# Presentation: 738052

## 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**

## 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])**

## 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)
 |

## 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**_**.**

## 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:  ****107 human ID50/g
- USA estimate for brain:  105 human ID50/g
**Reduction in infectivity remaining on instrument by decontamination (cleaning, chemical, heat, &c)**
- UK estimate for cleaning: 102 to 103
- USA estimate for cleaning: 104
- UK & USA estimates for disinfection+ sterilization:  >103
**Tissues of subsequent patient exposed to instrument**
**Susceptibility of exposed patient**
- _____________________________________________________________
- UK: CJD Incidents Panel.  Consultation Paper 2001 <www.doh.gov.uk/cjd/consultation>
- USA: Rutala WA, Weber DJ. Clin Infec Dis 2001;32:1348-56

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

## 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 105 to 107 LD50/gm
**Other human tissues ? ********1000 LD50/gm**

## 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)

## Advice Offered in UK and USA Concerning Surgical Instruments Exposed to CJD Agent

**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.”**
**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 <www.doh.gov.uk/cjd/consultation>
- USA: Rutala WA, Weber DJ. Clin Infec Dis 2001;32:1348-56

## 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.**

## 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.”**

## 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.”**

## 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**
**NaOH or ****NaOCl**** 20 000 ppm x 60’ ; transfer to H****2****0; GD autoclave 121****o****C x 60’; clean &c**
**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**
**NaOH, boil x 10’ atm; clean &c**
**NaOCl (preferred) or NaOH (alternative) rm temp temp x 60’; clean &c**

## 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.”**

## 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.)**

## Four Situations Requiring Decisions Regarding TSE Agent Decontamination

|  | TSE confirmed or suspected | TSE 
not suspected |
| --- | --- | --- |
| High-risk tissue | ?
 | ??
 |
| Lower-risk tissue | ?? | ? |

## 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**

## 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.**