[Federal Register Volume 68, Number 42 (Tuesday, March 4, 2003)]
[Rules and Regulations]
[Pages 10157-10160]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-4973]



Food and Drug Administration

21 CFR Part 610

[Docket No. 97N-0449]
RIN 0910-AB51

Revision to the General Safety Requirements for Biological 

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.


SUMMARY: The Food and Drug Administration (FDA) is amending the 
biologics regulations regarding general biological products standards 
by adding an administrative procedure for obtaining exemptions from the 
general safety test (GST) requirements. We are taking this action 
because the GST may not be relevant or necessary for certain biological 
products. The rule will permit manufacturers of biological products to 
apply for an exemption from the GST requirement provided they submit 
information to demonstrate that they use appropriate production 
controls and quality assurance safeguards.

DATES: This rule is effective May 5, 2003.


[[Page 10158]]

Evaluation and Research (HFM-17), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448, 301-827-6210.


I. Background

    Under Sec.  610.11 (21 CFR 610.11), manufacturers of biological 
products must perform a test for general safety on biological products 
intended for administration to humans. The GST is one of several tests 
listed in Part 610 General Biological Product Standards (21 CFR part 
610) that are intended to help ensure the safety, purity, and potency 
of biological products administered to humans. The test is used to 
detect extraneous toxic contaminants that may be present in the product 
in the final container from every final filling of each lot of the 
biological product.
    The source of such toxic contaminants may be bacterial and fungal 
by-products that persist after the bacteria are removed by filtration 
or killed by sterilization, or formulation errors that result in 
harmful levels of certain substances, e.g., preservatives. The test 
serves as a safety net to detect harmful contaminants.
    Technological advances have increased the ability of manufacturers 
to control and analyze the manufacture of many biotechnology derived 
biological products. After more then a decade of experience with these 
products, we found that we could evaluate many aspects of a biological 
product's safety, purity, or potency with tests other than those 
prescribed in part 610. In response to these developments, FDA 
published in the Federal Register on May 14, 1996 (61 FR 24227), a 
final rule exempting certain biotechnology and synthetic biological 
products from a number of regulations applicable to biological 
products, including the GST (see 21 CFR 601.2(c)).
    In the Federal Register of April 20, 1998, we published a direct 
final rule and a companion proposed rule (63 FR 19399 and 19431, 
respectively) to revise the general safety requirements for biological 
products. The direct final rule amended the regulations to exempt 
cellular therapy products from the GST requirement and added an 
administrative procedure for manufacturers of other biological products 
to request exemptions from performing the GST. We published a companion 
proposed rule to provide a procedural framework within which the rule 
could be finalized in the event we received any significant adverse 
comments regarding the direct final rule and we withdrew or severed the 
direct final rule.
    We received six comments. We did not receive any significant 
adverse comments to the amendment to specifically exempt ``cellular 
therapy products'' in Sec.  610.11(g)(1). We received significant 
adverse comments on the administrative procedure provision Sec.  
610.11(g)(2). In this rulemaking, we respond to all comments received.
    Accordingly, we published a notice in the Federal Register of 
August 5, 1998 (63 FR 41718), confirming in part and withdrawing in 
part the direct final rule amending the GST requirements. We confirmed 
a revision to Sec.  610.11(g)(1) to add ``cellular therapy products'' 
to the list of products excepted from the GST. Based on receipt of 
adverse comments, we withdrew the revision of Sec.  610.11(g)(2) that 
provided a general administrative procedure for requesting and 
obtaining exemptions from the GST. We applied the comments regarding 
the withdrawn portion of the rule to the companion proposed rule and 
considered them in developing this final rule.

II. Highlights of the Final Rule

    The final rule codifies, at Sec.  610.11(g)(2), an administrative 
procedure under which manufacturers of biological products may request 
and obtain exemptions from the GST. Many biological products are 
currently manufactured, or will be manufactured in the future, under 
highly controlled and rigorously monitored conditions. Therefore, under 
Sec.  610.11(g)(2) we will permit biological product manufacturers who 
employ appropriate production and final filling controls and quality 
assurance safeguards to apply for an exemption from the GST 
requirement. Manufacturers who request an exemption must provide 
supporting documentation to the Director, Center for Biologics 
Evaluation and Research (CBER), as to why a product should not be 
subject to the GST requirement. The request must include an explanation 
of why the GST is unnecessary or cannot be performed due to the mode of 
administration, the method of preparation, or the special nature of the 
product and must describe alternate procedures, if any, to be employed. 
The Director of CBER may grant an exemption if he/she finds that the 
manufacturer's submission justifies an exemption.
    Manufacturers wishing to obtain an exemption to the GST for a 
particular product should contact the appropriate CBER product division 
for specific information regarding how to apply and what information 
should be included in the application or supplemental application.

III. Comments on the Proposed Rule

    (Comment 1) Proposed Sec.  610.11(g)(1) would add ``cellular 
therapy products'' to the list of products excepted from the GST.
    One comment supported the amendment, and none of the comments 
objected to the amendment to add ``cellular therapy products'' to the 
list of exceptions.
    We confirmed a revision to Sec.  610.11(g)(1) in the Federal 
Register of August 5, 1998, notice to add ``cellular therapy products'' 
to the list of products excepted from the GST.
    (Comment 2) Proposed Sec.  610.11(g)(2) would add an administrative 
procedure for manufacturers to request and obtain an exemption from the 
GST. The proposal would require manufacturers to submit information as 
part of a biologics license application submission or a supplement to 
an approved biologics license application.
    One comment opposed proposed Sec.  610.11(g)(2) because the 
mechanism for requiring each licensed manufacturer to submit a license 
supplement to gain an exemption from the GST was too restrictive and 
alternative mechanisms should be available by which all manufacturers 
of a specific product or a group of products could be exempted.
    We disagree with this comment. The comment did not suggest an 
alternate mechanism for our consideration. We believe such changes 
should be addressed on a case-by-case basis through a biologics license 
application or supplement so that we can ensure appropriate controls 
are in place to detect contaminants ordinarily found by the GST.
    (Comment 3) One comment specifically objected that the 
administrative procedure in proposed Sec.  610.11(g)(2) would codify 
FDA's use of the biologics licensure process to achieve the regulatory 
objectives that should be achieved instead only through notice and 
comment rulemaking.
    We intend to revise our regulations only when a group of products 
which can be defined as a product type, such as ``cellular therapy 
products,'' can be excepted from a regulatory provision. Rulemaking is 
not an efficient vehicle for exempting specific or individual products 
or specific manufacturers, or when there are limitations to the 
exemptions, which should be outlined in some detail. We believe the 
biologics licensure process is a more efficient

[[Page 10159]]

process than rulemaking for granting exemptions to the GST.
    (Comment 4) Proposed Sec.  610.11(g)(2) would allow manufacturers 
to request an exemption from the GST; it would not allow other entities 
to request such exemptions.
    One comment argued that a letter from a trade association should 
suffice to obtain such an exemption.
    We disagree with this comment. The request for exemption represents 
an alternative to the regulations to establish a firm, enforceable 
commitment by the manufacturer to FDA as to specific obligations. 
Submissions by an association would not be suitable because it is the 
manufacturer that must follow the regulations. Trade associations 
cannot compel specific actions by their member manufacturers. In 
addition, trade associations do not have the authority to change an 
applicant's submission.
    However, anyone may submit a request to FDA, with supporting 
information, to revise the regulations to provide for exceptions from 
GST requirements.
    (Comment 5) One comment noted that the proposal did not create a 
procedural mechanism to allow for partial exemptions. The comment 
explained that partial exemptions could be appropriate for specific 
subclasses of products.
    We decline to amend the rule as suggested by the comment. The 
comment did not provide enough information that would allow us to 
determine the merits of or need for partial exemptions. However, under 
Sec.  610.11(g)(2), we may accept a request for an exemption in the 
form of a biologics license supplement for a limited group of products 
after a case-by-case evaluation. Section 610.11(g)(2) gives 
manufacturers a mechanism for obtaining exemptions for specific 
biological products on an individual basis, rather than for whole 
``classes'' of products, such as are excepted in Sec.  610.11(g)(1). We 
believe such exemptions should be addressed on a case-by-case basis 
through a biologics license application or supplement.
    (Comment 6) Two comments would revise the proposal to exempt 
allergenic products if each lot of stock concentrates of allergenic 
extracts and each lot of diluent contained in the final product 
satisfies the GST requirements. The comments requested that we modify 
21 CFR 680.3(b)(1) to exempt allergenic extracts from the requirement 
to perform the repeat GST on final products when a GST is performed on 
a stock concentrate. The comments explained that the suggested 
amendment would eliminate an unnecessary burden on the allergenic 
product industry that would result from separate rulemaking procedures.
    The issue of exempting allergenic products is outside the scope of 
this rulemaking. Consequently, we decline to amend the rule as 
suggested by the comment.

IV. Analysis of Impacts

    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 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles set forth in the Executive order. OMB has determined that 
the final rule is a significant regulatory action as defined by the 
Executive order and is subject to review under the Executive order.
    In accordance with the principles of Executive Order 12866, the 
final rule will provide increased flexibility for applications with 
approved biological products and may substantially reduce the burdens 
on some applicants seeking approval of certain biological products.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small business entities. Because the final rule has no compliance 
costs and does not result in any new requirements, the agency certifies 
that the final rule will not have a significant negative economic 
impact on a substantial number of small entities. Therefore, under the 
Regulatory Flexibility Act, no further analysis is required. This rule 
also does not trigger the requirement for a written statement under 
section 202(a) of the Unfunded Mandates Reform Act 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 one year.

V. Environmental Impact

    This agency has determined under 21 CFR 25.31(h) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 

VI. Paperwork Reduction Act of 1995

    This final 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 (44 U.S.C. 3501-3520). The title, 
description, and respondent description of the information collection 
provisions are shown below with an estimate of the annual reporting 
burden. Included in the estimate is the time for reviewing the 
instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing each 
collection of information.
    Title: Request for Exemptions from the General Safety Testing 
Requirements for Biological Products.
    Description: FDA is revising the requirements for GST set forth in 
Sec.  610.11. The test may detect harmful contaminants that may enter 
or be introduced through undetected failures in the manufacture of 
biological products. The revision would add an administrative procedure 
for obtaining exemptions from the GST requirements for biological 
products not already excepted under Sec.  610.11(g)(1). FDA is 
codifying the new administrative procedure because alternatives to the 
GST may be feasible or appropriate for some biological products. FDA 
anticipates that manufacturers requesting exemptions would have 
demonstrated a record of the GST compliance, well-documented in-process 
safety controls, and use sophisticated analytical techniques to 
adequately characterize the product and validate its safety. 
Manufacturers would submit their requests and documentation to the 
Director, CBER, who may grant the exemption if it is determined that 
the manufacturer's submission justifies such an action.
    Description of Respondents: Manufacturers of biological products.
    This final rule requires only those manufacturers requesting an 
exemption from the GST under Sec.  610.11(g)(2) to submit additional 
information as part of a biologics license application or supplement to 
an approved biologics license application. Based on our experience, we 
estimate that we will receive approximately 10 requests for 
administrative exemption from the GST under Sec.  610.11(g)(2) 
annually. We also estimate that an applicant will take 40 hours to 
complete and submit the appropriate information for the exemption 
request. Since the applicant

[[Page 10160]]

ordinarily compiles and organizes the information while performing the 
GST, we anticipate that the additional time needed to submit an 
exemption request will be minimal.

                                 Table 1.--Estimated Annual Reporting Burden \1\
                                            Annual Frequency   Total Annual
   21 CFR Section      No. of Respondents     per Response       Responses     Hours per Response    Total Hours
610.11(g)(2)                  10                    1              10                 40               400
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

    The direct final rule and companion proposed rule of April 20, 1998 
(63 FR 19399 and 19431, respectively) provided a 60-day public comment 
period on the information collection provisions reflected in this final 
rule. Although some comments objected to the license supplement 
mechanism of gaining approval for an exemption as being too burdensome, 
we received no comments on the actual burden estimates for submitting 
such supplements.

VII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the 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 rule does not contain policies that have federalism 
implications as defined in that the Executive order and, consequently, 
a federalism summary impact statement is not required.

List of Subjects in 21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR part 610 is amended as follows:


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

    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, 
    2. Section 610.11 is amended by adding paragraph (g)(2) to read as 

Sec.  610.11  General safety.

* * * * *
    (g) * * *
    (2) For products other than those identified in paragraph (g)(1) of 
this section, a manufacturer may request from the Director, Center for 
Biologics Evaluation and Research, an exemption from the general safety 
test. The manufacturer must submit information as part of a biologics 
license application submission or supplement to an approved biologics 
license application establishing that because of the mode of 
administration, the method of preparation, or the special nature of the 
product a test of general safety is unnecessary to assure the safety, 
purity, and potency of the product or cannot be performed. The request 
must include alternate procedures, if any, to be performed. The 
Director, Center for Biologics Evaluation and Research, upon finding 
that the manufacturer's request justifies an exemption, may exempt the 
product from the general safety test subject to any condition necessary 
to assure the safety, purity, and potency of the product.

    Dated: February 26, 2003.
William K. Hubbard,
Associate Commissioner for Policy and Planning.
[FR Doc. 03-4973 Filed 3-3-03; 8:45 am]