Document ID: FDA-2011-N-0080-0001
Agency: fda
Document Type: Proposed Rule
Title: Sterility Test Requirements for Biological Products
Posted Date: 2011-06-21T04:00Z

[Federal Register Volume 76, Number 119 (Tuesday, June 21, 2011)]
[Proposed Rules]
[Pages 36019-36027]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-15346]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 600, 610, and 680

[Docket No. FDA-2011-N-0080]

Amendments to Sterility Test Requirements for Biological Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) proposes to amend the 
sterility test requirements for biological products. This proposed rule 
is intended to provide manufacturers of biological products greater 
flexibility and to encourage use of the most appropriate and state-of-
the-art test methods for assuring the safety of biological products. We 
are taking this action as part of our continuing effort to review and, 
as necessary, update the biologics regulations.

DATES: Submit either electronic or written comments on this proposed 
rule by September 19, 2011. See section X of this document for the 
proposed effective date of any final rule that may publish based on 
this proposal.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2011-
N-0080, by any of the following methods:

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. FDA-2011-0080 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.

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

    Any product that purports to be sterile should be free of viable 
contaminating microorganisms to assure product safety (Sec.  600.3(q) 
(21 CFR 600.3(q)). Absolute sterility of a lot cannot be practically 
demonstrated without complete destruction of every finished article in 
that lot (United States Pharmacopeia (USP) Chapter 1211). Therefore, 
sterility assurance is accomplished primarily by validation of the 
sterilization process or of the aseptic processing procedures under 
current good manufacturing practice (CGMP), and is supported by 
sterility testing using validated and verified test methods. (See e.g., 
USP Chapter 71>, European Pharmacopeia 2.6.2.)
    In the Federal Register of November 20, 1973 (38 FR 32048), we 
reorganized and republished the biologics regulations, which included 
regulations governing sterility testing, as title 21 of the Code of 
Federal Regulations (CFR), subchapter F, parts 600 through 680 (21 CFR 
parts 600 through 680). Section 610.12 currently requires manufacturers 
to perform sterility tests for both bulk and final container material 
of most biological products \1\ for the detection of

[[Page 36020]]

viable contaminating microorganisms (e.g., bacteria, molds, and/or 
yeasts).
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    \1\ Sterility tests are not currently required to be performed 
for Whole Blood, Cryoprecipitated Antihemophilic Factor (AHF), 
Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox Vaccine, 
Reagent Red Blood Cells, Anti-Human Globulin, or Blood Grouping 
Reagents; or in cases where the Director of the Center for Biologics 
Evaluation and Research (CBER) or the Center for Drug Evaluation and 
Research (CDER), as appropriate, determines that the mode of 
administration, method of preparation, or special nature of the 
product precludes or does not require a sterility test or that the 
sterility of the lot is not necessary to assure the safety, purity, 
and potency of the product. (See 21 CFR 610.12(g)(4).)
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    Over the years, FDA has amended the biologics regulations, as 
necessary, to clarify and update the sterility test requirements. On 
March 11, 1976 (41 FR 10427) and March 2, 1979 (44 FR 11754), we 
updated Sec.  610.12 to clarify the procedures for repeat testing. On 
April 18, 1984 (49 FR 15186), we amended Sec.  610.12 by removing and 
reserving paragraph (g)(3) previously entitled Different Tests Equal or 
Superior and by adding Sec.  610.9 entitled Equivalent methods and 
processes to provide manufacturers of licensed biological products the 
flexibility to use alternate test methods or manufacturing processes 
that provide assurances of safety, purity, potency, and effectiveness 
equal or greater than those provided by the methods or processes 
specified in the regulations under parts 610 through 680. On December 
15, 1986 (51 FR 44903), we clarified and updated certain requirements 
for sterility testing to ensure the reliability of the growth-promoting 
qualities of the sterility test culture media and to provide greater 
consistency with the requirements of USP Chapter XXI. Finally, on 
September 15, 1997 (62 FR 48174), we incorporated by reference the 1995 
ed. of the USP concerning the procedures for the membrane filtration 
test method.
    Section 610.12 currently requires that the sterility of most 
licensed biological products \2\ be demonstrated through the 
performance of tests prescribed in Sec.  610.12(a) and (b). 
Specifically, Sec.  610.12 requires that the sterility of each lot of 
each product, with the exception of certain products,\3\ be 
demonstrated by the performance of prescribed sterility tests for both 
bulk and final container material, unless different sterility tests are 
prescribed in the license (see Sec.  610.12(g)(1)) or the manufacturer 
submits adequate data \4\ establishing that the mode of administration, 
the method of preparation, or the special nature of the product 
precludes or does not require a sterility test, or that the sterility 
of the lot is not necessary to assure the safety, purity, and potency 
of the product (Sec.  610.12(g)(4)(ii)).
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    \2\ See list of exemptions in Sec.  610.12(g)(4).
    \3\ Whole Blood, Cryoprecipitated AHF, Platelets, Red Blood 
Cells, Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood 
Cells, Anti-Human Globulin, or Blood Grouping Reagents (Sec.  
610.12(g)(4)(i)).
    \4\ The Director of CBER or CDER, as appropriate, will determine 
the adequacy of the data (Sec.  610.12(g)(4)(ii)).
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    The regulation, under Sec.  610.12, also specifies the test method 
and culture media to be used. For instance, the prescribed sterility 
test methods rely upon culture media (either Fluid Thioglycollate 
Medium or Soybean-Casein Digest Medium) to detect growth of 
microorganisms (Sec.  610.12(a)(1) and (a)(2)). Moreover, Sec.  610.12 
specifies criteria, such as incubation conditions (time and 
temperature) to be used during testing, suitable test organisms for the 
evaluation of the growth-promoting qualities of the culture media, 
storage and maintenance of test organism cultures, and storage and 
condition of media.
    Manufacturers of innovative products, such as cell and gene therapy 
products, as well as manufacturers of currently approved products, may 
benefit from sterility test methods with rapid and advanced detection 
capabilities. Advances in technology in recent years have allowed the 
development of new sterility test methods that yield accurate and 
reliable test results in less time and with less operator intervention 
than the currently prescribed methods. Some examples of novel methods 
with the potential to detect viable contaminating microorganisms 
include the Adenosine Triphosphate (ATP) bioluminescence, 
chemiluminescence, and carbon dioxide head space measurement.
    We are proposing to amend Sec.  610.12 to promote improvement and 
innovation in the development of sterility test methods, to address the 
challenges of novel products that may be introduced to the market in 
the future, and to potentially enhance sterility testing of currently 
approved products. This proposed revision would provide manufacturers 
the flexibility to take advantage of modern methods as they become 
available, provided that these methods meet certain criteria.

II. Highlights of This Proposed Rule

    We are proposing to amend the sterility test requirements for 
biological products to provide manufacturers with greater flexibility 
to encourage use of the most appropriate and state-of-the-art test 
methods. The most significant proposed changes include the following:
     Elimination of specified sterility test methods, culture 
media formulae (or formulations), and culture media test requirements;
     Elimination of specified membrane filtration procedure 
requirement for certain products;
     Elimination of specified sterility test requirements for 
most bulk material; \5\
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    \5\ See section III.A of this document for a detailed discussion 
of when sterility testing of bulk material may be necessary and 
appropriate.
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     Modification of the repeat sterility test requirements, so 
that repeat tests would occur only once for each lot. These tests would 
be limited to situations when the quality control unit conclusively 
determines, after conducting an investigation upon detection of viable 
microbial contamination during the initial test of the lot, that the 
contamination is the result of laboratory error or faulty materials 
used in conducting the sterility test;
     Replacement of the storage and maintenance requirements 
for cultures of test organisms used to determine the ``growth-promoting 
qualities'' of culture media with: (1) Validation requirements 
specifying that any sterility test used is able to consistently detect 
the presence of viable contaminating microorganisms and (2) 
verification of ``growth-promoting properties'' \6\ or microorganism-
detection capabilities of test and test components;
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    \6\ We are proposing to refer to ``growth-promoting properties'' 
rather than ``growth-promoting qualities'' as we believe ``growth-
promoting properties'' may reflect more accurate and current 
terminology. However, we invite comments on which term is most 
appropriate.
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     Replacement of the sample size or amount requirement with 
a requirement that the sample be appropriate to the material being 
tested;
     Replacement of the Interpretation of test results 
paragraph under Sec.  610.12(c) with a requirement that manufacturers 
establish, implement, and follow written procedures for sterility 
testing that describe, at a minimum, the test method used, the method 
of sampling, and the written specifications for acceptance or rejection 
of each lot; and
     Simplification of the Exceptions paragraph under Sec.  
610.12(c).

III. Description of This Proposed Rule

    This proposed rule is intended to promote improvement and 
innovation in the development of sterility test methods by allowing 
manufacturers flexibility needed for sterility testing of some novel 
products that may be introduced to the market, to enhance sterility 
testing of currently approved products, and to encourage manufacturers 
to benefit from scientific and technological advances in sterility test 
methods as they become available.

A. When is sterility testing required?

    Currently, sterility testing must be performed, with certain 
limited

[[Page 36021]]

exceptions, on both bulk and final container material for each lot of 
each biological product prior to release of that lot (Sec. Sec.  610.1 
and 610.12). A lot is defined as that quantity of uniform material 
identified by the manufacturer as having been thoroughly mixed in a 
single vessel (Sec.  600.3(x)).
    We propose to eliminate the sterility test requirement for most 
bulk materials. We have determined that, in most cases, for purposes of 
sterility testing, the most appropriate test material is the final 
container material. We recognize that, due to the nature of some 
biological products, testing the final container material may not 
always be feasible or appropriate. Thus, proposed Sec.  610.12 would 
require that prior to release, manufacturers of biological products 
must perform sterility testing of each lot of each biological product's 
final container material or other material (e.g., bulk material or 
active pharmaceutical ingredient (API), in-process material, stock 
concentrate material) as appropriate and as approved in the biologics 
license application (BLA) or BLA supplement. For example, certain 
allergenic and cell and gene therapy products may need to be tested for 
sterility at an in-process stage or some other stage of the 
manufacturing process (e.g., intermediate, API, bulk drug substance) 
instead of the final container material, because the final container 
material may interfere with the sterility test. Likewise, some cell 
therapy products and cell-based gene therapy products may need to be 
tested for sterility at an in-process stage or some other stage of 
manufacturing process because low production volumes may result in an 
insufficient final container material sample for sterility testing or a 
short product shelf-life may necessitate administration of the final 
product to a patient before sterility test results on the final 
container material are available. If it is determined that sterility 
testing needs to be performed on material other than the final product, 
due to the nature of the final product, we would expect the 
manufacturer, in its BLA or BLA supplement, to: (1) Describe the 
details of the sterility test method, including the procedure for 
testing the alternate material instead of the final container material 
and (2) provide the scientific rationale for selecting the specific 
test material.
    If this proposed rule is finalized, a manufacturer who desires to 
utilize an alternate sterility test method other than the one approved 
in its BLA must submit a BLA supplement in accordance with Sec.  
601.12(b).

B. What are the sterility test requirements?

1. Test Methods
    Currently, Sec.  610.12(a), (b), and (e) prescribe the culture-
based test method to be used for sterility testing, including the 
acceptable culture media (either Fluid Thioglycollate Medium or 
Soybean-Casein Digest Medium) and incubation conditions (time and 
temperature) to be used during testing, with exceptions provided in 
Sec.  610.12(g). In addition, Sec.  610.12(f) provides that a membrane 
filtration test method, set forth in (USP 23d revision, 1995), may be 
used to test bulk and final container materials or products containing 
oil products in water-insoluble ointments. We propose to eliminate 
references to specific test methods and culture media for sterility 
testing, and instead require that the sterility test be appropriate to 
the material being tested such that the material does not interfere 
with or otherwise hinder the test. We believe that this revision 
recognizes current practices and provides manufacturers the flexibility 
to take advantage of suitable modern sterility test methods and keep 
pace with advances in science and technology. Because we are proposing 
to expand potentially acceptable sterility test methods to include non-
culture-based methods in addition to culture-based methods, we also 
propose to remove the definition of a lot of culture medium currently 
defined in Sec.  610.12(e)(2)(i) as ``* * * that quantity of uniform 
material identified as having been thoroughly mixed in a single vessel, 
dispensed into a group of vessels of the same composition and design, 
sterilized in a single autoclave run, and identified in a manner to 
distinguish one lot from another. * * *'' Although we still consider 
this definition to apply, we believe that this concept is captured by 
the definition of ``lot'' in Sec.  600.3(x). This change also reflects 
our recognition that prepared culture media may be purchased, in which 
case a lot may be predetermined by the vendor.
    Section 610.12(e)(2)(i) currently provides an exception to the 
growth-promoting test requirements for dehydrated culture media 
provided that the manufacturer has an approved validation program for 
autoclaves used to sterilize these media and the manufacturer has 
received approval for this practice from the Director of CBER or CDER, 
as appropriate. We propose to eliminate this exception. Proposed Sec.  
610.12(h)(2) provides that all manufacturers seeking an exemption from 
the sterility test requirements must submit, in their BLA or BLA 
supplement, data that adequately establish that the route of 
administration, the method of preparation, or any other aspect of the 
product precludes or does not necessitate a sterility test.
    Additionally, current Sec.  610.12(e)(2)(ii) stipulates the test 
organisms, strains, characteristics, identity, and verification to be 
used. We propose to eliminate the requirement to test culture media 
with specific test organisms and to eliminate the requirement regarding 
the number of organisms that must be used to demonstrate the growth-
promoting qualities of the culture media. This flexibility would allow 
manufacturers to use sterility test methods that are either culture-
based or non-culture-based, which may necessitate different 
verification activities. Thus, instead of specifying the number and 
type of test organisms, proposed Sec.  610.12(b) would require the 
following: (1) Use of a sterility test method that is appropriate to 
the material being tested such that the material does not interfere 
with or otherwise hinder the test; (2) validation studies to 
demonstrate that the sterility test method used is capable of 
consistently detecting the presence of viable contaminating 
microorganisms; and (3) verification that the sterility test method and 
test components used can detect the presence of viable contaminating 
microorganisms.
    Due to the variety of currently available and potential future 
sterility test methods, we propose to eliminate specified incubation 
conditions (time and temperature) and visual examination requirements 
currently prescribed in Sec.  610.12. Because we propose to allow any 
validated sterility test method that is appropriate to the material 
being tested, rather than specifying the test and the media used, we 
also propose to eliminate the Fluid Thioglycollate Medium incubation 
temperatures prescribed in Sec.  610.12(a)(1)(ii) for the final 
container material containing a mercurial preservative.
2. Validation
    The International Conference on Harmonisation (ICH) Q2(R1) 
``Validation of Analytical Procedures: Text and Methodology'' dated 
November 2005, states that ``[t]he objective of validation of an 
analytical procedure is to demonstrate that it is suitable for its 
intended purpose.'' \7\

[[Page 36022]]

Similarly, USP General Chapter 1223, ``Validation of Alternative 
Microbiological Methods,'' states: ``Validation of a microbiological 
method is the process by which it is experimentally established that 
the performance characteristics of the method meet the requirements for 
the intended application.'' For sterility testing, this means that the 
test can consistently detect the presence of viable contaminating 
microorganisms.
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    \7\ This text was previously named ``Text on Validation of 
Analytical Procedures'' (Q2A) (approved by the Steering Committee in 
October 1994). An accompanying ``Guideline on Validation of 
Analytical Procedures: Methodology'' (Q2B) was subsequently 
developed and approved by the Steering Committee in November 1996. 
The parent guideline is now renamed Q2(R1) as the Guideline Q2B on 
Methodology has been incorporated into the parent guideline. See 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf.
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    We propose to eliminate the prescribed sterility test methods found 
in current Sec.  610.12 and instead allow the use of sterility test 
methods that are validated in accordance with established protocols, to 
be capable of consistently detecting the presence of viable 
contaminating microorganisms. If an established USP compendial 
sterility test method is used, a manufacturer must verify that this 
established method is suitable for application to the specific product; 
however, FDA considers established USP compendial sterility test 
methods to already have been validated using an established validation 
protocol, so their accuracy, specificity, and reproducibility need not 
be re-established to fulfill the proposed validation requirement. In 
contrast, novel methods and any methods that deviate from the USP 
compendial sterility test methods would require the detailed validation 
discussed in the following paragraphs.
    Proposed Sec.  610.12 allows the use of a material sample that does 
not interfere with or otherwise hinder the sterility test from 
detecting viable contaminating microorganisms. This requirement is 
crucial, because the material itself or substances added to the 
material during formulation may make some sterility tests inappropriate 
for use. A validated sterility test method is a critical element in 
assuring the safety and quality of the product. USP General Chapter 
1223, as well as the ICH Guideline for Industry (Text on Analytical 
Procedures), provide general descriptions of typical validation 
parameters, how they are determined, and which subset of each parameter 
is required to demonstrate validity, based on the method's intended 
use. Validation of each test method should be performed on a case-by-
case basis, to ensure that the parameters are appropriate for the 
method's intended use. In the context of reviewing sterility test 
methods as part of BLAs and BLA supplements, FDA may decide, as 
appropriate, to encourage the use of the compendial method as a 
benchmark or starting point for validation of novel methods and certain 
other methods. FDA is specifically seeking comments on whether the 
proposed requirements are sufficient to ensure adequate validation of 
novel sterility test methods or whether additional criteria or guidance 
is needed.
    It is important to consider validation principles, such as limit of 
detection, specificity, ruggedness, and robustness, while developing 
the validation protocol and performing validation studies. These terms 
are defined as follows:
     The limit of detection reflects the lowest number of 
microorganisms that can be detected by the method in a sample matrix. 
This is necessary to define what is considered contaminated.
     Specificity is the ability of the test method to detect a 
range of organisms necessary for the method to be suitable for its 
intended use. This is demonstrated by challenging the sterility test 
with a panel of relevant organisms in the sample matrix.
     Ruggedness is the degree of reproducibility of results 
obtained by analysis of the same sample under a variety of normal test 
conditions, such as different analysts, different instruments, and 
different reagent lots.
     Robustness is the capacity of the test method to remain 
unaffected by small, but deliberate variations in method parameters, 
such as changes in reagent concentration or incubation temperatures.
    Under 21 CFR 211.160(b), laboratory controls must include the 
establishment of scientifically sound and appropriate specifications, 
standards, sampling plans, and test procedures designed to assure that 
components, drug product containers, closures, in-process materials, 
labeling, and drug products conform to appropriate standards of 
identity, strength, quality, and purity. We consider such laboratory 
controls to be needed for both culture-based and non-culture-based 
sterility test methods. The manufacturer must establish and document 
the test method's accuracy, sensitivity, specificity, and 
reproducibility (Sec.  211.165(e) (21 CFR 211.165(e)), as specified in 
the BLA or BLA supplement (Sec. Sec.  601.2 and 601.12). For sterility 
tests, FDA believes that a validation protocol that would meet these 
standards would, at a minimum, include samples of the material to be 
marketed, and incorporate appropriate viable contaminating 
microorganisms to demonstrate the sterility test's growth-promoting 
properties or the method's detection system capabilities, depending on 
the type of test method used. In addition, validation protocols for 
culture-based methods should include both aerobic and anaerobic 
microorganisms when selecting test organisms and include microorganisms 
that grow at differing rates so that manufacturers can establish that 
the test media are capable of supporting the growth of a wide range of 
microorganisms.
    When utilizing culture-based methods, validation protocols should 
require that challenge organisms be added directly to the product prior 
to membrane filtration or direct inoculation. If this is not possible 
due to inhibition by the product, then validation protocols should 
require that the challenge organism be added to the final portion of 
sterile diluent used to rinse the filter if a membrane filtration test 
method is used, or directly to the media containing the product if a 
direct inoculation test method is used. For non-culture-based methods, 
the feasibility of identifying microorganisms from a contaminated 
sample should be evaluated during validation. If a method does not have 
the capability to identify microorganisms to the species level, the 
validation protocol should require that an additional method for 
species identification be utilized for investigation of detected 
contaminants. The test organisms selected should reflect organisms that 
could be found in the product, process, or manufacturing environment.
    The validation study design should contain the appropriate controls 
to evaluate the product sample's potential to generate false positive 
and false negative results. Validation of the sterility test should be 
performed on all new products, and repeated whenever there are changes 
in the test method that could potentially inhibit or enhance detection 
of viable contaminating microorganisms.
3. Verification
    Verification is the confirmation that specified requirements have 
been fulfilled as determined by examination and provision of objective 
evidence. While validation of a sterility test method is the initial 
process of demonstrating that the procedure is suitable to detect 
viable contaminating microorganisms, verification occurs over the 
lifetime of the sterility test method and is the process of confirming 
that the sterility test and test components continue to be capable of 
consistently detecting viable

[[Page 36023]]

contaminating microorganisms in the samples analyzed. This verification 
activity may be necessary periodically or each time a sample is tested, 
depending upon the test method used. We propose to require that the 
sterility test and test components be verified, as appropriate, to 
demonstrate that they can continue to consistently detect viable 
contaminating microorganisms. (See section III.E.2 of this document for 
a more detailed discussion of verification.)

C. What information is needed in written procedures for sterility 
testing?

    We propose to replace the requirement for Interpretation of test 
results in Sec.  610.12(c) with the requirement that manufacturers 
establish, implement, and follow written procedures for sterility 
testing. Written procedures are essential to ensure consistency in 
sampling, testing, and interpretation of results, and to provide 
prospective acceptance criteria for the sterility test. Written 
procedures should include all steps to be followed in the sterility 
test method for initial and repeat tests. Procedures should be detailed 
and clear to eliminate ambiguity. Under the CGMP regulations, 
manufacturers are required to document that a drug product 
satisfactorily conforms to final specifications for the drug product 
(Sec.  211.165(a)). As such, scientifically sound and appropriate 
specifications, standards, sampling plans, and test procedures must be 
designed and written to ensure that materials conform to appropriate 
standards of sterility; and written procedures must include a 
description of the sampling method and the number of units per batch to 
be tested. (See Sec.  211.165(c).)
    Proposed Sec.  610.12 allows the use of either culture-based or 
non-culture-based sterility test methods to evaluate material for 
sterility. There are marked differences between culture-based and non-
culture-based sterility tests. Proposed Sec.  610.12(c) provides the 
following minimum critical considerations that must be included in 
written procedures for both culture-based and non-culture-based 
sterility tests:
     The sterility test method to be used;
     The method of sampling, including the number, volume, and 
size of articles to be tested;
     Written specifications for the acceptance or rejection of 
each lot; and
     A statement of any other function critical to the 
particular sterility test method to ensure consistent and accurate 
results.
    For culture-based sterility test methods, FDA believes the minimum 
critical considerations include the composition of media, growth 
promotion test requirements, and incubation conditions (time and 
temperature). For non-culture-based sterility test methods, the Agency 
believes critical considerations include the composition of test 
components, test parameters, and the controls used to verify the test 
method's ability to consistently detect the presence of viable 
contaminating microorganisms.

D. What is an appropriate sample for sterility testing?

    Selection of an appropriate sample of a lot is critical for 
purposes of sterility testing. Current Sec.  610.12(d) prescribes the 
number of samples for testing bulk and final container material. Due to 
the variety of products covered under Sec.  610.12, including 
innovative products that may be introduced to the market in the future, 
such as cell and gene therapy products, we propose to eliminate the 
sample number requirement and instead require that the sample be 
appropriate to the material being tested. In selecting an appropriate 
sample size, proposed Sec.  610.12(d) requires that the following 
minimal criteria be considered:
     The size or volume of the final product lot. For example, 
a final product lot size of 100,000 units would necessitate a greater 
number of samples to be evaluated than a final product lot size of 
5,000 units;
     The duration of manufacturing of the drug product.\8\ For 
example, samples should be taken at different points of manufacture, 
which, at a minimum should include the beginning, middle, and end of 
manufacturing, in an effort to provide evidence of sterility of the 
drug product throughout the duration of the manufacturing process;
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    \8\ See 21 CFR 210.3(b)(4) for definition of ``drug product.''
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     The final container configuration and size. We believe 
this will ensure appropriate representation of the lot;
     The quantities or concentrations of inhibitors, 
neutralizers, and preservatives, if present, in the test material;
     For a culture-based test method, the volume of test 
material that results in a dilution of the product that was determined 
not to be bacteriostatic or fungistatic; and
     For a non-culture-based test method, the volume of test 
material that results in a dilution of the product that does not 
inhibit or otherwise hinder the detection of viable contaminating 
microorganisms.

E. What is required to verify the sterility test?

    Verification activities are necessary to demonstrate that sterility 
test methods can continue to reliably and consistently detect viable 
contaminating microorganisms. The degree of verification necessary 
depends upon the sterility test method employed. Depending upon the 
sterility test method, verification of each individual test might be 
appropriate. On the other hand, some sterility test methods may only 
need verification activities performed on the selected culture media or 
test organisms. We propose under Sec.  610.12(e) that manufacturers 
perform verification activities appropriate for the sterility test 
method chosen as follows:
    1. For culture-based test methods, manufacturers must conduct tests 
to demonstrate that the performance of the test organisms and culture 
media are acceptable to consistently detect the presence of viable 
contaminating microorganisms, including tests for each lot of culture 
media to verify its growth-promoting properties over the shelf-life of 
the media. Growth-promotion testing is important to demonstrate that 
the culture media are capable of supporting the growth of 
microorganisms.
    2. For non-culture-based test methods, manufacturers must include, 
within the test itself, appropriate controls to demonstrate the ability 
of the test method to continue to reliably and consistently detect the 
presence of viable contaminating microorganisms.

F. Can a sterility test be repeated?

    Current regulations in Sec.  610.12(b) allow one time repeat 
testing of the bulk material to verify results after a positive initial 
test. Repeat testing for final container sterility testing is permitted 
twice, provided there was no evidence of growth in any test of the bulk 
material. Under current Sec.  610.12(c), a lot meets the test 
requirements for sterility if no growth appears during the repeat 
tests. We propose to eliminate the reference to repeat testing of bulk 
material, because we are proposing that sterility testing will not be 
required on bulk material in most instances.\9\ We further propose to 
modify the provision for repeat testing to harmonize our regulatory 
expectations with current scientific understanding of quality 
manufacturing controls by eliminating the use of a second repeat test 
for final container material.
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    \9\ See section III.A of this document for discussion of when 
sterility testing of bulk material may be appropriate.
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    Consistent with USP Chapter 71, we propose that if the initial test 
indicates

[[Page 36024]]

the presence of microorganisms, then the product being examined does 
not comply with the sterility test requirements, unless a thorough 
investigation by the quality control unit can conclusively ascribe the 
initial evidence of microbial presence to a laboratory error or faulty 
materials used in conducting the test. If the test of the initial 
sample is found to be invalid, due to laboratory error or faulty test 
materials, the sterility test may be repeated one time. If no evidence 
of microorganisms is found in the repeat test, the product examined 
complies with the test requirements for sterility; if evidence of 
microorganisms is found in the repeat test, the product examined does 
not comply with the test requirements for sterility (USP Chapter 
71).\10\
---------------------------------------------------------------------------

    \10\ See also Barr, Fish, and Schwemer, Application of 
Pharmaceutical CGMPs, the Food and Drug Law Institute, p. 149, (``In 
the case of a clearly identified laboratory error, the retest 
results substitute for the original test results * * * If, on the 
other hand, no laboratory error could be identified in the first 
test, then there is no scientific basis for discarding the initial 
out-of-specification results in favor of passing retest results''), 
1997.
---------------------------------------------------------------------------

    We further propose that for repeat testing, comparable product that 
is reflective of the initial sample in terms of sample location and the 
stage in the manufacturing process from which it was taken, and the 
same sterility test method must be used for both the initial and repeat 
tests. This is intended to ensure that the same volume of material is 
used for the initial test and each repeat test, and that the 
interpretation of the results is conducted in the same manner.
    This proposed rule, if finalized, could result in the need for some 
manufacturers to modify their repeat test procedures. We consider these 
modifications to be minor changes in accordance with Sec.  601.12(d) 
and to have a minimal potential for an adverse effect on the identity, 
strength, quality, purity, or potency of the product as they may relate 
to the safety or effectiveness of the product. Therefore, such changes 
must be reported in an annual report within 60 days of the anniversary 
date of approval of the BLA.

G. What records must be kept relating to sterility testing?

    Currently, Sec.  610.12(h) incorporates by reference the 
recordkeeping and maintenance requirements contained in 21 CFR 211.167 
and 211.194. We propose to continue to maintain these requirements. 
This is intended to assure that data derived from sterility tests 
comply with established specifications. This includes describing the 
samples received for testing, stating the method used to test the 
samples, identifying the location of relevant validation or 
verification data, recording all calculations performed, and stating 
how the results of tests performed compare to set specifications.

H. Are there any exceptions to sterility test requirements?

    We propose to maintain the current exceptions to the sterility test 
requirements in Sec.  610.12(g)(4)(i) for Whole Blood, Cryoprecipitated 
AHF, Platelets, Red Blood Cells, Plasma, Source Plasma, Smallpox 
Vaccine, Reagent Red Blood Cells, Anti-Human Globulin, and Blood 
Grouping Reagent. However, we request comment on whether any of these 
current exceptions should be removed. For example, we specifically 
request comment on whether to remove the exemption for platelets. 
Bacterial contamination of platelets is a recognized public health risk 
and the blood collection industry has already called for and 
implemented methods to detect and limit or inactivate bacteria in 
platelet components. Requiring testing for platelets would be 
consistent with these industry practices.
    We propose to make minor modifications to the current exception in 
Sec.  610.12(g)(4)(ii), under which the Director of CBER or CDER, as 
appropriate, determines that data submitted adequately establish that 
the mode of administration, the method of preparation, or the special 
nature of the product precludes or does not require a sterility test or 
that the sterility of the lot is not necessary to assure the safety, 
purity, and potency of the product. Specifically, we refer to the 
``route of administration'' rather than the ``mode of administration'' 
and to the ``any other aspect of the product'' rather than ``the 
special nature of the product'' in proposed Sec.  610.12(h)(2) so as to 
account for novel products that may be introduced to the market in the 
future, such as cell and gene therapy products. This proposed exception 
allows the Director of CBER or CDER, as appropriate, to exempt 
biological material from the sterility test requirements of this 
section if, based upon the scientific evidence presented in the BLA or 
BLA supplement, the data adequately establish that the route of 
administration, method of preparation, or any other aspect of the 
product precludes or does not necessitate a sterility test to assure 
the safety, purity, and potency of the product. This proposed exception 
also would allow the Director of CBER or CDER, as appropriate, to 
require sterility testing of the bulk material subject to any 
conditions necessary to assure the safety, purity, and potency of the 
product.
    We propose to eliminate the current exceptions under Sec.  
610.12(g)(1) and (g)(2) because they are no longer necessary given the 
flexibility built into this proposal. Specifically, the current 
exception in Sec.  610.12(g)(1) allows for the use of different 
sterility test methods prescribed for certain products. We further 
propose to eliminate the current exception under Sec.  610.12(g)(2), 
for using two sterility tests, one at incubation temperatures of 
18[deg] to 22 [deg]C and one at 30[deg] to 37 [deg]C, in lieu of 
performing one test using an incubation temperature of 30[deg] to 35 
[deg]C. The proposed language in Sec.  610.12(b) requires the sterility 
test used to be ``* * * appropriate to the material being tested * * 
*'' and proposed Sec.  610.12(c) requires manufacturers to specify 
incubation conditions (time and temperature) in written procedures for 
sterility testing when culture-based media are used. These proposed 
changes are intended to provide sufficient flexibility for the use of 
different sterility test methods, as appropriate.
    We propose to eliminate the current exceptions for Number of final 
containers more than 20, less than 200 (Sec.  610.12(g)(5)), Number of 
final containers--20 or less, (Sec.  610.12(g)(6)), Samples--large 
volume of product in final containers, (Sec.  610.12(g)(7)), and Immune 
globulin preparations. (Sec.  610.12(g)(9)). Instead, we propose to 
require manufacturers to determine the appropriate sample volume and 
size for the material being tested. (See proposed Sec.  610.12(d).) 
Similarly, we propose to eliminate the special requirements in the 
Diagnostic biological products not intended for injection exception 
(Sec.  610.12(g)(8)). We believe the special requirements in current 
Sec.  610.12(g)(8) are no longer necessary because proposed Sec.  
610.12(b)(1) requires the sterility test to be ``appropriate to the 
material being tested'' and proposed Sec.  610.12(d) requires 
manufacturers to determine the appropriate sample volume and size for 
the material being tested.

IV. Proposed Revisions to Other Regulations

    In addition to the revisions to the sterility regulation in Sec.  
610.12, we are also proposing revisions to two other FDA regulations as 
a result of this proposed rule. These proposed revisions are as 
follows:
     Section 600.3(q): Current Sec.  600.3(q) defines 
``sterility'' to mean ``* * * freedom from viable contaminating 
microorganisms, as determined by the

[[Page 36025]]

tests prescribed in Sec.  610.12 of this chapter.'' We are proposing to 
reword this definition to eliminate the term ``prescribed'' since, as 
proposed, Sec.  610.12 would not prescribe specific test methods. Thus, 
we are proposing to amend Sec.  600.3(q) to define ``sterility'' as ``* 
* * freedom from viable contaminating microorganisms, as determined by 
tests conducted under Sec.  610.12 of this chapter.''
     Section 680.3(c): Currently, Sec.  680.3(c) states that: 
``A sterility test shall be performed on each lot of each Allergenic 
Product, as prescribed in Sec.  610.12 of this chapter, with the 
following exceptions: * * * When bulk material is not prepared, the 
sterility test prescribed for bulk material shall be performed on each 
container of each stock concentrate at the time a stock concentrate is 
prepared, and the test sample shall be no less than 1 ml. from each 
stock concentrate container. * * * For lots consisting of no more than 
5 final containers, the final container test shall be performed in 
accordance with Sec.  610.12(g)(6) of this chapter using the sample 
therein prescribed or using a sample of no less than 0.25 ml. of 
product from each final container, divided in approximately equal 
proportions for testing in Fluid Thioglycollate and Soybean-Casein 
Digest Media. The test sample in the later alternative method may be an 
overfill in the final container. * * * For products prepared in sets of 
individual dilution series, a test sample of 0.25 ml. shall be taken 
from a final container of each dilution, which samples may be pooled 
and one half of the pooled material used for the test with Fluid 
Thioglycollate Medium and one half used for the test with Soybean-
Casein Digest Medium. * * * Tablets and capsules need not be tested for 
sterility provided aseptic techniques are employed in their 
manufacture.''
    We are proposing to amend Sec.  680.3(c) to eliminate the term 
``prescribed''. As proposed, Sec.  680.3(c) would say that ``a 
sterility test shall be performed on each lot of each Allergenic 
Product, as required by Sec.  610.12 of this chapter.'' Additionally, 
we are proposing to eliminate Sec.  680.3(c)(1) through (c)(4), because 
these exceptions would no longer be necessary under the proposed 
revisions to Sec.  610.12. As proposed Sec.  610.12 would eliminate the 
sterility test requirement on most bulk material, so the exception in 
Sec.  680.3(c)(1) of how to test allergenic products when bulk material 
is not prepared, would no longer be needed. To the extent it is 
appropriate to perform the sterility test on bulk product for 
allergenics, the approach for such testing will be explained in the BLA 
or BLA supplement that is submitted by the manufacturer and approved by 
FDA. Moreover, Sec.  610.12, as proposed, would not prescribe a 
specific sample number and would not contain the specific exemption in 
Sec.  610.12(g)(6) referenced in Sec.  680.3(c)(2). The proposed 
requirement that the sample be appropriate to the materials being 
tested would accommodate the situation envisioned by current Sec.  
680.83(c)(2) for lots consisting of no more than five final containers. 
Current Sec.  680.83(c)(3) should similarly be accommodated by the 
flexible language of the proposal such that sterility tests for sets of 
individual dilution series can be done on test samples that are 
appropriate to these material and thus a specific exception would no 
longer be needed for the sterility testing of these products. Finally, 
current Sec.  680.83(c)(4) would be accommodated by the general 
exception in proposed Sec.  610.12(h)(2) and thus this fourth exception 
would also be rendered unnecessary.

V. 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, effective, pure, and potent, and to prevent the introduction, 
transmission, and spread of communicable disease.

VI. Analysis of Impacts

    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 as defined by 
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 this proposed rule generally increases 
flexibility for sterility testing and codifies an approach for 
retesting similar to the approach prescribed by the USP, and does not 
add any new regulatory responsibilities, the Agency proposes to certify 
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 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    These amendments would generally provide manufacturers of 
biological products with more flexibility as to how they evaluate the 
sterility of their products and reduce the number of evaluations 
required. The net effect would be to reduce costs.
    One part of these proposed amendments might impose some additional 
costs on manufacturers, however. Under the current regulations, if a 
biological product fails a sterility test, the test may be repeated. If 
the product passes a subsequent test, it is inferred that the first 
test was flawed and only the later results are used. Under the new 
regulations, the test may be repeated only if it is possible to 
``ascribe definitively'' the initial failure to ``a laboratory error or 
faulty materials used in conducting the sterility testing.''
    This change could increase costs for manufacturers because of the 
additional products that would be discarded. The size of the increase 
would be determined by the number of additional lots discarded, the lot 
sizes and the production costs per unit. Some or all of the costs of 
this change would be mitigated by the reduction in losses associated 
with the provision of contaminated products.
    This change is expected to affect few manufacturers. The method for 
sterility testing described in Chapter 71 of USP 33-NF 28 already 
limits the repetition of tests to circumstances similar to those 
described in these amendments. It is

[[Page 36026]]

anticipated that, in the absence of these amendments, the majority of 
manufacturers would limit the repetition of sterility tests in order to 
comply with USP Chapter 71. The Agency invites comment on the frequency 
with which manufacturers diverge from the retesting protocol of these 
amendments and the costs that limiting retests will impose.
    The benefit of limiting retests would be fewer illnesses caused by 
contaminated biological products. We are unable to quantify the value 
of the reduction in illnesses because we do not have an estimate of the 
risk of illness from contaminated biological products or the decline in 
that risk associated with limiting retests.

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

VIII. The Paperwork Reduction Act of 1995

    This proposed rule refers to previously approved collections of 
information 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). The collections of information in Sec. Sec.  211.165 
and 610.12 have been approved under OMB control number 0910-0139. 
Therefore, FDA tentatively concludes that the proposed requirements in 
this document are not subject to review by OMB because they do not 
constitute a ``new collection of information'' under the PRA.

IX. 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.

X. Proposed Effective Date

    FDA is proposing that any final rule that may issue based on this 
proposal be effective 90 days after the date of its publication in the 
Federal Register.

XI. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments 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

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 680

    Biologics, Blood, 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 parts 600, 
610, and 680 be amended as follows:

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    1. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

Sec.  600.3  [Amended]

    2. Section 600.3 is amended in paragraph (q) by removing the phrase 
``prescribed in'' and by adding in its place the phrase ``conducted 
under''.

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

    3. 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.

    4. Section 610.12 is revised to read as follows:

Sec.  610.12  Sterility.

    (a) The test. Except as provided in paragraph (h) of this section, 
manufacturers of biological products must perform sterility testing of 
each lot of each biological product's final container material or other 
material, as appropriate and as approved in the biologics license 
application or supplement for that product.
    (b) Test requirements. (1) The sterility test must be appropriate 
to the material being tested such that the material does not interfere 
with or otherwise hinder the test.
    (2) The sterility test must be validated to demonstrate that the 
test is capable of reliably and consistently detecting the presence of 
viable contaminating microorganisms.
    (3) The sterility test and test components must be verified to 
demonstrate that the test method can consistently detect the presence 
of viable contaminating microorganisms.
    (c) Written procedures. Manufacturers must establish, implement, 
and follow written procedures for sterility testing that describe, at a 
minimum, the following:
    (1) The sterility test method to be used;
    (i) If culture-based test methods are used, include, at a minimum:
    (A) Composition of the culture media;
    (B) Growth-promotion test requirements; and
    (C) Incubation conditions (time and temperature).
    (ii) If non-culture-based test methods are used, include, at a 
minimum:
    (A) Composition of test components;
    (B) Test parameters, including acceptance criteria; and
    (C) Controls used to verify the method's ability to detect the 
presence of viable contaminating microorganisms.
    (2) The method of sampling, including the number, volume, and size 
of articles to be tested;
    (3) Written specifications for the acceptance or rejection of each 
lot; and
    (4) A statement of any other function critical to the particular 
sterility test method to ensure consistent and accurate results.
    (d) The sample. The sample must be appropriate to the material 
being tested, considering, at a minimum:
    (1) The size and volume of the final product lot;
    (2) The duration of manufacturing of the drug product;
    (3) The final container configuration and size;
    (4) The quantity or concentration of inhibitors, neutralizers, and 
preservatives, if present, in the tested material;

[[Page 36027]]

    (5) For a culture-based test method, the volume of test material 
that results in a dilution of the product that is not bacteriostatic or 
fungistatic; and
    (6) For a non-culture-based test method, the volume of test 
material that results in a dilution of the product that does not 
inhibit or otherwise hinder the detection of viable contaminating 
microorganisms.
    (e) Verification. (1) For culture-based test methods, studies must 
be conducted to demonstrate that the performance of the test organisms 
and culture media are suitable to consistently detect the presence of 
viable contaminating microorganisms, including tests for each lot of 
culture media to verify its growth-promoting properties over the shelf-
life of the media.
    (2) For non-culture-based test methods, within the test itself, 
appropriate controls must be used to demonstrate the ability of the 
test method to continue to consistently detect the presence of viable 
contaminating microorganisms.
    (f) Repeat Test Procedures. (1) If the initial test indicates the 
presence of microorganisms, the product does not comply with the 
sterility test requirements unless a thorough investigation by the 
quality control unit can ascribe definitively the microbial presence to 
a laboratory error or faulty materials used in conducting the sterility 
testing.
    (2) If the investigation described in paragraph (f)(1) of this 
section finds that the initial test indicated the presence of 
microorganisms due to laboratory error or the use of faulty materials, 
a sterility test may be repeated one time. If no evidence of 
microorganisms is found in the repeat test, the product examined 
complies with the sterility test requirements. If evidence of 
microorganisms is found in the repeat test, the product examined does 
not comply with the sterility test requirements.
    (3) If a repeat test is conducted, the same test method must be 
used for both the initial and repeat tests, and the repeat test must be 
conducted with comparable product that is reflective of the initial 
sample in terms of sample location and the stage in the manufacturing 
process from which it was obtained.
    (g) Records. The records related to the test requirements of this 
section must be prepared and maintained as required by 21 CFR 211.167 
and 211.194 of this chapter.
    (h) Exceptions. Sterility testing must be performed on final 
container material or other appropriate material as defined in the 
approved biologics license application or supplement and as described 
in this section, except as follows:
    (1) Sterility testing is not required for Whole Blood, 
Cryoprecipitated Antihemophilic Factor, Platelets, Red Blood Cells, 
Plasma, Source Plasma, Smallpox Vaccine, Reagent Red Blood Cells, Anti-
Human Globulin, and Blood Grouping Reagents.
    (2) A manufacturer is not required to comply with the sterility 
test requirements if the Director of the Center for Biologics 
Evaluation and Research or the Director of the Center for Devices and 
Radiological Health, as appropriate, determines that data submitted in 
the biologics license application or supplement adequately establish 
that the route of administration, the method of preparation, or any 
other aspect of the product precludes or does not necessitate a 
sterility test to assure the safety, purity, and potency of the 
product.

PART 680--ADDITIONAL STANDARDS FOR MISCELLANEOUS PRODUCTS

    5. The authority citation for 21 CFR part 680 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.

    6. Section 680.3 is amended by revising paragraph (c) to read as 
follows:

Sec.  680.3  Tests.

* * * * *
    (c) Sterility. A sterility test shall be performed on each lot of 
each Allergenic Product as required by Sec.  601.12 of this chapter.

    Dated: June 16, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-15346 Filed 6-20-11; 8:45 am]
BILLING CODE 4160-01-P