Current Considerations on Plasma for Further Manufacturing Obtained from Whole Blood Donors Alan E. Williams, Ph.D. Associate Director for Regulatory Affairs,

Current Considerations on Plasma for Further

Manufacturing Obtained from Whole Blood Donors

Alan E. Williams, Ph.D.Associate Director for Regulatory Affairs,

OBRR, CBER, FDA

Blood Products Advisory CommitteeApril 28-29, 2011

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Plasma for Further Manufacturing

• Fractionated plasma products are manufactured from two distinct plasma pathways in the US– Source Plasma (SP) constitutes 90% of the

fractionated plasma product starting material in the US

• SP is collected by plasmapheresis exclusively for use in further manufacturing, generally from paid, frequent donors.

• Frequent SP donors must meet specific donation standards to ensure donor health.

• SP is frozen immediately after collection to preserve labile plasma proteins (e.g. FVIII).

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Plasma for Further Manufacturing (cont.) • Recovered plasma (RP) constitutes the remaining 10% of plasma

fractionation starting material

• RP is an unlicensed product obtained from conversion at any time of unused Whole Blood (WB) Fresh Frozen Plasma (FFP - frozen within 8hrs), PF24 - plasma frozen within 24 hrs, or other WB plasma.

• RP may also be derived from apheresis FFP (frozen within 8 hrs) after its one year outdate. (Defined in regulation)

• Once RP produced, there is limited regulatory oversight. Product standards are defined in “Short Supply Agreements” (SSA) between the Blood Establishment and the fractionator, and manufactured products may be injectable or non-injectable.

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Seeking Improvements to the Recovered Plasma Paradigm

1. Conversion of apheresis plasma for transfusion at any time for use in further manufacturing would enable more efficient inventory control at blood establishments.– increased plasma collection on mobile units– overall increase in plasma availability – conflicts with current regulatory definition of SP

Seeking Improvements to the Recovered Plasma Paradigm

2. FDA seeks to establish standards for WB-derived plasma shipped for further manufacturing into injectable plasma derivatives to reduce variability of the starting material.

Seeking Improvements to the Recovered Plasma Paradigm

3. Ensure that collections from WB donors are generally intended for transfusion consistent with donor expectations.

Seeking Improvements to the Recovered Plasma Paradigm

4. The blood community has requested that FDA consider defining a new plasma product (with a different name) that would replace RP with plasma products more closely resembling Source Plasma

History

• Defining major new plasma product standards has been complex

• 2004 FDA-sponsored Plasma Workshop to discuss plasma quality as a possible variable for fractionation

• Concurrent and Component Plasma product concepts described at April, 2009 BPAC

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CONCURRENT PLASMA

April, 2009 BPAC : Concurrent Plasma (CCP)

April, 2009 - CCP was proposed by FDA as plasma for further manufacturing separated from licensed Whole Blood collection, plasma collected concurrently with cellular components by apheresis, or one-way conversion (at any time) of existing licensed FFP or WB-PF24 collected concurrently with a cellular product. – “Intent” of collection for transfusion is inherent in Concurrent

Plasma definition.

– FDA described a multi-tiered approach to product labeling. 10

Concurrent Plasma (CCP)

• BPAC recommended clarification of product standards and simplification of labeling for concurrent plasma

• April, 2011 - Concurrent Plasma product standards and labeling are the major topic for discussion at today’s session.

Mark Weinstein, OBRR FDA

Freezing temperature (-20 degrees C)

Time to freezing (24, 72 hrs)

Shelf life (up to 3 years)

FVIII content (70 IU/ml)11

COMPONENT PLASMA

April, 2009 BPAC : Component Plasma (CMP)

• April, 2009 - Component Plasma was proposed by FDA as plasma collected as a sole plasmapheresis product from WB donors or through conversion at an time of FFP collected from WB donors as a sole plasmapheresis product.

• BPAC expressed concerns about collection of plasma for fractionation as sole product from WB donors due to donor expectation of donation for use in transfusion

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Current FDA Consideration Component Plasma (CMP)

• April, 2011 – Licensed apheresis FFP collected as a sole product can be converted to Component Plasma for further manufacturing after its one year outdate – Parallels current FFP conversion policy– Preserves concept of WB donation generally intended for

transfusion– Solo FFP collection uncommon per blood community

- FFP-stand alone collections likely to be male and AB (likely to be transfused)

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Current FDA Consideration Component Plasma (CMP)

• April, 2011 -

– Standards for Component Plasma are inherently met since derived only from FFP (frozen within 8 hours), or potential equivalent

– CP product shelf life will be 3 years from date of collection

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RECOVERED PLASMA

Recovered Plasma

• April, 2011 - Any Plasma not meeting standards for CCP or CMP may still be shipped for further manufacturing under short supply agreement.

• Limited to use for non-injectables.

Concurrent and Component PlasmaOverall FDA Considerations

√ Product names - Concurrent and Component Plasma

√ Define pathway for immediate conversion of concurrently collected apheresis FFP collected under WB donor standards and (potentially a future FP24)

√ Assure that transfusion remains the primary intent of WB donation (BPAC 2009)

√ Promote high quality starting material to make

injectable plasma derivatives18

Concurrent and Component Plasma Overall Considerations (cont.)

√ Investigate effects of time to freeze, time to separation, freezing and storage temperature

√ Labeling and processing compatible with current blood center and fractionation operations (Labeling simplified per BPAC recommendation April, 2009)

√ Additional standards under consideration are largely consistent with current fractionator practices for accepted plasma starting material

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Concurrent and Component Plasma Overall Considerations (cont.)

√Consider harmonization with EU plasma standards – desirable but not mandatory

√Retain regulatory pathway for plasma not meeting CCP or CMP standards to be used for non-injectable products

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Current Sources of Plasma for US Plasma Derivative Manufacture

Phlebotomy Whole Blood

Source Plasma

(Infrequent)

Unlicensedrecovered plasma

Plasma Derivatives or non - injectable products

Plasma for Transfusion (24 h Plasma, FFP, Plasma Cryo

Reduced)

Current Sources of Plasma for US Plasma Derivative Manufacture

AutomatedApheresis

Plasma for Transfusion ( Apheresis FFP)

collected + RBC, Plts

Convert anytime

Whole Blood Donor Standards

AutomatedPlasmapheresis

Source Plasma

Donor Standards

1 year before

conversion

Source Plasma

Current Sources of Plasma for US Plasma Derivative Manufacture

Phlebotomy Whole Blood

Source Plasma

(Infrequent)

Unlicensedrecovered plasma

Plasma Derivatives or non -injectable products

Plasma for Transfusion (24 h Plasma, FFP, Plasma CryoReduced)

Current Sources of Plasma for US Plasma Derivative Manufacture

AutomatedApheresis

Plasma for Transfusion (Apheresis FFP)

collected + RBC, Plts

Convert anytime

Whole Blood Donor Standards

1 year outdate

Phlebotomy Whole Blood

LicensedConcurrent Plasma

(with standards)

Plasma Derivatives or non-injectable products

Plasma for Transfusion (24 h Plasma, FFP, Plasma Cryo-Reduced)

FDA Current Consideration

Sources of Plasma for US Plasma Derivative Manufacture

Under Whole Blood Donor Standards

AutomatedApheresis

Plasma for Transfusion (Apheresis FFP)

collected + RBC, Plts

Convert anytime Convert

anytime

LicensedComponent Plasma

Plasma for Transfusion plasmapheresis FFP

1 year before conversion

Source

Plasma (Infrequent)

23Recovered Plasma option also remains available for non-injectable products

FDA Current Consideration

Sources of Plasma for US Plasma Derivative Manufacture

Under Whole Blood Donor Standards

Phlebotomy Whole Blood

LicensedConcurrent Plasma

(with standards)

Plasma Derivatives or non-injectable products

Plasma for Transfusion (24 h Plasma, FFP, Plasma Cryo-Reduced)

FDA Current Consideration

Sources of Plasma for US Plasma Derivative Manufacture

Under Whole Blood Donor Standards

AutomatedApheresis

Plasma for Transfusion (Apheresis FFP)

collected + RBC, Plts

Convert anytime Convert

anytime

LicensedComponent Plasma

Plasma for Transfusion plasmapheresis FFP

1 year before conversion

Source

Plasma (Infrequent)

ISSUE

FDA seeks the advice of the Committee on appropriate manufacturing standards for plasma products collected from Whole Blood donors to make injectable plasma derived products.

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