[Federal Register Volume 64, Number 93 (Friday, May 14, 1999)]
[Proposed Rules]
[Pages 26344-26348]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-11898]


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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); Companion 
Document to Direct Final Rule

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
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consistent with current practices and to remove unnecessary or outdated 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. This proposed rule is a 
companion document to the direct final rule published elsewhere in this 
issue of the Federal Register. FDA is taking this action because the 
proposed changes are noncontroversial and FDA anticipates that it will 
receive no significant adverse comment.
DATES: Submit written comments on or before July 28, 1999. If FDA 
receives any significant adverse comment regarding this rule, FDA will 
publish a document withdrawing the direct final rule within 30 days 
after the comment period ends. FDA then and will proceed to respond to 
the comments under this proposed rule using the usual notice and 
comment procedures. Any parties interested in commenting on this 
document should do so at this time.
    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 the direct final rule ends. 
The direct final rule will be effective September 27, 1999.
ADDRESSES: Submit written comments on the proposed 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, Rockville, MD 20852-1448, 301-827-
6210.

SUPPLEMENTARY INFORMATION: 

I. Background

     This proposed rule is a companion to the direct final rule 
published in the final rules section of this issue of the Federal 
Register. This companion proposed rule will provide the procedural 
framework to finalize the rule in the event that the direct final rule 
receives any adverse comment and is withdrawn. The comment period for 
this companion proposed rule runs concurrently with the comment period 
for the direct final rule. Any comments received under this companion 
rule will also be considered as comments regarding the direct final 
rule. FDA is publishing the direct final rule because the rule contains 
noncontroversial changes, and FDA anticipates that it will receive no 
significant adverse comment.
    A significant 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 no significant adverse comment is received in response to the 
direct final rule, no further action will be taken related to this 
proposed rule. Instead, FDA will publish a confirmation document within 
30 days after the comment period ends confirming that the direct final 
rule will go into effect on September 27, 1999. Additional information 
about FDA's direct rulemaking procedures is set forth in a guidance 
published in the Federal

[[Page 26345]]

Register of November 21, 1997 (62 FR 62466).
    For a variety of reasons, 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. 
FDA is issuing this companion proposed rule and the direct final rule, 
published elsewhere in this issue of the Federal Register, 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 plasma derivatives. The 
``Blood Initiative'' is discussed in detail in the preamble to the 
direct final rule.
    FDA emphasizes that for many of the changes discussed below, 
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.

II. Legal Authority

    FDA is proposing to promulgate 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 promulgate 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 Proposed Rule

    FDA is proposing to amend 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, would be made. As 
previously discussed, FDA is also 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. FDA is identifying each of the changes included in the 
proposed rule as follows.

A. Identification of Plasma as the Source Material for Derivative 
Products

    Sections 640.80(a), 640.90(a), and 640.100(a) (21 CFR 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. 
Under the proposal, Secs. 640.80(a), 640.90(a), and 640.100(a) would be 
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 proposing to change 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) would be 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) (21 CFR 640.81(c) and 640.91(c)) 
discuss microbial contamination of source material and would be 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 would 
be amended to clarify that the heating process shall be continuous for 
the time and at the temperature currently specified in the regulations. 
In addition, FDA is proposing to correct Secs. 640.81(e) and 640.91(e) 
by removing a degree sign to read ``60#0.5 C''.

D. Clarification for Stabilizer Used in Albumin (Human) and Plasma 
Protein Fraction (Human)

    Under the proposal, Secs. 640.81(f) and 640.91(f), Stabilizer, 
would be 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 0.08#0.016 millimole sodium 
caprylate, or 0.08#0.016 millimole sodium 
acetyltryptophanate and 0.08#0.016 millimole sodium 
caprylate per gram (/g) of protein. FDA is proposing the word 
``present'' be 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) would be amended to simplify calculations of stabilizer(s) 
content in Albumin (Human) and Plasma Protein Fraction (Human). Under 
the proposal, 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, under this proposal, if the measured concentration of 
sodium caprylate is 0.35 millimole/deciliter (dL) and the measured 
protein concentration is 5.15 percent (i.e., 5.15 g/dL), the sodium 
caprylate concentration may be calculated as 0.35 divided by 5, or 0.07 
millimole/g of protein.

E. Revision of Terminology

    Under the proposal, Secs. 640.82(a) and 640.82(d), Protein content 
and Sodium content, respectively, would be amended by replacing 
``content'' with ``concentration'' to be more precise.
    Sections 640.82(c), 640.92(c), and 640.101(b) would be 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. FDA is proposing to update the 
regulations by deleting the requirement for the determination of heme 
content and replacing it with a

[[Page 26346]]

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 proposed revision is also consistent with the current 
requirements in Sec. 640.92(e) for the closely related product, Plasma 
Protein Fraction.
    FDA is proposing that Secs. 640.84(a)(1), 640.84(a)(4), 640.92(a), 
640.92(d), 640.92(e), and 640.94(a), be amended by replacing 
``content'' with 1``concentration'' to be more precise.Under the 
proposal, Sec. 640.84(b) would be removed to be consistent with changes 
made to Sec. 640.80(a) and (b). Sections 640.84(a)(1) through (a)(4) 
would be redesignated as Sec. 640.84(a) through (d).

F. Correction of Spelling

    Under the proposal, Sec. 640.91(b)(2) and (c) would be amended by 
correcting the spelling of ``coefficient'' and ``contamination,'' 
respectively.

G. Revision of Range for Protein Concentration

    Under the proposal, Sec. 640.92(a), Protein concentration, would be 
corrected by changing ``5.0#0.3'' to ``5.0#0.30'' 
to reflect the precision of the value.

H. Revision of general requirements and sterilization and heating for 
Immune Globulin (Human).

    Under the proposal, Secs. 640.101(e)(3) and (e)(4) would be removed 
to be consistent with current practice. The use of the current 
attenuated strain of measles used 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.
    FDA is proposing to remove Sec. 640.101(f), Samples and protocols, 
to be consistent with current policy. Current policy permits 
manufacturers of biological products, including plasma derivatives, to 
request exemption from lot release by the Center for Biologics 
Evaluation and Research (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.
    FDA is proposing to amend Sec. 640.102(e), Sterilization and 
heating, by removing ``* * * 30 to * * *''. The effect of the 
regulation would be unchanged by this proposed 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 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 proposing to amend 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

    FDA is proposing to revise Sec. 640.104(b)(2), consistent with 
current accepted practice, by eliminating a specified numerical value 
for the measles neutralizing antibody level. This change would allow 
more flexibility for industry and FDA, in that the regulations will no 
longer become outdated each time a new reference standard is used. The 
regulation would be changed to read ``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.''
    FDA is proposing to revise Sec. 640.104(b)(3), 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. The 
regulation is changed to read ``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.''

K. Revision of Nomenclature for Reference Immune Globulin

    FDA is proposing to amend Sec. 640.104(c)(1) and (c)(2) by removing 
the word ``Serum'' to reflect the more precise nomenclature of 
``Reference Immune Globulin * * *''

IV. Analysis of Impacts

A. Review Under Executive Order 12866 and the Regulatory Flexibility 
Act and the Unfunded Mandates Act of 1995.

    FDA has examined the impact of the proposed rule under Executive 
Order 12866 and 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 proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order.
    The agency believes that this proposed rule is consistent with the

[[Page 26347]]

regulatory philosophy and principles identified in the Executive Order. 
This proposed 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 proposed rule amendments have 
no compliance costs and do not result in any new requirements, the 
agency certifies that the proposed 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 proposed 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.

V. The Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed 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.

VI. Request for Comments

    Interested persons may, on or before July 28, 1999, submit to the 
Docket Management Branch (address above) written comments regarding 
this proposal. Two copies of any comments are to be submitted, except 
that 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, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, it is proposed that 21 CFR part 640 be 
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 of 
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.

[[Page 26348]]

    (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:

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. 99-11898 Filed 5-13-99; 8:45 am]
BILLING CODE 4160-01-F