Good Manufacturing Practice: A Global Standard for Pharmaceutical Quality

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Good Manufacturing PracticeA Global Standard
forPharmaceutical Quality

• Asia Pacific Economic Cooperation
• Life Sciences Innovation Forum
• Second Asia Anti-Counterfeiting
• Medical Products Seminar
• March 30 April1 2008
• Furama River Front Hotel
• Singapore

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Best Practices

• Best Practice
• A concept of management that asserts that
  proper processes checks and testing can deliver
  or put out a desired outcome with fewer problems
  and unforeseen complications

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Best Practices

• Best Practice
• Definition of processes or methods to do
  something.
• Results in achievement of assurance of quality
  results and consistency by following the process
  (the practice) if the process is followed

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Best Practices

• Best Practices
• In the modern world the production of goods and
  services has become
• complex
• dependent on integration of many different
  specialty activities
• includes sophisticated equipment requiring
  design construction maintenance and operation

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Best Practices

• Best Practices
• Central axiom is best practice results in best
  outcome or
• Good practice results in good outcome (product)

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Best Practices

• Sweeping the world
• Industrial production
• Service
• Government
• Knowledge
• Applied in sales manufacturing teaching
  programming software road construction health
  care insurance and accounting etc

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Best Practices

• Good Operating Practice
• A strategy for management of activities to
  produce a desirable outcome/product
• 500 and more
• Organizations institutes consultants web
  sites etc

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Good Operating Practice

• Good Agriculture Practice
• Good Manufacturing Practice or GMP
• Good Management Practice or GMP
• Good Engineering Practice or GEP
• Good Laboratory Practice or GLP
• Good Safety Practice or GSP
• Good Clinical Practice or GCP
• Good Distribution Practice or GDP
• Good Research Practice or GRP
• Good Review Management Practice
• Good Recruitment Practice
• GxP

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Good Operating Practice

• To develop
• Complex
• Expensive

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Current Good Manufacturing Practice for
Pharmaceuticals

• Established by government
• Requirement of Law
• Definition or development

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US CGMP Legal Principles

• Adulterated drug due to lack of CGMPs
• Defined in 501(a)(2)(B) of FDC Act
• A drug shall be deemed adulteratedif the
  methods used in or the facilities or controls
  used for its manufacture processing packing
  or holding do not conform to or are not operated
  or administered in conformity with current good
  manufacturing practice to assure that such drug
  meets the requirements of the Act as to safety
  and has that identity and strength and meets the
  quality and purity characteristics which it
  purports or is represented to posses.

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CGMP legal principles

• Quality built into product
• By taking care in making medicine
• Cant test into product the quality
• Controls provided by the practice
• Without/Inadequate CGMP
• Product(s) adulterated(defects need not be shown)
• Firm and its management are responsible

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Potential Problems from Non-Compliance with CGMP

• Super-potency or Subpotency
• Contamination
• Safety and Efficacy effects
• Misbranding

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CGMP Requirements

• Apply to
• Finished Pharmaceuticals
• Drug Substances/APIs
• OTC and Rx products
• NDA and ANDA drug products
• Approved and unapproved drug products
• IND products administered in clinical studies
  (human or animal)

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US CGMP legal principles

• Excluded from the CGMP requirement
• Positron emission tomography per FDAMA (own
  CGMP to be developed)
• Drug products compounded per Section 503 Pharmacy
  Compounding (FDAMA)

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US CGMP Legal Principles

• C current
• Dynamic and evolve over time
• GMP Good Manufacturing Practices
• Minimal standards
• Not best practices unless best is in fact
  current minimal

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US CGMP Legal Principles

• Feasible and valuable
• No threshold for percentage in practice
• Doesnt have to be predominant
• Enforceable even if nobody is doing it
• Stronger case if someone is doing it

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The CGMP Regulation

• CGMP for Finished Pharmaceuticals 21 CFR 210 211
• First issued June 1963
• Todays version September 1978
• Scope
• Dosage forms for human/vet/biologics
• OTC Rx IND NDA Medical Gases
• Not pharmacies ingredients non-clinical
  research etc

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The CGMP Regulation

• CGMP for Finished Pharmaceuticals 21 CFR 210 211
• Substantive
• Force and effect of law
• Constitute major part of (not entire) CGMP

more...
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The CGMP Regulation

• CGMP for Finished Pharmaceuticals 21 CFR 210
  211
• Establish what to do not how to do
• Minimal standards
• Maximum flexibility
• Specific enough to addressproblems
• e.g. Penicillin contamination control
• Technology neutral
• Scalable

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CGMP Requirements

• 21 CFR Parts 210 and 211contain the minimum CGMP
  regulations for the preparation of finished
  pharmaceuticals for administration to humans and
  animals
• Encompass
• Organization and Personnel (e.g. Quality Control
  Unit)
• Buildings and Facilities
• Equipment
• Components and drug product containers
• Production and Process Controls
• Packaging and Labeling controls
• Laboratory Controls
• Holding and Distribution
• Records and Reports

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Overview of CGMP requirements in the regulation

• CGMP Regulations
• 21 CFR 210
• Status of the regulations
• Applicability of the regulations
• Definitions
• Batch
• Lot
• In-process material
• Quality control unit
• Representative sample
• etc

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Overview of CGMP requirements in the regulation

• CGMP Regulations
• 21 CFR 211
• Subpart A General Provisions
• Subpart B Organization an Personnel
• Subpart C Buildings and Facilities
• Subpart D Equipment
• Subpart E Control of Cmpnts/Cntr/Closures
• Subpart F Production and Process Controls
• Subpart G Packaging and Labeling Controls

more...
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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart H Holding and Distribution
• Subpart I Laboratory Controls
• Subpart J Records and Reports
• Subpart K Returned and Salvaged Drug Products

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Overview of CGMP requirements in the regulation

• CGMP Regulations
• 21 CFR 211
• Subpart A General Provisions
• this is minimum CGMP

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Overview of CGMP requirements in the regulation

• CGMP Regulations
• 21 CFR 211
• Subpart B Organization and Personnel
• There shall be a quality control unit
• quality control unit responsibility to
  approve/reject

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart C Buildings and Facilities
• buildings shall be.suitable
• operations to be in specifically defined
  areas.separate. Or such other control systems
  for .operations as are necessary to prevent
  contamination or mix-ups. (see list includes
  aseptic processing)
• separate facilities for penicillin
• building.shall be.clean and sanitary

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart D Equipment
• surfaces .shall not be reactive additive or
  absorptive
• Equipment.shall be cleaned maintained and
  sanitized.

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart E Control of Components Containers and
  Closures
• containers and closures .handled in a manner to
  prevent contamination.
• Testing or examination of c/c/cs
• test to identify each component
• tests on components for conformance with specs
• test c/c/cs microscopically for adulterants
  microscopically

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart F Production and Process Controls
• written procedures for production and process
  control
• formulated not less than 100
• portions of components identified examined by a
  2nd person before dispensed for use in
  manufacture
• sampling and testing of in-process materials and
  products some specified
• time limits
• reprocessing allowed but controlled

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart G Packaging and Labeling Controls
• examination approval of labels labeling
• strict control over labeling issue and return to
  stock
• written procedures physical separation of
  labeling operations
• examination of materials before use
• inspection of facilities immediately before
• tamper resistant packaging (for OTC products)
• expiration dating

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart H Holding and Distribution
• Subpart I Laboratory Controls
• Subpart J Records and Reports
• Subpart K Returned and Salvaged Drug Products

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart H Holding and Distribution
• quarantine before release
• store under appropriate conditions

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart I Laboratory Controls
• establish specs standards sampling plans test
  procedures
• calibration of laboratory equipment
• test each batch of drug product
• adequate acceptance criteria
• validate test methods
• conduct stability program

more....
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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart I Laboratory Controls
• Special tests
• sterility and pyrogenicity
• ophthalmic ointments for foreign/abrasive
  particles
• controlled release products for rate of release
• keep reserve samples
• test non-penicillin products for penicillin when
  reasonable possibility of exposure to presence of
  penicillin

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart J Records and Reports
• keep records make available for inspection
• conduct annual review of each drug product for
  changes to specs control procedures
• keep equipment cleaning and use log
• keep component container closure and labeling
  records more....

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart J Records and Reports
• have SOP for master production and control
  record maintain record
• use batch production and control records for
  manufacture keep records
• records to be reviewed/approved by qual control
  unit
• complete data derived from all tests necessary to
  assure compliance

more....
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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart J Records and Reports
• distribution records with lot numbers(except
  medical gases)
• complaint files

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Overview of CGMP requirements

• CGMP Regulations
• 21 CFR 211
• Subpart K Returned and Salvaged Drug Products
• if conditions cast doubt returned product shall
  be destroyed unless proved ok by test
  examination investigation
• salvage only if evidence from tests and
  inspection show all standards met

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CGMP Changes

• Change/Update is continuous
• Establishment inspections
• Industry changes/problems
• Defect reports/complaints/recalls
• Litigation
• Agency application reviews
• Trade/scientific literature
• Citizen petitions

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Input for CGMP Changes

• Establishment inspections
• Industry changes/problems
• Defect reports/complaints/recalls
• Litigation
• Agency application reviews
• Trade/scientific literature
• Citizen petitions

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Latest CGMP Initiative - 2002

• Pharmaceutical CGMPs for the 21st Century A
  Risk-Based Approach
• Announced in August 2002
• Applies to human and veterinary drugs and select
  human biological products such as vaccines
• Involved all aspects of FDAs regulation of
  product quality not just CGMPs
• Submission review --- CMC
• Inspections
• Standard setting

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CGMP Initiative

• Why did FDA undertake this initiative
• The last major changes to FDAs system for
  regulating drug quality occurred 29 years ago
  when FDA substantially changed its CGMP
  regulations
• Significant changes in the environment of
  pharmaceutical regulation have occurred over the
  last 29 years including many challenges and
  opportunities
• Opportunity to modernize FDAs regulation of
  pharmaceutical manufacturing and product quality

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CGMP Initiative

• Challenges
• Decline in inspectional resources
• Increased number and wider range of drugs being
  manufactured
• Increase in foreign manufacturing sites
• Dramatic advances in pharmaceutical science
• Application of biotechnology to drug discovery
  and manufacturing
• More complex and diverse manufacturing processes
  lead to longer inspections
• Larger number of manufacturing supplements
  submitted to FDA for review

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CGMP Initiative

• Opportunities
• Major advances in manufacturing
  science/technology
• Advances in the science of quality management
  (e.g. quality systems approaches)
• Systems-based drug inspection program
• Advances in application of risk
  analysis/management
• Risk management approaches gaining wider
  acceptance in other regulatory agencies (e.g.
  EPA OSHA IRS)

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CGMP Initiative 2004 Report

• Major Accomplishments
• Adoption of Quality Systems Model for Agency
  Operations
• Implementation of Risk-Based Management Plan
• International Collaboration
• New Language on the FDA-483
• Creation of the Pharmaceutical Inspectorate
• Changed Procedures for Drug CGMP Warning Letters
• Technical Dispute Resolution Process for CGMP
  Disputes
• Product Specialists more readily used for
  inspections
• http//www.fda.gov/cder/gmp/gmp2004/GMP_finalrepor
  t2004.htm

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SYSTEMS BASED APPROACH to GMP

• Described in CPGM 7356.002 Drug Process
  Inspections
• Systems
• Quality
• Facilities and Equipment
• Materials
• Production
• Packaging and Labeling
• Laboratory Control
• Every inspection needs to cover at least 2
  systems
• Quality System is covered on every inspection

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QUALITY SYSTEM

• Quality Control Unit
• Responsibility and authority to review and
  approve all
• Procedures - adequate for their intended use
• Batch production records
• Training/qualification of personnel
• Recordkeeping systems
• Quality Control Unit evaluates
• Data collected to identify quality problems
• Annual Product Reviews Complaints OOS findings
  
• Problems to determine what corrective and
  preventative actions are needed
• Movie
• Lack of QCU oversight 21 CFR 211.22
• Inadequate employee training 21 CFR 211.25

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FACILITIES AND EQUIPMENT SYSTEM

• Facilities
• Adequate design to prevent cross-contamination or
  mix-up
• Readily cleanable and are sanitizing agents
  effectively used
• Properly maintained
• Adequate storage conditions for components etc.
• Air-handling systems functioning and separate if
  necessary (e.g. penicillin beta-lactams
  steroids hormones cytotoxics)
• Control system in place for implementing changes
• Adequate lighting temperature humidity controls
• Movie
• Failure to prevent cross-contamination 21 CFR
  211.42(b)

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FACILITIES AND EQUIPMENT SYSTEM

• Equipment
• installation and operational qualification where
  appropriate
• Adequate design size and location
• Equipment surfaces should not be reactive
  additive or absorptive
• Controls to prevent contamination
• Cleaning procedures and cleaning validation
• Calibration and maintenance
• Equipment use logs
• Control system for implementing changes in the
  equipment
• Movie
• Failure to clean equipment to prevent
  contamination 21 CFR 211.67(a)

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MATERIALS SYSTEM

• Components Drug Product Containers and Closures
• Quarantined until tested or examined and released
  (or rejected)
• Representative samples collected tested or
  examined (e.g. containers and closures should
  not be additive reactive or absorptive to the
  drug product)
• At least one specific identity test is conducted
  on each lot of each component
• A visual identification is conducted on each lot
  of containers and closures
• Testing or validation of suppliers test results
  for components containers and closures
• First in-first out (FIFO) use of components
  containers closures
• Water is a major component that is evaluated
  during most CGMP inspections
• Movie
• Failure to test incoming component 21 CFR 211.84

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PRODUCTION SYSTEM

• Components Charge In
• Formulation/manufacturing at not less than 100
• Equipment properly identified - contents
• Actual yields percentage of theoretical yields
• Containers and closures - cleaning/sterilization/
  depyrogenation
• Batch production documentation contemporaneous
  complete
• Time limits for completion of phases of
  production

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PRODUCTION SYSTEM(cont.)

• In-process controls tests and examinations
  (e.g. pH adequacy of mix weight variation
  clarity)
• Environmental controls - prevent objectionable
  microorganisms
• Process validation
• Computerized or automated processes - validation
  and security
• Change control
• Movie
• Failure to include complete information relating
  the production of each batch 21 CFR 211.188

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PACKAGING AND LABELING SYSTEM

• Adequate storage controls for labels and labeling
  - both approved and returned after issued
• Control of labels which are similar in size
  shape and color for different products
• Cut labels require 100 verification
• Packaging records include specimens of all labels
  used
• Control of issuance/reconciliation of labels and
  labeling
• Examination of the labeled finished product
• Physical/spatial separation between different
  labeling packaging lines
• Line clearance inspection and documentation
• Conformance to tamper-evident (TEP) packaging
  requirements OTC
• Movie
• Failure to have adequate label controls to
  prevent mix-ups 21 CFR 211.130(a)

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LABORATORY CONTROL SYSTEM

• Staffing
• Equipment and facilities
• Calibration and maintenance of analytical
  instruments and equipment (e.g. system
  suitability checks on chromatographic systems)
• Reference standards
• Specifications standards and representative
  sampling plans
• Validation/verification of analytical methods

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LABORATORY CONTROL SYSTEM (cont.)

• Complete analytical records includes retention
  of raw data
• Documented investigation into any unexpected
  discrepancy/Out of Specification (OOS)
• Reserve samples
• Stability testing program
• Movie
• Failure to perform finished product testing to
  assure conformance to final specifications
  including the identity and strength of each
  active ingredient prior to release 21 CFR
  211.165(a)

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Compliance Terms and Phrases related to CGMP
issues

• Adulteration
• Quality controls quality assurance quality
  systems
• Contamination (e.g. lack of assurance of
  sterility)
• Cross-contamination (e.g. dirty manufacturing
  facilities)
• Out-of-specification (OOS) findings
• Equipment-related issues calibration/maintenance
• Standard Operating Procedures (SOPs)
• Code of Federal Regulations (CFR) Parts 210 and
  211
• Form FDA-483 (Inspectional Observations)
• EIR (Establishment Inspection Report)
• CR (Collection Report)
• Regulatory Actions Warning Letters recall
  seizure injunctions application approvals
  suspensions revocations and import detention

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CGMP Resources

• Internet website for DMPQ
• http//www.fda.gov/cder/dmpq
• Link to CGMP Regulations (21 CFR 210 and 211)
• Ongoing or proposed changes to CGMP regulations
• Guidance documents
• Links to Field Compliance Programs

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CGMP Resources The Preamble to the CGMPs

• Detailed discussion explaining the regulations in
  21 CFR Part 211
• Published September 29 1978
• www.fda.gov/cder/dmpq/preamble.txt
• Policy level discussion

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CGMP ReferencesRegulatory Tool Box

• The Act Federal Food Drug and Cosmetic Act
• CFR Code of Federal Regulations
• Title 21 (Food and Drugs) Parts 210 and 211 (drug
  CGMPs)
• IOM Investigations Operations Manual
• CPGM Compliance Program Guidance Manual
• CPG Compliance Policy Guides
• RPM Regulatory Procedures Manual
• GIIT Guide to International Inspections Travel
• Guide to Inspections of
• Websites
• http//www.fda.gov/ora/compliance_ref/default.ht
  m http//www.fda.gov/ora/inspect_ref/default.htm

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CGMP ReferencesRegulatory Tool Box

• Compliance Programs  (Posted 9/11/2003)
• 7346.832 Pre-Approval Inspections/Investigations
  
• 7346.843 Post-Approval Audit Inspections
• 7356.002 Drug Process Inspections
• 7356.002A Sterile products manufacture
• 7356.002B Repackers and relabelers
• 7356.002C Radioactive drugs
• 7356.002E Compressed medical gases
• 7356.002F Bulk pharmaceutical chemicals
• 7356.002M Inspections of Licensed Biological
  Therapeutic Drug Products

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CGMP Implementation Tools

• CGMP Guides to Inspection of.
• Help field investigators apply CGMP
• Uncover need for CGMP changes
• Specific to topics (e.g. cleaning validation)

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CGMP Implementation Tools

• Compliance Policy Guides
• Specific actions we do related to CGMP
• Examples
• Sub Chapter 410 Bulk Drugs
• The regulations for finished pharmaceuticals will
  be applied as guidelines for bulk drugs
• Sub Chapter 420 Compendial (USP)/Test
  Requirements ExUSP not required for release test
• Other Sub Chapters
• Labeling and Repackaging
• Stability/Expiration
• Process Validation
• Etc

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CGMP Implementation Tools

• CGMP Guidance Documents
• Principles
• Not requirements
• Agency current thinking
• Detailed technical
• Expression of How to meet what to do
  (requirements)
• Shape industry behavior
• offers routes to efficiency in meeting CGMP
  requirement evaluation of compliance

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CGMP Implementation Tools

• CGMP Guidance Documents (Examples)
• General Principles of Process Validation
• Compressed Medical Gases
• Sterile Drug Products Produced by Aseptic
  Processing
• Guideline on the Preparation of Investigational
  New Drug Products

more...
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CGMP Implementation Tools

• CGMP Guidance Documents
• Investigating Out of Specification Test Results
  for Pharmaceutical Production
• Manufacturing Processing or Holding of Active
  Pharmaceutical Ingredients

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CGMP Implementation Tools

• CGMP Compliance Programs Instructions to FDA
  inspectors
• Drug Manufacturing Inspections Program
• Systems-based assessment of site
• Preapproval Inspection Program
• Points to inspect
• Laboratory support
• Regulatory approaches

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Management of CGMP Regulatory Program

• FDA/CDER
• OC/Division of Manufacturing and Product Quality
• maintenance of the regulation
• definitive interpretation
• manage guidance development
• develop operate evaluate programs
• train FDA/outreach to industry

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Nicholas Buhay Deputy Director Division of
Manufacturing and Product Quality Center for
Drug Evaluation and Research
E-mail Nicholas.Buhay_at_fda.gov
Federal Research Center White Oak Building 51
Room 4348 10903 New Hampshire Avenue Silver
Spring Maryland 20993