1. Transmissible Spongiform Encephalopathies: Decontamination of Agent and FDA-Regulated Products Food and Drug Administration Transmissible Spongiform Encephalopathies Advisory Committee 17 July 2003 Holiday Inn Bethesda, Maryland David M. Asher, MD Laboratory of Bacterial, Parasitic and Unconventional Agents Division of Emerging and Transfusion-Transmitted Diseases Office of Blood Research and Review Center for Biologics Evaluation and Research United States Food and Drug Administration e-mail address: asher@cber.fda.gov

2. FDA, TSEs and Decontamination Mission: Protection from contaminated products Inactivation of TSE agents is context-dependent:  Scrapie agent in aqueous suspension is substantially if not always completely inactivated by moist heat.  Scrapie agent is not completely inactivated after drying. TSE agents are substantially inactivated in solutions of NaOH, NaOCl, [other chemicals]. WHO consultants recommended decontamination in “healthcare environments” using combined NaOH or NaOCl and moist heat. Other authorities doubt need for NaOH, NaOCl. Situations requiring TSEAC advice (CDRH, CBER, [CDER]: Instruments, surfaces) Situations for which TSEAC advice is not solicited (FDA: Food, feeds [Other: USDA, EPA])

3. Six Cases of CJD Plausibly Attributable to Contaminated Neurosurgical Instruments Report No of Cases (months post exposure) Cleaning Procedures Terminal Sterilization Nevin & al. (Brain 1960;83:519) [69yom,68yom,47yof] Probable source case of 1, 2 from Will & Matthews. J Neurol Neurosurg Psych 1982:45:235 2 or 3 (15 *,17 *,17 ? ) [*Source case identified later.] ? Routine surgical ? Dry heat Bernoulli & al. (Lancet 1977;i:478) [23yof,17yom] 2 (16,20) Source case confirmed. Benzene, ethanol Formaldehyde vapor Foncin & al. (Revue Neurologique 1980;136:280) [48yom] 1 (28) Source case confirmed. ? Routine surgical Dry heat (Poupinel oven)

4. Variable Effects of Heat on TSE Infectivity: Examples (Taylor DM. Vet J 2000;159:10-17) Strains of TSE agent differ in thermal stability:  301V BSE > 22A Scr > 263K Scr > ME7 Scr Dry heat: some strains survived 200 o C x 1 h Autoclaving reduces infectivity titer markedly, sometimes to limit of detection but not always.  Gravity displacement: Some infectivity survived at 132 o C x 1 h  Vacuum:  Unmacerated tissue lost all detectable infectivity after 134 o C- 138 o C x 18 min  Macerated tissue contained residual infectivity after 134 o C-138 o C x 1 h Conclusion: In “worst-case” scenarios, autoclaving has not been validated to decontaminate all TSE agents completely.

5. Four Factors to Consider in Assessing Whether a Contaminating Instrument Might Transmit CJD: Example of Uncertainties Infectivity of CJD patient tissue touching instrument  UK estimate for brain:  10 7 human ID50/g  USA estimate for brain: 10 5 human ID50/g Reduction in infectivity remaining on instrument by decontamination (cleaning, chemical, heat, &c)  UK estimate for cleaning: 10 2 to 10 3  USA estimate for cleaning: 10 4  UK & USA estimates for disinfection+ sterilization: >10 3  Tissues of subsequent patient exposed to instrument  Susceptibility of exposed patient _____________________________________________________________ UK: CJD Incidents Panel. Consultation Paper 2001 USA: Rutala WA, Weber DJ. Clin Infec Dis 2001;32:1348-56

6. Infectivity of Neural Tissues from 300 Humans with TSEs (Brown P et al. Ann Neurol 1994;35:513-529)

7. Estimated Amounts of Infectivity in Tissues of Persons Dying with TSEs (Brown P et al. Ann Neurol 1994;35:513-529) Human TSE brains usually contained  10,000 primate intracerebral lethal doses per gram of tissue (“pooled” data 10 4.8 LD50 per gm). - 27 positive brains tested in dilutions > 1 % (sCJD 21, kuru 3, GSS 2, fCJD 1) - 73 % (19/26) of brains were positive at 1:10,000 - 43 % (6/15) were positive at 1:1,000,000 - 13 % (1/8) were positive at 1:100,000,000 - None of 6 was positive at 1:1,000,000,000 Primate brains contained 10 5 to 10 7 LD50/gm Other human tissues ?  1000 LD50/gm

8. Infectivity of Materials from Humans with TSEs: Uncertainties of Negative Transmission Attempts (Brown P et al. Ann Neurol 1994;35:513-529) Small sample sizes were studied.  Small numbers of specimens  Small volumes of tissues and fluids Species barriers reduce sensitivity of infectivity assays.  (Incubation periods in primates drop on first primate-to-primate serial passage, then remain stable on subsequent passages. That suggests the presence of some species barriers between non-human primates and humans.) Limits of detection in primates for infectivity present in human materials are unknown. There may be variation in distribution of infectivity in tissues of humans with TSEs. - Clinical illness - Asymptomatic incubation periods (not amenable to study)

9. Advice Offered in UK and USA Concerning Surgical Instruments Exposed to CJD Agent l UK: “While the risk of transmitting CJD through invasive medical procedures is uncertain, precautionary action should be taken … withdrawing all those that might be implicated as soon as possible. … In general, instruments that have undergone ten or fewer decontamination cycles since being used on the index patient with CJD should be incinerated.” l USA: “… [Cleanable critical or semicritical] devices [in contact with high-risk tissues of CJD patient] … (e.g., surgical instruments) can be cleaned and then sterilized by autoclaving either at 134 o C for  18 min in a prevacuum sterilizer or at 121 o C-132 o C for 1 h in a gravity displacement sterilizer.” _____________________________________________________________________ UK: CJD Incidents Panel. Consultation Paper 2001 USA: Rutala WA, Weber DJ. Clin Infec Dis 2001;32:1348-56

10. WHO General Considerations for Effective TSE Agent Decontamination in Healthcare Settings (WHO: www.who.int/emc-documents/tse/docs/whocdscsraph20003.pdf) Decontamination is “context-dependent” and may not be completely effective under all circumstances. Cleaning facilitates decontamination by reducing infectivity and “organic load.” Use the best “validated” methods available. Use “orthogonal” strategy––two different methods––whenever possible.

11. WHO-Recommended Procedures for Handling of TSE- agent-contaminated Surgical Instruments: WHO Caveats (WHO/CDS/CSR/APH/2000.3) Single-use instruments are strongly recommended. For maximum safety, destroy re-usable instruments. Quarantine instruments potentially exposed to TSE agents until Dx of TSE is ruled out. “In some healthcare situations [when instruments cannot be discarded] … less effective methods may be preferred.”

12. WHO-Recommended Procedures for Handling of TSE-agent-contaminated Surgical Instruments: WHO Caveats (WHO/CDS/CSR/APH/2000.3) “Policy makers are encouraged to adopt the highest decontamination methods feasible until studies are published which clarify the risk of re-using contaminated instruments.” Recommended alternative decontamination methods are listed “in order of decreasing effectiveness.”

13. WHO-Recommended Procedures for Handling of TSE-agent- contaminated Heat-Resistant Surgical Instruments (WHO/CDS/CSR/APH/2000.3) Incineration: “Preferred method for all instruments exposed to high infectivity tissues.”  ___________________________________________________________________________________________________________________________________________________ Other methods “ in order of more to less effectiveness”:  NaOH 1N+gravity-displacement (GD) autoclave 121 o C x 30’; clean; rinse; routine sterilization 2. NaOH or NaOCl 20 000 ppm x 60’ ; transfer to H 2 0; GD autoclave 121 o C x 60’; clean &c 3. NaOH or NaOCl x 60’ rm temp; rinse; GD autoclave 121 o C or porous-load (PL) autoclave 134 o C x 60’; clean &c 4. NaOH, boil x 10’ atm; clean &c 5. NaOCl (preferred) or NaOH (alternative) rm temp temp x 60’; clean &c

14. WHO-Recommended Procedures for Handling of TSE-agent-contaminated Heat-Resistant Surgical Instruments CONTINUED (WHO/CDS/CSR/APH/2000.3) Other methods “ in order of more to less effectiveness” (continued): 6. Autoclave at 134 o C for 18 minutes. * ________________________________________________ * “In [worst-case] scenarios (brain tissue bake- dried on to surfaces) infectivity will be largely but not completely removed.”

15. WHO-Recommended Decontamination Regimens for Surfaces & Heat-Sensitive Instruments (modified from WHO/CDS/CSR/APH/2000.3) Flood with NaOH 2N or NaOCl (40 000 ppm available Cl) and let stand x 60’.  Mop and rinse with water.  Dispose of absorbents and fluids as contaminated waste. Alternative (not fully satisfactory)  If surfaces cannot tolerate exposure to NaOH or NaOCl, then clean thoroughly and decontaminate with a partially effective method. (Then consider the surfaces to be potentially contaminated.)

16. Four Situations Requiring Decisions Regarding TSE Agent Decontamination TSE confirmed or suspected TSE not suspected High-risk tissue ??? Lower-risk tissue ???

17. TSE Agent Decontamination: TSEAC Program 17-18 July 2003 General principles of cleaning and decontamination for TSE agents (R. Rohwer) Review of effective decontamination and WHO advice (D. Taylor) Experience with hospital decontamination in UK and USA (P. Edwards*, W. Rutala) Incineration (E. Rau) Decontamination models (S. Brown, D. Asher, C. Weissmann, C. Kempf)  * in absentia, presentation by P. Piccardo, CBER

18. TSE Agent Decontamination: TSEAC Issues 18 July 2003 CDRH: Reprocessing of medical devices (L. Gill, M. O’Lone, C. Durfor) CBER: Decontamination of facilities and equipment used to process human-tissue-derived and plasma products (R. Solomon, E. Heck, D. Scott, C. Kempf, A. Bailey) [CDER: Aware of relevance to FDA-regulated drugs made with human-derived or animal-derived materials]  CFSAN, CVM: Production processes for food and feeds differ markedly from CDRH/ CBER/ CDER products.  USDA, EPA: Share some common issues with FDA but have different advisory committees.