Topic 1. Validation of Procedures to Prevent Contamination and CrossContamination with TSE Agents of

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Topic 1. Validation of Procedures to Prevent
Contamination and Cross-Contamination with TSE
Agents of Human Tissue Intended for
Transplantation

• TSEAC June 26, 2002

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Issue

• FDA requests advice from TSEAC on
• Measures for donor screening
• Measures for tissue recovery and processing
• Clearance of TSE agents (design of a study)
• Appropriate to prevent contamination and
  cross-contamination of human cells, tissues, and
  cellular and tissue-based products (HCT/Ps) by
  TSE agents

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Background

• Three approaches to reduce risk of TSE
  transmission
• (1) careful screening of donor for TSE and risk
  factors of TSE (testing if and when validated)
• (2) control of recovery and processing to prevent
  contamination/cross-contamination
• (3) use of steps during manufacturing to remove
  or inactivate (clear) TSE agents

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Iatrogenic transmission through HCT/Ps

• Human dura mater transplantation
• 100 cases worldwide (3 in U.S.)
• Most from dura mater that had been commingled
  during processing
• Human corneal transplantation
• 1 definite case (U.S., 1974)
• 1 probable case (Japan, 1994)
• 1 possible case (Germany, 1997)
• Potential cases (U.K., 1999)
• Human pituitary-derived hormone administrationto
  be discussed

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Potential Transmission of CJD/vCJD by Other HCT/Ps

• Experimental evidence in animals
• Brown P et al. Annals of Neurology 1994300
  cases of experimentally transmitted human
  spongiform encephalopathies

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FDAs Regulatory Approach to TSE Transmission
(actual and potential) by HCT/Ps

• Current regulations (rules)
• Current recommendations (guidance)
• Proposed regulations
• Proposed recommendations

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Current Regulations

• 21 CFR part 1270Human Tissue Intended for
  Transplantation--1997
• Screening and testing of potential donors for
  HIV, HBV, HCV (TSE not included) written
  procedures records
• Validated procedures to prevent infectious
  disease contamination or cross-contamination by
  tissue during processing-1270.31(d)
• Inspection and enforcement provisions

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Current Recommendations

• (1) Guidance for Industry Screening and Testing
  of Donors of Human Tissue Intended for
  Transplantation (97)--defer donors with
• Diagnosis of CJD
• Family history of CJD
• History of receiving dura mater transplant
• History of receiving human pituitary growth
  hormone

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Current Recommendations, cont.

• (2) Guidance for Industry Validation of
  Procedures for Processing of Human Tissues
  Intended for Transplantation (3/02)clarifies
  1270.31
• Infectious disease contamination includes viral,
  bacterial, fungal and TSE agents
• Validated methods to prevent contamination by
  viruses, bacteria, fungi now
• Validated methods to prevent contamination by TSE
  agentsif and when such methods are agreed upon
  by scientific experts become available

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Current Recommendations, cont.

• (3) Guidance for the Preparation of a Premarket
  Notification Application for Processed Human Dura
  Mater (10/99)
• All of above donor suitability recommendations
  any degenerative or demyelinating disease of CNS
  death in a neurological/psychiatric hospital
• Gross and histological exam of full brain
• Disinfection by a method validated to reduce CJD
  infectivity
• Prohibition of batch processing

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Proposed Regulations

• (1) Suitability Determination for Donors of Human
  Cellular and Tissue-Based Products Proposed Rule
  (9/30/99)
• Screening (including medical history interview)
  for risk factors and clinical evidence of HIV,
  HBV, HCV, TSEs additional screening for
  particular HCT/Ps
• Testing for HIV, HBV, HCV, syphilis additional
  testing for particular HCT/Ps

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Proposed Regulations, cont.

• (2) Current Good Tissue Practice for
  Manufacturers of HCT/Ps Inspection and
  Enforcement Proposed Rule (1/8/01)
• Controls over facilities, personnel, equipment,
  environment, incoming materials, labeling,
  storage, process controls, process validation,
  record keeping, adverse reaction and product
  deviation reporting, tracking
• Inspection and enforcement

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Proposed Regulations, cont.

• (2) GTP
• Prohibition of pooling (placing in physical
  contact or mixed in a single receptacle)
• Exemption or alternative from any GTP
  requirementsubmit request with valid data
• Ex.-request for an exemption from pooling
  prohibition FDA would weigh potential increased
  risk of contamination and cross-contamination
  with emerging infectious disease agents (e.g.,
  TSE agents) against potential benefit of improved
  elimination of conventional infectious disease
  agents (virus, bacteria, fungi)

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Proposed Recommendations

• Draft guidance for comment about donor screening
  and deferral to reduce possible risk of CJD/vCJD
  transmission by HCT/Psrisk factors for CJD and
  vCJD--deferrals for travel/residence in
  BSE-affected countriessimilar to guidance for
  blood donors (1/02)

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Additional Donor Screening Measures

• (1) Upper age limit for donors
• Median age at death from CJD is 68 years
• ?incubation period--?infectious during incubation
  period
• Proposed for blood donors, but not implemented
• May seriously reduce tissue supply (e.g., 50 of
  U.S. donors of ocular tissue are age 61 or older)
• Not recommended by tissue bank or eye bank
  standards, except semen donors
  
  discretion of individual medical director

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Additional Donor Screening Measures, cont.

• (2) Exclusion for head trauma
• To avoid possible CNS contamination
• Not addressed in industry standards
• May reduce tissue supply (e.g., 13 of eye
  donors cause of death is trauma)

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Additional Donor Screening Measures, cont.

• (3) Negative brain autopsy
• Delay in distributing time-sensitive HCT/Ps
  (e.g., cornea)
• (4) Negative brain biopsy
• Would need to be validated to show that is it
  predictive of autopsy diagnosis of TSE

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Charge

• Evaluate appropriateness of the measures and
  controls discussed (or other) to prevent TSE
  transmission to recipients of HCT/Ps
• Additional donor screening criteria
• Specified methods of recovery and processing
• specific methods of decontamination
• removal and/or inactivation of TSE agents

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Charge, cont.

• Should pooling (commingling) of HCT/Ps from
  different donors during manufacturing ever be
  permitted? If so, what controls should FDA
  require in assessing whether a request for an
  exemption from the proposed pooling prohibition
  should be granted?

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Questions for the Committee

• 1. Which of the following measures and controls
  is (are) appropriate to prevent TSE agent
  transmission to recipients of human cells and
  tissues?

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Questions, cont.

• 1. A. Recommend additional donor
  eligibility/exclusion criteria
• Upper age limit
• Head trauma exclusion
• Negative brain autopsy or biopsy

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Questions, cont.

• 1. B. Recommend specified methods of HCT/P
  recovery and/or processing to prevent
  contamination and cross-contamination by TSE
  agents
• Decontamination of instruments and surfaces
• Methods for removal and/or inactivation of TSE
  agents during manufacturing
• Single donor aseptic processing or permit pooled
  processing under certain circumstances (which
  ones?) with adequate controls (which ones?)

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Questions, cont.

• 1. C. Other appropriate measures and controls

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Questions, cont.

• 2. Please comment on the design of a
  satisfactory TSE agent clearance study for
  HCT/Ps, in terms of the following criteria
• A. Suitable TSE agent strain and animal model
• B. Accept measurement of abnormal forms of prion
  protein alone, or require infectivity assays

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Questions, cont.

• 2. Design of a clearance study, cont.
• C. Accept substantial reduction (how much?) or
  require complete elimination of detectable prion
  protein and/or infectivity
• D. Accept a single validated method or require
  that more than one validated method for
  eliminating TSE agents be included in the study
• E. Other