[Federal Register Volume 65, Number 167 (Monday, August 28, 2000)]
[Rules and Regulations]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-21897]
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: Final rule.
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consistent with current practices and to remove unnecessary or outdated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 taking this action as part of the agency's ``Blood
Initiative'' in which FDA is reviewing and revising, when appropriate,
its regulations, policies, guidance, and procedures related to blood
products, including blood derivatives.
DATES: This rule is effective September 27, 2000.
FOR FURTHER INFORMATION CONTACT: Nathaniel L. Geary, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
In the Federal Register of May 14, 1999 (64 FR 26282), FDA
published a direct final rule to amend the biologics regulations in
part 640 (21 CFR part 640) 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consistent with current practices and to remove unnecessary or outdated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 issued these amendments directly as a final rule
because the agency believed they were noncontroversial and that there
was little likelihood that there would be comments opposing the rule.
In the Federal Register of May 14, 1999 (64 FR 26344), FDA published a
companion proposed rule under FDA's usual procedures for notice and
comment in the event the agency received any significant adverse
comments to the direct final rule. FDA received three significant
adverse comments during the comment period, and the agency has
considered these comments in developing the final rule.
In the Federal Register of March 14, 2000 (65 FR 13678), FDA
published a direct final rule with a confirmation in part and technical
amendment. The document confirmed those provisions for which there were
no adverse comments. This final rulemaking responds to those proposed
provisions for which there were significant adverse comments.
II. Responses to Comments on the Proposed Rule
A. Proposed Sec. 640.81(e)
The proposed changes to Sec. 640.81(e) were: (1) The insertion of
the word ``continuously,'' to clarify that the heating process shall be
continuous for the time and at the temperature specified in the
regulations and (2) the removal of an extraneous degree sign.
One comment did not object to the proposed changes to
Sec. 640.81(e), but it recommended deletion of the sentence that
currently precedes the sentence for which the changes are proposed.
That sentence reads: ``Heating of the final containers of Albumin
(Human) shall begin within 24 hours after completion of filling.'' The
comment also stated that the proposed rule should be broadened to allow
for heat treatment to occur in bulk during the manufacturing process.
FDA disagrees with the comment. Even though the comment did not
address the proposed rule, but rather the regulation as it currently
exists, the agency has considered the comment and the arguments listed
in support of the recommended deletion and/or broadening. The comment
listed several potential advantages of heating in bulk over heating in
the final containers. These included better control and monitoring,
obviation of the need for a water bath and the attendant potential
microbial contamination of the product, and diminished leaching of
contaminants from the containers. The comment noted that heating in
bulk would allow the product to be filled in a post-viral-inactivation
Despite these theoretical advantages, the agency does not find that
they provide sufficient assurance of safety equal to or greater than
that provided by the current process to warrant deleting this portion
of the regulation. Furthermore, the agency is not aware that any of the
disadvantages of the current process implied by the comment cannot be
overcome by appropriate process validation and adherence to current
good manufacturing practice.
Nothing in the current regulation or the proposed rule precludes
heat treatment in bulk during the manufacturing process for Albumin
(Human), provided that it is conducted according to current good
manufacturing practice and described in an approved Biologics License
Application (BLA). An applicant who wishes to include such a step in
the manufacture of Albumin (Human) should describe it in a BLA or
Biologics License Supplement that addresses such matters as validation
of the process and demonstration that the treatment does not affect
adversely the characteristics of the product, including its purity,
safety, and stability.
However, the agency has concluded that heat treatment in bulk, even
for 10 to 11 hours at 600.5 deg.C, does not permit the
manufacturer to forgo heating Albumin (Human) in the final containers,
as prescribed in Sec. 640.81(e). This requirement is intended to
minimize the occurrence of viral transmission by albumin-containing
products (Ref. 1).
B. Proposed Sec. 640.81(f)
The proposed changes to Sec. 640.81(f) would clarify the acceptable
amounts of stabilizers that must be present in Albumin (Human) and
Plasma Protein Fraction (Human) to reflect the amounts of those
stabilizers that are currently used in these products.
One comment objected to the proposed quantity of sodium caprylate
per gram (/g) of protein and
recommended that the range be increased to allow higher quantities of
caprylate/g of protein or, alternatively, that the quantity of sodium
caprylate not be specified in the regulation.
The rationale for this recommendation included: (1) Caprylate is a
more effective stabilizer than is acetyltryptophanate, which is
currently used as a stabilizer in conjunction with caprylate; (2) the
denaturation temperature of albumin is increased as the quantity of
caprylate/g of protein is increased; and (3) the additional quantity of
caprylate infused will not be expected to have any adverse effect.
FDA does not agree with the comment. The agency agrees that
caprylate is a more effective stabilizer of albumin than is
acetyltryptophanate. The observation that 0.08 millimole sodium
caprylate/g of protein stabilizes albumin nearly as effectively as 0.08
millimole sodium acetyltryptophanate plus 0.08 millimole sodium
caprylate/g of protein (Refs. 2 and 3) was one of the reasons
underlying the proposed rule. The agency also agrees that increasing
the quantity of caprylate/g of protein increases the denaturation
temperature of albumin. For the heat treatment required by Sec. 640.81
during the processing of albumin, however, the important factor is the
effectiveness of stabilization at 60 deg.C. Once the quantity of
stabilizer is sufficient to assure that the temperature at which
denaturation is initiated is significantly above 60 deg.C, further
increase in the quantity of stabilizer would not be expected to enhance
the stability of albumin at this temperature (Ref. 3). This expectation
has been confirmed in practice. When albumin was heated for 10 hours at
60 deg.C, increasing the ratio of caprylate to protein resulted in
progressively better stabilization up to a ratio of 0.08 millimole
sodium caprylate/g of protein; above that, little or no further
stabilization occurred (Ref. 3). Furthermore, when sodium caprylate was
present at a ratio of 0.08 millimole/g of protein, albumin remained as
stable during continued heating (up to 24 hours) at 60 deg.C as it was
after 10 hours at this temperature (Ref. 3).
Numerous biological effects of caprylate have been reported. Even a
nonexhaustive listing reveals a broad array, including: (1)
Hypoglycemia (Refs. 4 to 6); (2) hyperventilation (Refs. 7 and 8); (3)
narcotic action in various animal species (Refs. 6, 9, and 10); (4)
increased oxygen consumption and decreased clearance of long-chain
fatty acids by the liver (Refs. 11 and 12); (5) vasodilation (Ref. 13);
(6) decreased muscle contractility (Refs. 14 to 6); (7) altered
epithelial and membrane permeability (Refs. 17 and 18), including
alteration of the blood-brain barrier (Refs. 19 and 20); (8) inhibition
of platelet reactivity (Refs. 21 and 22); (9) increased release of
insulin and enzymes from pancreatic cells (Refs. 23 to 26); (10)
altered carbohydrate metabolism (Refs. 5, 15, and 27 to 30), including
glucose production (Refs. 4, and 31 to 33); (11) increased catabolism
of muscle proteins (Ref. 34), decreased incorporation of amino acids
into protein (Ref. 35), and alterations in amino acid metabolism (Refs.
36 and 37); (12) decreased ammonia production and metabolism (Refs. 31
and 38); and (13) depressed synthesis of DNA (Deoxyribonucleic acid)
and RNA (ribonucleic acid) (Refs. 39 to 41).
In view of this broad range of demonstrated effects, it is
difficult to predict the outcome of increased caprylate infusion in
different patients and different clinical settings. For this reason,
the agency believes that the ratio of caprylate to protein should not
be increased above that necessary to stabilize albumin.
Many factors contribute to the stability of albumin during heating.
These include not only the stabilizers noted here but also the pH (Ref.
42) and the chloride content of the solution (Ref. 3). Moreover, the
contributions of these factors to the stability of albumin appear to be
additive (Ref. 3). Therefore, conditions can be chosen to maximize the
stability of albumin without increasing the quantity of caprylate above
that specified in the proposed rule.
C. Proposed Sec. 640.102(e)
The proposed change to Sec. 640.102(e) would delete ``30 to'' in
One comment on proposed Sec. 640.102(e) raised no objection, but it
objected to the wording of other parts of the paragraph. The comment
recommended that the first sentence be amended with definitions to
provide increased clarity. It stated that the second sentence, as
worded in both the current regulation and the proposed rule, seems not
to allow for heating of the product at elevated temperature for the
purpose of viral inactivation; and it recommended that it be amended to
incorporate this possibility.
The agency agrees that the parts of the regulation noted in the
comment, as well as others that were not included, could be clarified
and improved. The agency believes that making such changes should be
done as part of an overall revision of the regulation and is beyond the
scope of this rulemaking. With regard to the comment about the second
sentence, if an applicant believes that heating at elevated temperature
would improve the safety of Immune Globulin (Human) without
compromising its other characteristics, such as purity and stability,
the applicant should describe the process in a BLA or Biologics License
Supplement and submit it to the agency as a request for an alternative
procedure under Sec. 640.120.
FDA has considered all comments in response to the proposed rule
and has determined that proposed Sec. 640.81(e) and (f) and
Sec. 640.102(e) should be issued as a final rule.
III. 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 impacts of the final rule under Executive
Order 12866 the Regulatory Flexibility Act (5 U.S.C. 601-612 (as
amended by subtitle D of the Small Business Regulatory Fairness Act of
1996 (Public Law 104-121)), and the Unfunded Mandates Reform Act of
1995 (Public Law 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 impacts;
and equity). The agency believes that this final rule is consistent
with the regulatory philosophy and principles identified in the
Executive Order. In addition, the 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 final rule amendments have no
compliance costs and do not result in any new requirements, the agency
certifies that the 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.
The Unfunded Mandates Reform Act (2 U.S.C. 1501 et seq.) requires
that agencies prepare an assessment of anticipated costs and benefits
before proposing any rule that may result in expenditures by State,
local, and tribal governments, in the aggregate, or by the private
sector, of $100 million or more in any one year. Because this rule does
not result in expenditures by State, local, and tribal governments, in
the aggregate, or by the private sector, of $100 million or more in any
one year, FDA concluded that the proposed regulation is consistent with
the principles of the Unfunded Mandates Reform Act without the need for
B. Environmental Impact
The agency has determined under 21 CFR 25.31(h) 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.
IV. The Paperwork Reduction Act of 1995
This 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.
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
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6. Journal of Laboratory and Clinical Medicine, 101:930-939,
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List of Subjects in 21 CFR Part 640
Blood, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and 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
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
2. Section 640.81 is amended by revising the last sentence in
paragraph (e) and by revising paragraph (f) to read as follows:
Sec. 640.81 Processing.
* * * * *
(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 600.5 deg.C.
(f) Stabilizer. 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 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
* * * * *
3. Section 640.102 is amended by revising the last sentence of
paragraph (e) to read as follows:
Sec. 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
Dated: August 4, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-21897 Filed 8-25-00; 8:45 am]
BILLING CODE 4160-01-F