Guidance for Industry 

Submission of Documentation in Applications for 

Parametric Release of Human and Veterinary Drug 

Products Terminally Sterilized by Moist Heat 

Processes

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only. 

Comments and suggestions regarding this draft document should be submitted within 60 days of 

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments 

should be identified with the docket number listed in the notice of availability that publishes in 

the Federal Register. 

For questions regarding this draft document contact Marla Stevens-Riley (CDER) at 240-276-

9310 or Mai Huynh (CVM) at 240-276-8273 or Deborah Trout (CBER) at 301-827-3031. 

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) 

August 2008 

CMC 

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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 

Additional copies are available from: 

Office of Training and Communication 

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/cder.guidance/index.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/cvm/guidance/published.htm

and/or 

Office of Communication, Training, and Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Rockville,, MD 20852-1448 

(Tel) 800-835-4709 or 301-827-1800 

http://www.fda.gov/cber/guidelines.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) 

August 2008 

CMC 

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TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 2

III. CONTENT OF SUBMISSIONS FOR PARAMETRIC RELEASE ............................ 3

A. Control Strategy for the Terminal Sterilization Cycle ...............................................................4

B. Risk Assessment, Process Understanding, and Prior Knowledge .............................................4

C. Documentation for Parametric Release Process .........................................................................5

IV. FILING REQUIREMENTS ............................................................................................ 6

V. REFERENCES.................................................................................................................. 6

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Guidance for Industry1

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 draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 

8 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

9 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

10 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

11 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call 

12 the appropriate 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 post-marketing 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. 

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 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. 

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 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 biological products. In addition, refer to United 

States Pharmacopeia (USP) General Chapters: <1> (Injections), <71> (Sterility), and <1041> (Biologics). Shortlived 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 GMPs 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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This guidance does not provide information on procedures, studies, and 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 CGMP requirements for process validation are found at 21 CFR 211.100 

and, for sterile products in particular at 21 CFR 211.113(b). 

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. We recommend discussion with the review division to determine appropriateness of the 

guidance regarding submission filing and content details. 

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 

Sterility testing by cultivation of finished units drawn from the batch is limited in its ability to 

detect contamination because of: (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 

effects of the sterilization process on the product itself, and the microorganisms associated with 

the product. Parametric release of the batch is then based on documented evidence of the control 

of critical parameters, removing the need for testing of samples drawn from the finished product. 

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 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://fda.gov/cder/guidance/index.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://fda.gov/cvm/guidance/published.htm, and CBER 

guidance documents can be found at http://www.fda.gov/cber/guidelines.htm.

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The sterilization load monitor,

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 either in the form of a chemical indicator9 or a biological 

indicator, is included with each load to demonstrate that the sterilization cycle has occurred and 

the criteria for critical parameters have been met. The load monitor is placed in an appropriate 

position in the load, based on the evaluation of development and qualification data. The load 

monitor can be a direct measurement of lethality delivered to the load, or an indirect lethality 

measurement system; however, direct measurement is preferred. Either of these approaches can 

satisfy the CGMP requirement for a laboratory test10 when used in combination with a sterility 

assurance program that is in a demonstrated state of control. 

FDA conducts scientific evaluation of the parametric release program as part of a cooperative 

effort between the review staff, compliance staff, and field investigators to ensure the overall 

state of control of the sterile processing of human and veterinary drug products. Information 

included in an approved application or supplement is subject to CGMP requirements and 

inspection.

FDA has accepted the practice of parametric release for products terminally sterilized by moist 

heat since 1985. Parametric release, described in ICH Q6A,

11 is endorsed by regulatory and/or 

pharmaceutical manufacturing groups in the US, EU, and Japan.12 

III. CONTENT OF SUBMISSIONS FOR PARAMETRIC RELEASE 

An application to FDA is required to obtain approval for parametric release.13 The approval of 

parametric release practices is based on an assessment of the applicant’s proposed critical 

process parameters and how they are controlled. As always, adherence to CGMPs is required for 

marketed products. Demonstrated reliability of the production terminal sterilization cycle, 

microbiological control and monitoring and control of production cycle parameters within 

established validated limits is part of this assessment. The specific terminal sterilization process 

for the product proposed for parametric release should be the same as the process already 

approved in the application and for original applications, 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.14

FDA approval of the parametric release program will be based on how well the firm has 

addressed the risks to product sterility. A statement that describes how the risk assessment 

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 See section III. C., bullet 5. 

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 See reference 2 in section V. 

10 See 21 CFR 211.167(a). 

11 ICH Guidance on Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and 

New Drug Products: Chemical Substances, Federal Register, Vol. 65, No. 251, December 29, 2000. See also 

footnote 7. 

12 See references 1, 3, and 4 in section V. 

13 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; 21 CFR 601.2(a) for biological 

products. 

14 See footnotes 6 and 7. 

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includes current control strategies for the terminal sterilization cycle, the risk that these strategies 

might fail to assure sterility, and how prior manufacturing experience and knowledge were 

incorporated into the risk assessment should be provided in the application. 

A. Control Strategy for the Terminal Sterilization Cycle 

The control strategy assures that the acceptance criteria of the parametric release process and 

terminal sterilization cycle are consistently met, thus assuring the sterility of the product. 

The control strategy should include: 

 

• The rationale for the methods implemented for monitoring and control of the terminal 

sterilization process used for the product release cycle (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. 

• A description of the microbiological monitoring plan for the product and components 

prior to terminal sterilization, with emphasis on spore detection and heat resistance of 

bioburden in the product, or a statement that the plan has not changed since last approved 

and validated. 

If you are referencing information previously submitted to meet these recommendations, it 

should include the identity of the file by name, application number, volume, and page number in 

the Agency’s records where the information can be found.15 

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 sterility for each unit of every batch. The risk assessment should include: 

• Consistency of performance of the terminal sterilization cycle within the approved, 

validated limits. 

15 See 21 CFR 314.50(g)(1) or 21 CFR 601.2. 

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• A discussion of any changes made to the original submission regarding: 1) the production 

terminal sterilization cycle (e.g., the established minimum limit cannot be lowered; 

however, maximum limits can be increased with appropriate stability data to support the 

increase), 2) the production loading patterns, and 3) the container closure system 

(including secondary packaging). You should also include an assessment of the risk to 

sterility associated with these changes. 

• Experience with the proposed or similar product (and container closure system), the 

overall risks to sterility, and the steps you have taken to assess and control these risks. 

• 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: 

• The application/supplement number(s), including approval date(s), of the submission(s) 

that provides for the current terminal sterilization cycle, as applicable. 

• Identification of the critical process parameters (process/cycle parameters 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 the parametric release system is the primary release test and that 

test results based on drawing samples from the finished product will not be used to 

overrule it. In the event of failure to meet the parametric release critical parameter 

criteria, the specific sterilizer load will be rejected by the quality control unit and will not 

be released unless there is a provision for resterilization. In such cases, issues of stability 

and container closure integrity also become relevant. 

• Acknowledgement that regardless of the batch release technique used, any specimen 

tested according to the referee test method for sterility (e.g., compendium or CFR) will 

meet the criteria for sterility (such as during testing for stability or postmarketing 

investigations). 

• A description of the sterilization load monitor including indication of: 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 in 

International Standards Organization (ISO) document 11140 (see section V, reference 2). 

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• Revision of the certificates of analysis for batch release 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 in the 

certificate of analysis either a reference to an SOP or a description of the parametric 

release acceptance criteria 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 can 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 approval before its 

implementation, unless a different agreement is reached with the FDA (e.g., comparability 

protocol). If you have current experience using parametric release with the same 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 you can meet the filing 

requirements with a special report (21 CFR 314.81(b)(3)(ii)) or annual report (21 CFR 514.8 

(b)(4)). 

V. REFERENCES 

1. The European Agency for the Evaluation of Medicinal Product (EMEA); Committee for 

Proprietary Medicinal Products: Note for Guidance on Parametric Release, February 

221 2001, CPMP/QWP/3015/99. Internet address: http://www.emea.europa.eu 

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2. International Standards Organization (ISO) 11140. Sterilization of Health Care ProductsChemical Indicators. 2005, ISO, Geneva, Switzerland. 

3. PDA Journal of GMP and Validation in Japan, Parametric Release for Moist Heated 

Pharmaceutical Products in Japan, Tsuguo Sasaki, Volume 4, Number 1 (2002). 

4. Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme 

(PIC/S): Guidance on Parametric Release, September 2007. Internet address: 

231 http://www.picscheme.org. 

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5. United States Pharmacopeia (USP), General Chapter <71> Sterility Tests. 

6. FDA Compliance Policy Guide (CPG) 460.800. 

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