Transmissible Spongiform Encephalopathies Advisory Committee
Meeting on June 28&29, 2001
Topic 2. Safety of FDA-Regulated Plasma Derivatives Prepared in Establishments Proposing to Use, on the Same Manufacturing Line, Plasma Which Does and Plasma Which Does Not Comply with Anticipated U.S. Standards with Regard to Donor Deferral for vCJD Risk Factors
Issue: FDA-licensed fractionators currently may use common manufacturing lines to process European and U.S. Plasma. If, as a vCJD precaution, the FDA recommends deferral of blood and plasma donors based on residence or travel in Europe, the agency will need to consider the safety implications of use of common manufacturing lines to process plasma which does and which does not meet FDA donor deferral recommendations for vCJD.
Most major manufacturers are licensed to use common equipment for the manufacture of plasma derivatives from U.S.-licensed plasma (for the U.S. market), and for European plasma, for non-U.S. products. The equipment is cleaned between sequential manufacturing campaigns, according to approved standard operating procedures. Common equipment is used in the preparation of anti-hemophilic factor (AHF), intravenous immune globulin (IGIV), albumin, and other plasma derivatives. A substantial proportion of the U.S. plasma derivative supply, including some unique products, may be affected by the issue under discussion. Some IGIV products, and potentially other investigational products which are under study for potential licensure in the U.S. also could be affected.
Since November 1999, FDA has recommended that blood and plasma not be collected from donors with a history of six or more months of residence or travel from 1980 through 1996 in the United Kingdom. Plasma from the United Kingdom also is not used for fractionation anywhere in Europe. At meetings in June 2000 and January 2001, the TSEAC was asked to review the current FDA policy in the context of current scientific data. At the January 2001 meeting, the TSEAC articulated concerns about the increasing BSE epidemic in Europe, and vCJD cases in France among people who had not lived in the United Kingdom. The TSEAC recommended deferral of donors who had lived in France, Portugal, or Ireland for 10 years or more between 1980 and the present, for risk of vCJD. FDA has considered this recommendation and, on June 28th, the TSEAC will be asked to provide additional advice on whether a donor deferral policy based on risk of BSE exposure should be adopted for all of Europe.
To date, no transmission of vCJD by blood or plasma derivatives has been reported. However, the possibility exists that plasma from a vCJD-incubating European donor could be processed with equipment that subsequently is used for processing of U.S. plasma, for U.S. licensed products. FDA seeks to be advised about a) the significance of the theoretical risk of contamination of U.S. products with vCJD based on plasma derivative manufacturing using common lines, and b) any additional precautions that should be taken to minimize such risks.
The scheduled presentations will provide the following information: (1) Review of the issue, with introduction of strategies to address the potential risk of vCJD contamination of U.S. products, (2) Review of scientific information about decontamination methods for TSEs, with attention to BSE/vCJD, and (3) Industry presentations on risk assessments, cleaning and decontamination methods currently in place, plans for cleaning and decontamination method validation for TSEs, studies relevant to TSEs in the setting of current common equipment usage, and effects upon supply of plasma derivatives in the U.S. and in Europe, if process changes or dedicated (i.e. separate) manufacturing lines were to be instituted.
Although epidemiological and laboratory-based studies have been negative to date, the risk of vCJD transmission by blood and plasma derivatives remains unknown. However, a single case of transfusion-transmission of BSE has been reported in a sheep, raising concerns that vCJD blood could be infectious (Lancet 356:999-1000, 2000 [In package for Issue 1]).
Abundant evidence exists that classical CJD transmission by blood is rare or non-existent. Furthermore, laboratory studies with several different TSE agents have suggested that plasma fractionation results in reduction of TSE infectivity (Refs. 1-3). However, little information is available to determine whether the vCJD/BSE agent behaves similarly to other TSE agents with regard to removal by plasma processing. Additionally, it is not well understood whether susceptibility of the vCJD agent to inactivation is similar to that of more thoroughly studied TSE agents. It is well established, however, that different TSE strains may demonstrate different levels of resistance to inactivation procedures. In the context of these uncertainties, FDA has chosen to address the issue of manufacturing equipment which could be exposed to vCJD contamination from European plasma, and which is subsequently used for U.S. products. The options to be considered include:
Questions for the Committee:
In the light of the TSEACís recommendations on donor deferral for risk of BSE exposure, and considering the available scientific data on risk of vCJD from transfusion, removal of TSE agents in plasma fractionation, and inactivation of TSE infectivity by standard decontamination procedures,
REFERENCES [included with package]
2. Foster, P.R. Prions and Blood Products. Ann. Med. 2000; 32: 501-13.
3. Lee, D.C., Stenland, C.J., Hartwell, R.C., Ford,
E.K., Cai, K., Miller, J.L.C., Gilligan,
K.J., Rubenstein, R., Fournel, M., and Petteway, S.R. jr. Monitoring plasma processing
steps with a sensitive Western blot assay for the detection of the prion protein. J. Virol.
Methods 2000; 84: 77-89.
4. Rutala, W. A. and Weber, W.J.
Creutzfeldt-Jakob Disease: Recommendations for
disinfection and sterilization. Clin. Inf. Dis. 2001; 32:1348-56.
5. Taylor, D.M., Inactivation of transmissible degenerative
encephalopathy agents: a
review. The Veterinary Journal 2000; 159: 10-17.
6. Section 6, WHO Infection Control Guidelines for