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Current Good Tissue Practice (CGTP) Draft Guidance

Current Good Tissue Practice (CGTP) Draft Guidance.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 Regulatory basis - CGTP Scope of draft guidance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Current Good Tissue Practice (CGTP) Draft Guidance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 Current Good Tissue Practice (CGTP) Draft Guidance Martha Wells, MPH Division of Human Tissues OCTGT, CBER, FDA March 30, 2009 AATB Spring Meeting, Orlando FL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 To Discuss Today • Regulatory basis - CGTP • Scope of draft guidance • Selected draft guidance recommendations and examples.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: http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2009_register&docid=fr16ja09-101 • Guidance: http://www.fda.gov/cber/gdlns/tissuehctps.htm

  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)

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