Parametric Release Defined
For the purposes of this paper, parametric release is discussed specifically for drug products terminally sterilized by moist heat. Parametric release can be 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 Code of Federal Regulations (CFR) 211.165(a) and 211.167(a) and then release a product for commercial sale (Guidance for Industry: Submission of Documentation of Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes, 2010).
The following examples explain the basic difference between parametric release and sterility test release. For a product released using the United States Pharmacopeia (USP) <71> Sterility Tests, once the drug product is terminally sterilized, there is an incubation period of a minimum of 14 days to allow for possible microbial growth in samples before obtaining results from this test. During this waiting period, the drug product is placed on hold (not released for sale), potentially occupying valuable space, but more importantly delaying patient access to critical drug products. For a product released using parametric release, once the drug product is terminally sterilized and the acceptance criteria for the critical process parameters are documented as being met, the product can be released for commercial sale (provided that all other release test criteria have been met). A sterility test is not performed on any units, so there is no waiting period associated with the sterility test and/or subsequent investigations.
Benefits of Parametric Release
One of the most obvious benefits of parametric release is the savings of time and resources. There is no performance of a sterility test, so no waiting for results and no additional delays due to investigations of common “false” sterility test positive results. Another benefit may be financial savings from the absence of expenses related to sterility testing and product holding. Moving product to commercial sale quickly could also lead to the saving of space. Additionally, other less obvious benefits include manufacturing flexibility (moving product to market quickly in cases of drug shortage) and possibly better process understanding and manufacturing control. Given the small sampling size of test lots required for sterility testing, the USP <71> Sterility Tests methodology has limited capability to detect small numbers of contaminated units. The development of process understanding for implementation of a parametric release process could arguably lead to better sterility assurance.
History
The Center for Drug Evaluation and Research (CDER) approved the first firm to use parametric release in 1985. In 1996, a second firm submitted an application for parametric release and received approval. Currently, 12 pharmaceutical firms have received approval from CDER for parametric release of one or more drug products, resulting in a significant number of drug products currently released by this program. These firms demonstrated Quality by Design approaches, process knowledge, and manufacturing history and have benefited from a parametric release program for almost 3 decades.
Existing Guidance
In 2010, the Agency finalized a guidance for industry describing the submission requirements for parametric release. The Guidance for Industry: Submission of Documentation of Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes is a multi-center guidance that represents the current thinking of CDER, the Center for Veterinary Medicine (CVM), and the Center for Biologics Evaluation and Research (CBER). In 2012, CDER’s Office of Compliance finalized a revision of the Compliance Policy Guide Sec. 490.200 Parametric Release-Parenteral Drug Products Terminally Sterilized by Moist Heat. This document describes the FDA’s compliance policy related to critical aspects of a parametric release program.
Despite the existence of these guidance documents, only 2 firms have pursued parametric release with a single firm being approved after the publication of these documents. Perhaps additional information is needed to ensure that firms understand the benefits/advantages of a parametric release program (when appropriate). With these considerations in mind, this paper provides additional explanation of some of the submission expectations for an application requesting parametric release as the finished product release method.
Deconstructing Parametric Release Recommendations
As described in the Guidance for Industry: Submission of Documentation of Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes, 3 elements form the foundation of a parametric release program, and these are evaluated in a submission requesting parametric release: 1) process understanding, 2) process control, and 3) parametric release documentation.
Process understanding is the knowledge gained from the development of a scientifically sound terminal sterilization cycle. Validation of terminal sterilization cycles is addressed in other Agency guidances, as well as in other pharmaceutical industry publications, so the details of this process will not be addressed here.
Process control is demonstrated through monitoring and controlling microbial contamination at relevant points during the manufacturing process. For a terminally sterilized product, monitoring of the bulk drug product and components is critical. Microbial contamination introduced by raw materials or components during the manufacturing process and allowed to multiply unchecked, although inactivated by terminal sterilization, can adulterate a product (e.g., endotoxins, cell debris, etc).
Specific parametric release documentation includes all information related to the execution of the program. This documentation can be categorized as follows: control strategy, risk assessment, commitments, and batch records (as described in the Guidance for Industry: Submission of Documentation of Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes).
- The control strategy includes the description of the terminal sterilization process and how the process will be monitored, controlled, and evaluated. Critical process parameters are designated, and the acceptance criteria of these parameters must be met for batch release after each sterilization process. The description of the load monitor(s) (eg, temperature probe, biological indicator, or chemical indicator) is also part of the control strategy.
- The risk assessment includes an evaluation of the points for potential failure in the sterilization process (where there is a risk to the sterility of the product) and of the efforts to mitigate these problems. Production experience/historical data are an important element of the risk assessment. To demonstrate the ability to execute a successful terminal sterilization cycle, data are submitted as part of the risk assessment. These data represent the experience using the terminal sterilization cycle with the specific product, specific container closure system(s), specific load size(s), specific sterilizer(s), and the same facility as proposed for parametrical release. The results collected from the established terminal sterilization cycle parameters, the sterility testing of sterilized batches, and the monitoring of the bulk product and components for bioburden provide assurance that an effective terminal sterilization process of the drug product can be consistently achieved under conditions specified in the application.
- Because parametric release is the method for finished product release in lieu of sterility testing, commitments are included in the submission to acknowledge the requirements for a successful parametric release program and the consequences of failure. The achievement of the acceptance criteria for all critical process parameters substitutes for the performance of sterility testing. Therefore, the failure of any of the critical process parameters results in overall failure of the parametric process, and the batch cannot be released. The result of the load monitor(s) is always a critical process parameter, and the load monitor(s) acceptance criteria must be met to allow batch release. Finally, the sterility test cannot be used for product release if there is failure of any critical process parameters, unless there is a provision for reprocessing established in the approved application.
- Because the terminally sterilized batch of drug product is no longer being subjected to a finished product sterility test, the batch records are revised to indicate that an approved parametric release program is being used as the method to achieve sterility. The revised release records should include or refer to the standard operating procedure(s) or document(s) that contain the parametric release requirements, commitments, and acceptance criteria for the critical process parameters.
Parametric Release Challenges
Two challenges potentially encountered when implementing a parametric release program are the understanding of the role of the sterilization load monitor(s) and acquiring production experience/historical data. The reading of the results of the sterilization load monitor(s) satisfies the requirement for a laboratory test for sterility as required by 21 CFR 211.167(a) to allow commercial release of a drug product. In addition, the load monitor(s) provides evidence that the load has been exposed to sterilization. Therefore, the use of these devices in each load is a requirement for a parametric release program, and the load monitor(s) is considered a critical process parameter. Load monitors can either directly or indirectly measure the lethality delivered to the load, and they are available in physical, biological, and chemical forms. If a chemical indicator is chosen, the Agency recommends a Class 5 indicator as defined in the American National Standard Institute document “Sterilization of Health Care Products-Chemical Indicators-Guidance for Selection, Use, and Interpretation of Results” (15882:2008); however, there are circumstances where a Class 3 indicator may be appropriate. The types of load monitors that have been proposed and approved by CDER include both chemical and physical indicators, and in some cases, both types are included in a sterilizer load. It is important to provide a complete description of the load monitor(s) in the submission, including details such as identity (what is it?), general function (what does it measure and how does it do this?), location (where is it placed and why?), and functionality data (how does it work with the specific product, container closure system, load, sterilization cycle, and sterilizer?).
The approval of a parametric release program is dependent on the ability to demonstrate successful and reproducible execution of the specific terminal sterilization cycle for the drug product using the container closure system(s), production load configuration(s), and production sterilizer(s) at the location(s) proposed for commercial production. Generally “experience” is acquired from the performance of successful terminal sterilization and release of a product based on the results of a sterility test for a period of time. The data acquired from the manufacture of these batches support the request for parametric release, and the type of data collected includes results from bioburden monitoring, terminal sterilization cycle execution, and sterility testing.
Initially the necessity for production experience or historical data can appear limiting and suggest that a drug product must be approved and manufactured for a period of time prior to the submission of a post-approval change requesting parametric release, ie, an original application for parametric release might not be possible. However, there may be circumstances when alternate data may suffice. If there is no experience/data from the terminal sterilization cycle and subsequent sterility testing of the drug product proposed for parametric release, data from the terminal sterilization of a similar approved product in a similar container closure system, using a similar cycle, similar load configuration, and similar sterilizer at the same facility may support the requirement for experience/historical data. However, the definition of “similar” will be determined by the Agency upon review of the submission. (A firm may consider contacting the Agency prior to a submission if they are unsure if their process and conditions would be considered “similar.” Such pre-submission discussions can optimize both Agency and a firm’s resources and avoid a lengthy review process.)
Implementation Options
If a firm is interested in seeking approval for parametric release of a drug product, there are 2 general submission methods for this request. For a drug product with an approved application using a sterility test for commercial release, a firm files a prior approval supplement providing information as recommended in the parametric release guidance cited above. Results from bioburden monitoring, terminal sterilization, and sterility testing during commercial manufacture and release serve as the production experience/historical data. For an unapproved drug product, a firm files an original application with the information supporting this application. However, a firm also provides information as recommended in the parametric release guidance to support the request for parametric release. As indicated above, bioburden monitoring, terminal sterilization, and sterility testing results collected from the manufacture of a “similar” drug product could serve as the experience/data for the proposed drug product.
Summary
Utilizing parametric release can be a great benefit to pharmaceutical firms and optimize their resources, as well as provide patients quicker access to critical drug products. The basis for approval of parametric release is having a validated terminal sterilization cycle, manufacturing process control and understanding, and documentation for the parametric release program. The essential elements of a parametric release program include critical process parameters, sterilization load monitor(s), terminal sterilization control strategy, risk assessment of the process, supporting production experience from the manufacturer of the drug product, commitments to the process, acknowledgements of the consequences of failure, and revision of the release records to reflect the use of a parametric release program. However, lack of production experience with terminal sterilization of the drug product may not necessarily be a road block to approval of parametric release. Data acquired from the successful terminal sterilization and sterility testing of a similar drug product could provide adequate evidence of necessary production experience. This means that the request for parametric release should not be viewed as only a post-approval dream for the future, but a reality for the present.
Acknowledgement
The author would like to thank Lynne Ensor, Alicia Mozzachio, Brian Hasselbalch, and Ashley Boam for review of this manuscript.
Author Biography
Dr. Stevens-Riley is currently a Senior Microbiologist in the Division of Regulations, Guidance, and Standards in the Office of Policy for Pharmaceutical Quality in CDER. She was the lead author on the guidance “Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes.”