[Federal Register Volume 65, Number 167 (Monday, August 28, 2000)]
[Rules and Regulations]
[Pages 52016-52018]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-21897]



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consistent with current practices and to remove unnecessary or outdated 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-
1448, 301-827-6210.


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consistent with current practices and to remove unnecessary or outdated 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 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

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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 
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 
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, 
    6. Journal of Laboratory and Clinical Medicine, 101:930-939, 
    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:


    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 
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 

    Dated: August 4, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-21897 Filed 8-25-00; 8:45 am]