GTPs vs. cGMPs
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GTPs vs. cGMPs



General comparison of the 21CFR 1271 and the 21CFR 211 Regulations for Cell Based Biologics Manufacturing

General comparison of the 21CFR 1271 and the 21CFR 211 Regulations for Cell Based Biologics Manufacturing



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    GTPs vs. cGMPs GTPs vs. cGMPs Presentation Transcript

    • WR Tolbert & Associates Consultants to the Biopharmaceutical Industry 11483 Cypress Woods Drive San Diego, CA 92131-3535 858-693-8163 /
    • Dogs Bark, Cows Moo, Regulators Regulate... Frank Young, M.D. former FDA Commissioner
    • FDA History
      • 1820 U.S. PHARMACOPEIA
        • 1901 – 13 Children Died of Tetanus due to Contaminated Diphtheria Antitoxin
      • 1906 FOOD AND DRUGS ACT
    • FDA’s Purpose
      • To ensure the
        • Safety
        • Efficacy
        • Quality (Identity, Strength/Potency, Purity)
      • of Drug, Biologic and Device Products by control of manufacturing, advertising and distribution though various licensing and approval requirements.
    • FDA “Centers”
      • CDER – Center for Drug Evaluation and Research (Small Molecule Drugs and Specified Biotechnology Products).
      • CBER – Center for Biologic Evaluation and Research (Vaccines, Blood, Non-Specified Biotechnology Products).
      • CDRH – Center for Devices and Radiological Health (Medical Devices).
    • FDA Inspections
      • ORA – Office of Regulatory Affairs (Regional and District Offices)
      • All inspections except for CBER pre-approval (PAI) for biologic products.
    • Foreign Regulatory Agencies
      • Health Canada -Health Products and Food Branch
      • []
      • EMEA (EU Regulatory Body) []
      • Japan Ministry of Health, Labour and Welfare []
    • Information Sources
      • FDA Home Page []
      • CDER Home Page []
      • CBER Home Page []
      • CDRH Home Page []
      • ORA Home Page []
      • FDA Search Page []
    • Information Sources
      • Federal Register: 1994 – 2005 []
      • The Code of Federal Regulations []
      • CLIA Home Page []
    • The Primary Requirement / Roadblock
      • FDA Market Approval
        • NDA, ANDA - CDER
        • BLA - CBER
        • PMA, 510K - CDRH
      • Obtained by data on Safety and Efficacy collected during clinical trials. (IND/IDE)
    • FDA Tools
      • Laws
        • The Federal Food Drug and Cosmetic (FDC) Act (1938)
        • The Public Health Service Act (1944 – Biologics)
        • Medical Device Amendments (1976)
      • Regulations – Title 21 Code of Federal Regulation (21 CFR) – May be enforced in court.
      • Guidelines – Provide FDA’s current regulatory positions/thinking on various topics.
      • ICH Guidelines – Internationally accepted.
    • Cross Regulation Themes and Concerns
      • Documentation.
      • Personnel qualification and training.
      • Independent oversight by the Quality Unit (Quality Assurance and/or Quality Control Unit).
      • Data integrity.
      • Personal Responsibility.
    • The Existing Regulatory Environment
      • 21 CFR PART 820—QUALITY SYSTEM REGULATION [ Medical Device GMPs ]
      • 42 CFR 493—LABORATORY REQUIREMENTS [ Clinical Laboratory Improvement Amendments of 1988 – CLIA ]
    • How are Cell-Based Products Different?
      • Potential for adventitious agents in starting material - possible lack of adequate methods for testing or removal.
      • Requirement for “aseptic
      • processing”
      • Inability to effectively “sterilize” the product and often implantation must occur before testing is complete.
    • FDA Driving Forces & Challenges for Cell Products
      • Previous approach (pre 1997) fragmented inadequate inadequate
      • New products (e.g. stem cells, tissue-engineered, etc.)
      • New manufacturing technologies, degree of manipulation
      • Increasing public health concern
      • Increasing demand for cells and tissues
      • Public confidence in products - expectation for expectation for safe & effective product
      • Industry standards not always followed, not enforceable
    • Cell and Tissue Characteristics
      • Autologous vs. Allogeneic
      • Viable vs. Nonviable
      • Banked vs. Unbanked
      • Homologous vs. Non-homologous function
      • Minimal vs. More than minimal manipulation
      • Structural vs. Systemic function
      • Combination product– device, biologic or drug
    • FDA Regulation of Cellular and Tissue-based Products
      • Human cells, tissues, or cellular or tissue-based products based products [ HCT/P’s ]
        • Articles containing human cells or tissues that are intended for transplantation, infusion or transfer into a human recipient
        • Not including vascularized organs, allogeneic bone marrow transplantation, transfusable blood/blood components, xenotransplantation
      • Provides a unified, comprehensive regulatory framework
      • Provides a tiered regulatory approach
        • level of regulation proportional to the degree of risk
    • New FDA Regulation
        • Subpart A—General Provisions
        • Subpart B—Procedures for Registration and Listing
        • Subpart C—Donor Suitability
        • Subpart D—Current Good Tissue Practice ( cGTPs )
        • Subpart E—Additional Requirements for Establishments Described in § 1271.10 (PHS 361 Products)
        • Subpart F—Inspection and Enforcement of Establishments Described in § 1271.10 (PHS 361 Products)
      • Final Rule is effective May 25, 2005.
    • 21 CFR Part 1271
    • Regulatory Requirements for HCT/P’s
    • 21 CFR Part 1271 Establishment Registration and Listing
      • Requires establishments to register with FDA and list HCT/P’s
        • Exclusions for some (e.g., storage, carriers, contractors engaging only in recovery and transport)
      • Lists criteria to determine if HCT/P’s regulated solely under 361 PHS Act
    • 21 CFR Part 1271 Donor Eligibility
      • Screening and testing of most cell and tissue donors for relevant communicable diseases
        • Exception for autologous donor/ sexually intimate partner
      • Donor must be eligible prior to HCT/P administration
        • Free of risk factors & clinical evidence of communicable disease
        • Acceptable test results
        • Limited exception to use when eligibility determination not completed
          • urgent medical need, w/o other comparable HCTP available
        • Limited use of HCT/P from an ineligible donor
    • 21 CFR Part 1271 Good Tissue Practices
      • Procedures and controls to prevent introduction, transmission and spread of communicable disease by HCT/P’s
        • communicable disease agents – prior to and during manufacturing
      • Organized around core requirements, with supporting requirements
        • Follow all GTP requirements applicable to function performed
        • Requirement for a Quality Program
      • Flexibility to determine how to meet requirements
    • 21 CFR Part 1271 Inspection and Enforcement
      • Applicability
        • Above the line (351 HCT/Ps) – Same as for other Biologics and Devices (Clinical, Pre Approval, Post Approval)
        • Below the line (361 HCT/Ps) – New requirements specified (Any time after registration)
      • Inspections
        • May include your establishment, facilities, equipment, finished and unfinished materials, containers, processes, HCT/Ps, procedures, labeling, records, files, papers, and controls required to be maintained under Part 1271.
        • May question the personnel of the establishment as necessary to determine compliance
        • May take samples, may review and copy any records required to be kept under this part, and may use other appropriate means to record evidence of objectionable observations
        • The inspection may be made with or without prior notification
        • The frequency of inspection will be at the agency’s discretion
    • 21 CFR Part 1271 Inspection and Enforcement
      • HCT/Ps offered for import
        • Importer must notify, either before or at the time of importation, the appropriate district director of the FDA (ORA)
        • Must provide sufficient information for FDA to make an admissibility decision
        • Does not apply to peripheral blood stem/progenitor cells regulated solely under PHS section 361, unless unreasonable risk of communicable disease
      • Enforcement Actions
        • Include orders of retention, recall, destruction, and cessation of manufacturing
    • Compliance to cGMPs, QSRs, and Biologics Regulations vs. cGTPs
      • “ The current good manufacturing practice regulations in parts 210 and 211 of this chapter and the quality system regulations in part 820 of this chapter supplement , and do not supersede , each other unless the regulations explicitly provide otherwise. In the event that a regulation in part 1271 of this chapter is in conflict with a requirement in parts 210, 211, or 820 of this chapter, the regulations more specifically applicable to the product in question will supersede the more general.” (For PHS 351 Products)
    • Comparison cGMPs vs. cGTPs
      • No corresponding procedure
      • Personnel
        • Appropriate education, training, and experience
        • Specific training requirements
        • Specific responsibilities
        • Adequate number of personnel and supervisors
      • Exemptions and alternatives
        • Procedure to request changes in cGTPs for specific products
      • Personnel
        • Appropriate education, training, and experience
        • Train all personnel to perform their assigned responsibilities adequately.
        • Sufficient personnel to ensure compliance
    • Comparison cGMPs vs. cGTPs
      • Responsibilities of quality control unit
        • Must be independent
        • Authority to review production records and to assure that errors have been fully investigated
        • Responsibility and authority to approve or reject all components, in-process materials, drugs and drug products
        • Responsibility and authority or reject all procedures and specifications
        • The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed.
        • Adequate testing facilities shall be available
      • Establishment and maintenance of a quality program
        • Preventing the introduction, transmission, or spread of communicable diseases through the manufacture and use of HCT/Ps.
        • Ensuring that procedures exist for receiving, investigating, evaluating, and documenting information relating to core cGTP requirements
        • Providing audits and ensuring appropriate corrective actions relating to core cGTP requirements
        • Investigating and documenting HCT/P deviations relating to core CGTP requirements
        • Validate the performance of computer software
    • Comparison cGMPs vs. cGTPs
      • Buildings and Facilities
        • Buildings shall be of suitable size, construction and location to facilitate cleaning, maintenance and proper operations.
        • Buildings shall have adequate space for equipment and materials and for process flows to prevent mix-up and contamination
        • Specific defined areas for operations to prevent mix-up and contamination
        • Other general and specific requirements for HVAC, plumbing, lighting, sanitation and maintenance
        • Specific aseptic processing requirements, as needed (2004 Aseptic Guidelines)
        • Requirements for written procedures and documentation.
      • Facilities
        • Must be of suitable size, construction, and location to prevent contamination and to ensure orderly handling of HCT/Ps without mix-ups.
        • Must maintain the facility in a good state of repair with suitable lighting, ventilation, plumbing, drainage, and sanitation to prevent the introduction, transmission, or spread of disease
        • Must divide a facility used in the manufacture of HCT/Ps into separate or defined areas of adequate size for each operation
        • Specific environmental control and monitoring requirements
        • Must document, and maintain records of, all cleaning and sanitation activities
    • Comparison cGMPs vs. cGTPs
      • Equipment
        • Equipment shall be of appropriate design, adequate size and suitably located for its intended use
        • Product contact surfaces shall not be reactive, additive, or absorptive
        • Equipment shall be cleaned, maintained, and sanitized
        • Written procedures shall be established
        • Automatic equipment, including computers or related systems shall be routinely calibrated and inspected and input to and output shall be checked for accuracy
        • Appropriate controls shall be exercised to assure that only authorized changes
        • Records shall be kept of maintenance, cleaning, sanitizing, and inspection
      • Equipment
        • Equipment must be of appropriate design for its use and must be suitably located and installed to facilitate operations, including cleaning and maintenance. Any automated, mechanical, electronic, or other equipment used for inspection, measuring, or testing must be capable of producing valid results
        • Where appropriate, you must routinely calibrate all automated, mechanical, electronic, or other equipment used for inspection, measuring, and testing in accordance with this part
        • You must document and maintain records of all equipment maintenance, cleaning, sanitizing, calibration, and other activities performed
    • Comparison cGMPs vs. cGTPs
      • Control of components and Containers and Closures
        • Written procedures are required for receipt, quarantine storage, status labeling and release
        • Specific procedures are require for sampling, testing and release or rejection and first in/first out shall be used to rotate released components
        • Rejected components shall be identified and controlled under a quarantine procedure
        • Containers and closures shall be clean and where appropriate, sterile and pyrogen free and shall not be reactive, additive, or absorptive
        • Standards/specifications and methods for testing, cleaning, sterilization, and depyrogenation shall be written
      • Supplies and reagents
        • Must not use supplies and reagents until they have been verified to meet specifications. Verification may be accomplished by the using establishment, or by the vendor of the supply or reagent
        • Reagents used in processing and preservation of HCT/Ps must be sterile, where appropriate.
        • Must validate and/or verify the processes used for production of in-house reagents
        • Must maintain records of the receipt, including the type, quantity, manufacturer, lot number, date of receipt, and expiration date; records of the verification; certificate of analysis and records of the lot of supply or reagent used in the manufacture of each HCT/P.
    • Comparison cGMPs vs. cGTPs
      • Production and Process Controls
        • Written procedures are required for production and process control, change control and deviations must be recorded and justified
        • Adequate supervision and second person required to verify all critical steps
        • Equipment shall be uniquely identified and identification number recorded in the batch production record
        • Appropriate sampling and testing of in-process materials is required and v alid in-process specifications shall be consistent with drug product final specifications and where possible determined by suitable statistical procedures
      • Processing and Process Controls
        • Must recover and process each HCT/P in a way that does not cause contamination or cross-contamination
        • Human cells or tissue from two or more donors must not be pooled during manufacturing
        • Must ensure that specified requirements for in-process controls are met, and that each in-process HCT/P is controlled until the required inspection and tests or other verification activities have been completed, or necessary approvals are received and documented. Sampling of in-process HCT/Ps must be representative of the material to be evaluated.
    • Comparison cGMPs vs. cGTPs
      • Production and Process Controls
        • Control procedures shall be established to monitor and validate the performance of the manufacturing process to ensure uniformity
        • When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product
        • Procedures for non-sterile drug products shall be designed to prevent contamination. Procedures for sterile products and sterilization systems shall be validated
        • Written procedures shall be established for reprocessing batches. Reprocessing shall have quality control unit approval
      • Processing and Process Controls
        • Any change to a process must be verified or validated to ensure that the change does not create an adverse impact elsewhere in the operation, and must be approved before implementation by a responsible person
        • Where the results of processing cannot be fully verified by subsequent inspection and tests, you must validate and approve the process according to established procedures. Changes to a validated process must be reviewed and revalidation performed where appropriate
        • A published validated process must be verified in your establishment
    • Comparison cGMPs vs. cGTPs
      • Packaging and Labeling Control
        • There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination and/or testing of labeling and packaging materials, including label specifications; quarantine and release; destruction of rejected or obsolete labels and reconciliation of label quantities issued, used, and returned
      • Holding and Distribution
        • Written procedures are required for holding, quarantine, and storage of a drug product
        • Written procedures are required for distribution of drug products and the distribution system shall facilitate recall, if necessary
      • Labeling controls
        • Must establish and maintain procedures to control the labeling of HCT/Ps and must design these procedures to ensure proper HCT/P identification and to prevent mix-ups.
        • Must include verification of label accuracy, legibility, and integrity.
      • Storage
        • Must control storage areas and stock rooms to prevent mix-ups, contamination, and cross-contamination of HCT/Ps, supplies, and reagents
        • Must establish acceptable storage conditions of HCT/Ps at each step of the manufacturing process to inhibit the growth of infectious agents and must document storage conditions.
    • Comparison cGMPs vs. cGTPs
      • Laboratory Controls
        • Specifications, standards, sampling plans and other laboratory controls shall be reviewed and approved by the quality control unit
        • Out-of-specification results shall be appropriately investigated. OOS events shall be tracked (Bar Decision-not specifically listed in regulation)
        • All laboratory operations shall be documented at the time of performance
        • Calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program
      • No Corresponding Laboratory Requirements
      • Receipt, predistribution
        • Must evaluate each incoming HCT/P for the presence and significance of microorganisms and inspect for damage and contamination.
        • Must determine whether to accept, reject, or place in quarantine each incoming HCT/P, based upon pre-established criteria designed to prevent communicable disease transmission
        • Shipments prior to distribution must ensure prevention of disease transmission
    • Comparison cGMPs vs. cGTPs
      • Laboratory Controls
        • The accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented (Methods Validation)
        • Release testing is required prior to drug product distribution and products failing to meet specifications and any other relevant quality control criteria shall be rejected
        • There are specific requirements for stability testing and establishment of expiration dates
        • Appropriately identified reserve sample(s) representative of each product lot and active ingredient shall be retained
      • Distribution of an HCT/P
        • Prior to distribution must review HCT/P manufacturing and tracking records and must verify and document that the release criteria have been met. A responsible person must document and date the determination that an HCT/P is available for distribution
        • Must not make available for distribution an HCT/P that is in quarantine, is contaminated, or is recovered from a donor who has been determined to be ineligible
        • Packaging and shipping containers must be designed and constructed to protect the HCT/P from contamination
        • You must establish and maintain procedures, including release criteria, for the these activities
    • Comparison cGMPs vs. cGTPs
      • Records and Reports
        • There are specific requirements for record retention and storage, either as originals or as true copies by an accepted method
        • All documents and records shall be readily available for inspection
        • Records must be maintained to facilitate annual review of data for evaluation of product specifications and production procedures. Written procedures shall be established and followed for such evaluations
        • Responsible officials of the firm shall be notified in writing of any investigations, recalls, reports of inspectional observations issued by the FDA, or any regulatory actions relating to cGMPs
      • Procedures
        • Must establish and maintain procedures appropriate to meet core cGTP requirements for all steps that you perform in the manufacture of HCT/Ps and must design these procedures to prevent increased risk of the introduction, transmission, or spread of communicable diseases. Before implementation, a responsible person must review and approve these procedures.
        • If adopt current standard procedures from another organization, must verify that the procedures meet the cGTP requirements and are appropriate for your operations.
        • These procedures must be readily available to the operating personnel
    • Comparison cGMPs vs. cGTPs
      • Records and Reports
        • Equipment cleaning and use log
        • Component, drug product container, closure and labeling records
        • Master and Batch Production and Control Records (MPR and BPR)
        • Distribution records
        • All records must be reviewed and approved by the quality control unit
        • Thorough investigation is required for any failure or discrepancy, including other related product batches
        • A written record shall be made of the investigation and shall include the conclusions and follow-up
      • Records
        • Must maintain records concurrently with the performance of each step required by the cGTPs
        • All records must be accurate, indelible, and legible and must identify the person performing the work and the dates of the various entries, and must be as detailed as necessary to provide a complete history of the work performed
        • Must establish and maintain a records management system relating to core cGTP requirements. Under this system, records pertaining to a particular HCT/P must be maintained in such a way as to facilitate review of the HCT/Ps history before making it available for distribution
    • Comparison cGMPs vs. cGTPs
      • Laboratory Records
        • Shall include complete data derived from all tests necessary to assure compliance with established specifications and standards
        • A description of the sample received for testing with identification of source, quantity, lot number, date sample was taken, and date sample received
        • A statement of each method used in the testing of the sample and a complete record of all data secured in the course of each test
        • A record of all calculations performed in connection with the test and a statement of the results of tests and how the results compare with established standards/specifications
      • Records
        • May maintain required records electronically, as original paper records, or as true copies. Electronic records must be backed up
        • Must retain all records for 10 years after their creation, unless stated otherwise and retain the records pertaining to a particular HCT/P at least 10 years after the date of its administration
      • Tracking
        • Must establish and maintain a system that enables the tracking of all HCT/Ps from donor to the consignee or final disposition and from consignee or final disposition to the donor.
        • Must ensure that each HCT/P is assigned and labeled with a distinct identification code
    • Comparison cGMPs vs. cGTPs
      • Records and Reports
        • The signature of the person who performs each test and the date(s) the tests were performed and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards
        • Complete records shall be maintained for
          • Any modification of an established method
          • Any testing and standardization of reference standards, reagents, and standard solutions
          • Periodic calibration of laboratory instruments, apparatus, gauges, and recording devices
          • All stability testing performed
    • Comparison cGMPs vs. cGTPs
      • Complaint File
        • Written procedures describing the handling of all written and oral complaints regarding a drug product shall be established and followed
          • Procedures shall include provisions for review by the quality control unit, of any complaint involving the possible failure of a drug product to meet any of its specifications
          • Procedures shall include provisions for review to determine whether the complaint represents a serious and unexpected adverse drug experience which is required to be reported to the FDA
        • A written record of each complaint shall be maintained in the file
      • Complaint File
        • Must establish and maintain procedures for the review, evaluation, and documentation of complaints relating to core current good tissue practice (cGTP) requirements, and the investigation of complaints as appropriate
        • Must maintain a record of complaints that you receive in a file designated for complaints that is available for review and copying upon request from FDA
        • Must determine if the complaint is related to an HCT/P deviation or to a adverse reaction, and whether an Adverse Reaction Report to the FDA is required
    • Comparison cGMPs vs. cGTPs
      • Complaint File
        • Specific retention times for the complaint files are listed
        • The written record shall include the following information, where known: the name and strength of the drug product, lot number, name of complainant, nature of complaint, and reply to complainant
        • Where an investigation is conducted, the written record shall include the findings of the investigation and followup
        • Where an investigation is not conducted, the written record shall include the reason that an investigation was found not to be necessary and the name of the responsible person making such a determination
      • Complaint File
        • As soon as practical, you must review, evaluate, and investigate each complaint that represents an event required to be reported to FDA or a complaint relating to core cGTP requirements
        • When no investigation is made, you must maintain a record that includes the reason no investigation was made, and the name of the individual(s) responsible for the decision not to investigate.
    • Comparison cGMPs vs. cGTPs
      • Returned drug products
        • Returned drug products shall be identified as such and held until appropriate disposition
        • If the conditions under which returned drug products have been held, stored, or shipped casts doubt on drug quality attributes, it shall be destroyed
        • A drug product may be reprocessed provided the subsequent drug product meets appropriate standards, specifications, and characteristic
        • Records of returned drug products shall be maintained
      • Drug product salvaging
        • Drug products that have been subjected to improper storage conditions shall not be salvaged and returned to the marketplace
      • Return to inventory
        • You must establish and maintain procedures to determine if an HCT/P that is returned to your establishment is suitable to be returned to inventory
    • FDA Inspections
      • Except for pre-approval inspections associated with PMA (Devices), BLA (Biologics) or NDA/ANDA (Drugs) applications, FDA inspectors will arrive unannounced.
      • FDA inspectors are the equivalent of law enforcement officers and if refused admittance will return with a Federal Marshal
      • Drug and biologic manufacturing facilities producing approved products will be inspected on a two year cycle
      • Any facility may be inspected for cause at any time
      • Testing facilities are most likely to be inspected as an extension of an FDA inspection of a client organization
    • cGMP Sanctions
      • The ultimate sanction for a cGMP violation is jail for executives and responsible individuals
      • Lesser sanctions include fines, closing of the facility, warning letters, consent decrees, disqualification of testing results, etc.
      • All negative findings including 483’s are available to anyone through the Freedom of Information Act
    • Additional Valuable cGMP Information
      • Compliance Program Guidance Manual  for FDA Staff – Inspections []
      • FDA/ORA Compliance Policy Guides Manual []
      • ICH Guideline Q7A - Good Manufacturing Practices for Active Pharmaceutical Ingredients [ ]
      • Aseptic Processing Guideline [ ]
    • Open vs. Closed Manufacturing Systems
      • FDA Cleared or Approved Sterile Tube Connecting Device (STCD) – Tubing Welders Developed for the Blood industry.
      • STCDs may be used for interconnecting sterile bag systems for cell and gene therapy applications.
    • WRT&A
    • Material and Supply Flow WRT&A
    • WRT&A
    • WRT&A