Current Good Tissue Practice (CGTP) Draft Guidance

Martha Wells, MPHDivision of Human Tissues

OCTGT, CBER, FDA

March 30, 2009AATB Spring Meeting, Orlando FL

To Discuss Today Regulatory basis - CGTP Scope of draft guidance Selected draft guidance recommendations and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)

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

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

CGTP Requirements 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

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

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

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

Subpart E

Reporting Adverse reaction reports HCT/P deviation reports

Labeling Information that must appear on the

label or accompany the HCT/P

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

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

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

Selected Draft Guidance Recommendations and

Examples

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

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))

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))

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

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)

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

Example of Manufacturing ArrangementProcessor 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 temperaturesConsiders 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

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)

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

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

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)

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)

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)

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

or processing

1271.190(c)

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)

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)

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

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)

RecoveryProcedures and Records

Recovery is a core CGTP, therefore procedures and records must be established and maintained for:FacilitiesEnvironmental controlEquipmentSupplies and reagentsLabeling controlsStorage and Receipt, predistribution shipment and distribution

1271.215

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)

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

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 eliminateIdentification of multiple cultures for enteric or pathogenic microorganisms

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)