# Presentation: 573954

## Current Good Manufacturing Practices(CGMP’s)

- FDA Proposal for Dietary Supplements

## Introduction

- What are CGMP’s designed to do?
- Why CGMP’s?
- Legal authority
- How was proposal developed?
- Proposed requirement highlights
- Comment invited
- Next Steps

## What are CGMP’s Designed To Do?

- 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 _not safety or efficacy of dietary ingredients_

## Why CGMP’s?

- Congress saw need by authorizing
- Food, Drug, and Cosmetic Act gives authority for CGMP’s
- Product recalls and independent lab testing demonstrate need for CGMP’s
- Industry and consumers support CGMP’s

## Why CGMP’s?

- Product recalls and independent laboratory testing demonstrate need for CGMP’s:
- Poor sanitation--bacterial contamination
- Ingredient misidentification--Digitalis lanata mistaken for plantain (Plantago spp.)
- Superpotent--selenium
- Subpotent--folic acid
- Contaminated with prescription drugs

## Why CGMP’s?

- 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

## Why CGMP’s?

- 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

## Legal Authority

- 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)

## Legal Authority

- Sec. 701(a) and Sec. 704
- gives authority for requirements for efficient enforcement
- Sec. 361 of Public Health Service Act
- gives authority for requirements to prevent introduction, transmission, or spread of communicable diseases from one State to another

## How was Proposal Developed?

- 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

## How was Proposal Developed?

- 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

## How was Proposal Developed?

- 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

## Representative Manufacturing Steps

## 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)

## 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

## 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

## 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 mixups
- screening to keep out pests
- maintenance and sanitation
- water meets EPA drinking water requirements
- plumbing, bathroom, lighting, ventilation, trash requirements to prevent contamination

## 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

## 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

## Proposed Requirement Highlights

- Consumer product quality complaints related to CGMP=s
- product quality complaint examples include superpotent, subpotent, 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

## Proposed Requirement Highlights

- Holding and Distributing
- to ensure that identity, purity, quality, strength, and composition are not adversely affected
- hold and distribute under
- appropriate conditions of temperature, humidity, and light
- conditions that do not  lead to mixup, contamination, or deterioration

## Proposed Requirement Highlights

- Records and Recordkeeping--performance records for
- calibration, master manufacturing and batch production, and consumer complaints
- keep for 3 years beyond date of manufacture of batch and
- FDA access to records when requested

## Production and Process Controls

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

## Production and Process Controls

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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## Production and Process Controls

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

## 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

## 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

**Notes:**
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## 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

**Notes:**
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## 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

**Notes:**
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## Laboratory Operations

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

**Notes:**
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## Laboratory Operations

- Test or examination must use at least one of the following:
- gross organoleptic,
- microscopic,
- chemical, or
- other test

**Notes:**
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## 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

**Notes:**
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## 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**

**Notes:**
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## 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

**Notes:**
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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)

**Notes:**
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## Comment Invited on Possible Additional Provisions

- Certain personnel records
- Written procedures
- Equipment verification
- Expiration dating and related testing
- Animal-derived dietary ingredients and
- Persons who handle raw agricultural commodities

## Next Steps

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

## Post Publication Outreach

- April 29, 2003 in College Park, Maryland
- May 4, 2003 in Secaucus, NJ (preceding  SupplySide East)
- May 6, 2003 in Oakland, CA
- May 9, 2003 satellite downlink
- See CFSAN/FDA website at
- http://www.cfsan.fda.gov/~news/whatsnew.html

## Public Comment Procedure

- 90-day comment period after date of publication in Federal Register
- comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD  20852, Docket Number 96N-0417 or
- submit electronic comments to http://www.fda.gov/dockets/ecomments, Docket Number 96N-0417