Revisions to the Requirements Applicable to Blood, Blood Components, and Source Plasma; Companion Document to Direct Final Rule

SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

the biologics regulations by removing, revising, or updating specific

regulations applicable to blood, blood components, and Source Plasma to

be more consistent with current practices in the blood industry and to

remove unnecessary or outdated requirements. FDA is taking this action

as part of the agency's ``Blood Initiative'' in which FDA is reviewing

and revising, when appropriate, its regulations, policies, guidance,

and procedures related to blood, blood components, and Source Plasma.

This proposed rule is a companion document to the direct final rule

published elsewhere in this issue of the Federal Register. FDA is

publishing this companion proposed rule under FDA's usual procedure for

notice and comment to provide a procedural framework to finalize the

rule in the event the agency receives a significant adverse comment and

withdraws the direct final rule.

DATES: Submit written comments on or before December 3, 1999. If FDA

receives any significant adverse comment regarding this rule, FDA will

publish a document withdrawing the direct final rule within 30 days

after the comment period ends. FDA then will proceed to respond to the

comments under this proposed rule using the usual notice and comment

procedures. Any parties interested in commenting on this document

should do so at this time.

If FDA receives no significant adverse comments within the

specified comment period, the agency intends to publish a document

confirming the effective date of the final rule in the Federal Register

within 30 days after the comment period on the direct final rule ends.

The direct final rule will be effective February 11, 2000.

ADDRESSES: Submit written comments on the proposed rule to the Dockets

Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers

Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Dano B. Murphy, Center for Biologics

Evaluation and Research (HFM-17), Food and Drug Administration, 1401

Rockville Pike, Rockville, MD 20852-1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background

This proposed rule is a companion to the direct final rule

published in the final rules section of this issue of the Federal

Register. This companion proposed rule will provide the procedural

framework to finalize the rule in the event that the direct final rule

receives any adverse comment and is withdrawn. The comment period for

this companion proposed rule runs concurrently with the comment period

for the direct final rule. Any comments received under this companion

rule will also be considered as comments regarding the direct final

rule. FDA is publishing the direct final rule because the rule contains

noncontroversial changes, and FDA anticipates that it will receive no

significant adverse comment.

A significant comment is defined as a comment that explains why the

rule would be inappropriate, including challenges to the rule's

underlying premise or approach, or would be ineffective or unacceptable

without a change. In determining whether a significant adverse comment

is sufficient to terminate a direct final rulemaking, FDA will consider

whether the comment raises an issue serious enough to warrant a

substantive response in a notice-and-comment process. Comments that are

frivolous, insubstantial, or outside the scope of the rule will not be

considered significant or adverse under this procedure. A comment

recommending a rule change in addition to the rule would not be

considered a significant adverse comment, unless the comment states why

the rule would be ineffective without additional change. In addition,

if a significant adverse comment applies to an amendment, paragraph, or

section of this rule and that provision can be severed from the

remainder of the rule, FDA may adopt as final those provisions of the

rule that are not subjects of a significant adverse comment.

If no significant adverse comment is received within the specified

comment period, FDA will publish a document within 30 days after the

comment period ends confirming that the direct final rule will be

effective February 11, 2000. Additional information about FDA's direct

rulemaking procedures is set forth in a guidance published in the

Federal Register of November 21, 1997 (62 FR 62466).

For a variety of reasons, FDA has decided to comprehensively review

and, as necessary, revise its regulations, policies, guidance, and

procedures related to the licensing and regulation of blood products.

FDA is issuing this companion proposed rule and the direct final rule,

published elsewhere in this issue of the Federal Register, as part of

the agency's ``Blood Initiative'' in which FDA is reviewing and

revising, when appropriate, its regulations, policies, guidance, and

procedures related to blood, blood components, and Source Plasma. The

``Blood Initiative'' is discussed in detail in the preamble to the

direct final rule. FDA emphasizes that for many of the changes

discussed below, additional issues related to the regulations now being

amended continue to be under consideration by the agency. Further, more

substantive changes may be proposed at a later date. Accordingly, any

comment recommending an additional change to these regulations will not

be considered to be an ``adverse comment'' unless the comment

demonstrates that the change being made in the direct final rule

represents a major departure from current regulations or accepted

industry standards, or cannot be implemented without additional

amendments to the regulations.

II. Legal Authority

FDA is proposing to issue this new rule under the biological

product and communicable disease provisions of the Public Health

Service Act (the PHS Act) (42 U.S.C. 262-264) and the drug, device, and

general administrative provisions of the Federal Food, Drug, and

Cosmetic Act (the act) (21 U.S.C. 321, 331, 351-353, 355, 360, 360j,

371, and 374). Under these provisions of the PHS Act and the act, FDA

has the authority to issue and enforce regulations designed to ensure

that biological products are safe, pure, potent, and properly labeled

and to prevent the introduction, transmission, and spread of

communicable disease.

III. Highlights of the Proposed Rule

FDA is proposing to amend the biologics regulations by removing,

revising, or updating specific regulations applicable to blood, blood

components, and Source Plasma to be more consistent with current

practices and to remove unnecessary or outdated requirements. As,

previously discussed, FDA is also issuing these amendments as a direct

final rule because the agency

[[Page 45376]]

has concluded they are noncontroversial and that there is little

likelihood that there will be comments opposing the rule. FDA

emphasizes that for many of the changes discussed in this document,

additional issues related to the regulations now being amended continue

to be under consideration by the agency. Further, more substantive

changes may be proposed at a later date. Accordingly, any comment

recommending additional changes to these regulations will not be

considered to be an ``adverse comment'' unless the comment demonstrates

that the change being made in the direct final rule represents a major

departure from current regulations or accepted industry standards, or

cannot be implemented without additional amendments to the regulation.

Below FDA is identifying each of the changes included in the proposed

rule.

Part 606 (21 CFR part 606) would be amended as follows:

Section 606.3, Definitions, would be amended to update the

definitions provided in the section for consistency with current

practice and usages.

The definition of ``Component'' in proposed Sec. 606.3(c), would be

amended to clarify that blood is obtained from a single donor and would

no longer include the wording ``single-donor unit.'' This change is to

clarify that blood components may be collected by means other than

separation from a unit of whole blood, such as by automated

plasmapheresis.

The definition of ``Plasmapheresis'' in proposed Sec. 606.3(e),

would be amended by removing the restriction that plasmapheresis may be

``immediately repeated, once'' because current automated plasmapheresis

collection practices often use more than two cycles of collection.

The definition of ``Plateletpheresis'' in proposed Sec. 606.3(f)

would be amended to provide for the common practice of collecting

plasma as a by-product of a plateletpheresis procedure in lieu of

returning all of the residual plasma to the donor.

The definition of ``Compatibility testing'' in proposed

Sec. 606.3(j) would be amended by removing the reference to serological

tests and making the definition more general to apply to all tests

performed to establish the matching of a donor's blood or blood

components with that of a recipient. This change will provide for

current practices used in compatibility testing, such as the electronic

crossmatch and the immediate spin crossmatch.

Section 606.100(b) and (d) would be amended to reflect changes in

terminology, requirements for testing, and availability of standard

operating procedures (SOP's) to be consistent with current practices.

Section 606.100(b) would also be amended by removing the references to

homologous and autologous transfusion because subpart F of part 606

applies to all blood products intended for transfusion. In addition,

the phrase ``unless this is impractical'' would be removed because it

is current good manufacturing practice (CGMP) to make the applicable

SOP's available in all areas where procedures are performed. Section

606.100(b)(7) would be amended by removing ``including testing for

hepatitis B surface antigen as prescribed in Sec. 610.40 of this

chapter'' because other tests, in addition to tests for hepatitis B

surface antigen, are now required and specific reference to this test

is unnecessary. Section 606.100(b)(18) would be amended by removing the

bracketed term ``salvaged'' because its use in Sec. 606.100 is

inconsistent with the use of ``salvaged plasma'' in Sec. 640.76 (21 CFR

640.76). Section 606.100(d) would be amended by removing references to

specific organizations because any SOP's meeting FDA requirements would

be acceptable, regardless of their source, and because FDA cannot

assure that SOP's adopted by particular organizations remain in

compliance with FDA regulatory requirements.

Section 606.121(a) would be amended by removing the reference that

the ``Guideline for Uniform Labeling of Blood and Blood Components'' is

available from the Docket Management Branch as this is no longer the

appropriate office from which to request this document and by removing

the reference to the American Blood Commission because the organization

no longer exists.

Section 606.121(d)(2) specifies the color requirements for

printing the container label and would be amended by adding ``or in

solid black'' because some blood centers use on-demand printers for

printing labels that do not have the capability to print in multiple

colors.

Section 606.121(e)(1)(ii) prescribes the specific anticoagulants

that shall be identified on the container label. Section

606.121(e)(1)(ii) would be amended by removing the references to the

names of specific anticoagulants. This change will allow for more

flexibility for the acceptance and use of new anticoagulants or changes

in nomenclature of existing anticoagulants without requiring amendments

to the regulations.

Section 606.122(f) specifies the warning statement required in the

instruction circular and would be amended by removing the reference to

``hepatitis'' and adding ``infectious agents'' to include a reference

to the additional infectious disease marker tests routinely performed

on blood and blood components because the product intended for

transfusion carries the risk of transmitting other infectious agents.

Section 606.122(n)(4) specifies that the instruction circular for

cryoprecipitated AHF shall contain instructions to thaw the product at

a temperature of 37 deg.C and would be changed to allow instructions

for thawing between 30 and 37 deg.C, permitting more flexibility in

the preparation of the component.

Section 606.151(b) would be amended, consistent with current

accepted practices, to permit SOP's to include use of recipient serum

samples less than 3-days old for compatibility testing if the recipient

has been pregnant or transfused within the proceeding 3 months.

Section 606.151(c) describes compatibility testing and would be

amended by changing ``the testing of the donor's cells with the

recipient's serum'' to ``the testing of the donor's cell type with the

recipient's serum type'' and by replacing ``agglutinating, coating, and

hemolytic antibodies, which shall include the antiglobulin method''

with ``incompatibility.'' This change is intended to accommodate the

use of such procedures as an immediate spin crossmatch and an

electronic crossmatch.

Section 606.151(e) would be amended by changing ``by the physician

requesting the procedure'' to ``by a physician'' to take into account

that a patient may have more than one physician in attendance at any

time.

Section 606.160(b)(2)(v) would be amended by changing ``person(s)

responsible'' to ``the person(s) performing the procedure'' to clarify

that the person(s) performing the labeling procedure is responsible for

documenting the performance of that procedure.

Section 606.170(b) would be amended by removing ``telegraph'' and

adding ``facsimile, express mail, or electronically transmitted mail''

to the possible methods by which the Director, Office of Compliance and

Biologics Quality, Center for Biologics Evaluation and Research, shall

be notified of a complication of blood collection or transfusion

resulting in a fatality.

Part 640 (21 CFR part 640) would be amended as follows:

Section 640.2(b) would be removed because Whole Blood collection

in open systems is no longer acceptable or has

[[Page 45377]]

it being performed for many years. Section 640.2(d) is removed. In

Sec. 640.2 paragraphs (c), (e), and (f) would be redesignated as

paragraphs (b), (c), and (d), respectively. Redesignated paragraphs (b)

and (c)(2) would be revised by removing references to the original

blood container because, to be consistent with current accepted

practices such as washing, freezing, deglycerolization, and division of

units using sterile connecting devices, the original blood container

may, in many cases, no longer be the final container.

Section 640.3(b) would be amended by adding a reference to

autologous donations to permit the collection of autologous Whole Blood

at intervals of less than 8 weeks, consistent with the current practice

of shorter time intervals between collections of blood and blood

components from donors participating in autologous collection programs.

Section 640.3(b)(3) would be amended to provide hematocrit and

hemoglobin values to be used when determining whether a potential donor

can donate Whole Blood, by adding to the end of the current paragraph

``or a hematocrit value of 38 percent, and for autologous donations, a

blood hemoglobin level which shall be demonstrated to be no less than

11.0 g of hemoglobin per 100 mL of blood or a hematocrit value of 33

percent.'' The acceptable hemoglobin and hematocrit values for

autologous donors are consistent with current industry practice and the

American Association of Blood Banks technical manual, 12th edition.

Sections 640.3(c)(1) and 640.63(c)(11) would be amended by

inserting ``after the age of eleven'' after the term ``hepatitis''

because establishments may collect Whole Blood from donors who have a

history of hepatitis prior to age eleven to be consistent with

recommendations in the FDA memorandum dated April 23, 1992, entitled ``

Exemptions to Permit Persons with a History of Viral Hepatitis Before

the Age of Eleven to Serve as Donors of Whole Blood and Plasma:

Alternative Procedure'' (21 CFR 640.120). Additional issues concerning

donors who have a history of viral hepatitis continued to be reviewed

by the agency and may be addressed in future rulemaking objectives.

Sections 640.3(c)(2) and 640.63(c)(12) would be amended by

changing the deferral period for donors of Whole Blood who have had

close contact with an individual having viral hepatitis from ``six

months'' to ``12 months.'' Similarly, Secs. 640.3(c)(3) and

640.63(c)(13) would be amended by changing the deferral period from

``six months'' to ``12 months'' for donors of Whole Blood who received

human blood, or any derivative of human blood which the Food and Drug

Administration has identified as a possible source of viral hepatitis.

These changes are consistent with recommendation made in the FDA

memoranda dated April 23, 1992, entitled ``Revised Recommendations for

the Prevention of Human Immunodeficiency Virus Transmission by Blood

and Blood Products and Revised Recommendations for Testing Whole Blood,

Blood Components, Source Plasma and Source Leukocytes for Antibody to

Hepatitis C Virus Encoded Antigen (Anti-HCV).'' In addition,

Secs. 640.3(c)(3) and 640.63(c)(13) would be amended by changing the

reference from a ``licensed establishment'' to a ``blood

establishment'' to clarify that the regulation applies to all

establishments engaged in the collection of blood and blood products.

Sections 640.3(e), 640.31(c), and 640.51(c) would be removed

because FDA has concluded that it is no longer necessary to defer

donors participating in red blood cell immunization programs.

Previously, donors participating in red blood cell immunization

programs were deferred for 12 months because fresh red blood cells were

used to immunize donors. Red blood cells now used in immunization

programs are carefully screened and quarantined thereby minimizing the

risk of transmitting known infectious agents. See FDA memorandum dated

March 14, 1995, entitled ``Revised Recommendations for Red Blood Cell

Immunization Programs for Source Plasma Donors'' for additional

information about current red blood cell immunization practices.

Section 640.4(b) would be amended by removing the word ``clinic''

and replacing it with the word ``center'' to reflect current

terminology and by changing the word ``licensed'' to ``blood'' to

clarify that the regulation applies to all blood establishments engaged

in the collection of blood and blood products. Section 640.4(d) would

be amended by removing the reference to the specific anticoagulant

formulae. Section 640.4(d)(1) through (d)(4) would be removed because

FDA has determined it is unnecessary to provide specific formulae for

anticoagulant solutions in the regulations and that manufacturers

should be able to use any anticoagulant approved by FDA for such use.

Sections 640.13(a), 640.22(a), 640.32(a), and 640.52(a) would be

amended to delete references to Sec. 640.4(d)(2) and (h), which would

be being removed. Section 640.4(g)(5) would be changed to include the

use of different anticoagulants in segments for compatibility testing

to be consistent with the use of different approved anticoagulants in

the manufacture of blood and blood products. Section 640.4(h) would be

removed because heparin anticoagulant solutions are no longer used for

the routine collection of blood.

Section 640.5(c) would be amended to be consistent with current Rh

factor testing practices by removing ``and for other Rh-Hr factors,''

because these tests are not routinely performed. The section would also

be changed to specify that blood testing negative using Anti-D Blood

Grouping Reagents may only be labeled ``Rh Negative'' if the

confirmatory testing includes tests for weak expressions of D. These

changes would be made to be consistent with current accepted practices

which designate that tests for weak expressions of D be performed and

the product labeled consistent with the results of those tests.

Sections 640.6(c) and 640.15(c) would be removed because the use

of more modern methods of manufacturing and equipment have eliminated

the use of pilot tubes attached to the blood units. In Sec. 640.15

paragraph (d) is redesignated as paragraph (c).

Section 640.16(a) would be amended by inserting ``or additive

solution'' after ``cryoprotective substance'' to reflect an additional

procedure for prolonging shelf life now in use in which all the plasma

is removed from a unit of blood.

Section 640.16(b) would be amended by removing all but the first

sentence. The removed text describes blood collection procedures to be

followed when using open vented systems. Use of open vented systems is

no longer consistent with CGMP and has not been used for many years.

All references to ``pilot tubes'' and ``pilot samples'' would be

replaced with the words ``sample(s)'' or ``segment(s)'' to reflect

current terminology for various testing specimens. The following

sections would be amended by replacing ``pilot tubes,'' ``pilot

samples,'' or ``pilot sample tubes'' with ``segments'' or ``samples''

as appropriate in Secs. 640.2(e)(1), 640.4(g) introductory text, and

paragraphs (g)(1), (g)(2), (g)(4), and (g)(5), 640.5, 640.15(a) through

(c), and 640.69(d) introductory text, and paragraphs (d)(1) through

(d)(4).

Section 640.23(a) would be amended to include the preparation of

Platelets prepared by automated collection procedures and to allow the

group and typing tests performed on Platelets prepared by apheresis to

be valid for a

[[Page 45378]]

period not to exceed 3 months, thereby, eliminating the necessity of

repeat testing of blood samples from donors participating in frequent

plasmapheresis collection procedures.

Section 640.24(b) would be amended by changing the time period for

separation of the platelet concentrate from ``4 hours'' to ``within the

time period specified in the directions for use for the specific

device.'' Similar changes would be made to the timeframe for the

storage of plasma that is set forth in Sec. 640.34(a) through (d) and

(e)(1) and the freezing of plasma set forth in Sec. 640.54(a)(2). These

changes, consistent with current accepted practices, permit more

flexibility by permitting different timeframes depending on the

particular blood collection device being used.

Sections 640.25(b) and 640.56(a) would be amended to require

testing only in those months in which blood products would be prepared

for use. This eliminates the need for performing quality control

procedures during those months when product is not being manufactured.

Sections 640.25(c), 640.56(c), and 640.71(a) would be amended to

update references to cite the ``Clinical Laboratories Improvement

Amendments of 1988 (CLIA)'' consistent with nomenclature in the

regulations implementing CLIA in 42 CFR part 493.

Section 640.34(d) would be amended by removing the reference to

storing platelet rich plasma at temperatures between 1 and 6 deg.C

because storage at such temperatures adversely affects platelet

function.

Section 640.34(e)(2) and (e)(3) would be amended to include the

proper name of the product ``Plasma, Cryoprecipitate Reduced'' as per

recommendations of the Blood Products Advisory Committee at the meeting

of September 18 and 19, 1997. Section 640.34(g)(2) would be amended to

permit for proof of continuous monitoring of the temperature to be

within acceptable ranges for the product as an alternative to requiring

the storing of the product in a manner to show evidence of thawing. FDA

believes that, with current technology, monitoring systems of freezers

used for storage are adequately sensitive and reliable to detect any

significant rise in storage temperature.

Section 640.62 requiring that a qualified licensed physician be on

the premises when donor suitability is being determined would be

amended to require a qualified licensed physician to be physically

available on the premises, or be available to attend to the donor

within 15 minutes, when a pheresis procedure is being performed, for

consultation and management of donor adverse reactions, except that the

qualified licensed physician shall be physically available on the

premises when red blood cell immunizations are being performed. FDA has

determined that a qualified licensed physician must always be readily

available, if needed, and shall be on the premises for red blood cell

immunizations.

Section 640.63(c)(3) would be amended by adding at the end of the

sentence ``or a hematocrit level of 38 percent,'' which is equivalent

to a hemoglobin level of 12.5 grams per 100 milliliters of blood, to be

consistent with current accepted practices.

Section 640.63(c)(5) would be amended by adding ``or total

plasma'' after ``A total serum'' to be consistent with current accepted

practice of using a capillary tube coated with anticoagulant for

fingerstick sample collection.

Section 640.65(b)(4) would be amended by changing ``in any 48-hour

period'' to ``2-day'' to permit more flexibility in scheduling donor

appointments and by adding the word ``manual'' to the phrases ``during

a plasmapheresis procedure'' to clarify that the regulation applies to

a manual plasmapheresis collection procedure, but does not apply to

automated apheresis.

Section 640.65(b)(5) would be amended by adding ``during a manual

plasmapheresis procedure'' after the phrases ``removed from the donor''

to clarify that the regulation applies to a manual plasmapheresis

collection procedure, but does not apply to automated apheresis.

Section 640.65(b)(8) would be added to address the collection of

Source Plasma using automated collection devices. The regulation

describes the frequency of collection consistent with Sec. 640.65(b)(4)

and (b)(5) and the volume of plasma to be collected during such

procedures consistent with the plasma collection volumes approved for

each device and with recommendations included in the FDA memorandum to

all plasma establishments dated November 4, 1992, entitled ``Volume

Limits for Automated Collection of Source Plasma.''

Section 640.72(a)(1) would be amended by replacing ``compiled

every 3 months'' with ``shall be available'' to eliminate the necessity

of compiling documents for review at specified periods of time.

IV. Analysis of Impacts

A. Review Under Executive Order 12866 and the Regulatory Flexibility

Act and the Unfunded Mandates Reform Act of 1995

FDA has examined the impact of the companion proposed rule under

Executive Order 12866 and the Regulatory Flexibility Act (5 U. S. C.

601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impact; and equity). The agency believes that

this proposed rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. This proposed rule is not

a significant regulatory action as defined by the Executive Order and

therefore is not subject to review under the Executive Order.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options to minimize any significant impact of a rule on

small business entities. Because the proposed rule amendments have no

compliance costs and do not result in any new requirements, the agency

certifies that the proposed rule will not have a significant negative

economic impact on a substantial number of small entities. Therefore,

under the Regulatory Flexibility Act, no further analysis is required.

This proposed rule also does not trigger the requirement for a written

statement under section 202(a) of the Unfunded Mandates Reform Act

because it does not impose a mandate that results in an expenditure of

$100 million or more by State, local, and tribal governments in the

aggregate, or by the private sector in any 1 year.

B. Environmental Impact

The agency has determined under 21 CFR 25.31(j) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

V. Paperwork Reduction Act of 1995

FDA tentatively concludes that this proposed rule contains no

collections of information. Therefore, clearance by the Office of

Management and Budget under the Paperwork Reduction Act of 1995 is not

required.

[[Page 45379]]

VI. Request for Comments

Interested persons may, on or before December 3, 1999, submit to

the Docket Management Branch (address above) written comments regarding

this proposal. Two copies of any comments are to be submitted, except

that individuals may submit one copy. Comments are to be identified

with the docket number found in brackets in the heading of this

document. Received comments may be seen in the office above between 9

a.m. and 4 p.m., Monday through Friday.

List of Subjects

21 CFR Part 606

Blood, Labeling, Laboratories, Reporting and recordkeeping

requirements.

21 CFR Part 640

Blood, Labeling, Reporting and recordkeeping requirements.

Therefore under the Federal Food, Drug, and Cosmetic Act, the

Public Health Service Act, and authority delegated by the Commissioner

of Food and Drugs, it is proposed that 21 CFR parts 606 and 640 be

amended as follows:

PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD

COMPONENTS

1. The authority citation for 21 CFR part 606 continues to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371,

374; 42 U.S.C. 216, 262, 263a, 264.

2. Section 606.3 is amended by revising paragraphs (c), (e), (f),

and (j) to read as follows:

Sec. 606.3 Definitions.

* * * * *

(c) Component means that part of a single-donor's blood separated

by physical or mechanical means.

* * * * *

(e) Plasmapheresis means the procedure in which blood is removed

from the donor, the plasma is separated from the formed elements and at

least the red blood cells are returned to the donor.

(f) Plateletpheresis means the procedure in which blood is removed

from a donor, a platelet concentrate is separated, and the remaining

formed elements are returned to the donor along with a portion of the

residual plasma.

* * * * *

(j) Compatibility testing means the tests performed to establish

the matching of a donor's blood or blood components with that of a

potential recipient.

3. Section 606.100 is amended by revising the introductory text of

paragraphs (b) and (d), and by revising paragraphs (b)(7) and (b)(18)

to read as follows:

Sec. 606.100 Standard operating procedures.

* * * * *

(b) Written standard operating procedures shall be maintained and

shall include all steps to be followed in the collection, processing,

compatibility testing, storage, and distribution of blood and blood

components for transfusion and further manufacturing purposes. Such

procedures shall be available to the personnel for use in the areas

where the procedures are performed. The written standard operating

procedures shall include, but are not limited to, descriptions of the

following, when applicable:

* * * * *

(7) All tests and repeat tests performed on blood and blood

components during manufacturing.

* * * * *

(18) Procedures for preparing recovered plasma, if performed,

including details of separation, pooling, labeling, storage, and

distribution.

* * * * *

(d) In addition to the requirements of this subpart and in

conformity with this section, any facility may utilize current standard

operating procedures such as the manuals of the organizations, as long

as such specific procedures are consistent with, and at least as

stringent as, the requirements contained in this part.

* * * * *

4. Section 606.121 is amended by revising paragraphs (a), (d)(2),

and (e)(1)(ii) to read as follows:

Sec. 606.121 Container label.

(a) The container label requirements are designed to facilitate the

use of a uniform container label for blood and blood components (except

Source Plasma) by all blood establishments.

* * * * *

(d) * * *

(2) The proper name of the product, any appropriate modifier(s),

the donor classification statement, and the statement ``properly

identify intended recipient'' shall be printed in solid red or in solid

black.

* * * * *

(e) * * *

(1) * * *

(ii) The name of the applicable anticoagulant immediately preceding

and of no less prominence than the proper name approved for use by the

Director, Center for Biologics Evaluation and Research.

* * * * *

5. Section 606.122 is amended by revising paragraphs (f) and (n)(4)

to read as follows:

Sec. 606.122 Instruction circular.

* * * * *

(f) The statements: ``Warning. The risk of transmitting infectious

agents is present. Careful donor selection and available laboratory

tests do not eliminate the hazard.''

* * * * *

(n) * * *

(4) Instructions to thaw the product for no more than 15 minutes

at a temperature between 30 and 37 deg.C.

* * * * *

6. Section 606.151 is amended by revising paragraphs (b), (c), and

(e) to read as follows:

Sec. 606.151 Compatibility testing.

* * * * *

(b) The use of fresh recipient serum samples less than 3-days old

for all pretransfusion testing if the recipient has been pregnant or

transfused within the previous 3 months.

(c) The testing of the donor's cell type with the recipient's serum

type by a method that will demonstrate incompatibility.

* * * * *

(e) Procedures to expedite transfusion in life-threatening

emergencies. Records of all such incidents shall be maintained,

including complete documentation justifying the emergency action, which

shall be signed by a physician.

7. Section 606.160 is amended by revising paragraph (b)(2)(v) to

read as follows:

Sec. 606.160 Records.

* * * * *

(b) * * *

(2) * * *

(v) Labeling, including initials of the person(s) performing the

procedure.

* * * * *

8. Section 606.170 is amended by revising paragraph (b) to read as

follows:

Sec. 606.170 Adverse reaction file.

* * * * *

(b) When a complication of blood collection or transfusion is

confirmed to be fatal, the Director, Office of Compliance and Biologics

Quality, Center for Biologics Evaluation and Research, shall be

notified by telephone,

[[Page 45380]]

facsimile, express mail, or electronically transmitted mail as soon as

possible; a written report of the investigation shall be submitted to

the Director, Office of Compliance and Biologics Quality, Center for

Biologics Evaluation and Research, within 7 days after the fatality by

the collecting facility in the event of a donor reaction, or by the

facility that performed the compatibility tests in the event of a

transfusion reaction.

(Information collection requirements approved by the Office of

Management and Budget under control number 0910-0116)

PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS

9. The authority citation for 21 CFR part 640 continues to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42

U.S.C. 216, 262, 263, 263a, 264.

10. Section 640.2 is amended by removing paragraphs (b) and (d), by

redesignating paragraphs (c), (e), and (f) as paragraphs (b), (c), and

(d), respectively, and by revising newly redesignated paragraphs (b)

and (c)(2) to read as follows:

Sec. 640.2 General requirements.

* * * * *

(b) Blood container. The blood container shall not be entered

prior to issue for any purpose except for blood collection. Such

container shall be uncolored and transparent to permit visual

inspection of the contents and any closure shall be such as will

maintain an hermetic seal and prevent contamination of the contents.

The container material shall not interact with the contents under the

customary conditions of storage and use, in such a manner as to have an

adverse effect upon the safety, purity, or potency of the blood.

(c) * * *

(2) A segment is properly attached and has not been removed, except

that blood lacking a properly attached segment may be reissued in an

emergency provided it is accompanied by instructions for sampling and

for use within 6 hours after entering the container for sampling;

* * * * *

11. Section 640.3 is amended by revising the introductory text of

paragraph (b), by revising paragraphs (b)(3), (c)(1), (c)(2), and

(c)(3) and by removing and reserving paragraph (e) to read as follows:

Sec. 640.3 Suitability of donor.

* * * * *

(b) Qualifications of donor; general. Except as provided in

paragraph (f) of this section and for autologous donations, a person

may not serve as a source of Whole Blood more than once in 8 weeks. In

addition, donors shall be in good health, as indicated in part by:

* * * * *

(3) For allogeneic donors, a blood hemoglobin level which shall be

demonstrated to be no less than 12.5 grams (g) of hemoglobin per 100

milliliters (mL) of blood; or a hematocrit value of 38 percent, and for

autologous donors, a blood hemoglobin level which shall be demonstrated

to be no less than 11.0 g of hemoglobin per 100 mL of blood or a

hematocrit value of 33 percent.

* * * * *

(c) * * *

(1) A history of viral hepatitis after the age of eleven;

(2) A history of close contact within 12 months of donation with an

individual having viral hepatitis;

(3) A history of having received within 12 months of donation,

human blood or any derivative of human blood which the Food and Drug

Administration has advised the blood establishment is a possible source

of viral hepatitis.

* * * * *

12. Section 640.4 is amended by removing paragraphs (d)(1) through

(d)(4) and (h), by redesignating paragraph (i) as paragraph (h), and

revising paragraphs (b) and (d), the introductory text of paragraph

(g), and paragraphs (g)(1), (g)(2), (g)(4), and (g)(5) to read as

follows:

Sec. 640.4 Collection of the blood.

* * * * *

(b) The donor center. The pertinent requirements of Secs. 600.10

and 600.11 of this chapter shall apply at both the blood establishment

and at any other place where the bleeding is performed.

* * * * *

(d) The anticoagulant solution. The anticoagulant solution shall

be sterile and pyrogen-free. Anticoagulant solutions shall be

compounded and used according to a formula approved by the Director,

Center for Biologics Evaluation and Research.

* * * * *

(g) Samples for laboratory tests. Samples for laboratory tests

shall meet the following standards:

(1) One or more segments shall be provided with each unit of blood

when issued or reissued except as provided in Sec. 640.2(e)(2) and all

segments shall be from the donor who is the source of the unit of

blood.

(2) All samples for laboratory tests performed by the manufacturer

and all segments accompanying a unit of blood shall be collected at the

time of filling the original blood container.

* * * * *

(4) All segments accompanying a unit of blood shall be attached to

the whole blood container before blood collection, in a tamper proof

manner that will conspicuously indicate removal and reattachment.

(5) Segments for compatibility testing shall contain blood mixed

with the appropriate anticoagulant.

* * * * *

13. Section 640.5 is amended by revising the introductory text and

paragraph (c) to read as follows:

Sec. 640.5 Testing the blood.

All laboratory tests shall be made on a specimen of blood taken

from the donor at the time of collecting the unit of blood, and these

tests shall include the following:

* * * * *

(c) Determination of the Rh factors. Each container of Whole Blood

shall be classified as to Rh type on the basis of tests done on the

sample. The label shall indicate the extent of typing and the results

of all tests performed. If the test, using Anti-D Blood Grouping

Reagent, is positive, the container may be labeled ``Rh Positive''. If

this test is negative, the results shall be confirmed by further

testing which shall include tests for the Rho variant

(Du). Blood may be labeled ``Rh Negative'' if further

testing is negative. Units testing positive after additional more

specific testing shall be labeled as ``Rh Positive.'' Only Anti-Rh

Blood Grouping Reagents licensed under, or that otherwise meet the

requirements of, the regulations of this subchapter shall be used, and

the technique used shall be that for which the reagent is specifically

designed to be effective.

* * * * *

Sec. 640.6 [Amended]

14. Section 640.6 Modifications of Whole Blood is amended by

removing paragraph (c).

15. Section 640.13 is amended by revising paragraph (a) to read as

follows:

Sec. 640.13 Collection of the blood.

(a) The source blood shall be collected as prescribed in

Sec. 640.4.

* * * * *

16. Section 640.15 is revised to read as follows:

[[Page 45381]]

Sec. 640.15 Samples for testing.

Samples collected in integral tubing shall meet the following

standards:

(a) One or more segments of either the original blood or of the Red

Blood Cells being processed shall be provided with each unit of Red

Blood Cells when issued or reissued.

(b) Before they are filled, all segments shall be marked or

identified so as to relate them to the donor of that unit of red cells.

(c) All segments accompanying a unit of Red Blood Cells shall be

filled at the time the blood is collected or at the time the final

product is prepared.

17. Section 640.16 is amended by revising paragraphs (a) and (b) to

read as follows:

Sec. 640.16 Processing.

(a) Separation. Within the timeframe specified in the directions

for the use of the specific devices, Red Blood Cells may be prepared

either by centrifugation, done in a manner that will not tend to

increase the temperature of the blood, or by normal undisturbed

sedimentation. A portion of the plasma sufficient to insure optimal

cell preservation shall be left with the red cells except when a

cryoprotective substance or additive solution is added for prolonged

storage.

(b) Sterile system. All surfaces that come in contact with the red

cells shall be sterile and pyrogen-free.

* * * * *

18. Section 640.22 is amended by revising paragraph (a) to read as

follows:

Sec. 640.22 Collection of source material.

(a) Whole blood used as the source of Platelets shall be collected

as prescribed in Sec. 640.4.

* * * * *

19. Section 640.23 is amended by revising paragraph (a) to read as

follows:

Sec. 640.23 Testing the blood.

(a) Blood from which plasma is separated for the preparation of

Platelets or Platelets, Pheresis shall be tested as prescribed in

Secs. 610.40 and 610.45 of this chapter and Sec. 640.5(a), (b), and

(c). Results of tests performed in accordance with Sec. 640.5(b) and

(c) for Platelets, Pheresis products shall be valid for a period not to

exceed 3 months.

* * * * *

20. Section 640.24 is amended by revising paragraph (b) to read as

follows:

Sec. 640.24 Processing.

* * * * *

(b) Immediately after collection, the whole blood or plasma shall

be held in storage between 20 and 24 deg.C, unless it must be

transported from the collection center to the processing laboratory.

During such transport, all reasonable methods shall be used to maintain

the temperature as close as possible to a range between 20 and 24

deg.C until it arrives at the processing laboratory where it shall be

held between 20 and 24 deg.C until the platelets are separated. The

platelet concentrate shall be separated within the timeframe specified

in the directions for use for the specific device used for the

collection of the unit of whole blood or plasma.

* * * * *

Sec. 640.31 [Amended]

21. Section 640.31 Suitability of donors is amended by removing

paragraph (c).

22. Section 640.32 is amended by revising the first sentence of

paragraph (a) to read as follows:

Sec. 640.32 Collection of source material.

(a) Whole blood shall be collected, transported, and stored as

prescribed in Sec. 640.4. * * *

* * * * *

23. Section 640.34 is amended by revising paragraphs (a) through

(d), (e)(1) through (e)(3), and (g)(2) to read as follows:

Sec. 640.34 Processing.

(a) Plasma. Plasma shall be separated from the red blood cells and

shall be stored at -18 deg.C or colder within the timeframe specified

in the directions for use for the specific device after transfer to the

final container, unless the product is to be stored as Liquid Plasma.

(b) Fresh Frozen Plasma. Fresh Frozen Plasma shall be prepared from

blood collected by a single uninterrupted venipuncture with minimal

damage to and minimal manipulation of the donor's tissue. The plasma

shall be separated from the red blood cells, frozen solid within the

timeframe specified in the directions for use for the specific device,

and stored at -18 deg.C or colder.

(c) Liquid Plasma. Liquid Plasma shall be separated from the red

blood cells and shall be stored at a temperature of 1 to 6 deg.C

within the timeframe specified in the directions for use for the

specific device after filling the final container.

(d) Platelet Rich Plasma. Platelet Rich Plasma shall be prepared

from blood collected by a single uninterrupted venipuncture with

minimal damage to and manipulation of the donor's tissue. The plasma

shall be separated from the red blood cells by centrifugation within

the timeframe specified in the directions for use for the specific

device after completion of the phlebotomy. The time and speed of

centrifugation shall have been shown to produce a product with at least

250,000 platelets per microliter. The plasma shall be stored at a

temperature between 20 and 24 deg.C, immediately after filling the

final container. A gentle and continuous agitation of the product shall

be maintained throughout the storage period, if stored at a temperature

of 20 to 24 deg.C.

(e) * * *

(1) Platelets shall be separated as prescribed in subpart C of part

640, prior to freezing the plasma. The remaining plasma may be labeled

as ``Fresh Frozen Plasma,'' if frozen within the timeframe specified in

the directions for use for the specific device after filling the final

container.

(2) Cryoprecipitated AHF shall be removed as prescribed in subpart

F of part 640. The remaining plasma shall be labeled ``Plasma,

Cryoprecipitate Reduced.''

(3) Plasma remaining after both Platelets and Cryoprecipitated AHF

have been removed may be labeled ``Plasma, Cryoprecipitate Reduced.''

* * * * *

(g) * * *

(2) With the exception of Platelet Rich Plasma and Liquid Plasma

the final product shall be inspected for evidence of thawing or

breakage at the time of issuance, however, the containers need not be

stored in a manner that shows evidence of thawing if records of

continuous monitoring of the storage temperature establish that the

temperature remained at -18 deg.C or colder. If continuous monitoring

of the product is not available, the final product shall be stored in a

manner that will show evidence of thawing and shall not be issued if

there is any evidence of thawing.

* * * * *

Sec. 640.51 [Amended]

24. Section 640.51 Suitability of donors is amended by removing

paragraph (c).

25. Section 640.52 is amended by revising paragraph (a) to read as

follows:

Sec. 640.52 Collection of source material.

(a) Whole blood used as a source of Cryoprecipitated AHF shall be

collected as prescribed in Sec. 640.4. Whole blood from which both

Platelets and Cryoprecipitated AHF is derived shall be maintained as

required under Sec. 640.24 until the platelets are removed.

* * * * *

[[Page 45382]]

26. Section 640.54 is amended by revising paragraph (a)(2) to read

as follows:

Sec. 640.54 Processing.

(a) * * *

(2) The plasma shall be frozen solid after blood collection within

the timeframe specified in the directions for use for the specific

device. A combination of dry ice and organic solvent may be used for

freezing: Provided, That the procedure has been shown not to cause the

solvent to penetrate the container or leach plasticizer from the

container into the plasma.

* * * * *

27. Section 640.56 is amended by revising the introductory text of

paragraph (c) to read as follows:

Sec. 640.56 Quality control test for potency.

* * * * *

(c) The quality control test for potency may be performed by a

clinical laboratory which meets the standards of the Clinical

Laboratories Improvement Act of 1988 (CLIA) (42 U.S.C. 263a) and is

qualified to perform potency tests for antihemophilic factor. Such

arrangements must be approved by the Director, Center for Biologics

Evaluation and Research, Food and Drug Administration. Such testing

shall not be considered as divided manufacturing, as described in

Sec. 610.63 of this chapter, provided the following conditions are met:

* * * * *

28. Section 640.62 is revised to read as follows:

Sec. 640.62 Medical supervision.

A qualified licensed physician shall be available to attend to the

donor within 15 minutes when donor suitability is being determined,

immunizations are being made, whole blood is being collected, and red

blood cells are being returned to the donor, except that during the

administration of immunization red blood cells a qualified licensed

physician shall be on the premises.

29. Section 640.63 is amended by revising paragraphs (c)(3),

(c)(5), (c)(11), (c)(12), and (c)(13) to read as follows:

Sec. 640.63 Suitability of donor.

* * * * *

(c) * * *

(3) A blood hemoglobin level of no less than 12.5 grams of

hemoglobin per 100 milliliters of blood or a hematocrit level of 38

percent;

* * * * *

(5) A total serum or total plasma protein of no less than 6.0 grams

per 100 milliliters of blood;

* * * * *

(11) A history of viral hepatitis after the age of eleven;

(12) Freedom from a history of close contact within 12 months of

donation with an individual having viral hepatitis;

(13) Freedom from a history of having received, within 12 months,

human blood or any derivative of human blood which the Food and Drug

Administration has advised the blood establishment is a possible source

of viral hepatitis, except for specific immunization performed in

accordance with Sec. 640.66.

* * * * *

30. Section 640.65 is amended by revising paragraphs (b)(4) and

(b)(5) and by adding paragraph (b)(8) to read as follows:

Sec. 640.65 Plasmapheresis.

* * * * *

(b) * * *

(4) The amount of whole blood, not including anticoagulant, removed

from a donor during a manual plasmapheresis procedure or in any 2-day

period shall not exceed 1,000 milliliters unless the donor's weight is

175 pounds or greater, in which case the amount of whole blood, not

including anticoagulant, removed from the donor during a manual

plasmapheresis procedure or in any 2-day period shall not exceed 1,200

milliliters.

(5) The amount of whole blood, not including anticoagulant, removed

from a donor during a manual plasmapheresis procedure within a 7-day

period shall not exceed 2,000 milliliters unless the donor's weight is

175 pounds or greater, in which case the amount of whole blood, not

including anticoagulant, removed from a donor during a manual

plasmapheresis procedure within a 7-day period shall not exceed 2,400

milliliters.

* * * * *

(8) The volume of plasma collected during an automated

plasmapheresis collection procedure shall be consistent with the

volumes specifically approved by the Director, Center for Biologics

Evaluation and Research, and collection shall not occur less than 2

days apart or more frequently than twice in a 7-day period.

31. Section 640.69 is amended by revising paragraph (d) to read as

follows:

Sec. 640.69 General requirements.

* * * * *

(d) Samples. If samples are provided, they shall meet the following

standards:

(1) Prior to filling, all samples shall be marked or identified so

as to relate them directly to the donor of that unit of plasma.

(2) All samples shall be filled at the time the final product is

prepared by the person who prepares the final product.

(3) All samples shall be representative of the contents of the

final product or be collected from the donor at the time of filling the

collection container.

(4) All samples shall be collected in a manner that does not

contaminate the contents of the final container.

32. Section 640.71 is amended by revising the introductory text of

paragraph (a) to read as follows:

Sec. 640.71 Manufacturing responsibility.

(a) All steps in the manufacturing of Source Plasma, including

donor examination, blood collection, plasmapheresis, laboratory

testing, labeling, storage, and issuing shall be performed by personnel

of the establishment licensed to manufacture Source Plasma, except that

the following tests may be performed by personnel of an establishment

licensed for blood and blood derivatives under section 351(a) of the

Public Health Service Act, or by a clinical laboratory that meets the

standards of the Clinical Laboratories Improvement Act of 1988 (CLIA)

(42 U.S.C. 263a): Provided, The establishment or clinical laboratory is

qualified to perform the assigned test(s).

* * * * *

33. Section 640.72 is amended by revising paragraph (a)(1) to read

as follows:

Sec. 640.72 Records.

(a) * * *

(1) Documentation shall be available to ensure that the shipping

temperature requirements of Sec. 600.15 of this title and of

Sec. 640.74(b)(2) are being met for Source Plasma intended for

manufacture into injectable products.

* * * * *

Dated: April 20, 1999.

Jane E. Henney,

Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 99-21293 Filed 8-18-99; 8:45 am]

BILLING CODE 4160-01-F