[Federal Register Volume 75, Number 60 (Tuesday, March 30, 2010)]
[Proposed Rules]
[Pages 15639-15642]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-7073]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 610

[Docket No. FDA-2010-N-0099]
RIN 0910-AG15


Revision of the Requirements for Constituent Materials

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 to permit the Director of the Center for 
Biologics Evaluation and Research (CBER) or the Director of the Center 
for Drug Evaluation and Research (CDER), as appropriate, to approve 
exceptions or alternatives to the regulation for constituent materials. 
FDA is taking this action due to advances in developing and 
manufacturing safe, pure, and potent biological products licensed under 
a section of the Public Health Service Act (the PHS Act) that, in some 
instances, render the existing constituent materials regulation too 
prescriptive and unnecessarily restrictive. This rule provides 
manufacturers of licensed biological products with flexibility, as 
appropriate, to employ advances in science and technology as they 
become available, without diminishing public health protections.

DATES:  Submit electronic or written comments on the proposed rule on 
or before June 28, 2010. Submit comments on information collection 
issues under the Paperwork Reduction Act of 1995 by April 29, 2010, 
(see the ``Paperwork Reduction Act of 1995'' section of this document).

ADDRESSES:  You may submit comments, identified by Docket No. FDA-2010-
N-0099 and/or RIN number 0910-AG15, by any of the following methods, 
except that comments on information collection issues under the 
Paperwork Reduction Act of 1995 must be submitted to the Office of 
Regulatory Affairs, Office of Management and Budget (OMB) (see the 
``Paperwork Reduction Act of 1995'' section of this document).
Electronic Submissions
    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the agency name 
and Docket No. and Regulatory Information Number (RIN) for this 
rulemaking. All comments received may be posted without change to 
http://www.regulations.gov, including any personal information 
provided. For additional information on submitting comments, see the 
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Information Collection Provision: The information collection 
provisions of this proposed rule have been submitted to OMB for review. 
Interested persons are requested to fax comments regarding information 
collection by April 29, 2010, to the Office of Information and 
Regulatory Affairs, OMB. To ensure that comments on information 
collection are received, OMB recommends that written comments be faxed 
to the Office of Information and Regulatory Affairs, OMB, Attn: FDA 
Desk Officer, FAX: 202-395-7285.

FOR FURTHER INFORMATION CONTACT:  Paul E. Levine, Jr., 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

    Constituent materials regulated under Sec.  610.15 (21 CFR 610.15) 
include ingredients, preservatives, diluents, adjuvants, extraneous 
protein and antibiotics that are contained in a biological product. FDA 
is proposing to amend the regulation for constituent materials at Sec.  
610.15 to allow the Director of CBER or the Director of CDER, as 
appropriate, to approve an exception or alternative to the requirements 
under Sec.  610.15, when data submitted with the exception or 
alternative establish the safety, purity, and potency of the biological 
product. This proposed rule provides manufacturers of biological 
products with flexibility, as appropriate, to employ advances in 
science and technology as they become available, without diminishing 
public health protections. Examples of how the proposed rule would 
provide flexibility to manufacturers in the use of preservatives and 
aluminum in biological products are provided below. However, the 
proposed rule would also provide flexibility to the existing 
requirements regarding extraneous protein and antibiotics (Sec.  
610.15(b) and (c)), provided that each request for an alternative or 
exception to these requirements is submitted with data that establish 
the safety, purity, and potency of the biological product.
    Standards for certain constituent materials present in biological 
products are provided under Sec.  610.15. Section 610.15(a) requires 
that all ingredients used in a licensed product, and any diluent 
provided as an aid in the administration of the product, meet generally 
accepted standards of purity and quality. Any preservative used shall 
be sufficiently nontoxic so that the amount present in the recommended 
dose of the product will not be toxic to the recipient, and in the 
combination used it shall not denature the specific substances in the 
product to result in a decrease below the minimum acceptable potency 
within the dating period when stored at the recommended temperature. 
Products in multiple-dose containers shall contain a preservative, 
except that a preservative need not be added to Yellow Fever Vaccine; 
Poliovirus Vaccine Live Oral; viral vaccines labeled for use with the 
jet injector; dried vaccines when the accompanying diluent contains a 
preservative; or to an Allergenic Product in 50 percent or more volume 
in volume glycerin. An adjuvant shall not be introduced into a product 
unless there is satisfactory evidence that it does not affect adversely 
the safety or potency of the product.
    These regulations also require that the amount of aluminum in the 
recommended individual dose of a biological product not exceed the 
following:

[[Page 15640]]

     0.85 milligrams if determined by assay;
     1.14 milligrams if determined by calculation on the basis 
of the amount of aluminum compound added; or
     1.25 milligrams determined by assay provided that data 
demonstrating that the amount of aluminum used is safe and necessary to 
produce the intended effect are submitted to and approved by the 
Director of CBER or the Director of CDER.
    This regulation establishes requirements for the presence of 
certain constituent materials in final licensed, biological products 
and/or strictly limits the amount of certain constituent materials 
present in licensed biological products. For example, the regulation 
contains requirements as to preservatives. Preservatives are compounds 
that kill or prevent the growth of microorganisms, particularly 
bacteria and fungi. In the Federal Register of January 10, 1968 (33 FR 
367 at 369), the National Institutes of Health (NIH) issued the 
precursor regulation to constituent materials (Sec.  610.15) (the 1968 
regulation).\1\ This regulation, in part, set forth the requirements 
for preservatives in biological products in multiple-dose containers 
and included exceptions to this requirement. Prior to NIH's issuance of 
the 1968 regulation, there had been reports in the scientific 
literature of serious injuries and deaths associated with bacterial 
contamination of multiple-dose containers of vaccines that did not 
contain a preservative. This concern regarding contamination was the 
scientific basis for the requirement that products in multiple-dose 
containers contain a preservative.\2\ However, the regulation also 
provided for certain exceptions from the preservative requirement. 
These exceptions included live viral vaccines that had been licensed 
under section 351 of the PHS Act (42 U.S.C. 262) and that were in 
production when NIH issued the 1968 regulation.\3\
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    \1\ In 1968, NIH regulated biological products, through its 
Division of Biologics Standards. In the Federal Register of June 29, 
1972 (37 FR 12865), an amended Statement of Organization, Functions 
and Delegations of Authority of the Department of Health, Education 
and Welfare was published reflecting a transfer of the Division of 
Biologics Standards to the Food and Drug Administration. In the 
Federal Register of August 9, 1972 (37 FR 15993), FDA published 
regulations that further reflected these organizational changes. As 
a result of this organizational change, the regulations pertaining 
to biological products under Part 73 of Title 42 of the Code of 
Federal Regulations were transferred to the newly established Part 
273 of Title 21 of the Code of Federal Regulations.
    \2\ See ``The National Vaccine Advisory Committee Sponsored 
Workshop on Thimerosal Vaccines'' at 21-24 (August 11, 1999). See 
also Wilson, Hazards of Immunization, 1967.
    \3\ Biological products had contained preservatives prior to 
1968. ``The National Vaccine Advisory Committee Sponsored Workshop 
on Thimerosal Vaccines'' at 24 (August 11, 1999).
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    Preservatives in multiple-dose containers have a long record of 
safe and effective use in preventing microbial growth in the event that 
the vaccine is accidentally contaminated, as might occur with repeated 
punctures of multiple-dose containers. The use of preservatives has 
significantly declined in recent years with the development of new 
products presented in single-dose containers. However, some biological 
products, such as inactivated influenza virus vaccines, are still 
presented in multi-dose containers and contain a preservative.
    However, the requirements in connection with preservatives are too 
prescriptive and unnecessarily restrictive because, for example, state-
of-the art technologies, such as the development of devices to ensure 
aseptic withdrawing, offer an alternative to the use of preservatives 
in multiple-dose containers. FDA believes that providing the option to 
manufacture vaccine in multiple-dose containers without use of a 
preservative would be acceptable, provided that appropriate safeguards, 
such as adequate storage, aseptic withdrawing techniques and timely use 
of the product (e.g., use of the vaccine within a defined period of 
time) are followed to ensure that the safety, purity, and potency of 
the product are not compromised. Furthermore, the current regulation 
under Sec.  610.15(a) does not provide FDA with flexibility to consider 
situations (outside of the listed exceptions) in which to allow the use 
of preservative-free vaccines in multiple-dose containers. The proposed 
rule would permit the Director of CBER or the Director of CDER, as 
appropriate, to approve a request to market a biological product in 
multiple-dose containers without use of a preservative, if the 
manufacturer demonstrates the safety, purity, and potency of the 
product.
    Another example where the current requirements are too prescriptive 
and unnecessarily restrictive pertains to the amount of aluminum 
permitted under Sec.  610.15(a) in the recommended single human dose of 
a biological product. Aluminum, in the form of an aluminum salt, is 
used as an adjuvant in certain biological products. The existing 
regulation limits the amount of aluminum per dose to no more than 0.85 
milligrams (mg) if determined by assay or 1.14 mg if determined by 
calculation on the basis of the amount of aluminum compound added. In 
the Federal Register of October 23, 1981 (46 FR 51903), FDA published a 
rule entitled ``General Biological Products Standards; Aluminum in 
Biological Products'' (the October 1981 rule). The October 1981 rule 
amended Sec.  610.15(a) to increase the permissible level of aluminum 
per dose to 1.25 mg both to make the regulation consistent with World 
Health Organization standards,\4\ and because it appeared that certain 
groups (such as renal dialysis patients), who were understood to be at 
high risk of contracting hepatitis, might require a higher dosage of 
the hepatitis B vaccine, which would in turn, require amounts of 
aluminum as high as 1.25 mg per dose. (See also ``General Biological 
Products Standards for Aluminum in Biological Products'' (46 FR 23765, 
April 28, 1981)).
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    \4\ More specifically, the amendment permitted the use of up to 
1.25 mg of aluminum determined by assay provided that data 
demonstrating that the amount of aluminum used is safe and necessary 
to produce the intended effect are submitted to and approved by the 
Director, Bureau of Biologics.
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    The aluminum content per dose in the formulation of a licensed 
biological product, as specified in Sec.  610.15(a), reflects the NIH 
Minimum Requirements for Diphtheria Toxoid (1947)\5\ and Tetanus Toxoid 
(1952)\6\. The proposed rule would not alter the existing requirements 
regarding the amount of aluminum in a biological product. Instead, in a 
change that is analogous to the one FDA issued in the October 1981 
rule, involving the groups who were at high risk of contracting 
hepatitis, the proposed rule would allow either the Director of CBER or 
the Director of CDER to approve an exception or alternative when the 
Director determines that a biological product meets the requirements 
for safety, purity, and potency but contains an amount of aluminum that 
is higher than currently permitted by Sec.  610.15, such as a 
therapeutic vaccine for treating patients with cancer that contains 
aluminum salts at levels higher than currently allowed, but still meets 
the requirements of safety, purity, and potency.
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    \5\ National Institute of Health, ``Minimum Requirements for 
Diphtheria Toxoid,'' 4th Revision, 1947.
    \6\ National Institutes of Health, ``Minimum Requirements for 
Tetanus Toxoid,'' 4th Revision, 1952.
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    The proposed rule enables FDA to assess the constituent materials 
in these and other products and provides sufficient flexibility for FDA 
to employ advances in science and technology as they become available, 
without diminishing public health protection.
    Manufacturers seeking approval of an exception or alternative to a 
requirement under Sec.  610.15 would be required to submit a request in 
writing.

[[Page 15641]]

The request may be submitted as part of the original biologics license 
application, as an amendment to the original, pending application or as 
a prior approval supplement to an approved application.

II. Highlights of the Proposed Rule

    FDA is proposing to amend Sec.  610.15 by adding new paragraph (d) 
that would permit the Director of CBER or the Director of CDER, as 
appropriate, to approve exceptions or alternatives to the regulatory 
requirements for constituent materials, when the data submitted with 
the exception or alternative establish the safety, purity, and potency 
of the biological product. All requirements under Sec.  610.15 would 
remain in effect, except those for which the Director approves an 
exception or alternative. Manufacturers seeking approval of an 
exception or alternative must submit a request in writing, as described 
in section I of this document.
    FDA is proposing this rule to permit the Director of CBER or the 
Director of CDER, as appropriate, to approve exceptions or alternatives 
to the regulations for constituent materials, when the data submitted 
with the exception or alternative establish the safety, purity, and 
potency of the biological product. All requirements under Sec.  610.15 
would remain in effect, except those for which the Director approves an 
exception or alternative. Manufacturers seeking approval of an 
exception or alternative must submit a request in writing, as described 
in section I of this document.

III. Legal Authority

    FDA is issuing this regulation under the biological products 
provisions of the Public Health Service Act (42 U.S.C. 262 and 264) and 
the drugs and general administrative provisions of the Federal Food, 
Drug, and Cosmetic Act (sections 201, 301, 501, 502, 503, 505, 510, 
701, and 704 (21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 371, and 
374)). Under these provisions of the Public Health Service Act and the 
Federal Food, Drug, and Cosmetic Act, we have the authority to issue 
and enforce regulations designed to ensure that biological products are 
safe, pure, and potent; and prevent the introduction, transmission, and 
spread of communicable disease.

IV. Analysis of Impacts

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

    FDA has examined the impacts 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 (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 proposed rule is not a significant regulatory action 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 entities. Because the proposed rule would allow the Director 
of CBER or the Director of CDER, as appropriate, to approve exceptions 
or alternatives to the regulations for constituent materials, this 
action would increase flexibility and reduce the regulatory burden for 
affected entities. Therefore, the agency proposes to certify that the 
proposed rule will not have a significant economic impact on a 
substantial number of small entities. We request detailed comment 
regarding any potential economic impact of this proposed rule.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $133 million, using the most current (2008) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The benefits of this regulatory action are that the proposed rule 
would reduce burdens on industry (e.g., developers of biological 
products) due to greater flexibility and reduced regulatory 
requirements. These issues are discussed in greater detail in section I 
of this document.
    Any costs associated with this regulatory action are expected to be 
minimal and widely dispersed among affected entities. Based on FDA 
experience, we estimate that we would receive a total of approximately 
three requests annually for an exception or alternative under Sec.  
610.15. FDA experience with similar information collection requirements 
suggests that approximately 1 hour would be required to prepare and 
submit such a request.

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 
adverse effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

C. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
the agency has concluded that the proposed rule does not contain 
policies that have federalism implications as defined in the Executive 
order and, consequently, a federalism summary impact statement is not 
required.

V. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). A description of these provisions is given below with an 
estimate of the annual reporting burden. Included in the estimate is 
the time for reviewing instructions, searching existing data sources, 
gathering and maintaining the data needed, and completing and reviewing 
each collection of information.
    FDA invites comments on the following topics: (1) Whether the 
proposed collection of information is necessary for the proper 
performance of FDA's functions, including whether the information will 
have practical utility; (2) the accuracy of FDA's estimate of the 
burden of the proposed collection of information, including the 
validity of the methodology and assumptions used; (3) ways to enhance 
the quality, utility, and clarity of the information to be collected; 
and (4) ways to minimize the burden of the collection of information on 
respondents, including through the use of automated collection 
techniques, when appropriate, and other forms of information 
technology.

[[Page 15642]]

    Title: Revision of the Requirements for Constituent Materials.
    Description: The proposed rule would permit the Director of CBER or 
the Director of CDER, as appropriate, to approve a manufacturer's 
request for exceptions or alternatives to the regulation for 
constituent materials. This proposed rule provides manufacturers of 
biological products with flexibility, as appropriate, to employ 
advances in science and technology as they become available, without 
diminishing public health protections. Manufacturers seeking approval 
of an exception or alternative must submit a request in writing. The 
request must be clearly identified with a brief statement describing 
the basis for the request and supporting data. The request may be 
submitted as part of the original biologics license application, as an 
amendment to the original, pending application or as a prior approval 
supplement to an approved application. The information to be collected 
will assist FDA in identifying and reviewing requests for an exception 
or alternative to the requirements for constituent materials.
    Description of Respondents: Manufacturers of biological products.

                                 Table 1.--Estimated Annual Reporting Burden\1\
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                         No. of        Annual Frequency     Total Annual        Hours per
  21 CFR Section      Respondents        per Response        Responses           Response         Total Hours
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610.15                             3                  1                  3                  1                  3
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    Based on FDA experience, we estimate that we will receive a total 
of approximately 3 requests annually for an exception or alternative 
under Sec.  610.15. The hours per response are based on FDA experience 
with similar information collection requirements.
    In compliance with the PRA (44 U.S.C. 3507(d)), the agency has 
submitted the information collection provisions of this proposed rule 
to OMB for review. Interested persons are requested to send comments 
regarding information collection to OMB (see DATES and ADDRESSES).

VI. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) electronic or written comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper 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 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

List of Subjects in 21 CFR Part 610

    Biologics, Labeling, Reporting and Recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, it is proposed that 21 CFR part 610 be 
amended as follows:

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

    1. The authority citation for 21 CFR part 610 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 
264.
    2. Amend Sec.  610.15 by adding new paragraph (d) to read as 
follows:


Sec.  610.15  Constituent materials.

* * * * *
    (d) The Director of the Center for Biologics Evaluation and 
Research or the Director of the Center for Drug Evaluation and Research 
may approve an exception or alternative to any requirement in this 
section. Requests for such exceptions or alternatives must be in 
writing.

    Dated: March 25, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-7073 Filed 3-29-10; 8:45 am]
BILLING CODE 4160-01-S