[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consistent with current practices and to remove unnecessary or outdated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