TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
ADVISORY COMMITTEE MEETING
February 12 and 13, 2004
Silver Spring, MD
Issue Summary, Topic 4.C
The Use of Bovine-derived Products in the Manufacture of
Vaccines and Allergenic Products
Current Regulatory
Approach to Vaccines and Allergenic Products Manufactured with Bovine-derived Materials
Vaccines and allergenic products may utilize bovine-derived
materials during manufacturing or in the final formulation. FDA and CBER have requested, in a series of
letters and in a Points to Consider document on cell substrates (1993), that
materials from cattle born, raised, or slaughtered in countries where BSE is
known to exist not be used in the manufacture of FDA-regulated products
intended for administration to humans
; FDA has referenced the USDA (APHIS) list of BSE-countries. Since BSE has spread beyond Europe, it has become increasingly difficult to ensure consistent sourcing of all bovine materials from BSE-free areas. Switching sources for bovine-derived materials to countries not on the USDA list requires considerable time and raises a number of issues related to products that are in distribution, products that are in the process of being manufactured, as well as cell and seed banks that have been established prior to the recognition of BSE in a country.
Bovine-derived
products are used during the manufacture or formulation of a large number of
vaccines and allergenic products (molds). The bovine-derived products that are
commonly used include: fetal calf serum, beef muscle/organ extracts, gelatin,
and a variety of small molecules (such as, protein digests, lactose, Tween, and
glycerol). These materials are used in the derivation of master and working
cell banks, master and working bacterial and viral seed banks, cell culture and
fermentation, immunogen purification, and product formulation.
In an effort to minimize risks from TSE agents, FDA has:
·
Requested manufacturers to source bovine materials from
non-BSE countries
·
Reviewed the use of all bovine-derived materials and
their sources for licensed and IND products
·
Encouraged the use of non-animal sources when feasible
In addition to these measures,
product labeling provides risk communication and the Office of Vaccines
Research and Review website contains a discussion of BSE-related issues that
have arisen (vide infra). For
products that contain human serum albumin (e.g., the mumps, measles, and
rubella vaccine), the warnings section of the package insert contains the
statement: “This product contains
albumin, a derivative of human blood. Based on effective donor screening and
product manufacturing, it carries an extremely remote risk for transmission of
viral diseases. Although there is a theoretical risk for transmission of
Creutzfeldt-Jakob disease (CJD), no cases of transmission of CJD or viral
disease have ever been associated with the use of albumin.”
In 2000, CBER learned that its
recommendations regarding sourcing of bovine-derived materials were not
universally followed for all vaccines and allergenic products. OVRR reviewed
the use of bovine-derived products and their sources for all vaccines and
allergenic products. Recommendations were made to the affected manufacturers
and subsequently discussed in a joint session with the TSE Advisory Committee
and the Vaccines and Related Biological Products Advisory Committee [see, http://www.fda.gov/cber/bse/bse.htm]. Issues that were discussed included: the use
of fetal calf serum from the U.K. in the establishment of several master and
working seeds and cell banks, the use of European-sourced beef muscle/organ
extract for bacterial fermentation, the use of European-sourced gelatin
derivatives, and the use of a number of European-sourced low molecular weight
materials in vaccine manufacture. In assessing the potential risk of
vaccines, CBER and the joint Committees considered: (1) the likelihood that any
cattle that were used might be infected (i.e., the time period and country of
origin) and animal husbandry procedures; (2) the amount of bovine material that
might be present in the final vaccine; and (3) the inherent infectivity of the
various types of bovine materials that were used. The joint Committees
concluded that the risk of vCJD posed by vaccines in the scenarios presented
was theoretical and remote. They also noted that the benefits of vaccination
far outweigh any remote risks of vCJD. However, the
joint Committees recommended that: (1) bovine-derived materials used in the
routine production of vaccines and sourced from countries on the USDA list
should be replaced with bovine-derived materials from countries not on the USDA
list; (2) working bacterial and viral seed banks and working cell banks that
were established using bovine-derived material from countries on the USDA list
be re-derived using bovine-derived materials from countries not on the USDA
list; (3) master cell and seed banks established using bovine-derived materials
from countries on the USDA list need not be re-derived with bovine-derived
materials from countries not on the USDA list, the risk to altering the vaccine
through re-derivation being significantly greater than the theoretical risk
from the BSE agent; (4) these issues are of public concern and the public
should be informed about the safety of vaccines that used bovine-derived
materials from countries on the USDA list and the assessment of the nature of
any risk for vCJD from such vaccines.
These recommendations from CBER and the Advisory Committees have been
implemented for vaccines. Several similar issues were identified with
allergenic mold extracts; the mold master stocks were re-derived.
A number of bovine-derived
materials that are used in U.S.-licensed vaccines, and in vaccines under
development, are sourced from, inter alia, North America (the U.S. or Canada)
or Canada. These bovine-derived materials are used either in manufacture or in
the derivation or cell and seed banks. Based on an continuing assessment of
risks and benefits, the Office of Vaccines Research and Review has not
requested manufacturers to seek alternate sources of bovine-derived materials
for products where Canadian sourced materials are, or have been, used.