ? • Congress saw need by authorizing • Food, Drug, and Cosmetic Act gives authority to FDA for cGMPs • Industry and consumers support cGMPs • Product recalls and independent lab testing demonstrate need for cGMPs 미 국회, 미FDA, 생산자, 소비자 모두가 GMP 규정을 원하고 있음.

6. Why cGMPs? Product recalls and independent laboratory testing demonstrate need for CGMPs: • Poor sanitation--bacterial contamination • Ingredient misidentification • Super-potent--selenium • Sub-potent--folic acid • Contaminated with prescription drugs 회수품, 연구기관의 평가에서 나타난 사항 - 미생물 오염 (청소 및 소독 등 위생문제) - 오인, 혼동에 의한 배합실수 - 표시된 것 보다 낮거나 높은 역가 - 처방의약품의 오염

7. 소비자도 필요하다고 생각 ! • Consumers want assurance of product quality • 1999 consumer survey showed that 37% thought supplements are adequately tested for safety, purity, and consistency of dosage before marketed1 • 1999 consumer survey showed that 60% said there is not as much regulation as is needed to make sure supplements are pure and dosages are consistent1 • 2000 consumer survey showed that 77% of 50+ year olds said the federal governmentshould review safety data and approve a product before it is sold2 • 1999 consumer survey showed that 34% were very confident that the vitamin/mineral and 32% were confident that the herbal product label is accurate3 1NPR/Kaiser Family Foundation, 1999 2AARP, 2000 3Prevention Magazine, 1999

8. FDA와 산업체도 인정 • FDA believes market pressure alone does not prevent adulteration and misbranding • FDA also believes self-regulation does not sufficiently set industry-wide minimum requirements • Industry wants GMP “seal of approval” 미FDA와 산업체의 견해차 - 정부 : 관리 - 산업체 : 지정, 인정

9. 시장상황에 대한 산업체의 생각 • Industry challenges • eroding strength of consumer confidence in dietary supplement products • safety concerns about some products • quality issues about some products • inaccurate and/or unsubstantiated label claims 미 FDA는 산업체가 이대로 가게 되면 미국 Dietary supplement에 소비자 신뢰를 실추시키고 안전성 및 품질, 정보표시 등에 문제가 제기되어 어려움을 겪게 될 것이라고 생각

10. 관련 법규 Some of the sections cited include: • Sec. 402(g) • gives authority for CGMP’s • states may not impose (testing) standard if no current and generally available methodology • Sec. 402 • describes circumstances when product would be adulterated • Sec. 403 • describes when a product would be misbranded • gives authority for label nutrition information • gives authority for identification of dietary ingredient and source (if botanical) GMP 규정에 따르지 않으면 부정불량식품으로 취급

11. 입안시 고려한 사항 Considerations and Process: • How products are manufactured (e.g. tablets, capsules, powders, liquids) • Unique properties of dietary ingredients and dietary supplements (e.g. vitamins, minerals, botanicals) • Desire for clear, enforceable regulation • Considered the estimated costs and benefits 미규정을 준비하면서 고려한 사항 - 어떤 제품을 제조하는지 - 제품의 특징인 - 명확하고 단속가능한 규정 - 규제평가(비용-편익분석)

12. 입안하기까지 경과 Considerations and Process: • White House Commission on Dietary Supplement Labels 1997 Report supported CGMP’s and CGMP recordkeeping • Food Advisory Committee Working Group-1998-1999 • Dietary Supplement manufacturers visited by FDA supported CGMP’s • 8 sites visited in 1999 • Small business meetings supported CGMP’s but expressed concern about costs • 3 meetings held in 1999 대통령위원회, FDA 자문회의 등 자문회의 업체 방문(소기업 포함)

13. 다른 GMP 규정들에 대한 고려 Considerations and Process: • Analyzed other CGMP’s for common principles and requirements. Other CGMP’s included: • FDA CGMP’s, for example, • Food CGMP’s--Food (Part 110), Low Acid Canned Food, Juice, Fish & Fishery Products, Infant Formula (proposed) • Drug and Device for CGMP principles • Industry CGMP’s • ANPRM industry outline, USP, NNFA 기존규정 및 협회등에 자율실시 내용 검토

14. Formula (Recipe) Flexible Testing Components Warehouse Bulk Production Packaging Shipping Mixer/ Blender Count Fill Container Label Segregate Materials Tableting Capsuling Consumer Complaints 입안예고(안) 마련시 고려한 제조공정 개념도 Records

15. Part 111- Current Good Manufacturing Practice in manufacturing, packaging, or holding dietary ingredients and dietary supplements Subpart A - General Provisions Subpart B - Personnel Subpart C - Physical Plant Subpart D - Equipment and Utensils Subpart E - Production and Process Controls Subpart F - Holding and Distributing Subpart G - Consumer Complaints Subpart H - Records and record keeping 8개의 하위규정을 두고 있음.

16. Subpart A-General Provisions • 111.1 Who is subject to these regulations? • 111.2 What are these regulations intended to accomplish ? • 111.3 What definitions apply to this part ? • 111.5 Do other statutory provisions and regulations apply ? • 116. Exclusions 일반규정을 두고 있음. 종래와 달리 질의 응답형으로 규정을 정리함.

17. General Provisions • CGMP would apply to domestic firms • CGMP would apply to foreign firms that want to export dietary ingredients or dietary supplements into the U.S. • Must comply with other applicable regulations (e.g., Fish/Fishery Products HACCP if dietary ingredient is a fish oil) 미국내 회사 및 미국에 수출하는 국외회사도 대상 다른 규정도 준수하여야 함.

18. General Provisions • CGMP would apply to activities associated with • manufacturing • packaging • holding • Distributing • Manufacturer would need to comply with requirements applicable to operations performed • contractor would need to comply with applicable requirements and • contracting firm responsible for contractor’s performance

19. Subpart B-Personnel • 111.10 What microbial contamination and hygiene requirements apply ? • 111.12 What personnel qualification requirements apply ? • 111.13 What supervisor requirements apply ?

20. Proposed Requirement Highlights • Personnel • qualified employees • employees must have training and experience to perform assigned duties • disease control, and hygienic practices • assign qualified supervisors to oversee implementation of cGMP’s

21. Subpart C-Physical Plant • 111.15 What sanitation requirements apply to your physical plant ? • 111.20 What design and construction requirements apply to your physical plant? 규정은 what to do를 정하고 How to do는 업체가 자율적으로 하도록 하고 있어 미국에서도 이점에 대하여 매우 어려워하는 부분임

22. Proposed Requirement Highlights • Physical plant internal environment • design and construction • ceilings, floors, and walls that are easily cleaned and maintained • separate areas or systems for specific operations to avoid mix-ups • screening to keep out pests • maintenance and sanitation • water meets EPA drinking water requirements • plumbing, bathroom, lighting, ventilation, trash requirements to prevent contamination

23. Subpart D-Equipment and Utensils • 111.25 What requirements apply to the equipment and utensils you use ? • 111.30 What requirements apply to automatic, mechanical, or electronic equipment?

24. Proposed Requirement Highlights • Equipment and utensils • design or select equipment that will meet pre-established specifications • maintain, clean, and sanitize • calibrate, inspect, or check to ensure proper performance • ensure that equipment functions as intended

25. Subpart E-Production and Process Controls • 111.35 What production and process controls must you use? • 111.37 What requirements apply to quality control ? • 111.40 What requirements apply to components, dietary ingredients, dietary supplements, packaging, and labels you receive ?

26. 111.45 What requirements apply to establishing a master manufacturing record ? • 111.50 What requirement apply to establishing a batch production record ? • 111.60 What requirements apply to laboratory operations ? • 111.65 What requirements apply to manufacturing operations ? • 111.74 What requirements apply to rejected components, dietary ingredients, dietary supplements,packaging, and labels ?

27. Proposed Requirement Highlights • Production and process controls • quality control unit • master manufacturing and batch production records • specifications for incoming, in-process, and final product and • testing final product or incoming and in-process materials

28. Proposed Requirement Highlights • Consumer product quality complaints related to cGMPs • product quality complaint examples include super-potent, sub-potent, wrong ingredient, contaminant (e.g., bacteria, pesticide, toxin, glass, lead, drug) • review product quality complaints • investigate product quality complaint when possible relationship between consumption and an adverse event • keep consumer product quality complaints related to CGMP’s • Consumer complaint NOT related to CGMP is related to safety of a particular dietary ingredient independent of whether the product is produced under cGMP’s

29. Production and Process Controls • System of production and process controls • Quality control unit • Manufacturing operations • Holding and distributing • Recordkeeping

30. Production and Process Controls • System of production and process controls • specifications • testing • monitoring, material review, disposition decision • master manufacturing record • batch production record

31. Production and Process Controls Specifications would be required • Where control is necessary to prevent adulteration, e.g., heating steps • For identity, purity, quality, strength, and composition of • incoming components • dietary ingredients • ingredients • if not dietary ingredient, must be approved food additive or GRAS • substances used but not in final product • in-process where control is necessary • final product and • packaging and labels

32. Production and Process Controls Specifications would be required • For packaging and labels • safe and suitable for intended use, • comply with all other applicable statutory regulatory requirements, and • not be reactive or absorptive to affect dietary ingredient and dietary supplement safety

33. Production and Process Controls • Monitor • to ensure specifications are met and detect unanticipated occurrence • Material review and disposition decision when • specifications are not met or unanticipated occurrence may lead to adulteration • master manufacturing record step is not completed • instrument or control calibration suggests a problem • dietary ingredient or dietary supplement is returned • Material review and disposition documentation of • specific deviation, investigation, actions taken, what was done with the material

34. Production and Process Controls • Quality control unit: One or more persons to • approve or reject procedures, specifications, controls, tests, and deviations or modifications • approve or reject materials received and product manufactured, packaged, and labeled • review and approve master manufacturing and batch production records

35. Production and Process Controls • Quality control unit • requirements include (cont.) • review CGMP-related consumer complaints to determine if quality problem exists • investigate CGMP-related consumer quality complaints when possible relationship exists between dietary supplement quality and a reported adverse event

36. Production and Process Controls Master manufacturing record (recipe) • Prepare and follow • Include list of components • dietary ingredients (section 201(ff)) • A vitamin • A mineral • An herb or other botanical • An amino acid • A dietary substance for use by man to supplement the diet by increasing the total dietary intake • A concentrate, metabolite, constituent, extract, or combination of any of the above • ingredients (appear in finished product) • substance that does not appear in finished product

37. Production and Process Controls Master manufacturing record (cont.) • Specifications where control is necessary to prevent adulteration • Weight or measure for each component • Instructions for adding, mixing, sampling, testing • Expected yields • Specifications for packaging and label to use • Keep master manufacturing record

38. Production and Process Controls Batch production record • Accurately follows master manufacturing record • Includes quality control unit review and approval of • batch production record • cross reference of receiving and batch production records • any material review and disposition decision • reprocessing • release for distribution • Keep for 3 years beyond date of batch production

39. Production and Process Controls Batch production record (cont.) • Includes, in part, • Batch, lot, or control number • Identity of equipment and processing lines used • Date and time of the maintenance, cleaning, and sanitizing of the equipment and processing lines used • Incoming shipment lot identifier • Identity and weight or measure of each component used

40. Production and Process Controls Batch production record (cont.) • Includes, in part, • date and initials of person(s) completing and verifying steps • date batch produced • test results • any material reviews and disposition decisions • documentation that final product specifications are met • Copy(ies) of label used

41. Production and Process Controls • Manufacturing operations • design or select to ensure specifications achieved • conduct in accordance with sanitation principles • take precautions to prevent contamination

42. Production and Process Controls • Precautions would include • protecting against growth of microorganisms and potential for contamination • washing or cleaning components that contain soil or other contaminants • preventing the growth of microorganisms and decomposition • preventing against inclusion of foreign material • identifying all processing lines and major equipment used during manufacturing to indicate their contents, batch/lot number, and when necessary phase of manufacturing

43. Laboratory Operations • Establish and follow laboratory controls • Use adequate facilities in-house or from outside sources to perform testing and examinations • Keep laboratory test and examination records

44. Laboratory Operations • Establish and follow laboratory controls to test • dietary ingredients and dietary supplements manufactured or • components, dietary ingredients and dietary supplements received and • in-process materials as specified in master manufacturing record and • water to ensure that it meets EPA National Drinking Water regulations

45. Laboratory Operations • Test finished batch of dietary ingredient or dietary supplement to ensure identity, purity, quality, strength, and composition If analytical methods are not available for testing finished batch then… • Test incoming components, dietary ingredients, or dietary supplements to determine whether specifications are met AND • Test in-process in accordance with the master manufacturing record to ensure the identity, purity, quality, strength, and composition of dietary ingredients or dietary supplements

46. Laboratory Operations • Test for types of contamination that may adulterate, i.e., • filth, insects, or other extraneous material • microorganisms, and • toxic substances

47. Laboratory Operations • Test or examination must use at least one of the following: • gross organoleptic, • microscopic, • chemical, or • other test

48. Laboratory Operations • Establish and follow laboratory controls to • Select and use appropriate validated testing method • FDA interprets this to mean that the test is • appropriate, i.e., suitable for the measurement being made • validated, i.e., method is validated according to guidelines from • FDA • internationally accepted guidelines

49. Laboratory Operations • Sources of Methods* • AOAC, USP, other Compendia • Peer reviewed journals • In-House or proprietary *Regardless of source, all methods must be validated in the testing laboratory

50. Laboratory Operations • Testing practices that would not be permitted • Supplier or laboratory certificate of analysis for a shipment not supported by testing of all specifications • Skip lot testing • Single testing certification of supplier