# Presentation: 346616

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

**TSEAC      June 26, 2002**

## 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**

## 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**

## 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 administration—to be discussed**

## Potential Transmission of CJD/vCJD by Other HCT/Ps

**Experimental evidence in animals**
**Brown P et al.  Annals of Neurology 1994—300 cases of experimentally transmitted human spongiform encephalopathies**

## FDA’s Regulatory Approach to TSE Transmission (actual and potential) by HCT/Ps

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

## Current Regulations

**21 CFR part 1270—Human 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**

## 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**

## 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 agents—if and when such methods are agreed upon by scientific experts; become available**

## 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**

## 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**

## 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**

## Proposed Regulations, cont.

**(2) GTP **
**Prohibition of pooling (placing in physical contact or mixed in a single receptacle)**
**Exemption or alternative from any GTP requirement—submit 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)**

## Proposed Recommendations

**Draft guidance for comment about donor screening and deferral to reduce possible risk of CJD/vCJD transmission by HCT/Ps—risk factors for CJD and vCJD--deferrals for travel/residence in BSE-affected countries—similar to guidance for blood donors (1/’02)**

## 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 <40; oocyte donors <35; donors of cardiovascular tissue <61; at the discretion of individual medical director**

## 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)**

## 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**

## 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**

## 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?**

## 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?**

## Questions, cont.

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

## 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?)**

## Questions, cont.

**1. C.  Other appropriate measures and controls**

## 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**

## 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 **