[Federal Register Volume 64, Number 93 (Friday, May 14, 1999)]
[Rules and Regulations]
[Pages 26282-26287]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-11897]


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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consistent with current practices and to remove unnecessary or outdated 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

[[Page 26286]]

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