Transmissible Spongiform Encephalopathies: Decontamination of Agent and FDA-Regulated Products

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Transmissible Spongiform EncephalopathiesDeconta
mination 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_at_cber.fda.gov

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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)

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Six Cases of CJD Plausibly Attributable to
Contaminated Neurosurgical Instruments
Report No of Cases (months post exposure) Cleaning Procedures Terminal Sterilization
Nevin al. (Brain 196083519) 69yom,68yom,47yof Probable source case of 1,2 from Will Matthews. J Neurol Neurosurg Psych 198245235 2 or 3 (15,17,17?) Source case identified later. ? Routine surgical ? Dry heat
Bernoulli al. (Lancet 1977i478) 23yof,17yom 2 (16,20) Source case confirmed. Benzene, ethanol Formaldehyde vapor
Foncin al. (Revue Neurologique 1980136280) 48yom 1 (28) Source case confirmed. ? Routine surgical Dry heat (Poupinel oven)
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Variable Effects of Heat on TSE
InfectivityExamples (Taylor DM. Vet J
200015910-17)

• Strains of TSE agent differ in thermal stability
• 301V BSE gt 22A Scr gt 263K Scr gt ME7 Scr
• Dry heat some strains survived 200oC x 1 h
• Autoclaving reduces infectivity titer markedly,
  sometimes to limit of detection but not always.
• Gravity displacement Some infectivity survived
  at 132oC x 1 h
• Vacuum
• Unmacerated tissue lost all detectable
  infectivity after 134oC-138oC x 18 min
• Macerated tissue contained residual infectivity
  after 134oC-138oC x 1 h
• Conclusion In worst-case scenarios,
  autoclaving has not been validated to
  decontaminate all TSE agents completely.

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Four Factors to Consider in Assessing Whether
aContaminating Instrument Might Transmit
CJDExample 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 gt103
• Tissues of subsequent patient exposed to
  instrument
• Susceptibility of exposed patient
• __________________________________________________
  ___________
• UK CJD Incidents Panel. Consultation Paper 2001
  ltwww.doh.gov.uk/cjd/consultationgt
• USA Rutala WA, Weber DJ. Clin Infec Dis
  2001321348-56

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Infectivity of Neural Tissuesfrom 300 Humans
with TSEs(Brown P et al. Ann Neurol
199435513-529)
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Estimated Amounts of Infectivityin Tissues of
Persons Dying with TSEs (Brown P et al. Ann
Neurol 199435513-529)

• 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 gt 1
• (sCJD 21, kuru 3, GSS 2, fCJD 1)
• 73 (19/26) of brains were positive at 110,000
• 43 (6/15) were positive at 11,000,000
• 13 (1/8) were positive at 1100,000,000
• None of 6 was positive at 11,000,000,000
• Primate brains contained 105 to 107 LD50/gm
• Other human tissues ? ?1000 LD50/gm

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Infectivity of Materials from Humans with
TSEsUncertainties of Negative Transmission
Attempts (Brown P et al. Ann Neurol
199435513-529)

• 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)

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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 134oC for ?18 min in a prevacuum sterilizer or
  at 121oC-132oC for 1 h in a gravity displacement
  sterilizer.
• __________________________________________________
  ___________________
• UK CJD Incidents Panel. Consultation Paper 2001
  ltwww.doh.gov.uk/cjd/consultationgt
• USA Rutala WA, Weber DJ. Clin Infec Dis
  2001321348-56

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WHO General Considerations for Effective TSE
Agent Decontamination in Healthcare Settings
(WHO www.who.int/emc-documents/tse/docs/whocdscs
raph20003.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 strategytwo different
  methodswhenever possible.

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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.

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WHO-Recommended Procedures for Handling of
TSE-agent-contaminated Surgical InstrumentsWHO
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.

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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 1Ngravity-displacement (GD) autoclave 121oC
  x 30 clean rinse routine sterilization
• NaOH or NaOCl 20 000 ppm x 60 transfer to H20
  GD autoclave 121oC x 60 clean c
• NaOH or NaOCl x 60 rm temp rinse GD autoclave
  121oC or porous-load (PL) autoclave 134oC x 60
  clean c
• NaOH, boil x 10 atm clean c
• NaOCl (preferred) or NaOH (alternative) rm temp
  temp x 60 clean c

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WHO-Recommended Proceduresfor Handling of
TSE-agent-contaminatedHeat-Resistant Surgical
Instruments CONTINUED(WHO/CDS/CSR/APH/2000.3)

• Other methods in order of more to less
  effectiveness (continued)
• 6. Autoclave at 134oC for 18 minutes.
• ________________________________________________
• In worst-case scenarios (brain tissue
  bake-dried on to surfaces) infectivity will be
  largely but not completely removed.

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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.)

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

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TSE Agent DecontaminationTSEAC Issues 18 July
2003

• CDRH Reprocessing of medical devices (L. Gill,
  M. OLone, 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.