Revision of Requirements Applicable to Albumin (Human), Plasma Protein Fraction (Human), and Immune Globulin (Human); Companion Document to Direct Final Rule

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consistent with current practices and to remove unnecessary or outdated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