Revisions to the Requirements Applicable to Blood, Blood Components, and Source Plasma

SUMMARY: The Food and Drug Administration (FDA) is amending 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remove unnecessary or outdated requirements.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 issuing these

amendments directly as a final rule because they are noncontroversial

and there is little likelihood that FDA will receive any significant

comments opposing the rule. Elsewhere in this issue of the Federal

Register, FDA is publishing a proposed rule under FDA's usual

procedures for notice and comment in the event the agency receives any

significant adverse comments. If FDA receives any significant adverse

comment sufficient to terminate the direct final rule, FDA will

consider such comments on the proposed rule in developing the final

rule. FDA is issuing this rule 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.

DATES: This rule is effective February 11, 2000. Submit written

comments on or before December 3, 1999. If no timely significant

comments are received, the agency will publish a document in the

Federal Register within 30 days after the comment period on this direct

final rule ends, confirming the effective date of the final rule. If

timely significant adverse comments are received, the agency will

publish a document in the Federal Register withdrawing the direct final

rule before its effective date.

ADDRESSES: Submit written comments on the direct final 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. Blood Initiative

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.

In the Federal Register of June 3, 1994 (59 FR 28821 and 59 FR 28822,

respectively), FDA issued two documents entitled ``Review of General

Biologics and Licensing Regulations'' (Docket No. 94N-0066) and

``Review of Regulations for Blood Establishments and Blood Products''

(Docket No. 94N-0080). The documents announced the agency's intent to

review biologics regulations, 21 CFR parts 600, 601, 606, 607, 640, and

660 and requested written comments from the public. Interested persons

were given until August 17, 1994, to respond to the documents. In

response to requests for additional time, FDA twice extended the

comment period, as announced in the Federal Register of August 17, 1994

(59 FR 42193), and November 14, 1995 (59 FR 56448). In addition, FDA

responded to requests for a public meeting to allow for the

presentation of comments regarding the agency's intent to review the

biologics regulations. On January 26, 1995, FDA held a public meeting

to provide an opportunity for all interested individuals to present

their comments and to assist the agency in determining whether the

regulations should be revised, rescinded, or continued without change.

Since the time of the regulation review, FDA has implemented a number

of changes to its regulations and policies applicable to the general

biologics and licensing regulations, some of which applied to blood

products as well as other biological products. (See, e.g., the final

rules issued on May 14, 1996 (61 FR 24313); August 1, 1996 (61 FR

40153); November 6, 1996 (61 FR 57328); July 24, 1997 (62 FR 39890);

and October 15, 1997 (62 FR 53536).)

Because of the importance of a safe national blood supply, the U.S.

House of Representatives Committee on Government Reform and Oversight,

Subcommittee on Human Resources and Intergovernmental Relations (the

Subcommittee) and other groups such as the General Accounting Office

(GAO), and the Institute of Medicine (IOM) have reviewed the agency's

polices, practices, and regulations. Reports issued following the

respective reviews contained a number of recommendations as to how FDA

might improve the biologics regulations, particularly as they apply to

the continued safety of blood products. The relevant reports are: (1)

``Protecting the Nation's Blood Supply From Infectious Agents: The Need

for New Standards to Meet New Threats,'' by the Subcommittee (August 2,

1996); (2) ``Blood Supply: FDA Oversight and Remaining Issues of

Safety,'' by GAO (February 25, 1997); (3) ``Blood Supply: Transfusion-

Associated Risks,'' by GAO (February 25, 1997); and (4) ``HIV and the

Blood Supply: An Analysis of Crisis Decisionmaking,'' by IOM (July 13,

1995). These reports are on file with the Dockets Management Branch

(address above) under the docket number found in brackets in the

heading of this document.

FDA has reviewed these reports and agrees with the majority of the

recommendations contained within them. However, rather than to only

respond specifically to the recommendations from the Subcommittee, GAO,

IOM, and the public, FDA has convened a number of internal task forces

to review a variety of issues related to the regulation of blood and

blood products, including how to most appropriately update the existing

regulations applicable to blood and blood products. In the future, FDA

intends to issue a number of blood-related regulations that various FDA

task groups are preparing. FDA emphasizes that for many of the changes

discussed in section III of 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 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.

FDA is not describing the specific recommendations it received and

the numerous objectives of the Blood Initiative in this document.

Future rulemaking and other notices will describe and discuss specific

recommendations and regulatory objectives as they apply to each

rulemaking.

II. Legal Authority

FDA is issuing this new rule under the biologics products and

[[Page 45367]]

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 Direct Final Rule

FDA is amending 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. FDA is issuing these

amendments as a direct final rule because the agency 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

following changes, 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. In the following paragraphs, FDA

discusses each of the rule changes in the direct final rule.

Part 606 (21 CFR part 606) is amended as follows:

Section 606.3, Definitions, is amended so that the definitions

provided in the section are consistent with current meanings and

usages.

The definition of ``Component'' in Sec. 606.3(c) is amended to

apply to blood obtained from a single donor and no longer includes 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 Sec. 606.3(e) is amended by

removing the restriction that plasmapheresis may be ``immediately

repeated, once'' because current automated plasmapheresis collection

practices often use more than two cycles for collection.

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

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

potential 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) are 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) is also 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'' is 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) is 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) is 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.

Section 606.100(d) is 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's regulatory requirements.

Section 606.121(a) is amended by removing the reference that the

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

available from Dockets 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 is 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) is amended by deleting 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 is 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 is amended to allow instructions for

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

preparation of the component.

Section 606.151(b) is 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 preceding 3 months.

Section 606.151(c) describes compatibility testing and is 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) is 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) is amended by changing ``person(s)

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

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procedure'' to clarify that the person(s) performing the labeling

procedure is responsible for documenting the performance of that

procedure.

Section 606.170(b) is amended by deleting ``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) is amended as follows:

Section 640.2(b) is removed because Whole Blood collection in open

systems is no longer acceptable nor has it been performed for many

years. Section 640.2(d) is revised. In Sec. 640.2 paragraphs (c), (e),

and (f) are redesignated as paragraphs (b), (c), and (d), respectively.

Redesignated Sec. 640.2(b) and (c)(2) are revised by removing

references to the original blood container because, 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) is 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) is 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) are 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) are 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) are 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 FDA has identified as a possible source of viral

hepatitis. These changes are consistent with recommendations 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) have been

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) are 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 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) is 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) is amended by

removing the reference to the specific anticoagulant formulae. Section

640.4(d)(1) through (d)(4) is 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) are amended to remove references to

Sec. 640.4(d)(2) and (h), which are being removed.

Section 640.4(g)(5) has been 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) is removed

because heparin anticoagulant solutions are no longer used for the

routine collection of blood.

Section 640.5(c) is 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 is also 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 have

been 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) are removed because the use of more

modern methods of manufacturing and equipment have eliminated the use

of pilot tubes attached to blood units. In Sec. 640.15 paragraph (d) is

redesignated as paragraph (c).

Section 640.16(a) is 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) is 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'' have been

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

current terminology for various testing specimens. The following

sections are amended by replacing ``pilot tubes,''

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

``samples'' as appropriate: Secs. 640.2(e)(2), 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) is 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 period not to exceed 3 months, thereby, eliminating the

necessity of repeat testing of blood samples from donors participating

in frequent plateletpheresis collection procedures.

Section 640.24(b) is 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 are 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) are amended to require testing

only in those months in which blood products are 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) are 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) is amended by deleting 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) are amended to include the proper

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

recommendations of the Blood Products Advisory Committee at its

September 18 and 19, 1997 meeting. Section 640.34(g)(2) is amended to

permit 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 is 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) is 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 g per 100 mL of blood, to be consistent

with current accepted practices.

Section 640.63(c)(5) is 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) is 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) is 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) is added to address the collection of Source

Plasma using automated collection devices. The regulation delineates

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) is amended by replacing ``compiled every 3

months'' with ``shall be available'' to eliminate the necessity of

compiling documents at specified time intervals.

IV. Rulemaking Action

In the Federal Register of November 21, 1997 (62 FR 62466), FDA

described its procedures on when and how FDA will employ direct final

rulemaking. FDA has determined that this rule is appropriate for direct

final rulemaking because FDA views this rule as including only

noncontroversial amendments and anticipates no significant adverse

comments. Consistent with FDA's procedures on direct final rulemaking,

FDA is publishing elsewhere in this issue of the Federal Register, a

companion proposed rule to amend the biologics regulations by removing,

revising, and updating existing regulations to be more consistent with

current accepted practices. The companion proposed rule provides a

procedural framework within which the rule may be finalized in the

event the direct final rule is withdrawn because of any significant

adverse comment. The comment period for the direct final rule runs

concurrently with the companion proposed rule. Any comment received

under the companion proposed rule will be considered as comments

regarding the direct final rule.

FDA has provided a comment period on the direct final rule of 75

days after August 19, 1999. If the agency receives any significant

adverse comment, FDA intends to withdraw this direct final rule action

by publication of a document in the Federal Register within 30 days

after the comment period ends. A significant adverse 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

[[Page 45370]]

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 any significant adverse comment is received during the comment

period, FDA will publish, within 30 days after the comment period ends,

a document withdrawing the direct final rule. If FDA withdraws the

direct final rule, any comments received will be applied to the

proposed rule and will be considered in developing a final rule using

the usual Administrative Procedure Act notice-and-comment procedures.

If FDA receives no significant adverse comments during the

specified comment period, FDA intends to publish a confirmation

document within 30 days after the comment period ends confirming the

effective date.

V. Analysis of Impacts

A. Review Under Executive Order 12866 and the Regulatory Flexibility

Act and Unfunded Mandates Reform Act of 1995

FDA has examined the impact of the direct final rule under

Executive Order 12866, 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 direct final rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. This direct final 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 direct final rule amendments have

no compliance costs and do not result in any new requirements, the

agency certifies that the direct final 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 direct final 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.

VI. The Paperwork Reduction Act of 1995

This direct final rule contains no collection of information.

Therefore, clearance by the Office of Management and Budget under the

Paperwork Reduction Act of 1995 is not required.

VII. Request for Comments

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

the Docket Management Branch (address above) written comments regarding

this final rule. 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, 21 CFR parts 606 and 640 are 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:

[[Page 45371]]

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, 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

[[Page 45372]]

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:

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

[[Page 45373]]

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.

* * * * *

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

[[Page 45374]]

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. 99-21292 Filed 8-18-99; 8:45 am]

BILLING CODE 4160-01-F