UNITED STATES OF AMERICA

P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S

8:34 a.m.

DR. SMALLWOOD: Good morning, and welcome

to the second day of the 81st Meeting of the Blood

Products Advisory Committee.

I'm Linda Smallwood, the Executive

Secretary. I will be reading a brief announcement

that pertains to the proceedings for today.

This brief announcement is in addition to

the Conflict of Interest Statement read at the

beginning of the meeting on yesterday, and it is a

part of the public record for the Blood Products

Advisory Committee Meeting on October 22nd, 2004.

This announcement addresses conflicts of

interest for Topic 3. Drs. Charlotte Cunningham‑

Rundles, Jonathon Goldsmith, Liana Harvath, Matthew

Kuehnert, Kenrad Nelson, Keith Quirolo and George

Schreiber, have been appointed as temporary voting

members.

The Food and Drug Administration has

prepared General Matter Waivers for the special

government employees participating in this meeting who

required a waiver under Title 18, United States Code

Section 208.

Dr. Michael Busch is employed by Blood

Systems. He has contracts, is a researcher, speaker

and an advisor for firms that could be affected by the

discussions.

Dr. Theresa Smith is employed by the

National Center for Infectious Diseases, in Fort

Collins, Colorado, and Dr. Susan Stramer is employed

by the American Red Cross.

In addition, there maybe regulated

industry and other outside organization speakers

making presentations. These speakers have financial

interests associated with their employer, and with

other regulated firms.

They were not screened for these conflicts

of interest. At this time I am asking if there are

any declarations to be made by any of the participants

at this meeting, please do so at this time?

(No response.)

DR. SMALLWOOD: For those who were not here

yesterday, I just wanted to announce the tentative

meetings, the tentative meeting dates for 2005, for

the Blood Products Advisory Committee.

Those dates are March 17th and 18th, July

21st and 22nd, December 1st and 2nd. Again, these are

tentative and you will be notified when these dates

are confirmed through the normal, appropriate

channels.

At this time I will turn over proceedings

of this meeting to the Acting Chairman, Dr. James

Allen.

DR. ALLEN: Good morning. We'll start our

deliberations this morning by listening to a series of

updates. The first is the summary of the Plasma

Workshop held August 31st, through September 1st, this

year, by Dr. Mark Weinstein.

DR. WEINSTEIN: Thank you, we have the

slides, please. You'll be controlling the slides?

Okay, thank you.

I would like to review topics that were

discussed at the Workshop on Plasma Standards. I will

give you a review of the, next slide please. Of the

objectives of the workshop, a meeting summary, a

summary of the agenda, and some of the highlights that

were addressed during the meeting.

And some of our future actions. Can I

have the next slide? The objective of the meeting was

to obtain information to aide us in the development of

regulatory standards for plasma.

Particularly for recovered plasma,

including labeling, freezing, storage and shipping

conditions. We also wish to review the scientific

data, regulatory requirements and current industry

practices, regarding freezing, storage and shipping of

plasma.

Another objective was to see whether we

could help to harmonize our regulations with those of

other regulatory bodies. And fourth objective was to

ensure that any regulatory decisions that are made,

are based on the science, the need for change and the

practicality of implementing any change in

regulations. Next slide.

Regarding our, the goals of the, with

regard to policy making, we want one to be able to

identify the quality of plasma through labeling, that

indicates the conditions under which the plasma was

prepared, including conditions of freezing.

We want to remove barriers to conversion

of plasma collected with the intention of its use in

transfusion, to its use in fractionation. Current

regulations reduce the flexibility to do this.

While relaxing some barriers, we need to

retain some distinctions, but only those that are

important. The distinctions that are being considered

include labeling that would distinguish plasma coming

from a whole blood collection, versus an apheresis

collection, product characterization based on intended

use at the time of collection, and conditions of

freezing.

We also wish to have our regulatory

standards conform to the scientific state‑of‑the‑art.

Next. Now to review the agenda of the meeting.

On the first day of the workshop we have

a presentation about recommendations of the June,

2003, BPAC, that addressed recovered plasma standards,

and we also had an overview of current FDA

regulations.

In brief, there was a lack of regulations

for recovered plasma, and there was a need to develop

specifications for allowable storage conditions and

dating periods.

We had a presentation from the consumer

community that emphasized the need for high quality

plasma products in the United States and

internationally.

We also have a very extensive review of

the scientific literature that covered the effects of

freezing, of rate of freezing and storage temperatures

on the integrity of plasma proteins.

The purpose of this review was to help

provide us with a scientific rationale for regulations

that might be proposed. Next slide, please.

We then had presentations from the

international community on their standards and the

rationale, and their rationale for freezing, storage

and shipping conditions of plasma.

This included standards presented by the

Council of Europe, European Pharmacopoeia, Canada and

Australia. Representatives of plasma fractionation

and blood collection industries, reviewed their

current practices about freezing, storage and shipping

of plasma, and raised their concerns about the impact

of potential changes on their operations.

The panel discussion followed these

presentations, which further clarified regulatory and

industry positions. Next slide, please. Here are

some of the major points that came about from the

review of the scientific literature.

And I think these are very important. It

gives a frame work for at least the scientific basis

of some of our thinking. Loss of factor activity, as

reflected in lower product yield, may be regarded as

one measure of a reduction in plasma quality.

Loss of activity indicates that proteins

are being altered, potentially through aggregation,

proteolysis or conformational change. Now is a

surrogate marker for proteins that can be altered

during this shipping, freezing, storage process.

Factor 8 is currently regarded as the most labile

therapeutic plasma protein.

Conditions affecting Factor 8, may affect

other plasma proteins in unknown ways. Again the

notion that Factor 8, can be considered as a surrogate

marker, and that the yield of Factor 8 can be

considered as a measure of plasma quality.

I mention that delayed freezing decreases

Factor 8 activity in plasma. Preservation of labile

components in plasma is optimal up to six hours after

donation.

Factor 8 loses about 15 percent of its

activity when stored from 16 to 24 hours before the

plasma is frozen. An additional losses can occur if

it is stored for longer than 24 hours.

A very important point that was raised,

emphasized the number of times during the scientific

presentation is that the rate of freezing is very

important.

Rapid freezing, such as freezing two minus

30 degrees in 30 minutes, gives a better Factor 8

yield than freezing it at minus 30 degrees over a much

longer period of time, say three to four hours, or

even longer.

Storage within minus 20, to minus 40

degrees, appears to have little affect on product's

quality, as long as freezing, as long as the freezing

rate is optimized.

It's more important to maintain a steady

storage temperature in this range of minus 20 to minus

40 degrees, than an absolute temperature.

And finally it is uncertain whether the

time to freeze, way to freeze in storage or shipping

temperatures, affect product safety. And this is an

area that needs further investigation. Next slide,

please.

The chart shows the current U.S. FDA

standards for plasma. One of our objectives was to

see about the chances of potentially harmonizing our

regulations with those of Europe.

I'll point out some of the areas that are

in contrast, that are now in contrast with the

European standards. First of all, our source plasma

is to be frozen immediately upon collection.

It is to be frozen at minus 20 degrees or

lower. Our regulations say nothing about the rate of

freezing. It can be stored at minus 20 degrees for

ten years, and it can be shipped at minus five

degrees.

One fact that emerged from the workshop,

is that the current shipping of plasma, that plasma is

generally now shipped at minus 20 degrees or below.

And so this standard of minus five degrees

is not really what is the industry standard at

present. Fresh frozen plasma made from whole blood or

plasm apheresis, should be frozen within eight hours.

It can be frozen, stored and shipped at minus 18

degrees or lower, and stored for a year.

The freezing, storage and shipping

temperatures of recovered plasma are not defined.

Next slide. In contrast, the European Pharmacopoeia

makes a distinction between plasma use to make labile

proteins, such as Factor 8, versus the so‑called non‑

labile proteins, like immunoglobulins and albumin.

The time to freeze from collection to

freezing, to the time to freeze can be within 24 or 72

hours, depending on the product to be made. And

again, this is in contrast to our source plasma which

is supposed to be frozen immediately.

Plasma is to be frozen at minus 30 degrees

or below, at, if the product is to made, that is to be

made is a labile protein. Or at minus 20 degrees or

below for non‑labile proteins.

Storage and shipping conditions are at

minus 20 degrees or below. For plasma for

transfusion, the Council of Europe recommends freezing

to minus 30 degrees, within one hour, and storage

temperatures at minus 18 to minus 25 degrees, for a

three‑month dating period, and minus 25 degrees and,

below minus 25 degrees, if there is a 24‑month dating

period.

So the idea of labile proteins freezing to

minus 30 degrees, the rapid rate of freezing are in

line with some of the scientific data that we heard

earlier on in the meeting, this idea of labile versus

non‑labile proteins is reflected in some of these

regulations and standards. Next slide, please.

The fractionation industry presented their

perspective on potential changes in the regulations

for freezing and storage and shipping of plasma.

These summarize a number of the points that were

raised by the industry.

Final products manufactured under current

storage and shipping requirements, are safe and

effective. Increased yield of plasma‑derived Factor

8 is not a driver for manufacturing. Yield is not a

regulatory issue.

Our current regulations that allow for

temperature excursions give flexibility to

manufacturers, changes in allowing for these

excursions would limit the availability of plasma for

use in manufacturing, and add to compliance

challenges.

Changing freezing temperatures would be

costly and increase the cost of plasma. And resources

spent in changing freezing and storage temperatures,

could be better spent elsewhere. Next slide.

The blood collection industry also

presented their perspective on proposed changes.

There was a wish not to change the definition or

expiration date of source plasma.

Most plasma is used to make non‑labile

proteins. Factor 8 activity decreases the time to

freeze, but there's no change in its efficacy. There

is no reason why preservation of Factor 8 activities

should drive the standards, since it is a small part

of the market.

Manufacturers specify the requirements of

plasma according to procedures they have already

validated. FDA should focus its efforts on donor

safety, donor qualifications and good manufacturing

practices.

Labeling can indicate expiration date,

anticoagulant time to freeze, freezing and storage

temperatures. And finally, there's no compelling

reason to change requirements for freezing and

storage.

The next day, meeting, next slide, please.

The second day of the workshop, we had a review of

concepts of regulations, what regulations of the

covered plasma.

And we had presentations by FDA, the blood

industry, the plasma industry, and this was followed

by a panel discussion. Next slide. This slide

summarizes some of the points made at the June, 2002,

BPAC meeting and FDA proposals for recovered plasma.

First of all, it was recommended that FDA

should develop standards for recovered plasma. FDA

proposed the term component plasma to replace the

terminology recovered plasma, because recovered plasma

has a negative connotation.

Component plasma would be defined as

plasma that is collected manually or by apheresis,

either separately or concurrently with other block

components from donors who meet all whole blood donor

suitability requirements.

Source plasma would be distinguished from

component plasma by defining source plasma as being

frozen immediately after collection.

Questions were raised at the 2002 BPAC

meeting, about having a ten year expiration date for

component plasma, and developing a time to freeze

standard for plasma used to manufacture labile

derivatives.

Again, reflecting the scientific evidence

that was available at the time. It was hoped at that

meeting that a workshop would provide data to address

the questions. Next.

This slide shows some other AABB proposed

standards for recovered plasma. These proposals were

derived in conjunction with America's blood centers,

the American Red Cross, ECA America, the Canadian

Blood Services, the Department of Defense, European

Blood Alliance and *(8:53:25).

PPTA, for the most part, endorsed these

recommendations, although they questioned a

recommended two‑year dating period for recovered

plasma. AABB proposed the name change for recovered

plasma to be plasma for manufacture.

The donor qualifications would be the same

as for allogeneic whole blood, including the

qualifications associated with infrequent plasma

apheresis donations.

Plasma for manufacture would be prepared

from plasma separated from whole blood, infrequent

plasma apheresis or by converting plasma for

transfusion to plasma for manufacture.

The expiration date is recommended to be

two years, and the label should state frozen within X

hours after phlebotomy and that the plasma should be

stored at minus 18 degrees and colder.

Next slide. There were some additional

comments, AABB proposed that freezing within a

certain, a specific time frame not be specified

because there are multiple types of products that can

become plasma for manufacture.

The fractionator can decide what plasma is

best, what is best for the manufacture of its product,

based on the labeled time to freeze. And short supply

agreements would not be necessary.

Regarding our future activity, last slide,

please. This workshop was only one opportunity to

collect information about standards for plasma. We

will continue information gathering through one‑on‑one

discussions with industry, particularly regarding

confidential or proprietary information.

And policy proposals w