Issue Summary

Blood Products Advisory Committee

June 13-14, 2002

# Topic I: Standards for Recovered Plasma

**Issue:**

Current standards for Source Plasma and recovered plasma are
inconsistent creating potential for inappropriate use of recovered
plasma that is unsuitable for the further manufacture of some products.

# Background:

Recovered plasma is a by-product derived from Whole Blood collection and
is distinguished from Source Plasma by the mode of collection and the
requirements for storage, pooling, dating and labeling of the product.
Source Plasma is collected by plasmapheresis, usually at volumes
significantly larger than that of recovered plasma and is frozen
immediately. Recovered plasma may be separated from individual units of
Whole Blood by aseptic techniques up to 5 days after expiration or
obtained from Fresh Frozen Plasma that has expired. Recovered plasma has
no expiration date and may be stored either in a frozen or liquid state.
The storage and shipping conditions for the product are dictated by the
short supply agreement the recovered plasma manufacturer has with the
consignee (as described below). Irrespective of the lack of standards
for recovered plasma and the requirements that are in place for Source
Plasma both products are used for further manufacture into the same
final products (i.e., IVIG, Factor VIII, IVD components, etc.).

# Presently there are only 4 citations in the CFR that relate to recovered plasma. These are:

# 

# 606.100(b)(18) -- \[SOP\] Procedures for preparing recovered plasma, if performed, including details of separation, pooling, labeling, storage, and distribution.

-   606.121(e)(5) -- Recovered plasma labels shall include:

    -   \(i\) In lieu of an expiration date, the date of collection of
        the oldest material in the container.

    -   \(ii\) The statement: "Caution: for further Manufacturing Use
        Only"; or "Caution: For Use in Manufacturing Nonjectable
        Products Only", as applicable

    -   \(iii\) For recovered plasma not meeting the requirements for
        manufacture into licensable products, the statement "Not for Use
        in Products Subject to License Under Section 351 of the Public
        Health Service Act."

-   606.160(b)(2)(iii) -- \[Records\] Separation and pooling of
    recovered plasma

-   606.106(d) -- \[Records\] When there is no expiration date, records
    shall be retained indefinitely.

To allow recovered plasma to be shipped in interstate commerce the
manufacturer must comply with the requirements for products deemed to be
in short supply as set forth in Title 21, Code of Federal Regulations,
Section 601.22 (21 CFR 601.22). To use the short supply provisions, the
licensed manufacturer of the final biological product (i.e., licensed
fractionator) must have in place with their supplier ".... such
procedures, inspections, tests or other arrangements as well as assure
full compliance with applicable regulations...."

# Historically there have been compliance issues associated with recovered plasma including:

-   Misbranding of plasma units

-   Lack of shipping or disposition records

-   Inadequate quarantine and destruction of unsuitable units

-   Shipment of untested, therapeutic, and autologous units

-   Lack of short supply agreements

-   Lack of product quality and consistency -- storage temperature and
    preparation failures

-   Non-uniform labels - registered facilities due not routinely submit
    labels for review

-   Labels incomplete or inaccurate

# 

**Discussion:**

# Due to the lack of consistency in the development of standard operating procedures, the complexity of donor screening procedures, infectious disease testing requirements, labeling requirements, and storage and shipping requirements defined under short supply agreements, the inadvertent release of inappropriate units of recovered plasma for further manufacture has been an on-going problem. Blood establishments that manufacturer recovered plasma must ensure that the plasma is collected from normal healthy donors who meet all donor suitability requirements. Keeping track of appropriate units for disposition can be a daunting task if the facility uses plasma from autologous collection for this purpose. The facility must ensure that the autologous donors are screened with the same medical history questionnaire used to screen allogenic donors, not an abbreviated questionnaire that is usually used for autologous collections, and that the autologous donors have met all other suitability requirements including the hemoglobin determination. The only exception to the donor suitability requirements that FDA has permitted has been the use of the plasma collected from autologous donors who donate more frequently than once in an 8 week period. FDA also requires that all appropriate infectious disease testing be perform and found negative or none reactive for each unit of recovered plasma to be use for further manufacture into injectable products with the exception of Hepatitis B Core antibody (anti-HBc). Units of recovered plasma that test either negative or positive for anti-HBc may be used for further manufacture into injectable products. The blood establishments must have procedures in place to ensure that units of plasma not suitable for further manufacture into injectable products are not released for that purpose. 

# In an effort to address concerns of deficiencies encountered over the years with the preparation, shipment, and use of recovered plasma, FDA is considering whether standards governing the manufacture and shipping of recovered plasma should be defined. This would provide a basis for FDA oversight and would allow for the manufacture of a more consistent product. Additionally, voluntary standards for recovered plasma are under discussion within the blood industry and FDA will need to decide whether to adopt industry standards through Agency guidance or rulemaking.

**Questions for the Committee:**

FDA seeks advice from the committee on the following issues:

1.  Should FDA develop specific product standards for recovered plasma?

2.  If yes, should the standards for recovered plasma include:

    a.  Negative screening tests results for anti-HBc and anti HTLV
        I/II?

    b.  Specification of allowable storage conditions and dating
        periods?

    c.  Labeling requirements similar to Source Plasma to distinguish
        appropriate use for manufacturing of injectables vs.
        non-injectables based on the preparation and storage conditions?

3.  Do committee members have additional suggestions regarding product
    standards for recovered plasma?