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Current Good Manufacturing Practice in
Manufacturing, Packing, or Holding Dietary
Ingredients and Dietary supplement

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• - 03.3.13 Proposed Rule(????) ?? -

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/dscgmps3.html ? ???? ??? ???.
2
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• Everyone making dietary supplements
• 1,566 Total Companies
• 1,228 Manufacturers
• 110 Ingredient Suppliers
• 110 Repackers/Relabelers
• 110 Holders
• 94 Others
• -FDA estimates

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???? 1,228?
????? 110?
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???? 110?
?? 94?
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• According to FDA
• Industry Compliance Cost 86 million
• Very Small 38,000/firm
• Small 61,000/firm
• Large
  47,000/firm

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• 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

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(??????) - misbranded food (??,????)
5
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• 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

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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

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• 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 government should 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

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FDA? ???? ??

• 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

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????? ?? ???? ??

• 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

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• Some of the sections cited include
• Sec. 402(g)
• gives authority for CGMPs
• 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)

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• 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

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• Considerations and Process
• White House Commission on Dietary Supplement
  Labels 1997 Report supported CGMPs and CGMP
  recordkeeping
• Food Advisory Committee Working Group-1998-1999
• Dietary Supplement manufacturers visited by FDA
  supported CGMPs
• 8 sites visited in 1999
• Small business meetings supported CGMPs but
  expressed concern about costs
• 3 meetings held in 1999

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?? GMP ???? ?? ??

• Considerations and Process
• Analyzed other CGMPs for common principles and
  requirements. Other CGMPs included
• FDA CGMPs, for example,
• Food CGMPs--Food (Part 110), Low Acid Canned
  Food, Juice, Fish Fishery Products, Infant
  Formula (proposed)
• Drug and Device for CGMP principles
• Industry CGMPs
• ANPRM industry outline, USP, NNFA

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Records
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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
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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

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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)

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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 contractors
  performance

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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 ?

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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 cGMPs

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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?

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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

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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?

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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

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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 ?

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• 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 ?

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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

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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 CGMPs
• Consumer complaint NOT related to CGMP is related
  to safety of a particular dietary ingredient
  independent of whether the product is produced
  under cGMPs

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Production and Process Controls

• System of production and process controls
• Quality control unit
• Manufacturing operations
• Holding and distributing
• Recordkeeping

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Production and Process Controls

• System of production and process controls
• specifications
• testing
• monitoring, material review, disposition decision
• master manufacturing record
• batch production record

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Production and Process Controls

• Manufacturing operations
• design or select to ensure specifications
  achieved
• conduct in accordance with sanitation principles
• take precautions to prevent contamination

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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

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Laboratory Operations

• Keep laboratory test and examination records of
• finished dietary ingredient and dietary
  supplements or
• components, dietary ingredients, or dietary
  supplements received and
• in-process materials where specified in the
  master manufacturing record and
• water that contacts components, dietary
  ingredients, dietary supplements or surfaces (to
  confirm water meets EPA National Primary Drinking
  Water requirements)

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Subpart F Holding and Distributing

• 111.80 What requirements apply to holding
  components, dietary ingredients, dietary
  supplements, packaging, and labels ?
• 111.82 What requirements apply to holding
  in-process material ?
• 111.83 What requirements apply to holding reserve
  samples of components, dietary ingredients, and
  dietary supplements ?
• 111.85 What requirements apply to returned
  dietary ingredients or dietary supplements ?
• 111.90 What requirements apply to distributing
  dietary ingredients or dietary supplements ?

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Subpart G Consumer and Complaints

• 111.95 What requirements apply to consumer
  complaints ?

Subpart H- Records and record keeping

• 111.125 What requirements apply to record keeping
  ?

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2003.4 ?? ? FDA? ????

• Analyze public comments
• Prepare final rule
• Publish in Federal Register
• 1-year large business implementation
• 3-year phase in of small business implementation

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? FDA ??? ?? ????

• We are currently reviewing and evaluating more
  than 1,600 pages of comments, and publication of
  the dietary supplement cGMP final rule is one of
  the agency's highest priorities.
• -Lester Crawford, CRN Annual Meeting, Oct 25, 2004

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????(?) ????? ????

• 1995-Framework submitted by industry
• Feb.6 1997-ANPRM published
• 1998-Dietary Supplement Working Group established
• June 1999-Working Group report finished
• 2000-2003-GMPs bounced between Congress, OMB, FDA
• March 13, 2003-proposed GMPs published

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?? Dietary supplement GMP !!

• Large companies are ready for GMPs
• Small companies are not
• 65 of all firms follow some type of GMP model
  (primarily food GMPs)
• 30 follow drug GMPs (10 ??? ????)
• 35 do not follow any GMP model (25 ??? ????)
• Compliance will be difficult and expensive,
• but the supplement industry must cooperate to
  rebuild quality in the minds of consumers.
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