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[Federal Register: August 28, 2000 (Volume 65, Number 167)]
[Rules and Regulations]
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[DOCID:fr28au00-6]
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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: 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to be more consistent with current practices and to remove unnecessary or outdated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 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- 1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
I. Background
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with current practices and to remove unnecessary or outdated requirements.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 filling suite.
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 60
<plus-minus>0.5 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
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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 urrently 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 Sec. 640.102(e).
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
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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 further analysis.
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.
V. References
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.
1. American Journal of Epidemiology, 103:399-407, 1976.
2. Vox Sanguinis, 47:7-18, 1984.
3. Vox Sanguinis, 47:28-40, 1984.
4. Metabolism, 14:1311-1323, 1965.
5. Canadian Journal of Physiology and Pharmacology, 45:29-38, 1967.
6. Journal of Laboratory and Clinical Medicine, 101:930-939, 1983.
7. Neurology, 28:940-944, 1978.
8. Research in Experimental Medicine, 189:347-354, 1989.
9. Journal of Pharmacology and Experimental Therapeutics, 191:10-16, 1974.
10. American Journal of Gastroenterology, 69:187-190, 1978.
11. European Journal of Biochemistry, 141:223-230, 1984.
12. Proceedings of the Society for Experimental Biology and Medicine, 167:36-39, 1981.
13. American Journal of Physiology, 261:H561-H567, 1991.
14. Biomedica Biochimica Acta, 45:S45-S50, 1986.
15. Biochimica et Biophysica Acta 1093:125-134, 1991.
16. Folia Medica, 34:12-18, 1992.
17. Pharmaceutical Research, 8:1365-1371, 1991.
18. Journal of Pharmaceutical Sciences, 77:390-392, 1988.
19. Pediatric Neurology, 1:20-22, 1985.
20. Pediatric Neurology, 1:223-225, 1985.
21. Thrombosis Research, 4:479-484, 1974.
22. Scandinavian Journal of Clinical and Laboratory Investigation, 35:19-23, 1975.
23. Metabolism, 16:482-484, 1967.
24. American Journal of Physiology, 234:E162-E167, 1978.
25. Journal of Physiology, 356:479-489, 1984.
26. Journal of Comparative Physiology, B 166:305-309, 1996.
27. American Journal of Physiology, 217:715-719, 1969.
28. Journal of Reproduction and Fertility, 23:307-317, 1970.
29. European Journal of Biochemistry, 86:519-530, 1978.
30. Archives of Biochemistry and Biophysics, 309:254-260, 1994.
31. American Journal of Physiology, 231:880-887, 1976.
32. Biochimica et Biophysica Acta, 757:111-118, 1983.
33. Comparative Biochemistry and Physiology, B 91:339-344, 1988.
34. Folia Medica, 35:23-27, 1993.
35. Experientia, 34:232-233, 1978.
36. European Journal of Biochemistry, 97:389-394, 1979.
37. Journal of Biological Chemistry, 267:11208-11214, 1992.
38. Journal of Pharmacology and Experimental Therapeutics, 197:675-680, 1976.
39. Hepatology, 5:28-31, 1985.
40. Journal of Biological Chemistry, 267:14918-14927, 1992.
41. Journal of Lipid Research, 38:2548-2557, 1997.
42. Vox Sanguinis, 47:19-27, 1984.
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 follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42 U.S.C. 216, 262, 263, 263a, 264.
2. Section 640.81 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 60<plus-minus>0.5 deg.C.
(f) Stabilizer. Either 0.08<plus-minus>0.016 millimole sodium
caprylate, or 0.08<plus-minus>0.016 millimole sodium
acetyltryptophanate and 0.08<plus-minus>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).
* * * * *
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
hours.
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