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Current Good Tissue Practice (CGTP) Draft Guidance. Martha Wells, MPH Division of Human Tissues OCTGT, CBER, FDA March 30, 2009 AATB Spring Meeting, Orlando FL. To Discuss Today. Regulatory basis - CGTP Scope of draft guidance

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Current Good Tissue Practice (CGTP) Draft Guidance

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    1. Current Good Tissue Practice (CGTP) Draft Guidance Martha Wells, MPH Division of Human Tissues OCTGT, CBER, FDA March 30, 2009 AATB Spring Meeting, Orlando FL

    2. To Discuss Today • Regulatory basis - CGTP • Scope of draft guidance • Selected draft guidance recommendations and examples. These are focused on responses to identified: • Compliance issues • Frequent questions • Recovery issues • Relevance to AATB members • Because of time constraints, only Subpart D related sections will be discussed today (not Subpart E: Reporting and Labeling)

    3. Background: CGTP Regulation 21 CFR 1271 Subparts D and E • Proposed rule: January 8, 2001 • Final rule: November 24, 2004 • Addressed public comment • Effective date: May 25, 2005 for HCT/Ps recovered on or after this date • Most of subpart D and all subpart E requirements not currently effective for reproductive establishments

    4. Subpart D: CGTP • Requirements for methods, facilities, and controls for manufacturing • Manufacturers must recover, process, store, label, package, and distribute HCT/Ps, and screen/test donors, in a way that prevents introduction, transmission, and spread of communicable diseases/agents • Includes viruses, bacteria, fungi, parasites, and TSE agents • Broad goals applicable to wide range of HCT/Ps • Establishments determine how to meet these goals through their own procedures

    5. Exemptions/alternatives Quality Program Personnel Procedures Facilities Environmental control Environmental monitoring Equipment Supplies and reagents Recovery Processing/process controls Process changes Process validation Labeling controls Storage Receipt, pre-distribution shipment, and distribution Records Tracking Complaint file Donor eligibility determination CGTP Requirements

    6. Core CGTP Requirements • Are those requirements that directly relate to preventing the introduction, transmission, or spread of communicable disease by HCT/Ps • Other CGTP requirements discussed in the guidance support the core CGTP requirements • You must follow all CGTP requirements applicable to the manufacturing steps you perform • If you determine that an applicable requirement is not appropriate for your operations, then documentation of justification is required • Donor eligibility requirements are considered core CGTP

    7. Core CGTP Requirements • Facilities -1271.190(a) and (b) • General provisions/Cleaning and sanitation • Environmental control - 1271.195(a) • Equipment - 1271.200(a) • General provisions • Supplies and reagents -1271.210(a) and (b) • Verification/Regents • Recovery – 1271.215 • Processing and process controls - 1271.220

    8. Core CGTP Requirements • Labeling controls – 1271.250(a) and (b) • General provisions/Verification • Storage – 1271.260(a) through (d) • Control of storage areas/Temperature • Expiration date/Corrective action • Receipt, predistribution shipment, and distribution -1271.265 (a) through (d) • Receipt/Predistribution shipment • Availability for distribution/Packaging and shipping • Donor eligibility determinations, donor screening and testing - 1271. 50, .75, .80, and .85

    9. Subpart E • Reporting • Adverse reaction reports • HCT/P deviation reports • Labeling • Information that must appear on the label or accompany the HCT/P

    10. Draft CGTP Guidance • FDA recommendations for complying with 21 CFR part 1271, subparts D and E • CGTP • Reporting and Labeling. • Also addresses whether establishment registration and listing requirements apply in certain instances • FDA’s current thinking - for comment only • Docket No. FDA-2008-D-0659 - comments due April 16, 2009 • Federal Register Notice: • Guidance:

    11. Scope of Draft Guidance • Applies to establishments that manufacture HCT/Ps regulated: • Solely under section 361 of the Public Health Service (PHS) Act and 21 CFR part 1271 and • As drugs, devices, and/or biological products under Section 351 of the PHS Act and/or the Federal Food, Drug and Cosmetic Act • Applies to establishments that perform a manufacturing step under contract, agreement or other arrangement for another HCT/P establishment • Provides examples of how compliance can be addressed for CGTP, reporting and labeling requirements

    12. Scope of Draft Guidance • Includes many of the Q and A’s submitted by professional associations (AATB and EBAA) to FDA in 2005 • Many were modified in the FDA draft guidance • Some of the AATB/EBAA Q and A’s might not be consistent with FDA’s current thinking • Consider comparing with AATB’s 2006 Guidance to assess consistency with FDA’s current thinking • Includes issues identified by the FDA Human Tissue Task Force (established in 2006) evaluations and inspections of recovery establishments • Guidance recommendations are focused on preventing infectious disease contamination and cross contamination (including mix-ups) during manufacture

    13. Selected Draft Guidance Recommendations and Examples

    14. CGTP Not Covered by CGMP/QS Regulation • Provides explanations of what CGTP requirements apply if the HCT/P is not a 361 HCT/P • These requirements would be in addition to the • Drug current good manufacturing practice (CGMP) requirements for HCT/Ps regulated as biological products or • Quality system (QS) regulation requirements for HCT/Ps regulated as medical devices. • If there is a conflict, the more specific regulation would supersede the more general one

    15. CGTP Not Covered by CGMP/QS Regulation • All donor eligibility requirements (Subpart C) • Prevention of the introduction, transmission, or spread of communicable diseases (1271.145) • Certain parts of manufacturing arrangements (1271.150(c)(1)(ii) and (iii)) • Procedures for sharing with other establishments information pertaining to possible contamination or potential for transmission of communicable disease (1271.160(b)(2)) • Audits (only biological products not covered) (1271.160(c))

    16. CGTP Not Covered by CGMP/ QS Regulation • Prohibition on pooling (1271.220(b)) • Predistribution shipment (1271.265(b)) • HCT/P availability for distribution only after donor eligibility established (1271.265(c)(2)) • Packaging and shipping requirements (1271.265(d)) • Record keeping for 10 years (1271.270(d)) (facility cleaning and sanitation records for 3 years (1271.190(d)(2)) • Certain records for contracts and agreements (1271.270(e)) • Tracking (1271.290(a) – (g))

    17. Examples Where No Corresponding CGMP or QS Regulation • HCT/Ps from 2 or more donors may not be placed in physical contact or mixed in a single receptacle during manufacture (pooling) • Where there is shipment within or between establishments before making the HCT/P available for distribution, you must: • Establish criteria and document they are met that are designed to prevent communicable disease transmission • Ship in quarantine

    18. Manufacturing ArrangementsExamples of How to Ensure Compliance with CGTP Requirements • Responsibilities are listed and understood • Review test kit package inserts used by contract test laboratory • Review applicable procedures • Review certifications where appropriate (e.g., CLIA, Certificate of Analysis) • Review previous compliance actions 1271.150(c)(iii)

    19. Manufacturing Arrangements Recommendations Continued • Perform for cause and random comparisons of documentation provided by your contractor with source documents from the originator of the documents. (e.g., testing records) • Ensure the establishment has a quality program that addresses the operations they perform for you • Perform periodic audits that address review of compliance with all Part 1271 requirements applicable to the operations the establishment performs for you

    20. Example of Manufacturing Arrangement Processor receives HCT/Ps from a recovery establishment under contract and decides to audit the establishment for compliance with regulations for: • Recovery, donor medical history interview, obtaining specimens for communicable disease testing, and shipping at appropriate temperatures • Considers reviewing records provided by the recovery establishment to confirm accuracy of source such as • Attending physician • Testing laboratory • Coroner or hospital • Next of kin • Considers accompanying a recovery team to review adherence to procedures and quality program activities

    21. Quality Program and Sharing Information • Must ensure that procedures exist to share information (pertaining to possible contamination or transmission of a communicable disease) with other establishments known to have • Recovered HCT/Ps from the same donor • Performed manufacturing steps with the same HCT/P • Procedures must include provisions for assessing risk and appropriate follow-up, and notification of all entities involved as necessary • Recommend that procedures are defined in your contracts, agreements and other arrangements 1271.160(b)(2)

    22. Example of Information Sharing:Positive Test Results Received • Tissue establishment evaluates test results and determines if there are concerns for potential increase in risk of transmission of a relevant communicable disease agent or disease by the HCT/P (even if the test is not recommended by FDA) • Shares results with the establishment that recovered the HCT/Ps from the donor • Recovery establishment shares results with other establishments that received HCT/Ps from the same donor • Tissue establishments should notify consignees of released HCT/Ps

    23. Example of Information Sharing: Adverse Reaction • Recovery establishment recovers HCT/Ps for several processing establishments • Recovery establishment receives information from one processor that a recipient had developed a serious infection • Recovery establishment is responsible for sharing this information with other processing establishments that received HCT/Ps from the same donor

    24. Computer SoftwareValidation or Verification • Applicable if computer software is used to comply with any core CGTP requirement • Validation examples: • If you develop your own software to store information used to make donor eligibility determinations • If you use a computer generated labeling system developed for a different intended use (labeling blood products) • Verification example: If you use a commercial spread sheet to record donor testing results used to make a donor eligibility determination 1271.160(d)

    25. Availability of Procedures • Must be readily available to personnel in the area where operations are performed • Do not have to be physically maintained in the area of operation if impractical • Examples • Copies of applicable procedures on paper or electronically accessible should be taken to a recovery site • If not feasible to physically keep in the processing clean rooms, then can be in an adjacent area 1271.180(c)

    26. Facility Requirements: Examples Applicable to Recovery The area used for recovery should be evaluated for: • Suitable size, location and construction for aseptic procedure • Limited access • Good state of repair • Adequate lighting, ventilation and airflow • Access to running water and sink • Working surfaces – verified cleaning agents used and use documented • Recommend development of a checklist to document that the location meets established parameters each time a recovery is performed 1271.190(a)

    27. Facilities: Separate Areas Needed? • Evaluate the type of area that a task would require in order to prevent contamination or cross-contamination • Recommendation that it is not appropriate to utilize a clean-room used for processing for: • Preparing packaged, recently recovered HCT/Ps for shipment to another facility • Prepackaging freshly recovered HCT/Ps for quarantine • Handling blood specimens to be used for infectious disease testing • Decontaminating instruments used for recovery orprocessing 1271.190(c)

    28. Environmental Controls Related to Recovery • Procedures must be established and maintained to prevent contamination or cross-contamination • Environmental controls should be in place at each recovery site • Establish recovery site suitability parameters and verify that they have been met • Operating room setting is recommended but not required • If other types of facilities are used for recovery then they must provide adequate temperature and humidity controls and ventilation 1271.195(a)

    29. Equipment RecordsDocument and Maintain • Records for use of each piece of equipment including identification of each HCT/P manufactured with it • Cleaning and maintenance records of equipment including those instruments that are regularly washed and disinfected • For recovery instruments cleaned and sterilized by a contract facility: • Obtain and approve procedures and review records • Establish and maintain verification procedures for sterilization specifications • Contract facility does not have to register as this is not a manufacturing step 1271.200(e)

    30. Equipment for Recovery Recommendations • No requirement to segregate equipment used for different donors prior to cleaning • Acceptable to place multiple instrument trays into automated washers • Recommend if possible, that instruments used on the same type of tissue be cleaned together • Should ensure that automated washers operate consistently and are cleaned/maintained according to established procedures • Containers and solutions used in instrument cleaning can be reused per manufacturer’s instructions

    31. Supplies and ReagentsVerification of Specifications • Ensure that a verification system is in place to meet specifications by the: • Establishment that uses the supply or reagent or • Vendor • Verification examples for recovery supplies: • Designed to prevent leakage that could cause contamination or cross-contamination if used to wrap, package or store HCT/Ps • Shipping containers used to transport HCT/Ps are capable of maintaining expected storage environment relative to controlling contamination 1271.210(a)

    32. RecoveryProcedures and Records Recovery is a core CGTP, therefore procedures and records must be established and maintained for: • Facilities • Environmental control • Equipment • Supplies and reagents • Labeling controls • Storage and • Receipt, predistribution shipment and distribution 1271.215

    33. Recovery: Examples for Reducing Contamination/Cross Contamination • Evaluate technical procedures used such as • Aseptic technique • Use of published industry practices • Specific body cooling parameters established • Evaluate personnel involved for • Experience, education and training • Evaluate equipment, supplies, and reagents used for • Appropriate design • Records and procedures for maintenance, cleaning, sanitizing, calibration and other activities • Establish and document suitability of facilities where recovery takes place (including audits)

    34. Recovery: Examples for Verifying and Documenting Donor Identification • Critical for HCT/P tracking • Prior to recovery of HCT/Ps from a deceased donor, compare the donor’s identification with • Information on the consent/authorization documents • Relevant medical records • Other identifiers such as age, sex, race and weight • Document the methods used to verify donor identity and the source of information • Processor could periodically audit recovery establishment records to compare them with other available information related to the donor

    35. Processing: Recommendations for Pre-Processing Cultures Issues to take into consideration when you evaluate pre-processing culture results to determine whether to utilize a donor: • Capability of your microbiological testing, disinfection, and sterilization processes (validated to sterility assurance level of 10-6) • Identify rule out organisms (Clostridium, or Group A Streptococcus) that are difficult to eliminate • Identification of multiple cultures for enteric or pathogenic microorganisms

    36. Records: Methods for Retention • Maintain electronically, original paper records or as true copies such as photocopies, microfiche, or microfilm • Back-up is required if stored electronically • Examples of retention requirements: • Paper records are scanned into a computer file that is backed up. These are true copies so the paper records may be destroyed • Paper records are re-typed into a computer file. It is not possible to determine that these are true copies, so the original paper records must be kept 1271.270(c)