DRAFT ISSUE SUMMARY

**BLOOD PRODUCTS ADVISORY COMMITTEE MEETING**

## MARCH 14-15, 2002

**TOPIC 4.**

**Bacterial and Fungal Contamination of Human Tissue Intended for
Transplantation**

# ISSUE

FDA seeks general discussion from the Blood Products Advisory Committee
(BPAC) regarding mechanisms for preventing bacterial and fungal
contamination and infectious disease transmission by human tissue
intended for transplantation.

# BACKGROUND

In November 2001, the Minnesota Department of Health received reports of
three previously healthy persons who died unexpectedly following
uncomplicated knee surgery, prompting the state health department to
issue a one-week ban of elective knee surgery. \[MMWR 50(6):1035-6,
November 23, 2001\]. All three patients had a rapid clinical course
consistent with septic shock, and blood cultures from one of the
patients yielded Clostridium sordelli (an anaerobic, spore-forming,
gram-positive bacterium found in the human gastrointestinal tract.) This
23-year-old patient had received a fresh, human knee osteochondral
allograft obtained from a cadaveric donor by a tissue bank. CDC's
investigation revealed that the identical bacterium was isolated from
the donor's contralateral knee and other non-implanted tissue, although
the tissue bank cultures, prior to distributing the tissues, were
negative. CDC then became aware of 5 other cases of septic arthritis
(occurring in April 2001) due to Clostridium septicum, and these
patients had all received allografts from the same tissue bank. CDC also
reported on 4 cases of septic arthritis following anterior cruciate
ligament reconstruction using tendon allografts, occurring in Florida
and Louisiana in 2000 \[MMWR 50(48):1080-1083, December 7, 2001\]. A
variety of bacteria were cultured in these 4 cases. Two cases had
received tendons from the same donor, and these tendons had been
irradiated. The two other cases received tissue from the same donor, and
these tendons had not been irradiated, and were inadvertently released.
Through epidemiological surveillance, the Centers for Disease Control
and Prevention (CDC) have identified approximately 20 additional cases
of septic arthritis (personal communication), the majority involving
Clostridium. These will be discussed at the meeting.

FDA has been regulating human tissue intended for transplantation since
1993, when it issued an interim rule that focused on screening and
testing the tissue donor for Human Immunodeficiency Virus (HIV),
Hepatitis B (HBV) and Hepatitis C (HCV), because of concerns with
importing tissue from donors who harbored these infectious agents. The
interim rule also contained requirements for having written procedures
and maintaining records related to donor screening and testing. The
Interim Rule was finalized in 1997, and the requirements are codified at
21 CFR part 1270. Section 1270.31(d) of the final rule requires that a
tissue establishment prepare, validate, and follow written procedures
for prevention of infectious disease contamination or
cross-contamination during processing. The "infectious disease" agents
include HIV, HBV, HCV, as well as bacteria, fungi, and TSE-associated
prions. FDA has recently proposed additional requirements for good
tissue practices, which would control the recovery, processing, storage,
packaging, labeling, and distribution of human cells, tissues, and
cellular and tissue-based products, to prevent the introduction,
transmission and spread of communicable disease agents and diseases to
recipients of these products. The requirements would include controls
over the facility, personnel, environment, equipment, supplies and
reagents, process controls, process validation, labeling controls, and
would introduce the concepts of tracking tissue from donor to recipient,
and vice versa, and reporting of adverse reactions. Currently, FDA does
not require reporting, and receives such reports voluntarily, through
its MedWatch program.

The eye-banking and tissue-banking communities are also concerned about
the possible transmission of infectious diseases to the recipients of
human tissue. Professional organizations have developed standards, which
their accredited members must follow. For instance, the American
Association of Tissue Banks Standards for Tissue Banking include
standards for recovery using aseptic or clean techniques, validated
processing methods to prevent contamination and cross-contamination, and
microbiological testing of tissue, and reporting of adverse outcomes.
These standards cover aerobic, anaerobic, and fungal cultures taken
prior to exposure to antibiotics, disinfection during processing or
terminal sterilization, and final packaging cultures prior to release.
The Eye Bank Association of America Medical Standards include
procurement procedures that use aseptic technique, microbiologic culture
at the time of corneal preservation in tissue culture medium containing
antibiotics (no longer recommended) or at the time of surgery, and
reporting of adverse reactions. Ocular and other tissue released for
transplantation is not necessarily purported to be sterile, unless
labeled so.

# Discussion

This topic is being presented to inform the members about the recent
reported cases of bacterial transmission to recipients of human
musculoskeletal tissue, resulting in significant morbidity and
mortality. In its presentation, CDC will make recommendations that may
prevent such occurrences. The Center for Biologics Evaluation and
Research, FDA will summarize the current regulations that attempt to
safeguard human tissue intended for transplantation from communicable
disease contamination and cross-contamination, and will explain the
proposed good tissue practice (GTP) regulations that would further
strengthen FDA's ability to help ensure a safe tissue supply. In
addition, members of the tissue-banking and eye-banking communities will
inform the committee about the steps that they have taken to address
their concerns about this problem.

# Charge

Committee members will be asked to provide a general discussion on the
mechanisms for preventing bacterial and fungal contamination and
infectious disease transmission by human tissue intended for
transplantation.