Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes: Guidance for Industry

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Guidance for Industry
Submission of Documentation in Applications for
Parametric Release of Human and Veterinary Drug
Products Terminally Sterilized by Moist Heat
Processes
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Veterinary Medicine (CVM)
Center for Biologics Evaluation and Research (CBER)
February 2010
CMC

Guidance for Industry
Submission of Documentation in Applications for
Parametric Release of Human and Veterinary Drug
Products Terminally Sterilized by Moist Heat
Processes
Additional copies are available from:
Office of Communications
Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Avenue
Bldg. 51, rm. 2201
Silver Spring, MD 20993-0002
(Tel) 301-796-3400
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
Communications Staff, HFV-12
Center for Veterinary Medicine
Food and Drug Administration
7519 Standish Place, Rockville, MD 20855
(Tel) 240-276-9300
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm
and/or
Office of Communication, Outreach, and
Development, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448
(Tel) 800-835-4709 or 301-827-1800
ocod@fda.hhs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Veterinary Medicine (CVM)
Center for Biologics Evaluation and Research (CBER)
February 2010
CMC

Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	CONTENT OF SUBMISSIONS FOR PARAMETRIC RELEASE ............................ 3
A. 	Control Strategy for the Terminal Sterilization Program ......................................................... 4
B. 	Risk Assessment, Process Understanding, and Prior Knowledge ............................................. 5
C. 	Documentation for Parametric Release Process ......................................................................... 5
IV. 	FILING REQUIREMENTS ............................................................................................ 6
V. 	REFERENCES.................................................................................................................. 7

Contains Nonbinding Recommendations
Guidance for Industry1
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Submission of Documentation in Applications for Parametric
Release of Human and Veterinary Drug Products Terminally
Sterilized by Moist Heat Processes
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7 	This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It
8 	does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
9 	You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
10 	and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
11 	implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
12 	number listed on the title page of this guidance.
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I. 	INTRODUCTION
This guidance provides recommendations to applicants on information to include in support of
parametric release for sterile products2 terminally sterilized by moist heat when submitting a new
drug application (NDA), abbreviated new drug application (ANDA), new animal drug
application (NADA), abbreviated new animal drug application (ANADA), biologics license
application (BLA), or supplement or other postmarketing report.
Currently, FDA requires that sterile products meet certain sterility requirements before release to
the market.3, 4 In many cases, the requirements for batch release are fulfilled by conducting a
sterility test on finished units drawn from the batch. Parametric release is defined as a sterility
assurance release program where demonstrated control of the sterilization process enables a firm
to use defined critical process controls, in lieu of the sterility test, to fulfill the intent of 21 CFR
211.165(a), and 211.167(a).5 Under this strategy, market release of terminally sterilized products
can be based upon meeting the defined sterilization parameters and not on performing an
approved sterility test. Meeting the requirements of the parametric release process can provide
greater assurance that a batch meets the sterility requirement than can be achieved with a sterility
test of finished units drawn from the batch.
1 This guidance has been prepared by the Office of Pharmaceutical Science in the Center for Drug Evaluation and
Research (CDER) in cooperation with CDER’s Office of Compliance, the Center for Veterinary Medicine (CVM),
and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration.
2 The term product includes final products that are regulated by CDER, CVM, and CBER.
3 See 21 CFR 314.50(d)(1)(ii)(a) or 21 CFR 514.1(b)(5)(vii)(b).
4 See 21 CFR 211.167(a) for drug products or 21 CFR 610.12 for biologic products. In addition, refer to United
States Pharmacopeia (USP) General Chapters: <1> (Injections), <71> (Sterility), and <1041> (Biologics). Short-
lived radiopharmaceuticals, including positron emission tomography (PET) drugs, are subject to sterility testing;
however, they may be released prior to completion of this test (21 CFR 211.165(a)).
5 For information on how current good manufacturing practices will be applied for products subject to parametric
release that are within the scope of this guidance, see the FDA Compliance Policy Guide (CPG) 460.800.
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Contains Nonbinding Recommendations
This guidance does not provide information on procedures, studies, or data concerning efficacy
and qualification/validation of moist heat sterilization processes. This guidance also does not
provide information on sterility assurance validation programs. However, you may find
information relating to such topics in the Agency’s guidance for industry on Submission of
Documentation for Sterilization Process Validation in Applications for Human and Veterinary
Drug Products.6, 7 Current Good Manufacturing Practices (CGMP) requirements for process
validation are found at 21 CFR 211.100 and, for sterile products in particular, at 21 CFR
211.113(b). Adherence to CGMPs is required for all marketed products.
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The principles in the guidance may also be applicable to products sterilized by other terminal
sterilization processes, such as radiation sterilization, which may be suitable for parametric
release. For these types of applications, we recommend the applicant discuss with the review
division whether applying the guidance would be appropriate.
FDA's guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should
be viewed only as recommendations, unless specific regulatory or statutory requirements are
cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
II. 	BACKGROUND	55
Sterility testing by cultivation of finished units drawn from the batch is limited in its ability to
detect contamination because of the following: (1) the small number of samples required for
testing, which restricts the ability to capture those microorganisms dispersed in a large volume,
and (2) the limited ability of the prescribed culture media to stimulate growth of all potential
microorganisms. Typically, these tests will detect only major errors in the manufacturing
process that result in contamination of a large number of product units. However, data derived
from in-process controls of a validated terminal sterilization process can provide more accurate
information regarding product sterility because the probability of product bioburden surviving
the sterilization process in any single unit of a product can be calculated to be less than one in a
million.
Parametric release allows manufacturers to replace sterility testing of samples drawn from the
finished product as a release criterion with acceptance criteria for the control of identified
process parameters. These parameters, called critical parameters, are critical to a successful
sterilization process and are based on an in-depth knowledge of the process, the product, the
6 This guidance outlines the submission documentation for microbiological product quality of sterile products.
7 CDER guidance documents can be found on the Internet at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update guidances
periodically. To make sure you have the most recent version of a guidance, check the CDER guidance Web site.
CVM guidance documents can be found at
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm, and CBER
guidance documents can be found at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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Contains Nonbinding Recommendations
effects of the sterilization process on the product itself, and any microorganisms that become
associated with the product during the manufacturing process. Parametric release of the batch is
then based on documented evidence of the control of critical parameters, removing the need to
test samples drawn from the finished product.
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A sterilization load monitor,8 either in the form of a physical, chemical (ANSI 2008), or
biological indicator, is included with each load to satisfy the requirement for a laboratory test.9
In addition, the sterilization load monitor is always considered a critical process parameter. A
successful load monitor result, the meeting of the acceptance criteria of the critical parameters,
and having a well validated sterility assurance program demonstrate that there is a state of
control of the manufacturing process for the product. The load monitor(s) should be placed in
appropriate positions to indicate that the load was exposed to a sterilization process which was
measured and recorded for conformance with defined criteria for parametric release. This
position(s) is determined based on the evaluation of development and qualification data. The
location and number of monitors should be described and justified in the application. Alternative
procedures for demonstrating that a load or part of a load was exposed to a sterilization process
should be discussed with the review division(s) prior to submitting a plan for parametric release.
FDA conducts scientific evaluation of the parametric release program as part of a cooperative
effort among our review staff, compliance staff, and field investigators.
FDA has accepted the practice of parametric release for drug products terminally sterilized by
moist heat since 1985. Parametric release, described in the International Conference on
Harmonisation (ICH) Q6A (ICH 2000), 10 is endorsed by regulatory and/or pharmaceutical
manufacturing groups in the US (PDA 1999, USP 2009), EU (PIC/S 2007, EMEA 2001), and
Japan (Sasaki 2002).
III. 	CONTENT OF SUBMISSIONS FOR PARAMETRIC RELEASE
Section IV describes what submissions are required to obtain approval for parametric release.11
The approval of parametric release practices is based on an assessment of the applicant’s
proposed critical process parameters and how they are controlled. Demonstrated reliability of
the production terminal sterilization cycle, microbiological control, and monitoring and control
of production cycle parameters within established validated limits are part of this assessment.
The terminal sterilization process for the product proposed for parametric release should be
validated according to the Agency’s guidance for industry on Submission of Documentation for
Sterilization Process Validation in Applications for Human and Veterinary Drug Products.12
8 See section III. C., bullet 5.
9 See 21 CFR 211.167(a).
10 See footnote 7.
11 See 21 CFR 314.50(d)(1)(ii)(a) and 21 CFR 314.70(b)(2)(iii) for human drug products; 21 CFR
514.1(b)(5)(vii)(b) and 21 CFR 514.8(b)(2)(ii)(C) for veterinary drug products; or 21 CFR 601.2(a) for biologic
products.
12 See footnotes 6 and 7.
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Contains Nonbinding Recommendations
FDA approval of the parametric release program will be based on how well the firm has
addressed the risks to product sterility. A risk assessment statement consistent with the
principles of ICH Q9 (ICH 2006) should be provided that describes the following:
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• 	Current strategies for control of the terminal sterilization program;
• 	Risk that these strategies might fail to ensure sterility; and
• 	How prior manufacturing experience and knowledge were incorporated into the risk
assessment.13
A. 	Control Strategy for the Terminal Sterilization Program
A control strategy is used to ensure that the acceptance criteria of the parametric release process
and terminal sterilization cycle are met in order to ensure product sterility.
The control strategy should include the following:
• 	The rationale for the methods implemented to monitor and control the terminal
sterilization process used for the product release (the critical process parameters);
• 	The rationale for the selection of critical process parameter(s);
• 	A description of the acceptance criteria for parametric release;
• 	A description of the drug product and container closure system (including secondary
packaging, as applicable) that will be part of the parametric release program;
• 	A description of the proposed production loading patterns and verification that they are
within the validated limits for the terminal sterilization cycle, or a statement that they
have not changed since last approved and validated (as applicable); and
• 	A description of the microbiological monitoring plan for the product and components
prior to terminal sterilization or a statement that the plan has not changed since last
validated. Spore detection and heat resistance studies should be emphasized for
bioburden based sterilization cycles.
If you are referencing information previously submitted to meet these recommendations, it
should include the application number and submission date, and any other relevant citations to
the Agency’s records where the information can be found.14
13 Knowledge management and quality risk management can be used to continually improve manufacturing
capabilities throughout the life cycle for a terminal sterilization program.
14 See 21 CFR 314.50(g)(1) or 21 CFR 601.2.
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Contains Nonbinding Recommendations
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B. 	Risk Assessment, Process Understanding, and Prior Knowledge
Successful parametric release systems are based on the reliability of the control strategy of the
sterility assurance program. We recommend that your risk assessment focus on the risk of
failure to achieve the minimum required probability of a non-sterile unit for each unit of every
batch. The risk assessment should include the following:
• 	Consistency of performance of the terminal sterilization cycle within the validated limits.
• 	A discussion of risk to the sterility of the product relative to the following: (1) the
production terminal sterilization cycle, (2) the production loading patterns, (3) the
container closure system (including secondary packaging), and (4) any potential
contamination risks from the environment (as appropriate). For an approved application,
you should indicate any changes to the above items and provide an assessment of the risk
to the sterility of the product associated with those changes. For example, although the
established minimum sterilization time cannot be lowered, the maximum sterilization
time can be increased if the appropriate stability data are provided to support the increase.
• 	Experience with the proposed or similar product (and container closure system) and
proposed or similar sterilization process, the overall risks to sterility, and the steps you
have taken to assess and control these risks. For new products, prior knowledge from
developmental and registration/exhibit batches may suffice.
• 	A discussion of your overall prior knowledge and production and testing experience
relevant to the drug product that will be subject to parametric release.
C. 	Documentation for Parametric Release Process
The following information specific to the proposed parametric release process should also be
included in your submission:
• 	A citation to a complete and detailed description of the current relevant terminal
sterilization cycle.
• 	Identification of the critical process parameters (process/cycle parameters and appropriate
load monitors essential for product release) for the product(s) proposed for parametric
release, including the minimum and maximum limits for these critical parameters. The
critical process parameters should be within the limits that have been validated and
approved for sterility assurance of the subject product(s).
• 	Acknowledgement that adherence to the critical parameters of the parametric release
program will substitute for the performance of a sterility test as the primary release
criterion for the product and that sterility test results from the finished product will not be
used to overrule any failure to meet the acceptance criteria of the parametric release
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Contains Nonbinding Recommendations
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program. In the event of failure, the specific sterilizer load will be rejected by the quality
control unit and will not be released unless there is a provision for reprocessing.
• 	Acknowledgement that regardless of the batch release technique used, any specimen
tested according to the reference test method for sterility (e.g., compendium or FDA
regulations) will meet the criteria for sterility (such as during testing for stability or
postmarketing investigations).
• 	A description of the sterilization load monitor that indicates the following: (1) the type of
monitor being proposed, (2) how the load monitor will be used and analyzed, (3) what
functions are being measured by the monitor, and (4) the rationale for the location of the
monitor. Additionally, for indirect monitors, we recommend that you include a statement
justifying the classification of the indirect indicator that you are using as defined by the
American National Standard Institute (ANSI 2008). In certain circumstances a Class 3
indicator may be appropriate; however, a Class 5 indicator is recommended for most
situations.
• 	Documentation of the control system to verify exposure of the load to the sterilization
process.
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• 	Revision of the certificates of analysis or batch release records for each product subject to
parametric release to indicate that parametric release is now the method used to provide
assurance of the requirement of sterility. We recommend that you provide a reference to
show the link between batch release criteria and the commitments in the application.
IV. 	FILING REQUIREMENTS
To request parametric release in an original application submission, the request should include
information specific to parametric release along with sterilization validation information and
product release criteria. For changes to an approved application, the request for parametric
release should be submitted in a prior approval supplement under 21 CFR 314.70, 21 CFR
601.12 or 21 CFR 514.8(b)(2). The change to parametric release requires FDA approval before
its implementation. If the applicant has current experience using parametric release with a
comparable sterilization cycle at the same manufacturing site, and the proposed product's
manufacturing process fits into the same validation protocol for parametric release (e.g.,
container closure system, load patterns, cycle process parameters, and cycle acceptance criteria),
then the applicant should meet the filing requirements with a special report for a human drug
product,15 or an annual report for a veterinary drug product16 or a biologic product.17 If your
product fits into one of these filing categories, contact the review division for your product to
verify submission requirements.
15 21 CFR 314.81(b)(3)(ii)
16 21 CFR 514.8 (b)(4)
17 21 CFR 601.12(d)
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Contains Nonbinding Recommendations
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V. 	REFERENCES
American National Standard Institute (ANSI), Association for the Advancement of Medical
Instrumentation (AAMI), International Organization for Standardization (ISO) 15882, 2008,
Sterilization of Health Care Products-Chemical Indicators-Guidance for Selection, Use and
Interpretation of Results.
The European Agency for the Evaluation of Medicinal Product (EMEA), 2001; Committee for
Proprietary Medicinal Products: Note for Guidance on Parametric Release, March 2001,
CPMP/QWP/3015/99.
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Food and Drug Administration, 1987, Parametric Release - Terminally Heat Sterilized Drug
Products, Compliance Policy Guide (CPG) 460.800 (CPG 7132a.14), October 2, 1987.
International Conference Harmonisation (ICH), 2000, Guidance on Q6A Specifications: Test	248
Procedures and Acceptance Criteria for New Drug Substances and New Drug Products:	249
Chemical Substances, Guidance for Industry, Federal Register, Vol. 65, No. 251, December 29,
2000.
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ICH, 2006, Q9 Quality Risk Management, Guidance for Industry, Federal Register, Vol. 71, No.
106, June 2006.
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ICH, 2009, Q10 Pharmaceutical Quality System, Guidance for Industry, Federal Register, Vol.
74, No. 66, April 2009.
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PDA Journal of Pharmaceutical Science and Technology, Technical Report No. 30: Parametric
Release of Pharmaceuticals Terminally Sterilized by Moist Heat, Supplement, Volume 53, Number 4,
July-August 1999
Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme (PIC/S):
Guidance on Parametric Release, 2007, PI 005-3, September 25, 2007.	264
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Sasaki, T., 2002, Parametric Release for Moist Heated Pharmaceutical Products in Japan, PDA
Journal of GMP and Validation in Japan, Volume 4, Number 1.
United States Pharmacopeia (USP) 32-NF, General Chapter <1222> Terminally Sterilized
Pharmaceutical Products-Parametric Release, 2009.