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 1 

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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. 

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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 biologic 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 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. 

55 II. BACKGROUND 

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 

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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://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,

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 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 

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 See section III. C., bullet 5. 

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 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. 

248 International Conference Harmonisation (ICH), 2000, Guidance on Q6A Specifications: Test 

249 Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: 

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): 

264 Guidance on Parametric Release, 2007, PI 005-3, September 25, 2007. 

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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.