[Federal Register Volume 76, Number 71 (Wednesday, April 13, 2011)]
[Rules and Regulations]
[Pages 20513-20518]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-8885]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 610

[Docket No. FDA-2010-N-0099]


Revision of the Requirements for Constituent Materials

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the 
biologics regulations 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. 
A request for an exception or alternative will be considered for 
approval when the data submitted in support of such a request establish 
the safety, purity, and potency of the biological product for the 
conditions of use, including indication and patient population, for 
which the applicant is seeking approval. FDA is taking this action due 
to advances in developing and manufacturing safe, pure, and potent 
biological products licensed under 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 biological products with 
flexibility, as appropriate, to employ advances in science and 
technology as they become available, without diminishing public health 
protections.

DATES: This rule is effective May 13, 2011.

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

    In the Federal Register of March 30, 2010 (75 FR 15639), FDA 
published a proposed rule to amend the regulations for constituent 
materials under Sec.  610.15 (21 CFR 610.15). Constituent materials 
include ingredients, preservatives, diluents, adjuvants, extraneous 
protein and antibiotics that are contained in a biological product. FDA 
is amending the regulation for constituent materials 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. An 
exception or alternative will be considered for approval when the data 
submitted in support of such a request establish the safety, purity, 
and potency of the biological product for the conditions for which the 
applicant is seeking approval. Under the final rule, the Director of 
CBER or CDER would not approve an exception or alternative when the 
data or the conditions of use, including indication and patient 
population, for which the applicant is seeking approval, do not provide 
a sufficient scientific and regulatory basis for such an approval.
    The final rule provides manufacturers of biological products with 
flexibility, as appropriate, to employ advances in science and 
technology, as they become available. However, the final rule does not 
diminish public health protections that are provided by existing laws 
and regulations. The final rule gives manufacturers the potential to 
employ advances in science and technology if the data provide a 
sufficient regulatory basis for approval of the product. This means 
that each manufacturer's request for an exception or alternative will 
be considered on a case-by-case basis to determine whether the product 
at issue meets the statutory and regulatory criteria for safety, 
purity, and potency for use in the intended population. The Director of 
CBER or CDER will only approve a request for an exception or 
alternative after determining that the particular request meets this 
prescribed criteria for the intended population. Examples of how the 
final rule provides flexibility (such as alternatives to the use of 
preservatives and modifications to the amount of aluminum permitted in 
certain biological products), without diminishing public health 
protections, are provided in the paragraphs that follow.\1\
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    \1\ Although specific examples for use of extraneous protein and 
antibiotics are not provided, the final rule also allows for 
flexibility in applying the existing standards for extraneous 
proteins and antibiotics (Sec.  610.15(b) and (c)); provided that 
each request for an alternative or exception to these requirements 
is supported by data that establish the safety, purity, and potency 
of the biological product.
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    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 must 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 must 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 must 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 (v/v) glycerin. Furthermore, under Sec.  610.15, an adjuvant 
must not be introduced into a product unless there is satisfactory 
evidence that it does not affect adversely the safety or potency of the 
product.
    Section 610.15(a) also requires that the amount of aluminum in the 
recommended individual dose of a biological product not exceed:
    1. 0.85 milligrams if determined by assay;

[[Page 20514]]

    2. 1.14 milligrams if determined by calculation on the basis of the 
amount of aluminum compound added; or
    3. 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.
    Section 610.15 establishes standards for the presence of certain 
constituent materials in licensed, biological products and/or strictly 
limits the amount of certain constituent materials present in licensed 
biological products. However, in order to employ advancements in 
science and technology to benefit the public health, flexibility in 
applying these regulatory standards is needed.
    For example, Sec.  610.15 contains specific requirements as to 
preservatives. Preservatives are compounds that kill or prevent the 
growth of micro-organisms, particularly bacteria and fungi. The current 
requirements for preservatives were based, at least in part, on reports 
from scientific literature concerning serious injuries and deaths 
associated with bacterial contamination of multiple-dose containers of 
vaccines that did not contain a preservative.\2\ As discussed 
previously, Sec.  610.15 provides for limited exceptions from the 
preservative requirement. These exceptions include 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 the National Institutes of Health 
(NIH) issued the 1968 regulation.<SUP>3 4</SUP>
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    \2\ See ``The National Vaccine Advisory Committee Sponsored 
Workshop on Thimerosal Vaccines,'' pp. 21-25, August 11, 1999. See 
also Wilson, Graham S., Hazards of Immunization, 1967.
    \3\ With the creation of NIH, NIH had regulatory authority over 
biological products until 1972, at which time they were transferred 
to FDA. NIH issued the precursor regulation to constituent 
materials, Sec.  610.15, in the Federal Register of January 10, 1968 
(33 FR 367 at 369). See the Federal Register notice of June 29, 1972 
(37 FR 12865) and the Federal Register notice of August 9, 1972 (37 
FR 15993), for more information concerning the transfer of authority 
from NIH to FDA and how the regulations pertaining to biological 
products under 21 CFR part 73 were transferred to the then newly 
established 21 CFR part 273.
    \4\ Biological products had contained preservatives prior to 
1968. ``The National Vaccine Advisory Committee Sponsored Workshop 
on Thimerosal Vaccines,'' p. 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 a multiple-dose container. Even though the use of 
preservatives has significantly declined in recent years with the use 
of products filled in single-dose containers that do not require 
addition of a preservative, some biological products such as 
inactivated influenza virus vaccines are still presented in multi-dose 
containers with a preservative. The use of preservatives could also 
decline further as manufacturers develop and employ new technologies, 
such as multi-dose adaptors to prevent contamination of products in 
multiple-dose containers, without the use of preservative.
    However, 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. It is necessary for FDA to have 
flexibility in applying the regulatory requirements for preservatives 
when, for example, state-of-the art technologies, such as the 
development of devices to ensure aseptic withdrawing offer a safe 
alternative to the use of preservatives in multiple-dose containers. 
The final rule permits the Director of CBER or the Director of CDER to 
approve a request to market a biological product in multiple-dose 
containers without the use of a preservative, if the manufacturer 
demonstrates that sufficient measures, such as an aseptic withdrawing 
technique through the use of an appropriate device, ensure that the 
product continues to meet the statutory and regulatory requirements for 
safety, purity, and potency. Thus, the final rule allows flexibility in 
the use of advancements in technology to provide a public benefit, 
while continuing to ensure the safety, purity, and potency of the 
product.
    Another example where it is necessary for FDA to have flexibility 
in applying current regulatory requirements 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 1981, FDA 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,\5\ 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 ``General Biological Products Standards; Aluminum in 
Biological Products,'' 46 FR 51903, October 23, 1981. See also 
``General Biological Products Standards for Aluminum in Biological 
Products,'' 46 FR 23765, April 28, 1981).
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    \5\ More specifically, the amendment permitted the use of up to 
1.25 mg per dose 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. ``General Biological Products 
Standards; Aluminum in Biological Products,'' (46 FR 51903, October 
23, 1981).
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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) \6\ and Tetanus 
Toxoid (1952).\7\ The final rule does 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 1981, 
involving the groups who were at high risk of contracting hepatitis, 
the final rule allows 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 for the conditions for which the applicant is 
seeking approval, but contains an amount of aluminum that is higher 
than currently permitted by Sec.  610.15. For example, the final rule 
permits the Director of CBER or CDER to approve a manufacturer's 
request for an exception to use a proposed therapeutic vaccine for 
treating individuals with cancer, when the proposed vaccine contains 
aluminum levels higher than currently allowed but still meets the 
requirements of safety, purity, and potency.
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    \6\ NIH, Minimum Requirements for Diphtheria Toxoid, 4th 
Revision, 1947.
    \7\ NIH, Minimum Requirements for Tetanus Toxoid, 4th Revision, 
1952.
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II. Clarifications to the Preamble of the Proposed Rule

    FDA received comments on the rule from manufacturers, private and 
public interest groups, and the general public. In response to comments 
expressing concerns about the safety of a licensed product for which 
FDA grants an exception or alternative to current regulations, FDA 
emphasizes that a manufacturer's request for an exception or 
alternative will not be approved unless the submitted data meet the

[[Page 20515]]

statutory and regulatory criteria for safety, purity, and potency for 
use in the intended population. FDA also emphasizes that the product at 
issue must be shown to be safe, pure, and potent for the conditions of 
use, including proposed indication and patient population, for which 
the applicant is seeking approval, in determining whether the product 
may be approved. FDA further clarifies that consideration for approval 
of a request will be done case-by-case and will be based on review of 
the data submitted in support of a request.
    In addition, in response to comments, FDA clarifies that there is 
both a need for FDA to have flexibility in applying the regulatory 
standards in Sec.  610.15, and a need for manufacturers to have 
flexibility in employing advancements in science and technology for 
developing new safe, pure, and potent alternatives to current products. 
FDA provides more discussion on the need for flexibility in the 
responses to comments on the proposed rule.
    FDA considered all comments received in response to the proposed 
rule and has determined that the proposed rule should be issued as a 
final rule. Accordingly, FDA is issuing as a final rule the amendment 
to Sec.  610.15 under paragraph (d) to permit the Director of CBER or 
the Director of CDER, as appropriate, to approve an exception or 
alternative to the regulatory requirements for constituent materials, 
when the data submitted with the request for approval of an exception 
or alternative establish the safety, purity, and potency of the 
biological product, and is acceptable for use in the intended 
population. All requirements under Sec.  610.15 remain in effect, 
except those for which the Director approves an exception or 
alternative. FDA approval of an exception or alternative will be done 
case-by-case, based on the data submitted for a specific product. 
Manufacturers seeking approval of an exception or alternative must 
submit a request in writing. The request may be submitted as part of 
the original biologics license application (BLA) or as an amendment to 
the original, pending application or as a prior approval supplement to 
an approved application.

III. Comments on the Proposed Rule

    FDA received 15 letters of comment on the proposed rule, not 
including 1 duplicate letter from the same commenter. As stated 
previously, these comments were received from manufacturers, private 
and public interest groups, and the general public. Several of the 
comments supported the proposed rule and several comments disagreed 
with the proposed rule. Some of the comments on the proposed rule were 
similar to or duplicates of other comments received, and have been 
grouped together, where appropriate, to facilitate a uniform response.
    To make it easier to identify the comments and our corresponding 
responses, the word ``Comment'' followed by a number is placed in 
parentheses and is used to indicate a particular comment or set of 
similar comments, as appropriate. The word ``Response'' in parentheses 
precedes FDA's response to a comment. The order of comments and 
responses, as listed, do not represent a value assigned to the comment 
but is used for organizational purposes only.
    (Comment 1) Several comments supported the proposed rule. One such 
comment praised the rule for broadening the potential capacity for 
biologics manufacturers to provide medicines to the public without 
compromising the high level expectation of demonstrating safety, 
purity, and potency. Another comment supported the proposed rule for 
providing a means to advance ``innovative science'' and applications of 
use. Yet another comment expressed interest in seeing the ``reasonable 
flexibility'' provided in the proposed rule extended to other 
biopharmaceutical fields. Still another comment found the conditions 
and recommendations in the proposed rule to be comprehensible and 
useful.
    (Response) FDA acknowledges and appreciates the supportive 
comments. As previously stated, the rule allows FDA the flexibility to 
approve an exception or alternative to the constituent materials 
regulation, without diminishing public health protections. As such, the 
final rule provides patients safe access to important products 
resulting from advances in science and technology. FDA continues to 
review existing regulations and may propose modification of these 
regulations as appropriate for public health and safety.
    (Comment 2) One comment requests clarification as to whether a 
request for an exception or alternative to the requirements under Sec.  
610.15 can be made earlier in clinical development rather than waiting 
until submitting the original BLA.
    (Response) FDA clarifies that although a manufacturer may submit a 
request for an exception or alternative early in the clinical 
development of a biological product, FDA considers such a request to be 
timely when the data intended to support the request establish the 
safety, purity, and potency of the biological product for its intended 
use. In developing data necessary to support a request for an exception 
or alternative, manufacturers must comply with all applicable laws and 
regulations, including the procedures and requirements for 
investigational new drug applications (INDs) and BLAs under parts 312 
and 601 (21 CFR parts 312 and 601). Only after FDA determines that the 
biological product meets the statutory and regulatory criteria for 
safety, purity, and potency, and is acceptable for use in the intended 
population, may the Director of CBER or CDER approve a request for an 
exception or alternative.
    However, FDA strongly encourages early communication from 
manufacturers intending to submit a request for an exception or 
alternative to the requirements under Sec.  610.15. This includes pre-
IND and IND communications by which manufacturers may seek FDA advice 
concerning issues such as data needed to support the rationale for 
testing a biological product in humans, the design of nonclinical 
pharmacology, toxicology, and drug activity studies, initial 
development plans for the biological product, and regulatory 
requirements for demonstrating safety, purity, and potency. Early 
communications between FDA and manufacturers, as described previously, 
are intended to be advisory and are not to be interpreted as approval 
of a request for an exception or alternative.
    (Comment 3) One comment requests agreement from FDA that sponsors 
may administer multiple doses taken from individual preservative-free 
multi-dose vials in clinical trials prior to licensure, as long as the 
sponsor follows pre-approved aseptic procedures in defined time periods 
to support this format as part of the original license application.
    (Response) FDA does not agree with the comment. The current 
regulation for preservatives requires that products in multiple-dose 
containers contain a preservative, with listed exceptions. The final 
rule provides the Director of CBER or CDER with flexibility to approve 
a request for an exception or alternative to this requirement. However, 
FDA will consider each request for an exception or alternative on a 
case-by-case basis and approval of such a request will be based on the 
determination that the data submitted with the request establishes a 
regulatory basis for approval. Sponsors seeking to investigate the use 
of a new biological product in humans must follow the procedures and 
requirements for investigational drugs under part 312. (See also 
Response to Comment 4).

[[Page 20516]]

    (Comment 4) Several comments opposed the proposed rule because the 
commenters understood the rule to give the Director of CBER or CDER 
sole authority in the decisionmaking process to approve a request for 
an exception or alternative. Another comment stated that the proposed 
rule does not allow for a deliberative process for vaccine ingredient 
changes. Other comments stated that the drug industry had too much 
influence upon government agencies including FDA, and that all 
decisions about additives should reside with many experts, in order to 
avoid the potential of undue influence. One comment seeks greater 
transparency from FDA and manufacturers for all aspects of biologics. 
Another comment states that all changes to medicine, particularly those 
``which are proscribed by some government entities, should be subject 
to a public review.''
    (Response) FDA acknowledges and appreciates all comments on the 
proposed rule. FDA agrees with comments supporting public review and 
transparency. However, FDA disagrees with the comments opposing the 
authority of the Director of CBER or CDER to approve a biologic 
product. FDA also disagrees with the comments that the rule places the 
decisionmaking process in the hands of one person, does not allow for a 
deliberative process for vaccine ingredient changes, and that 
manufacturers will have an undue influence in the approval process.
    Under the provisions of the PHS Act, and the Federal Food, Drug, 
and Cosmetic Act (the FD&C Act), FDA has the authority to issue and 
enforce regulations designed to ensure that biological products are 
safe, pure, and potent. Through delegations of authority,\8\ the 
Directors of CBER and CDER have been given the authority to approve 
biological products. Thus, the Directors of CBER and CDER may approve a 
biologic product determined to be safe, pure, and potent, based on 
factors that include review of data, and in some cases, taking into 
account recommendations and input from independent experts (e.g., 
advisory committees), input from interested parties, and public 
comments.
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    \8\ Delegations of authority give certain officials in CBER and 
CDER the legal authority to take substantive actions and perform 
certain functions of the Commissioner of Food and Drugs. Staff 
Manual Guide 1410.702 available on the Internet at  http://www.fda.gov/AboutFDA/ReportsManualsForms/StaffManualGuides/ucm049563.htm (accessed October 22, 2010); ``Drug and Biological 
Product Consolidation,'' (68 FR 38067, June 26, 2003).
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    The PHS Act and the FD&C Act provide FDA with the authority to 
issue regulations that not only establish the requirements for product 
approvals but also establish the requirements for clinical 
investigations of unapproved biologics (21 U.S.C. 355(i) and 42 U.S.C. 
262(a)(2)(A)). In accordance with part 312, manufacturers seeking to 
investigate the use of a new biological product in humans must follow 
specified procedures and requirements for investigational biological 
products. During the IND process, manufacturers must submit, for FDA 
review, data and proposals for additional studies intended to support 
the safety, purity, and potency of a biological product. Manufacturers 
also are required to provide information on patient outcomes and 
adverse events observed during this investigation. FDA reviews the 
submitted data and, upon determining that the biological product does 
not represent an unreasonable risk to the safety of the persons who are 
the subjects of the clinical investigation, will allow a manufacturer 
to proceed with the investigational use of a biological product. A 
manufacturer, after developing data to support approval, may submit a 
BLA to FDA for review and approval.
    Under Sec.  601.2, the Director of CBER or CDER may approve a 
manufacturer's application for a biologics license only after a 
manufacturer submits an application accompanied by data derived from 
nonclinical laboratory and clinical studies that demonstrate that the 
manufactured product meets requirements of safety, purity, and potency. 
These data are reviewed by appropriate experts to determine whether the 
application meets the statutory and regulatory requirements. In 
addition to the recommendations made by these experts, the Director of 
CBER or CDER may seek input from other sources within and outside of 
FDA to determine whether the application should be approved. Further, 
FDA closely monitors the safety of a biological product during its pre-
approval and post-approval development, and may take corrective action, 
as necessary to protect the public.
    In addition to the review process described previously, a sponsor, 
applicant, or manufacturer of a biological product regulated under the 
PHS Act (42 U.S.C. 262), may request review of a scientific controversy 
by an appropriate scientific advisory panel (Sec.  10.75(b)(2) (21 CFR 
10.75(b)(2)). Also, under Sec.  10.75(c), interested persons outside of 
FDA may request internal review of a decision through established FDA 
channels of supervision or review.
    Thus, the current regulations establish procedures for review and 
evaluation of biological products, which include review by appropriate 
internal and external experts. In addition, the current regulations 
allow for public and private entities to participate in FDA's review 
process, as appropriate. This process serves to increase transparency 
and helps ensure that the public health is protected. The final rule 
maintains these important regulatory procedures and requirements while 
increasing FDA's flexibility in employing advances in science and 
technology.
    (Comment 5) Several comments opposed the proposed rule because the 
commenters believe the rule would make the use of vaccines less safe. 
One commenter stated that FDA is ignoring its mandate to make vaccines 
safer by any and all means at its disposal; that FDA is making vaccines 
less safe by removing the certainty as to the minimum standards that a 
biological product must meet; and that the proposed rule does not 
require that the written requests for such exemptions or alternatives 
include the appropriate proofs (toxicological and immunological) of the 
short-term and long-term safety to the most susceptible humans. A few 
comments stated that an increase in the amount of aluminum may 
compromise the safety of vaccines. Another comment stated that families 
do not feel that the current regulations are ``too prescriptive and 
unnecessarily restrictive,'' and that families would prefer more 
stringent rules. Other comments discussed specific concerns with 
already-approved vaccines.
    (Response) FDA acknowledges these comments, as many of the issues 
were considered in drafting the proposed rule. However, FDA disagrees 
with the assertion that the rule will result in a decrease in the 
safety of vaccines and other biological products for which a request 
for an exception or alternative to any requirement under Sec.  610.15 
is made and approved. These regulations will continue to be the 
criteria by which all license applications will be evaluated. However, 
in order to employ advancements in treatment for certain populations, 
such as treatment for individuals suffering from life-threatening 
conditions (e.g., cancer), FDA needs flexibility in applying the 
regulations. By analogy, as is stated in the drug regulations at 21 CFR 
314.105(c):

    While the statutory standards apply to all drugs, the many kinds 
of drugs that are subject to statutory standards, and the wide range 
of uses for those drugs demand flexibility in applying the 
standards. Thus FDA is required to exercise its scientific judgment 
to determine the kind and quantity of data and information an 
applicant is

[[Page 20517]]

required to provide for a particular drug to meet the statutory 
standards.

The final rule is consistent with this CDER regulation as it allows the 
Directors of CBER and CDER flexibility in applying current standards 
for the approval of an exception or alternative to Sec.  610.15, when 
data submitted with the request for an exception or alternative, 
establish the safety, purity, and potency of the biological product.
    Further, consistent with existing statutory and regulatory 
requirements, the Directors of CBER and CDER will not approve a 
biological product that is unsafe for the intended population. The 
final rule does not alter these statutory and regulatory requirements 
nor does it guarantee that a request for an exception or alternative 
will be approved. The final rule only allows the Director of CBER or 
CDER the flexibility to approve a manufacturer's request for an 
exception or alternative if the manufacturer demonstrates that the 
biological product is safe, pure, and potent for use in the intended 
population.
    With regard to comments expressing concern about the safety of 
previously licensed vaccines or specific ingredients in previously 
licensed vaccines, FDA notes that those comments concerning previously 
licensed vaccines are outside the scope of this rulemaking action 
because the rule only allows the Director of CBER or CDER to approve a 
manufacturer's request for an exception or alternative to any 
requirement in Sec.  610.15, when the data submitted in support of such 
a request establish the safety, purity, and potency of the biological 
product.
    (Comment 6) One comment opposed the proposed rule because the 
commenter did not know how FDA would monitor or enforce requirements 
for adequate storage, aseptic withdrawing techniques, and timely use of 
vaccines in multiple-dose containers without preservative or if 
additional training would be given to health care providers.
    (Response) In addressing this comment, FDA clarifies that all 
requests for an exception or alternative are subject to FDA regulations 
regarding the monitoring and enforcement of regulatory standards. These 
regulations were established to assure the quality and integrity of 
data submitted to FDA in support of new product approvals and to 
protect the rights and welfare of the public. FDA accomplishes this 
through various means, including conducting onsite inspections, data 
audits, product testing, and report monitoring. FDA also provides 
advice through guidances and other communications which are provided to 
assist interested parties in complying with regulatory standards for 
the safety, purity, and potency of a product.
    (Comment 7) One comment provided alternative revisions to the 
proposed rule and other subsections within Sec.  610.15. Specifically, 
the commenter proposed that FDA revise the proposed rule to read as 
follows:

    Alternatives. Except for the generally accepted standards of 
purity and quality, in keeping with the vaccine safening mandates 
set forth in 42 U.S.C. 300aa-27''; * * * ``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, provided the 
manufacturer proves that the exception or alternative would improve 
the safety of the biological drug product or, failing that, improves 
the effectiveness, not efficacy, or reduces the per dose cost, of 
the biological drug product without reducing the safety of said 
product''; and * * * ``include the findings, pro and con, of and the 
data from all of the studies conducted to support the request.

    (Response) FDA acknowledges the comment and appreciates the 
suggestions for revising Sec.  610.15. However, in accordance with the 
regulations, FDA is seeking public comment only on the proposed rule to 
permit the Director of CBER or the Director of CDER, as appropriate, to 
approve exceptions or alternatives to the regulation for constituent 
materials. FDA's response to the comments requesting revisions to the 
proposed rule are discussed in the paragraphs that follow.
    FDA disagrees with the commenter's suggested revisions to the 
proposed rule because the revisions inappropriately limit the 
application of the rule to vaccines; allow more flexibility than is 
intended for approving a manufacturer's request for an exception or 
alternative; may lead to confusion about the rule; and are unnecessary. 
As discussed previously, the final rule allows the Director of CBER or 
CDER flexibility to approve a request for an exception or alternative 
to a requirement under Sec.  610.15 provided that data are submitted 
that establish the safety, purity, and potency of the specific 
biological product. These statutory and regulatory requirements apply 
to the use of constituent materials in all biological products and not 
just to vaccines as the comment suggests. In addition, FDA may only 
approve a BLA for a vaccine or other biological product if it has been 
demonstrated to be ``safe, pure, and potent.'' The commenter's 
suggestions that FDA should take cost considerations into account when 
making a decision to approve a vaccine are inconsistent with FDA's 
regulatory authority. Although FDA is sensitive to issues of cost, 
current statutory standards for constituent materials are based on the 
safety, purity, and potency of the product. Furthermore, the suggested 
revisions to the proposed rule inappropriately limit what FDA may 
consider with respect to a request for an exception or alternative. 
Manufacturers are required by current regulations to submit all 
available data, including adverse event reports, with a BLA. FDA 
reviews the data to determine whether an application should be 
approved. The final rule, as consistent with current regulations, does 
not allow the Director of CBER or CDER to approve an application if the 
data are not sufficient to establish that the biological product is 
safe, pure, and potent in relation to the manufacturer's intended use 
of the product.

IV. Legal Authority

    FDA is issuing this regulation under the biological products 
provisions of the PHS Act (42 U.S.C. 262 and 264) and the drugs and 
general administrative provisions of the FD&C 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 PHS Act and 
the FD&C 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.

V. 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 final 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 impacts; and equity). The Agency believes that 
this final rule is not a significant regulatory action under the 
Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory

[[Page 20518]]

options that would minimize any significant impact of a rule on small 
entities. Because the final rule allows the Director of CBER or the 
Director of CDER, as appropriate, to approve exceptions or alternatives 
to the regulations for constituent materials, this action increases the 
flexibility and reduces the regulatory burden for affected entities. 
Therefore, FDA certifies that the final rule will not have a 
significant economic impact on a substantial number of small entities.
    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 $135 million, using the most current (2009) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The benefit of this regulatory action is its reduction, through 
greater flexibility in the regulatory requirements, of burdens on the 
biological products industry. These issues are discussed in greater 
detail in section I of this document. Industry cost reductions may 
result in consumers being offered lower prices or wider availability of 
existing and new biological products; this would have a positive effect 
on patients' welfare.
    Any administrative and paperwork 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 each such request.
    We received comments expressing concern that this rule would 
generate additional costs in the form of negative public health 
effects. FDA has considered the potential for adverse consequences, 
including increased morbidity and mortality, associated with allowing 
deviations from the constituent materials regulations set forth in 
Sec.  610.15(a) through (c), and will grant exemptions only in cases 
where data indicate that biological products in their exempted forms 
will be safe, pure, and potent for the conditions for which the 
applicant is seeking approval. As experience with the October 1981 rule 
has shown, FDA is able to conduct a constituent materials exemption 
process in a manner that is consistent with its public health mandate. 
For all these reasons, we believe the final rule will impose no overall 
public health cost.

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 final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the final 
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 final 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.

VI. Paperwork Reduction Act of 1995

    Section 610.15(d) of this final rule contains reporting 
requirements that were submitted for review and approval to the 
Director of the Office of Management and Budget (OMB), as required by 
section 3507(d) of the Paperwork Reduction Act of 1995. The 
requirements were approved and assigned OMB control number 0910-0666.

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, 21 CFR part 610 is amended as follows:

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

0
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.


0
2. Amend Sec.  610.15 by adding 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: April 7, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-8885 Filed 4-12-11; 8:45 am]
BILLING CODE 4160-01-P