1. TSEAC Meeting July 18, 2003 Topic 4 Ruth Solomon, M.D. DHT/OCTGT Methods to decontaminate facilities and equipment used in recovery and processing of HCT/Ps to prevent contamination and cross- contamination by TSE agents

2. Distribution of TSE Infectivity in the Human Body--WHO HIGH –Brain, spinal cord –Eye—some distinguish optic nerve and retina from other eye tissues (cornea, sclera) LOW –Kidney, liver, lung, lymph nodes, spleen, placenta NO DETECTABLE INFECTIVITY –Adipose tissue, adrenal, gingival tissue, heart muscle, intestine, peripheral nerve, prostate, skeletal muscle, testis, thyroid, blood, secretions and excretions

3. Approaches to Reduce Risk of TSE Transmission by HCT/P Transplants—TSEAC 6/26/02 Screen donors for risk factors and clinical evidence of TSE disease Control recovery and processing to prevent contamination Use manufacturing steps that remove or inactivate TSE Agents

4. Revision of FDA’s Question to the Committee 6/26/02 Do the committee members recommend that FDA define validated inactivation procedures for TSE decontamination of instruments and surfaces, and propose methods for removal and/or inactivation of TSE agents from HCT/Ps that may be contaminated by TSE agents, differentiating high-risk from low-risk tissues? ----unanimous YES vote

5. TSE Infectivity in Ocular Tissue Scrapie-infected hamsters: –Brain >10 7 ID 50/g –Optic nerve and retina >10 7 –Cornea, choroid, lens 10 4 -10 7 Patient with vCJD: –PrP Sc detected in brain –Retina-- 25% of brain level –Optic nerve-- 2.5% of brain level –Cornea, sclera, aqueous and vitreous humor, iris, lens-- <0.25% of brain level

6. Transmissions of TSE by Tissue Transplantation Human dura mater –4500 transplants /yr. (1997) –>100 cases Cornea –>50,000 transplants/yr. worldwide –3 cases: 1 definite (1974); 1 probable (1994); 1 possible (1997) Other tissues –>850,000 transplants/yr. No known cases

7. FDA Regulation of HCT/Ps— Final rules; proposed rules; guidance; draft guidance 1997—final rule and guidance—screening and testing of donors of musculoskeletal, skin, ocular tissues for HIV and hepatitis 1999—donor suitability rule (not final)— includes screening for TSE including CJD 2001—final registration and listing rule 2001—good tissue practice (GTP) rule (not final) 2002—guidance on validation; draft guidance on CJD/vCJD for HCT/P donors

8. GTP Proposed Rule Facilities –Contact surfaces disinfected between donors Equipment –Cleaned and maintained Instruments –Decontaminated, sterilized as appropriate Supplies and reagents –Verified to meet specifications, not contaminated Tracking to HCT/P –Equipment, instruments, reagents tracked to HCT/P Environment –Controlled and monitored for microbial growth

9. WHO Consultation on Infection Control for TSEs Instruments kept moist after use; mechanically cleaned Ineffective, sub-optimal decontamination methods vs. Effective decontamination methods Decontamination for confirmed or suspected TSE /level of tissue infectivity Low or no detectable infectivity—no additional decontamination, other than routine sterilization High infectivity—additional decontamination procedures recommended

10. WHO Recommended Decontamination Methods (in order of decreasing effectiveness and severity) Incineration—use for all disposable instruments; preferred method for all instruments exposed to high infectivity

11. Autoclave/chemical methods for heat-resistant instruments 1. Immerse in NaOH and heat in gravity displacement (g.d.) autoclave—121C for 30m; clean, rinse in water  routine sterilization 2. Immerse in NaOH or NaOCl for 1h.; transfer to water; heat in g.d. autoclave –121C for 1hr; clean;  routine sterilization 3. Immerse in NaOH or NaOCl for 1h; rinse in water; transfer to open pan; heat in g.d. autoclave (121C) or porous load autoclave (134C) for 1hr; clean;  routine sterilization

12. Cont. 4. Immerse in NaOH and boil for 10m at atmospheric pressure; clean; rinse in water;  routine sterilization 5. Immerse in NaOCl or NaOH at ambient temperature for 1h. Clean; rinse in water;  routine sterilization 6. Autoclave at 134C for 18m

13. Cleaning methods for surfaces and heat-sensitive instruments 1. Flood with 2N NaOH or undiluted NaOCl for 1h; rinse with water 2. Thoroughly clean; possibly use one of the partially effective methods

14. Number of Decontamination Cycles—CJD Incidents Panel Decontamination Cycle—(1) physical cleaning, e.g., washer; followed by (2) inactivation of any remaining infectious material, e.g., autoclaving First cleaning: 10 2 to 10 3 -fold reduction Subsequent cleaning: 0 to 10 2 –fold reduction First autoclaving: 10 3 to 10 6 –fold reduction Subsequent autoclaving: 0 to 10 3 –fold reduction First cleaning and autoclaving: at least 10 5 –fold Most instruments that have undergone 10 cycles are unlikely to pose a significant risk.

15. Factors to consider Any risk assessment has variables which are not known—extent of TSE agent reduction during processing; extent of possible cross-contamination One important risk is insufficient supply Resource limitations of small entities Corrosive effect of NaOH and NaOCl on longevity of stainless steel instruments

16. Questions to Committee Considering (a) current practices using conventional methods of cleaning facility work surfaces, equipment, and instruments used in the recovery and processing of HCT/Ps, (b) other precautions currently in place (e.g., aseptic techniques, donor screening for TSE), and (c ) concerns about availability of tissues-----

17. Questions, cont. 1. With regard to the recovery and processing of ocular tissue from donors later discovered to have TSE or possible TSE: –A. Does the committee believe that surgical instruments used in recovery and processing should be destroyed by incineration, if practical?

18. Questions, cont. –B. If destruction of instruments is not practical, does the committee believe that, at this time, there exist established, effective methods that are adequate for decontaminating instruments and surfaces? –C. If so, please comment on the specific methods listed in the WHO Guidelines. In particular, does the committee consider that only those WHO methods that use NaOH or NaOCl are adequate?

19. Questions, cont. –D. If so, should such methods by employed by eye banks in the circumstances noted above? –E. Does the committee believe that the number of decontamination cycles (physical cleaning and autoclaving) performed on the instruments after the index donor tissue was recovered and processed should determine whether or not these additional specified decontamination procedures are needed?

20. Questions, cont. 2. With regard to the recovery and processing of ocular tissue, should additional decontamination procedures discussed in question #1 be used routinely, i.e., even when TSE has not been suspected?

21. Questions, cont. 3. Should similar decontamination procedures be used for instruments and surfaces used to recover and process other tissues with a low risk of TSE infectivity from cases of known or suspected TSE? 4. With regard to other tissues with a low risk of TSE infectivity, should additional decontamination procedures be used routinely, i.e., even when TSE has not been suspected?