ISSUE SUMMARY—TOPIC 4 Part 2
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
ADVISORY COMMITTEE MEETING
July 18, 2003
Cleaning Procedures for Equipment Used in Manufacture of Plasma Derivatives, to Reduce the Theoretical Risk of Transmitting TSE Agents
Many major plasma derivative
manufacturers are licensed to use the same equipment to produce plasma
derivatives from U.S.-licensed plasma for the U.S. market and from European
plasma for non-U.S. products. The risk
of carryover contamination of any kind from one manufacturing lot to another is
minimized by rigorous cleaning of common equipment between lots and use of
dedicated tangential-flow membranes and chromatographic resins. All licensed facilities use specifically
validated, FDA-approved cleaning methods.
Typical practices include cleaning of tanks and other stainless steel
equipment with solutions of sodium hydroxide and/or sodium hypochlorite
followed by rinsing. These procedures
often are carried out at elevated temperatures. Cleaning effectiveness is usually assessed by testing for
residual protein or total organic carbon and/or by checking ionic strength of
rinsing solutions. In some cases,
notably columns that are reused for affinity chromatography, only mild cleaning
methods can be used, so as to maintain column integrity. Common equipment is used in the preparation
of anti-hemophilic factor (AHF), intravenous immune globulin (IGIV), albumin,
and other plasma derivatives. Validated
methods for decontamination of equipment
for TSE ’s have not yet been
established, in part because the relevant scientific information has not been
generated. At this meeting, the
committee will hear presentations about ongoing studies that are relevant to
Donor deferrals for risk of exposure to vCJD in the U.S. differ from those in Europe (see below).
U.K France Europe
3 months >
§ no deferral
U.K France Europe
Europe > 6 months- 0 – 6 months no deferral
Plasma for 5 years1,
U.S. Source Plasma donors are not
based both upon lower estimated risk of human dietary exposures to the BSE
agent in other parts of Europe compared to the UK and France , and upon the
experimentally demonstrated ability of manufacturing processes to remove TSE
Types of processes that can remove TSE agents under specific conditions include some precipitations, some filtrations, and the use of chromatographic resins. However, it remains the case that donors residing in Europe may have an increased risk of exposure to the BSE agent, compared to donors in the U.S., and that plasma manufactured from European donors may have a slightly higher chance of containing a donation from someone who is incubating vCJD. The risk that a European donor may be incubating vCJD is unknown. The vCJD epidemic in the UK is believed to be declining (Lancet. 2003 Mar 1; 361(9359): 751-2). To date, 132 deaths from probable or definite vCJD have occurred in the UK, 6 in France, and single cases in Italy and Ireland (http://www.doh.gov.uk/cjd/cjd_stat.htm; http://www.who.int/mediacentre/factsheets/fs180/en/; http://www.invs.sante.fr/publications/mcj/donnees_mcj.html)
To date, no transmission
of vCJD has been attributed to exposure to human blood, plasma, or plasma
derivatives. The UK CJD Incidents Panel
has categorized blood as a low-infectivity tissue (http://www.doh.gov.uk/cjd/consultation). Experimental studies with animal TSE models
suggest that blood and plasma may contain low titers of TSE agents. The possibility exists that plasma from a
European donor incubating vCJD might be processed with equipment that is
subsequently used to process
es. Plasma for U.S . licensed products.
June 2001, the TSEAC was asked whether FDA should be concerned about the
potential for cross-contamination of U.S. products with the vCJD agent from
European plasma during plasma fractionation.
The TSEAC was also asked whether any scientifically supported measures
should be taken to minimize such risks.
The committee heard presentations about methods and models for TSE
removal and inactivation. Industry
presented information that demonstrated the complexity of manufacturing
lines. At that time, the Plasma Protein
Therapeutics Association (PPTA) stated that about 50% of IGIV distributed in
the U.S. was manufactured in facilities that also manufacture separate batches
of non-U.S. plasma for the worldwide market.
Some unique products, such as fibrin sealant, were manufactured only in
facilities that also process non-U.S. plasma.
PPTA contended that the manufacturing of plasma derivatives in dedicated
lines reserved for U.S. plasma would not be feasible, because it would require
construction of new facilities and regulatory approvals that
would take years. The costs would be substantial, and
disruption of plasma derivative supplies would be inevitable. The TSEAC commented that, based on existing
studies, the risk of vCJD transmission by blood and plasma derivatives remains
unknown but is probably very low. They
also stated that precautions should be taken , but that
complete segregation of manufacturing lines for European and U.S. plasma is
the very low risk of significant cross-contamination. The TSEAC also urged development of validation methods for removal of
to provide information about the ability of cleaning methods in specific
(context-dependent) circumstances (http://www.fda.gov/ohrms/dockets/ac/cber01.htm#Transmissible%20Spongiform).
In this session the committee will hear an update of
methods and models to address the scientific question of how best to prevent
TSE cross-contamination of batches during manufacturing of products derived
from human plasma, a low-risk tissue.
Specific to today’s discussion of facilities and equipment used in plasma fractionation, the committee is asked to consider the following points:
· The risk that the starting material (plasma) might be contaminated with the agent of vCJD
· The likelihood that existing, conventional cleaning methods, especially those that include exposure to solutions of sodium hydroxide and/or sodium hypochlorite as cleaning agents for stainless steel equipment—methods that are validated by assessment of remaining total protein and/or total organic carbon—may clear contaminating TSE agents
· The removal of TSE infectivity by precipitations, filtrations, and discarding of resins during plasma processing
· Experimental observations that TSE infectivity may be retained by chromatographic columns
· The current state of knowledge about effective cleaning methods for TSE agents
Considering current facility cleaning practices, the low risk of vCJD infectivity in human plasma, and the ability of plasma fractionation methods to clear TSE agents:
Does the committee feel that current facility cleaning
methods, e.g. the
use of solutions of sodium hydroxide or sodium hypochlorite
, and extensive
rinsing cycles, are adequate to minimize the possibility that an infectious
dose of the vCJD agent may be carried over from one manufactured lot into the
2. Are the available scientific data sufficient for FDA to recommend specific methods for cleaning of equipment used in the manufacture of plasma derivatives with respect to TSE agent clearance or inactivation?
a. If so, please identify which methods can be recommended.
not, please studies would assist in
development of such recommendations. explain why.
 For residence between 1980 and 1996
 Plasma collected by plasmapheresis
 Plasma from units of whole blood
 For residence from 1980 to the present
 Most European countries do not have a donor deferral for France; 2 countries have a 6 month donor deferral for Ireland and France, and one country has a 6 month deferral for France alone.
 The majority of the European countries have a 6-month deferral for UK between 1980-1996.