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: 
 
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Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
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(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 
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(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 
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(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 
 
1
Guidance for Industry  
1 
Submission of Documentation in Applications for Parametric 
2 
Release of Human and Veterinary Drug Products Terminally 
3 
Sterilized by Moist Heat Processes 
4 
5   
6   
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.  
13   
14   
15   
16  I.  INTRODUCTION  
17   
18  This guidance provides recommendations to applicants on information to include in support of 
19  parametric release for sterile products2 terminally sterilized by moist heat when submitting a new 
20  drug application (NDA), abbreviated new drug application (ANDA), new animal drug 
21  application (NADA), abbreviated new animal drug application (ANADA), biologics license 
22  application (BLA), or supplement or other postmarketing report. 
23   
24  Currently, FDA requires that sterile products meet certain sterility requirements before release to 
25  the market.3, 4  In many cases, the requirements for batch release are fulfilled by conducting a 
26  sterility test on finished units drawn from the batch.  Parametric release is defined as a sterility 
27  assurance release program where demonstrated control of the sterilization process enables a firm 
28  to use defined critical process controls, in lieu of the sterility test, to fulfill the intent of 21 CFR 
29  211.165(a), and 211.167(a).5  Under this strategy, market release of terminally sterilized products 
30  can be based upon meeting the defined sterilization parameters and not on performing an 
31  approved sterility test.  Meeting the requirements of the parametric release process can provide 
32  greater assurance that a batch meets the sterility requirement than can be achieved with a sterility 
33  test of finished units drawn from the batch. 
34   
                                                 
1 This guidance has been prepared by the Office of Pharmaceutical Science in the Center for Drug Evaluation and 
Research (CDER) in cooperation with CDERs 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. 
  1 Contains Nonbinding Recommendations 
 
35  This guidance does not provide information on procedures, studies, or data concerning efficacy 
36  and qualification/validation of moist heat sterilization processes.  This guidance also does not 
37  provide information on sterility assurance validation programs.  However, you may find 
38  information relating to such topics in the Agencys guidance for industry on Submission of 
39  Documentation for Sterilization Process Validation in Applications for Human and Veterinary 
40  Drug Products.6, 7   Current Good Manufacturing Practices (CGMP) requirements for process 
41  validation are found at 21 CFR 211.100 and, for sterile products in particular, at 21 CFR 
42  211.113(b).  Adherence to CGMPs is required for all marketed products. 
43   
44  The principles in the guidance may also be applicable to products sterilized by other terminal 
45  sterilization processes, such as radiation sterilization, which may be suitable for parametric 
46  release.  For these types of applications, we recommend the applicant discuss with the review 
47  division whether applying the guidance would be appropriate. 
48   
49  FDA's guidance documents, including this guidance, do not establish legally enforceable 
50  responsibilities.  Instead, guidances describe the Agency's current thinking on a topic and should 
51  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
52  cited.  The use of the word should in Agency guidances means that something is suggested or 
53  recommended, but not required.  
54   
55  II.  BACKGROUND 
56   
57  Sterility testing by cultivation of finished units drawn from the batch is limited in its ability to 
58  detect contamination because of the following: (1) the small number of samples required for 
59  testing, which restricts the ability to capture those microorganisms dispersed in a large volume, 
60  and (2) the limited ability of the prescribed culture media to stimulate growth of all potential 
61  microorganisms.  Typically, these tests will detect only major errors in the manufacturing 
62  process that result in contamination of a large number of product units.  However, data derived 
63  from in-process controls of a validated terminal sterilization process can provide more accurate 
64  information regarding product sterility because the probability of product bioburden surviving 
65  the sterilization process in any single unit of a product can be calculated to be less than one in a 
66  million.  
67   
68  Parametric release allows manufacturers to replace sterility testing of samples drawn from the 
69  finished product as a release criterion with acceptance criteria for the control of identified 
70  process parameters.  These parameters, called critical parameters, are critical to a successful 
71  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. 
 
  2 Contains Nonbinding Recommendations 
 
72  effects of the sterilization process on the product itself, and any microorganisms that become 
73  associated with the product during the manufacturing process.  Parametric release of the batch is 
74  then based on documented evidence of the control of critical parameters, removing the need to 
75  test samples drawn from the finished product.  
76   
77  A sterilization load monitor,8 either in the form of a physical, chemical (ANSI 2008), or 
78  biological indicator, is included with each load to satisfy the requirement for a laboratory test.9  
79  In addition, the sterilization load monitor is always considered a critical process parameter.  A 
80  successful load monitor result, the meeting of the acceptance criteria of the critical parameters, 
81  and having a well validated sterility assurance program demonstrate that there is a state of 
82  control of the manufacturing process for the product.  The load monitor(s) should be placed in 
83  appropriate positions to indicate that the load was exposed to a sterilization process which was 
84  measured and recorded for conformance with defined criteria for parametric release.  This 
85  position(s) is determined based on the evaluation of development and qualification data.  The 
86  location and number of monitors should be described and justified in the application.  Alternative 
87  procedures for demonstrating that a load or part of a load was exposed to a sterilization process 
88  should be discussed with the review division(s) prior to submitting a plan for parametric release. 
89   
90  FDA conducts scientific evaluation of the parametric release program as part of a cooperative 
91  effort among our review staff, compliance staff, and field investigators.  
92   
93  FDA has accepted the practice of parametric release for drug products terminally sterilized by 
94  moist heat since 1985.  Parametric release, described in the International Conference on 
95  Harmonisation (ICH) Q6A (ICH 2000),10 is endorsed by regulatory and/or pharmaceutical 
96  manufacturing groups in the US (PDA 1999, USP 2009), EU (PIC/S 2007, EMEA 2001), and 
97  Japan (Sasaki 2002).  
98   
99  III.  CONTENT OF SUBMISSIONS FOR PARAMETRIC RELEASE 
100   
101  Section IV describes what submissions are required to obtain approval for parametric release.11  
102  The approval of parametric release practices is based on an assessment of the applicants 
103  proposed critical process parameters and how they are controlled.  Demonstrated reliability of 
104  the production terminal sterilization cycle, microbiological control, and monitoring and control 
105  of production cycle parameters within established validated limits are part of this assessment.  
106  The terminal sterilization process for the product proposed for parametric release should be 
107  validated according to the Agencys guidance for industry on Submission of Documentation for 
108  Sterilization Process Validation in Applications for Human and Veterinary Drug Products.12   
109   
                                                 
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. 
  3 Contains Nonbinding Recommendations 
 
110  FDA approval of the parametric release program will be based on how well the firm has 
111  addressed the risks to product sterility.  A risk assessment statement consistent with the 
112  principles of ICH Q9 (ICH 2006) should be provided that describes the following: 
113   
114    Current strategies for control of the terminal sterilization program; 
115   
116    Risk that these strategies might fail to ensure sterility; and 
117   
118    How prior manufacturing experience and knowledge were incorporated into the risk 
119  assessment.13 
120   
121  A.  Control Strategy for the Terminal Sterilization Program 
122   
123  A control strategy is used to ensure that the acceptance criteria of the parametric release process 
124  and terminal sterilization cycle are met in order to ensure product sterility.  
125    
126  The control strategy should include the following: 
127     
128    The rationale for the methods implemented to monitor and control the terminal 
129  sterilization process used for the product release (the critical process parameters); 
130   
131    The rationale for the selection of critical process parameter(s);  
132   
133    A description of the acceptance criteria for parametric release;  
134   
135    A description of the drug product and container closure system (including secondary 
136  packaging, as applicable) that will be part of the parametric release program; 
137   
138    A description of the proposed production loading patterns and verification that they are 
139  within the validated limits for the terminal sterilization cycle, or a statement that they 
140  have not changed since last approved and validated (as applicable); and 
141   
142    A description of the microbiological monitoring plan for the product and components 
143  prior to terminal sterilization or a statement that the plan has not changed since last 
144  validated.  Spore detection and heat resistance studies should be emphasized for 
145  bioburden based sterilization cycles. 
146   
147  If you are referencing information previously submitted to meet these recommendations, it 
148  should include the application number and submission date, and any other relevant citations to 
149  the Agencys 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. 
 
  4 Contains Nonbinding Recommendations 
 
150   
151  B.  Risk Assessment, Process Understanding, and Prior Knowledge 
152   
153  Successful parametric release systems are based on the reliability of the control strategy of the 
154  sterility assurance program.  We recommend that your risk assessment focus on the risk of 
155  failure to achieve the minimum required probability of a non-sterile unit for each unit of every 
156  batch.  The risk assessment should include the following: 
157   
158    Consistency of performance of the terminal sterilization cycle within the validated limits. 
159    A discussion of risk to the sterility of the product relative to the following:  (1) the 
160  production terminal sterilization cycle, (2) the production loading patterns, (3) the 
161  container closure system (including secondary packaging), and (4) any potential 
162  contamination risks from the environment (as appropriate).  For an approved application, 
163  you should indicate any changes to the above items and provide an assessment of the risk 
164  to the sterility of the product associated with those changes.  For example, although the 
165  established minimum sterilization time cannot be lowered, the maximum sterilization 
166  time can be increased if the appropriate stability data are provided to support the increase. 
167    Experience with the proposed or similar product (and container closure system) and 
168  proposed or similar sterilization process, the overall risks to sterility, and the steps you 
169  have taken to assess and control these risks.  For new products, prior knowledge from 
170  developmental and registration/exhibit batches may suffice. 
171    A discussion of your overall prior knowledge and production and testing experience 
172  relevant to the drug product that will be subject to parametric release. 
173   
174  C.  Documentation for Parametric Release Process 
175   
176  The following information specific to the proposed parametric release process should also be 
177  included in your submission:  
178   
179    A citation to a complete and detailed description of the current relevant terminal 
180  sterilization cycle.  
181   
182    Identification of the critical process parameters (process/cycle parameters and appropriate 
183  load monitors essential for product release) for the product(s) proposed for parametric 
184  release, including the minimum and maximum limits for these critical parameters.  The 
185  critical process parameters should be within the limits that have been validated and 
186  approved for sterility assurance of the subject product(s).  
187   
188    Acknowledgement that adherence to the critical parameters of the parametric release 
189  program will substitute for the performance of a sterility test as the primary release 
190  criterion for the product and that sterility test results from the finished product will not be 
191  used to overrule any failure to meet the acceptance criteria of the parametric release 
 
 
  5 Contains Nonbinding Recommendations 
 
192  program.  In the event of failure, the specific sterilizer load will be rejected by the quality 
193  control unit and will not be released unless there is a provision for reprocessing.   
194   
195    Acknowledgement that regardless of the batch release technique used, any specimen 
196  tested according to the reference test method for sterility (e.g., compendium or FDA 
197  regulations) will meet the criteria for sterility (such as during testing for stability or 
198  postmarketing investigations).  
199   
200    A description of the sterilization load monitor that indicates the following:  (1) the type of 
201  monitor being proposed, (2) how the load monitor will be used and analyzed, (3) what 
202  functions are being measured by the monitor, and (4) the rationale for the location of the 
203  monitor.  Additionally, for indirect monitors, we recommend that you include a statement 
204  justifying the classification of the indirect indicator that you are using as defined by the 
205  American National Standard Institute (ANSI 2008).  In certain circumstances a Class 3 
206  indicator may be appropriate; however, a Class 5 indicator is recommended for most 
207  situations.   
208   
209    Documentation of the control system to verify exposure of the load to the sterilization 
210  process. 
211   
212    Revision of the certificates of analysis or batch release records for each product subject to 
213  parametric release to indicate that parametric release is now the method used to provide 
214  assurance of the requirement of sterility.  We recommend that you provide a reference to 
215  show the link between batch release criteria and the commitments in the application.    
216   
217   
218  IV.   FILING REQUIREMENTS  
219   
220  To request parametric release in an original application submission, the request should include 
221  information specific to parametric release along with sterilization validation information and 
222  product release criteria.  For changes to an approved application, the request for parametric 
223  release should be submitted in a prior approval supplement under 21 CFR 314.70, 21 CFR 
224  601.12 or 21 CFR 514.8(b)(2).  The change to parametric release requires FDA approval before 
225  its implementation.  If the applicant has current experience using parametric release with a 
226  comparable sterilization cycle at the same manufacturing site, and the proposed product's 
227  manufacturing process fits into the same validation protocol for parametric release (e.g., 
228  container closure system, load patterns, cycle process parameters, and cycle acceptance criteria), 
229  then the applicant should meet the filing requirements with a special report for a human drug 
230  product,15 or an annual report for a veterinary drug product16 or a biologic product.17  If your 
231  product fits into one of these filing categories, contact the review division for your product to 
232  verify submission requirements.  
233   
                                                 
15 21 CFR 314.81(b)(3)(ii) 
16 21 CFR 514.8 (b)(4) 
17 21 CFR 601.12(d) 
  6 Contains Nonbinding Recommendations 
 
234  V.  REFERENCES 
235   
236  American National Standard Institute (ANSI), Association for the Advancement of Medical 
237  Instrumentation (AAMI), International Organization for Standardization (ISO) 15882, 2008, 
238  Sterilization of Health Care Products-Chemical Indicators-Guidance for Selection, Use and 
239  Interpretation of Results. 
240   
241  The European Agency for the Evaluation of Medicinal Product (EMEA), 2001; Committee for 
242  Proprietary Medicinal Products: Note for Guidance on Parametric Release, March 2001, 
243  CPMP/QWP/3015/99.     
244   
245  Food and Drug Administration, 1987, Parametric Release - Terminally Heat Sterilized Drug 
246  Products, Compliance Policy Guide (CPG) 460.800 (CPG 7132a.14), October 2, 1987. 
247   
248  International Conference Harmonisation (ICH), 2000, Guidance on Q6A Specifications: Test 
249  Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: 
250  Chemical Substances, Guidance for Industry, Federal Register, Vol. 65, No. 251, December 29, 
251  2000.   
252   
253  ICH, 2006, Q9 Quality Risk Management, Guidance for Industry, Federal Register, Vol. 71, No. 
254  106, June 2006.   
255   
256  ICH, 2009, Q10 Pharmaceutical Quality System, Guidance for Industry, Federal Register, Vol. 
257  74, No. 66, April 2009.   
258   
259  PDA Journal of Pharmaceutical Science and Technology, Technical Report No. 30: Parametric 
260  Release of Pharmaceuticals Terminally Sterilized by Moist Heat, Supplement, Volume 53, Number 4, 
261  July-August 1999 
262   
263  Pharmaceutical Inspection Convention/Pharmaceutical Inspection Co-operation Scheme (PIC/S):  
264  Guidance on Parametric Release, 2007, PI 005-3, September 25, 2007.  
265   
266  Sasaki, T., 2002, Parametric Release for Moist Heated Pharmaceutical Products in Japan, PDA 
267  Journal of GMP and Validation in Japan, Volume 4, Number 1. 
268   
269  United States Pharmacopeia (USP) 32-NF, General Chapter <1222> Terminally Sterilized 
270  Pharmaceutical Products-Parametric Release, 2009. 
  7