ISSUE SUMMARY---TOPIC 4.

**TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES**

**ADVISORY COMMITTEE MEETING**

**July 18, 2003**

Methods to Decontaminate Facilities and Equipment Used in Recovery and
Processing of Human Cells, Tissues and Cellular and Tissue-Based
Products (HCT/Ps) to Prevent Contamination and Cross-Contamination by
TSE Agents

# ISSUE

FDA requests advice from the Transmissible Spongiform Encephalopathies
Advisory Committee (TSEAC) on specific methods to decontaminate
facilities and equipment used in recovery and processing of ocular
tissue, to prevent contamination and cross-contamination by TSE agents.
Additionally, FDA asks whether the same methods should be applied when
low-risk tissues are recovered and processed. Should these methods be
used routinely, or only in cases of known or suspected TSE discovered
post-donation?

# BACKGROUND AND DISCUSSION

FDA is concerned about the transmission of TSE agents by transplantation
of HCT/Ps, particularly those of high infectivity. WHO Infection Control
Guidelines (1) has categorized infectivity into high, low and no
detectable infectivity. The Guidelines list brain, spinal cord and eye
as tissues of high infectivity. Low-infectivity organs and tissues
include kidney, liver, lung, lymph nodes, spleen and placenta. Other
tissues (adipose, gingival, heart muscle, skeletal muscle, peripheral
nerve, glands) and secretions, including blood, are considered to have
no detectable infectivity. The United Kingdom (UK) Creutzfeldt-Jakob
Disease (CJD) Incidents Panel (2) has categorized infectivity into high,
medium, and low categories, and has distinguished sporadic CJD (sCJD)
from variant CJD (vCJD). Thus, brain, spinal cord, cranial and spinal
ganglia, dura mater, optic nerve and retina are considered to be of high
infectivity for both sCJD and vCJD; other eye tissues are considered to
be of medium infectivity for both sCJD and vCJD; lymphoreticular tissues
are of low infectivity for sCJD but of medium infectivity for vCJD.
Blood and other tissues are considered to be of low infectivity for both
sCJD and vCJD.

FDA currently regulates human cells and tissues (HCT/Ps) intended for
transplantation, but FDA does not regulate solid organs for
transplantation. Three approaches to reduce the risk of TSE transmission
by human cells and tissues were discussed at the June 26, 2002, TSEAC
meeting (3). One approach is to carefully screen and defer potential
HCT/P donors with risk factors for or clinical evidence of TSE disease
(and to test donors, if and when validated screening tests become
available). A second approach is to control the recovery and processing
of HCT/Ps so as to prevent contamination and cross-contamination by TSE
agents. A third approach is to introduce into the manufacture of HCT/Ps
a step or steps to remove or inactivate TSE agents.

Regarding the second approach above, the committee was asked at that
meeting to recommend specific methods for HCT/P recovery and processing
to prevent contamination and cross-contamination by TSE agents. These
methods included decontamination of instruments and surfaces used during
manufacturing. The committee members did not vote on this question as
stated. Instead, the Chairman posed the following revised question: 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? The committee voted unanimously in favor of this
revised recommendation.

As a follow-up to this recommendation, FDA has presented for discussion
several methods for TSE agent decontamination of facility surfaces and
equipment/instruments, and now asks the committee to consider whether
any of these methods should be added to the current conventional
decontamination procedures for work surfaces and instruments used in
recovery and processing of tissues, and, if so, whether these additional
procedures should be performed routinely or only in cases of confirmed
or suspected TSE. The high-infectivity tissues regulated by FDA are
human dura mater and human ocular tissue. The discussion here will focus
on ocular tissue, e.g., cornea and sclera, currently regulated by the
Center for Biologics Evaluation and Research (CBER). At this time,
processed human dura mater is regulated as a medical device by the
Center for Devices and Radiological Health (CDRH), and has been
previously discussed at TSEAC meetings.

TSE infectivity in ocular tissues varies (2). In scrapie-infected
hamsters, the optic nerve and retina had infectivity levels similar to
those in brain, i.e., high infectivity (defined as \>10^7^ ID 50/g),
while the cornea, choroid and lens had 10 to 100 times less infectivity
than brain, i.e., medium infectivity (defined as 10^4^ to 10^7^ ID
50/g). In a single patient with vCJD, abnormal prion protein (PrP^Sc^ )
was detected in optic nerve (at 2.5% of the brain level) and retina (at
25% of the brain level), but not in sclera, aqueous and vitreous humor,
lens, iris or cornea (meaning less than 0.25% of the brain level.) Both
vCJD and sCJD contained similar levels of PrP^Sc^ in these tissues.
Corneas from patients with sCJD have transmitted infection to animals,
in experimental studies.

Iatrogenic transmissions of CJD by corneal transplantation have included
one definite case in the United States (4), one probable case in Japan
(5), and one possible case in Germany (6). In addition, a case of
potential transmission of CJD was reported in 1997, involving the
transplantation and subsequent explantation of two corneas and sclera
donated by a Scottish woman who was later determined to have CJD (7).
The first case, described in the U. S. in 1974, was that of a
55-year-old woman who received a cornea from a donor who had died of a
neurological illness characterized by ataxia, memory deficit, myoclonus,
and other involuntary movements. It is unlikely that this transmission
would have occurred if current FDA recommendations (8) and industry
standards for donor suitability had been followed (i.e., the donor would
have been excluded because of clinical CNS disease of unestablished
diagnosis). After the cornea was transplanted, the donor's autopsy
revealed spongiform changes consistent with CJD. The recipient became
ill 18 months after transplantation and died 8 months later; her autopsy
revealed spongiform encephalopathy consistent with CJD. The Japanese
report in 1994 was that of a 63-year-old woman who developed
neurological symptoms 15 months after receiving a cornea. She died 40
months later, and her brain had histological changes typical of CJD at
autopsy; full details about the donor's history were not published, but
brain autopsy reportedly showed CJD changes, and a link between her
disease and the previous corneal transplant was suggested. The German
case, published in 1997, was that of a 45-year-old woman who developed
neurological symptoms and EEG findings of CJD. She had received a
corneal transplant 30 years earlier. An autopsy was refused upon her
death 8 months later. Although the pathology slides from the donor were
no longer available for review, the original medical records and
necropsy reports indicated the donor had a 3-month history of
neurological symptoms, and spongiform encephalopathy was observed at
autopsy.

Under the legal authority of section 361 of the Public Health Service
Act, FDA has promulgated regulations and recommendations to prevent the
introduction, transmission and spread of communicable disease through
cell and tissue transplantation. Some of these rules are currently in
effect, and others have been proposed and are being finalized. The
following is a summary of the current and proposed requirements and
recommendations regarding controls for facilities and equipment used in
the manufacture of HCT/Ps, designed to prevent contamination and
cross-contamination.

Current regulations require that written procedures be prepared,
validated, and followed to prevent infectious disease contamination or
cross-contamination by tissue during processing (9). FDA guidance for
industry, published in March 2002, explained the agency's current
expectations with regard to viruses, bacteria and fungi, but stated
that, at the time of publication, there was no adequate validation
method for procedures intended to prevent contamination with TSE agents.
As technology progressed and validated procedures became available, the
TSE agents would be included in the requirement, when appropriate (10).

FDA's proposed rule regarding eligibility of HCT/P donors would require
that all donors be screened for human TSE, including CJD, by reviewing
the donor's relevant medical records and performing a donor history
interview and physical assessment (11). FDA draft guidance for industry,
published in June 2002, provided more detailed information about the
risk factors for and clinical evidence of sCJD and vCJD (12).

FDA's proposed rule regarding current good tissue practice would require
that procedures be established and maintained to ensure that HCT/Ps do
not become contaminated during any steps in manufacturing, not just
processing. This requirement would include tissue recovery (13). These
procedures would include establishing and maintaining effective controls
over facilities, personnel, equipment, environment, incoming materials,
labeling, and storage, as well as process controls and validation,
record keeping, reporting of adverse reactions and product deviations,
and tracking of HCT/Ps from the donor to the recipient and vice versa.

Specific to today's discussion about decontamination of facilities and
equipment, FDA's [proposed]{.underline} good tissue practices include
the following requirements:

1.  Facilities used for recovery and processing must be maintained and
    cleaned according to schedule, with documentation---e.g., ensuring
    that contact surfaces are cleaned with appropriate disinfecting
    agents, according to instructions, before each donation is processed
    and between donors.

2.  Equipment used in recovery and processing must be cleaned,
    maintained, and calibrated as appropriate, according to schedule,
    with documentation---e.g., ensuring that refrigerators are
    maintained at proper temperatures; thermometers calibrated.

3.  Instruments used in recovery and processing must be decontaminated
    and sterilized as appropriate---e.g., ensuring that decontamination
    solutions and procedures are adequate; sterilizer cycles are
    verified with each use, in that pressure, time and temperature meet
    established parameters, and biological indicators are used in each
    load.

4.  Supplies and reagents must be verified to meet
    specifications---e.g., ensuring that reagents are not contaminated
    upon receipt or during use.

5.  Equipment, instruments and reagents must be tracked to HCT/s.

6.  Environmental monitoring must take place---e.g., ensuring that
    laminar flow hoods are monitored for microbial growth.

At the June 26, 2002, TSEAC meeting, the committee learned about the
controls used to ensure safe corneal transplantation. In addition to
donor screening for risk factors and clinical evidence of CJD, aseptic
techniques are used during recovery and processing (e.g., a sterile
field is established, and sterile protective apparel is worn). Most
processing is performed under a laminar flow hood. The hood is cleaned
with disinfectants between donors. The equipment used for processing
includes sterile surgical instruments (a separate set for each donor),
slit lamp and specular microscopes, and refrigerators. Decontamination
of surgical instruments involves mechanical cleaning, followed by
autoclaving. \[It has been estimated that the first cleaning step would
remove 2-3 logs of TSE agent infectivity, while autoclaving would reduce
infectivity by 3-6 logs, giving a combined effect of at least a 5-log
reduction. Subsequent decontamination cycles probably have much less
effect (2). Microscopes cannot be autoclaved; however, the cornea is
immersed in a vial of disinfectant/preservative solution during
examination under the microscope, and it does not touch the equipment.\]

Speakers will discuss the current procedures for decontamination and
sterilization of surgical instruments, the effect of current procedures
on the longevity of these instruments, and the possible use of
disposable instruments when recovering and processing ocular tissue.

A WHO Consultation on Infection Control for TSEs (1) recommended general
measures for cleaning instruments and the environment. Instruments
should be kept moist and mechanically cleaned prior to decontamination.
The WHO Guidelines listed both ineffective and sub-optimal liquid
chemical and gaseous disinfectants and physical processes, and effective
decontamination methods (two or more different methods used in
combination, when possible). \[Please refer to the Appendix for these
lists.\] The most effective methods involve immersion in solutions of
sodium hydroxide or sodium hypochlorite for various periods of time,
followed by autoclaving and then cleaning and routine sterilization. It
is important to note that, in principle, sodium hydroxide does not
necessarily corrode stainless steel instruments, although in practice
some types of stainless steel can be damaged. Sodium hypochlorite is
corrosive both to stainless steel and autoclaves, and, if used, must be
completely rinsed off before autoclaving.

The WHO document also recommended that decontamination procedures for
confirmed or suspected cases of TSE and persons with known risk factors
for TSE be considered with regard to the level of infectivity of the
tissue involved. Instruments and surfaces in contact with tissues of low
or no detectable infectivity would generally undergo routine cleaning
and disinfection, and no additional decontamination steps would be
required, whereas contact with tissues of high infectivity would require
additional decontamination procedures.

Various risk assessment models for HCT/Ps were presented at the June
2002 TSEAC meeting. It was pointed out that, while certain components of
a risk assessment model are known (e.g., age-specific CJD deaths;
age-specific tissue donations), other components (variables) are less
well known (e.g., the extent that the amount of TSE agent might be
reduced during processing steps; the extent of possible
cross-contamination by instruments or equipment used during processing).
Additional data about these variables are needed in order to provide
more accurate estimates of risk of exposure to infected tissues.

In deliberating these issues, the TSEAC may appropriately consider---as
it has for donor deferral criteria---the potential effects that various
recommendations might have not only on safety but also on supply of
corneas. In any estimate of the risks and benefits for a life-enhancing
product, one important risk is an insufficient supply. Eye banks are
small entities that may lack the resources to comply with additional
requirements.

## References

1.  World Health Organization Infection Control Guidelines for
    Transmissible Spongiform Encephalopathies---Report of a WHO
    Consultation, March 1999.

> <http://www.who.int/csr/en>

2.  CJD Incidents Panel, October 2001. Management of possible exposure
    to CJD through medical procedures.

> <http://www.doh.gov.uk/cjd/consultation>

3.  Transcript of TSEAC meeting on June 26-27, 2002

> <http://www.fda.gov/ohrms/dockets/ac/cber02.htm#TransmissibleSpongiform>

4.  Duffy P., Wolf J., et al. Possible person-to-person transmission of
    Creutzfeldt-Jakob disease. *New England Journal of Medicine.* 1974;
    290:692-3.

5.  Uchiyama K, Ishida C, et al. An autopsy case of Creutzfeldt-Jakob
    disease associated with corneal transplantation. *Dementia* 1994;
    8:466-73.

6.  Heckmann JG, Lang CJG, Petruch F, et al. Transmission of
    Creutzfeldt-Jakob disease via a corneal transplant. *Journal of
    Neurology, Neurosurgery & Psychiatry* 1997; 63: 388-90.

7.  Hogan, RN; Brown, P, et al. Risk of prion disease transmission from
    ocular donor tissue transplantation. *Cornea* 1999; 18(1): 2-11.
    **\[attached\]**

8.  Guidance for Screening and Testing of Donors of Human Tissue
    Intended for Transplantation, July 1997.

> <http://www.fda.gov/cber/tissue/docs.htm>

9.  Human Tissue Intended for Transplantation. Final rule. 62 FR 40429,
    July 29, 1997.

> <http://www.fda.gov/cber/tissue/docs.htm>

10. Guidance for Industry: Validation of Procedures for Processing of
    Human Tissues Intended for Transplantation, March 2002.
    **\[attached\]**

11. Suitability Determination for Donors of Human Cellular and
    Tissue-Based Products. Proposed rule. 64 FR 52696, September 30,
    1999.

> <http://www.fda.gov/cber/tissue/docs.htm>

12. Draft Guidance for Industry: Preventive Measures to Reduce the
    Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and
    Variant Creutzfeldt-Jakob Disease (vCJD) by Human Cells, Tissues,
    and Cellular and Tissue-Based Products (HCT/Ps), June 2002.

> <http://www.fda.gov/cber/tissue/docs.htm>

13. Current Good Tissue Practice for Manufacturers of Human Cellular and
    Tissue-Based Products; Inspection and Enforcement; Proposed Rule. 66
    FR 1508, January 6, 2001.

> <http://www.fda.gov/cber/tissue/docs.htm>

# 

# CHARGE

FDA asks the TSEAC to consider whether specific methods for
decontamination of facility work surfaces and surgical instruments
should be introduced at this time, to prevent contamination and
cross-contamination by TSE agents during recovery and processing of
ocular tissue, in cases where post-donation information reveals that a
donor had or may have had a TSE. Should these methods be used routinely
by eye banks, or only as additional procedures in cases of known or
suspected TSE in a donor? Should these methods be used in recovery and
processing of other tissues with low risk of containing TSE infectivity,
either for cases of known or suspected TSE or routinely?

# 

# QUESTIONS

Considering (a) current practices using conventional methods of
decontaminating facility work surfaces and equipment/instruments used in
the recovery and processing of human tissues for transplantation, (b)
other precautions currently in place (e.g., aseptic techniques, donor
screening for TSE), and (c) concerns about availability of tissues\-\--

1.  With regard to the recovery and processing of [ocular
    tissue]{.underline} from donors later discovered to have [TSE or
    possible TSE:]{.underline}

    A.  Does the committee believe that surgical instruments used in
        recovery and processing should be destroyed by incineration, if
        practical?

    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 (see Appendix). In particular, does the committee
        consider that only those WHO methods using sodium hydroxide or
        sodium hypochlorite are adequate?

    D.  If so, should such methods be employed by eye banks in the
        circumstance noted above?

    E.  Does the committee believe that the number of decontamination
        cycles performed with the instruments after the index donor
        tissue was recovered and processed should determine whether or
        not these additional specified decontamination procedures are
        needed? A decontamination cycle involves two stages: physical
        cleaning, typically using a mechanical washer/drier, followed by
        inactivation of any remaining infectious material, e.g., by
        autoclaving (2).

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

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]{.underline} from [cases of known or
    suspected TSE?]{.underline}

4.  With regard to the recovery and processing of [other tissues with a
    low risk of]{.underline} [TSE infectivity]{.underline}, should
    additional decontamination procedures be used
    [routinely]{.underline}, i.e. even when TSE has not been suspected?

### Appendix

#### WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies

##### Annex III Decontamination methods for Transmissible Spongiform Encephalopathies

The following recommendations are based on the best available evidence
at this time and are listed in order of more to less severe treatments.
These recommendations may require revision if new data become available.

Annex III lists the decontamination methods recommended by the
consultation in order of decreasing effectiveness.

1.  **Incineration**

    1.  Use for all disposable instruments, materials, and wastes.

    2.  Preferred method for all instruments exposed to high infectivity
        tissues.

2.  **Autoclave/chemical methods for heat-resistant instruments**

    1.  Immerse in sodium hydroxide (NaOH) and heat in a gravity
        displacement autoclave at 121 C for 30 min; clean; rinse in
        water and subject to routine sterilization.

    2.  Immerse in NaOH or sodium hypochlorite for 1 hr; transfer
        instruments to water; heat in a gravity displacement autoclave
        at 121 C for 1 hr; clean and subject to routine sterilization.

    3.  Immerse in NaOH or sodium hypochlorite for 1 hr; remove and
        rinse in water, then transfer to open pan and heat in a gravity
        displacement (121 C) or porous load (134 C) autoclave for 1 hr;
        clean and subject to routine sterilization.

    4.  Immerse in NaOH and boil for 10 min at atmospheric pressure;
        clean; rinse in water and subject to routine sterilization;

    5.  Immerse in sodium hypochlorite (preferred) or NaOH (alternative)
        at ambient temperature for 1 hr; clean; rinse in water and
        subject to routine sterilization.

    6.  Autoclave at 134 C for 18 minutes.

3.  **Chemical methods for surfaces and heat sensitive instruments**

    1.  Flood with 2N NaOH or undiluted sodium hypochlorite; let stand
        for 1 hr; mop up and rinse with water.

    2.  Where surfaces cannot tolerate NaOH or hypochlorite, thorough
        cleaning will remove most infectivity by dilution and some
        additional benefit may be derived from the use of one or another
        of the partially effective methods listed in Section 5.1 (Table
        8).