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

# Background

## Use of Common Equipment for Manufacturing of U.S. and European Plasma in the Context of vCJD Risk

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
potentially exposed to TSE agents 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 equipment decontamination.

## Comparison of U.S. and European Donor Deferrals for vCJD Risk

Donor deferrals for risk of exposure to vCJD in the U.S. differ from
those in Europe (see below).

[U.K]{.underline} [France]{.underline} [Europe]{.underline}

U.S. [\>]{.underline} 3 months[^1] [\>]{.underline} 5 years^4^ no
deferral

Source Plasma[^2]

[U.K]{.underline} [France]{.underline} [Europe]{.underline}

U.S.

Recovered Plasma[^3] [\>]{.underline} 3 months^1^ [\>]{.underline} 5
years[^4] [\>]{.underline} 5 years^4^

Europe [\>]{.underline} 6 months- 0 -- 6 months[^5] no deferral

Plasma for 5 years^1,^[^6]

fractionation

U.S. Source Plasma donors are not deferred for residence in most
European countries, 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 agents. These laboratory-based
studies use samples of product intermediates spiked with TSE agents that
are then subjected to the manufacturing step being studied for TSE
clearance.

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>).

## Blood and Blood Component Risk of TSE Infectivity

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 plasma for U.S.-licensed products.

In 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
might 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
unwarranted, given the very low risk of significant cross-contamination.
The TSEAC also urged development of validation methods to assess the
removal of TSE agents, in order to provide information about the ability
of cleaning methods under specific (context-dependent) circumstances
([http://www.fda.gov/ohrms/dockets/ac/cber01.htm#Transmissible%20Spongiform](http://www.fda.gov/ohrms/dockets/ac/cber01.htm#Transmissible Spongiform)).

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

**Questions**

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:

1.  Does the committee feel that current facility cleaning methods,
    e.g., the use of solutions of sodium hydroxide or sodium
    hypochlorite followed by 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 next?

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.

    b.  If not, please describe what additional studies would assist in
        development of such recommendations.

[^1]: For residence between 1980 and 1996

[^2]: Plasma collected by plasmapheresis

[^3]: Plasma from units of whole blood

[^4]: For residence from 1980 to the present

[^5]: 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.

[^6]: The majority of the European countries have a 6-month deferral for
    UK between 1980-1996.