Revision of Requirements Applicable to Albumin (Human), Plasma Protein Fraction (Human), and Immune Globulin (Human)

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 640

[Docket No. 98N-0608]

Revision of Requirements Applicable to Albumin (Human), Plasma

Protein Fraction (Human), and Immune Globulin (Human)

AGENCY: Food and Drug Administration, HHS.

ACTION: Direct final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the

biologics regulations by removing, revising, or updating specific

regulations applicable to blood derivative products to be more

consistent with current practices and to remove unnecessary or outdated

requirements. FDA is issuing these amendments directly as a final rule

because the agency believes they are noncontroversial and that there is

little likelihood that there will be 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 any

significant adverse comment is received sufficient to terminate the

direct final rule within 30 days after the comment period ends, FDA

will consider such comments on the proposed rule in developing the

final rule. FDA is issuing this rule as

[[Page 26283]]

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 products, including plasma derivatives.

DATES: This rule is effective September 27, 1999. Submit written

comments on or before July 28, 1999. 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 this direct final rule ends. If timely significant adverse

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

Federal Register withdrawing this 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: Sharon A. Carayiannis, Center for

Biologics Evaluation and Research (HFM-17), Food and Drug

Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-

1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. The Blood Initiative

For a variety of reasons, discussed in this document, 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, ``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

(parts 600, 601, 606, 607, 610, 640, and 660 (21 CFR 600, 601, 606,

607, 610, 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

policies, 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 given 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 currently 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 has 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

communicable disease provisions of the Public Health Service Act (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 derivative products

to be more consistent with current practices and to remove unnecessary

or outdated requirements. In addition, minor editorial changes, such as

correction of punctuation, are being made. FDA is issuing these

amendments directly as a final rule because the agency believes they

are noncontroversial and that there is little likelihood that there

will be comments opposing the rule. In this section of this document,

FDA is identifying each of the changes included in the direct final

rule.

[[Page 26284]]

A. Identification of Plasma as the Source Material for Derivative

Products

Sections 640.80(a), 640.90(a), and 640.100(a) state the proper name

and definition for Albumin (Human), Plasma Protein Fraction (Human) and

Immune Globulin (Human), respectively. With the ubiquitous use of

modern anticoagulants, these products are prepared solely from human

plasma. Sections 640.80(a), 640.90(a), and 640.100(a) are changed from

``a sterile solution * * * human blood'' to ``a sterile solution * * *

derived from human plasma.''

Sections 640.80(b), 640.90(b), and 640.100(b) discuss source

material of Albumin (Human), Plasma Protein Fraction (Human), and

Immune Globulin (Human), respectively. With modern practice, these

products are no longer prepared from Whole Blood, sera or human

placentas. FDA is changing Secs. 640.80(b), 640.90(b), and 640.100(b)

to clarify and update the requirements for source material. Sections

640.80(b), 640.90(b), and 640.100(b) are changed to read ``The source

material of * * * shall be plasma recovered from Whole Blood prepared

as prescribed in Secs. 640.1 through 640.5, or Source Plasma prepared

as prescribed in Secs. 640.60 through 640.76.''

B. Clarification for Microbial Contamination During Processing

Sections 640.81(c) and 640.91(c) discuss microbial contamination of

source material and are amended to clarify that ``All processing steps

shall be conducted in a manner to minimize the risk of contamination

from microorganisms, pyrogens or other impurities.''

C. Clarification of Process for Heat Treatment

Sections 640.81(e) and 640.91(e) discuss heat treatment and are

amended to clarify that the heating process shall be continuous for the

time and at the temperature currently specified in the regulations. In

addition, Secs. 640.81(e) and 640.91(e) are corrected, by deleting a

degree sign, to read ``600.5 deg.C''.

D. Clarification for Stabilizer Used in Albumin (Human) and Plasma

Protein Fraction (Human)

Sections 640.81(f) and 640.91(f), stabilizer, are amended by

clarifying the range for acceptable amounts of stabilizer(s) that shall

be present in Albumin (Human) and Plasma Protein Fraction (Human),

respectively. Consistent with the amount of stabilizer(s) currently

used in these products, the regulations are amended to require either

0.080.016 millimole sodium caprylate, or

0.080.016 millimole sodium acetyltryptophanate and

0.080.016 millimole sodium caprylate per gram of protein.

The word ``present'' has been substituted for ``added'' in

Secs. 640.81(f) and 640.91(f) to clarify that the regulation pertains

to the amount of stabilizer in the final product. In addition,

Secs. 640.81(f) and 640.91(f) are amended to simplify calculations of

stabilizer(s) content in Albumin (Human) and Plasma Protein Fraction

(Human). Manufacturers may employ the labeled value for the protein

concentration. For example, if the measured protein concentration of a

lot of 5 percent Albumin (Human) is 5.15 percent, the calculations of

stabilizer(s) content may use the labeled value of 5 percent. Thus, if

the measured concentration of sodium caprylate is 0.35 millimole per

deciliter and the measured protein concentration is 5.15 percent (i.e.,

5.15 grams per deciliter), the sodium caprylate concentration may be

calculated as 0.35 divided by 5, or 0.07 millimole per gram of protein.

E. Revision of Terminology

Sections 640.82(a) and 640.82(d), protein content and sodium

content, respectively, are corrected by replacing ``content'' with

``concentration'' to be more precise.

Sections 640.82(c), 640.92(c), and 640.101(b) are amended by

changing the term from ``hydrogen ion concentration'' to ``pH'' to

reflect the more commonly used terminology.

Section 640.82(e), heme content, is replaced by potassium

concentration, which describes the acceptable potassium concentration

of the final product. Heme concentration is well controlled by the

procedures currently used to prepare plasma, and all recent lots of

Albumin (Human) have heme concentrations well below the maximum

specified in the current regulation. To update the regulations, the

requirement for the determination of heme content is deleted and

replaced with a requirement that ``the potassium concentration of the

final product shall not exceed 2 milliequivalents per liter.'' All

licensed manufacturers are currently manufacturing Albumin (Human) with

a potassium concentration that does not exceed 2 milliequivalents per

liter. This revision is also consistent with the current requirements

in Sec. 640.92(e) for the closely related product, Plasma Protein

Fraction.

Sections 640.84(a)(1) and (a)(4), 640.92(a), (d), and (e), and

640.94(a) are corrected by replacing ``content'' with ``concentration''

to be more precise. Section 640.84(b) is removed to be consistent with

changes made to Sec. 640.80(a) and (b). Section 640.84(a)(1) through

(a)(4) is redesignated as Sec. 640.84(a) through (d).

F. Correction of Spelling

Section 640.91(b)(2) and (c) are revised by correcting the spelling

of ``coefficient'' and ``contamination,'' respectively.

G. Revision of Range for Protein Concentration

Section 640.92(a), protein concentration, is corrected by changing

``5.00.3'' to ``5.00.30'' to reflect the

precision of the value.

H. Revision of General Requirements and Sterilization and Heating for

Immune Globulin (Human)

Section 640.101(e)(3) and (e)(4) are deleted to be consistent with

current practice. The use of the current attenuated strain of measles

in the manufacture of measles vaccines licensed in the United States

results in products that do not require the concomitant administration

of measles antibodies. Moreover, the labeling for measles vaccines

contains appropriate precautions regarding the effect of Immune

Globulin (Human). With the availability of a highly effective vaccine,

passive prophylaxis for poliomyelitis with Immune Globulin (Human),

which had only minimal effectiveness, was discontinued many years ago.

Section 640.101(f), samples and protocols, is deleted to be

consistent with current policy. Current policy permits manufacturers of

biological products, including plasma derivatives, to request exemption

from lot release by CBER. After review of the data submitted in support

of such a request, the Director, CBER, may grant the request, thus

decreasing the regulatory burden on the manufacturer and permitting

distribution of the product as soon as the manufacturer has completed

all necessary quality control procedures on a particular lot.

Section 640.102(e), sterilization and heating, is clarified by

deleting ``* * * 30 to * * *.'' The effect of the regulation is

unchanged by this revision.

I. Revision of Determination of Protein Composition of Final Product

for Immune Globulin (Human)

Section 640.103(b) describes the protein composition of the Immune

Globulin (Human) final product in terms of absolute electrophoretic

mobility. This value was computed from measurements made by moving

boundary electrophoresis. For at least 25 years, the instrumentation

necessary for

[[Page 26285]]

performing moving boundary electrophoresis has not been commercially

available. Accordingly, as such equipment was becoming less available,

all licensed manufacturers of Immune Globulin (Human) calibrated more

modern methods against moving boundary electrophoresis and amended

their product license applications for Immune Globulin (Human) to

provide for the use of the more modern methods. In addition, using more

modern methods of manufacturing and measurement, manufacturers are now

routinely making a more highly purified product. Accordingly, FDA is

amending Sec. 640.103(b) to read ``At least 96 percent of the total

protein shall be immunoglobulin G (IgG), as determined by a method that

has been approved for each manufacturer by the Director, Center for

Biologics Evaluation and Research, Food and Drug Administration.''

J. Revision of Minimum Levels for Measles Neutralizing Antibody and

Poliomyelitis Neutralizing Antibody

Section 640.104(b)(2) is revised, consistent with current accepted

practice, by eliminating a specified numerical value for the measles

neutralizing antibody level. This change allows more flexibility for

industry and FDA, in that the regulations will no longer become

outdated each time a new reference standard is used.

Section 640.104(b)(3) is revised, consistent with current accepted

practice, by eliminating a specified numerical value for the

poliomyelitis neutralizing antibody level. This change allows more

flexibility for industry and FDA, in that the regulations will no

longer become outdated each time a new reference standard is used.

K. Revision of Nomenclature for Reference Immune Globulin

Section 640.104(c)(1) and (c)(2) are corrected by deleting the word

``Serum'' to reflect the more precise nomenclature of ``Reference

Immune Globulin * * *.''

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 believes 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 proposed rule serves the purpose of

issuing notice under the usual notice and comment procedures in the

event the direct final rule is withdrawn because of any significant

adverse comment.

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

days from May 14, 1999. If the agency receives any significant adverse

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

publication 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 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 significant adverse

comments.

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 (5 U.S.C. 553)

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 that would 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

Commissioner 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 of 1995 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 collections 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 July 28, 1999, submit to the

Dockets Management Branch (address above) written comments regarding

this direct final rule. Two copies of any comments are to be submitted,

except that

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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 in 21 CFR Part 640

Blood, Labeling, Reporting and recordkeeping requirements.

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

Public Health Service Act, and under authority delegated to the

Commissioner of Food and Drugs, 21 CFR part 640 is amended as follows:

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

1. 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.

2. Section 640.80 is amended by revising the last sentence in

paragraph (a) and by revising paragraph (b) to read as follows:

Sec. 640.80 Albumin (Human).

(a) * * * The product is defined as a sterile solution of the

albumin derived from human plasma.

(b) Source material. The source material of Albumin (Human) shall

be plasma recovered from Whole Blood prepared as prescribed in

Secs. 640.1 through 640.5, or Source Plasma prepared as prescribed in

Secs. 640.60 through 640.76.

* * * * *

3. Section 640.81 is amended by revising the first sentence in

paragraph (c) and the last sentence in paragraph (e), and by revising

paragraph (f) to read as follows:

Sec. 640.81 Processing.

* * * * *

(c) Microbial contamination. All processing steps shall be

conducted in a manner to minimize the risk of contamination from

microorganisms, pyrogens, or other impurities. * * *

* * * * *

(e) Heat treatment. * * * Heat treatment shall be conducted so that

the solution is heated continuously for not less than 10 or more than

11 hours at an attained temperature of 60#0.5 +C.

(f) Stabilizer. Either 0.08#0.016 millimole sodium

caprylate, or 0.08#0.016 millimole sodium

acetyltryptophanate and 0.08#0.016 millimole sodium

caprylate per gram of protein shall be present as a stabilizer(s).

Calculations of the stabilizer concentration may employ the labeled

value for the protein concentration of the product as referred to in

Sec. 640.84(d).

* * * * *

4. Section 640.82 is amended by revising the headings in paragraphs

(a) and (c), and by revising paragraphs (d) and (e) to read as follows:

Sec. 640.82 Tests on final product.

* * * * *

(a) Protein concentration.* * *

* * * * *

(c) pH. * * *

(d) Sodium concentration. The sodium concentration of the final

product shall be 130 to 160 milliequivalents per liter.

(e) Potassium concentration. The potassium concentration of the

final product shall not exceed 2 milliequivalents per liter.

* * * * *

5. Section 640.84 is amended by revising the introductory

paragraph, by removing paragraph (a) introductory text and paragraph

(b), by redesignating paragraphs (a)(1) through (a)(4) as paragraphs

(a) through (d), respectively, and by revising newly redesignated

paragraphs (a) and (d) to read as follows:

Sec. 640.84 Labeling.

In addition to the labeling requirements of Secs. 610.60, 610.61,

and 610.62 of this chapter, the container and package labels shall

contain the following information:

(a) The osmotic equivalent in terms of plasma, and the sodium

concentration in terms of a value or a range in milliequivalents per

liter;

* * * * *

(d) The protein concentration, expressed as a 4 percent, 5 percent,

20 percent, or 25 percent solution.

6. Section 640.90 is amended by revising the last sentence in

paragraph (a) and by revising paragraph (b) to read as follows:

Sec. 640.90 Plasma Protein Fraction (Human).

(a) * * * The product is defined as a sterile solution of protein

composed of albumin and globulin, derived from human plasma.

(b) Source material. The source material of Plasma Protein Fraction

(Human) shall be plasma recovered from Whole Blood prepared as

prescribed in Secs. 640.1 through 640.5, or Source Plasma prepared as

prescribed in Secs. 640.60 through 640.76.

* * * * *

7. Section 640.91 is amended by revising paragraphs (b)(2) and (f),

and by revising the first sentence in paragraph (c) and the last

sentence in paragraph (e) to read as follows:

Sec. 640.91 Processing.

* * * * *

(b) * * *

(2) Contains less than 5 percent protein with a sedimentation

coefficient greater than 7.0 S.

(c) Microbial contamination. All processing steps shall be

conducted in a manner to minimize the risk of contamination from

microorganisms, pyrogens, or other impurities. * * *

* * * * *

(e) * * * Heat treatment shall be conducted so that the solution is

heated continuously for not less than 10 or more than 11 hours at an

attained temperature of 60#0.5 +C.

(f) Stabilizer. Either 0.08#0.016 millimole sodium

caprylate, or 0.08#0.016 millimole sodium

acetyltryptophanate and 0.08#0.016 millimole sodium

caprylate per gram of protein shall be present as a stabilizer(s).

Calculations of the stabilizer concentration may employ the labeled

value 5 percent for the protein concentration of the product.

* * * * *

8. Section 640.92 is amended by revising the headings of paragraphs

(a) and (c), and by revising paragraphs (d) and (e) to read as follows:

Sec. 640.92 Tests on final product.

* * * * *

(a) Protein concentration. * * *

* * * * *

(c) pH. * * *

(d) Sodium concentration. The sodium concentration of the final

product shall be 130 to 160 milliequivalents per liter.

(e) Potassium concentration. The potassium concentration of the

final product shall not exceed 2 milliequivalents per liter.

* * * * *

9. Section 640.94 is amended by revising paragraph (a) to read as

follows:

Sec. 640.94 Labeling.

* * * * *

(a) The osmotic equivalent in terms of plasma, and the sodium

concentration in terms of a value or a range in milliequivalents per

liter.

* * * * *

10. Section 640.100 is amended by revising the last sentence in

paragraph (a), and by revising paragraphs (b) and (c) to read as

follows:

[[Page 26287]]

Sec. 640.100 Immune Globulin (Human).

(a) * * * The product is defined as a sterile solution containing

antibodies derived from human plasma.

(b) Source material. The source material of Immune Globulin (Human)

shall be plasma recovered from Whole Blood prepared as prescribed in

Secs. 640.1 through 640.5, or Source Plasma prepared as prescribed in

Secs. 640.60 through 640.76.

(c) Additives in source material. The source material shall

contain no additives other than citrate or acid citrate dextrose

anticoagulant solution, unless it is shown that the processing method

yields a product free of the additive to such an extent that the

safety, purity, and potency of the product will not be affected

adversely.

Sec. 640.101 [Amended]

11. Section 640.101 General requirements is amended by removing the

heading of paragraph (b) ``Hydrogen ion concentration'' and by adding

in its place ``pH'' and by removing paragraphs (e)(3), (e)(4), and (f).

12. Section 640.102 is amended by revising the last sentence of

paragraph (e) to read as follows:

640.102 Manufacture of Immune Globulin (Human).

* * * * *

(e) * * * At no time during processing shall the product be exposed

to temperatures above 45 deg.C and after sterilization the product

shall not be exposed to temperatures above 32 deg.C for more than 72

hours.

13. Section 640.103 is amended by revising paragraph (b) to read as

follows:

Sec. 640.103 The final product.

* * * * *

(b) Protein composition. At least 96 percent of the total protein

shall be immunoglobulin G (IgG), as determined by a method that has

been approved for each manufacturer by the Director, Center for

Biologics Evaluation and Research, Food and Drug Administration.

14. Section 640.104 is amended by revising paragraphs (b)(2),

(b)(3), (c)(1), and (c)(2) to read as follows:

Sec. 640.104 Potency.

* * * * *

(b) * * *

(2) A measles neutralizing antibody level that, when compared with

that of a reference material designated by the Center for Biologics

Evaluation and Research (CBER), Food and Drug Administration, as

indicated in paragraph (c) of this section, demonstrates adequate

potency. The Director, CBER, shall notify manufacturers when a new

reference material will be used and will advise manufacturers of an

appropriate antibody level taking into account a comparison of the new

reference material to the previous reference material.

(3) A poliomyelitis Type 1, Type 2, or Type 3 neutralizing antibody

level that, when compared with that of a reference material designated

by the Center for Biologics Evaluation and Research, Food and Drug

Administration, as indicated in paragraph (c) of this section,

demonstrates adequate potency. The Director, CBER, shall notify

manufacturers when a new reference material will be used and will

advise manufacturers of an appropriate antibody level taking into

account a comparison of the new reference material to the previous

reference material.

(c) * * *

(1) Reference Immune Globulin for correlation of measles antibody

titers.

(2) Reference Immune Globulin for correlation of poliomyelitis

antibody titers, Types 1, 2, and 3.

Dated: April 20, 1999.

Jane E. Henney,

Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 99-11897 Filed 5-13-99; 8:45 am]

BILLING CODE 4160-01-F