In a bold move by FDA's Center for Biologics Evaluation and Research (CBER), sweeping changes are now being proposed for the sterility testing of biological products. Some of the proposed changes include the elimination of culture media formulae and test requirements, sterility test requirements for most bulk material, modification of the repeat sterility test requirements, changes to the storage and maintenance requirements for cultures of test organisms used during growth promotion, and replacement of the sample size requirement. What is most relevant to this blog is that the draft changes include promoting the use of rapid microbiological methods as an alternative to the standard USP <71>. In addition, the proposed rule provides guidance on validation expectations and references the USP information chapter <1223>, Validation of Alternative Microbiological Methods. Public comments on this proposed rule must be submitted by September 19, 2011.
The proposed changes, which were published in the June 21, 2011 U.S. Federal Register (Volume 76, Issue 119) come on the heels of CBER's guidance for industry on this same topic, when, in 2008, the FDA published "Validation of Growth-Based Rapid Microbiological Methods for Sterility Testing of Cellular and Gene Therapy Products.” The guidance applies to somatic cellular therapy and gene therapy products, and provides a roadmap for demonstrating that an alternative, growth-based RMM is equivalent to the conventional sterility test method.
There are a number of changes that encompass a variety of topics; however, I will focus only on those changes specifically dealing with rapid or alternative methods. An overview of these proposed changes is provided below, and you can read the entire proposed rule at http://www.gpo.gov/fdsys/pkg/FR-2011-06-21/pdf/2011-15346.pdf. As you read this overview, please remember that these changes are specifically intended for biological products that are regulated by CBER, and may not apply to pharmaceutical products regulated by other FDA Centers, such as CDER.
Amendments to Sterility Test Requirements for Biological Products
Summary
The Food and Drug Administration (FDA) proposes to amend the sterility test requirements for biological products. This proposed rule is intended to provide manufacturers of biological products greater flexibility and to encourage use of the most appropriate and state-of-the-art test methods for assuring the safety of biological products. We are taking this action as part of our continuing effort to review and, as necessary, update the biologics regulations.
Background
Manufacturers of innovative products, such as cell and gene therapy products, as well as manufacturers of currently approved products, may benefit from sterility test methods with rapid and advanced detection capabilities.
Advances in technology in recent years have allowed the development of new sterility test methods that yield accurate and reliable test results in less time and with less operator intervention than the currently prescribed methods. Some examples of novel methods with the potential to detect viable contaminating microorganisms include the Adenosine Triphosphate (ATP) bioluminescence, chemiluminescence, and carbon dioxide head space measurement.
We are proposing to amend § 610.12 to promote improvement and innovation in the development of sterility test methods, to address the challenges of novel products that may be introduced to the market in the future, and to potentially enhance sterility testing of currently approved products. This proposed revision would provide manufacturers the flexibility to take advantage of modern methods as they become available, provided that these methods meet certain criteria.
Description of the Proposed Rule
This proposed rule is intended to promote improvement and innovation in the development of sterility test methods by allowing manufacturers flexibility needed for sterility testing of some novel products that may be introduced to the market, to enhance sterility testing of currently approved products, and to encourage manufacturers to benefit from scientific and technological advances in sterility test methods as they become available.
Test Methods
Currently, § 610.12(a), (b), and (e) prescribe the culture-based test method to be used for sterility testing, including the acceptable culture media (either Fluid Thioglycollate Medium or Soybean-Casein Digest Medium) and incubation conditions (time and temperature) to be used during testing, with exceptions provided in § 610.12(g). In addition, § 610.12(f) provides that a membrane filtration test method, set forth in (USP 23d revision, 1995), may be used to test bulk and final container materials or products containing oil products in water-insoluble ointments.
We propose to eliminate references to specific test methods and culture media for sterility testing, and instead require that the sterility test be appropriate to the material being tested such that the material does not interfere with or otherwise hinder the test. We believe that this revision recognizes current practices and provides manufacturers the flexibility to take advantage of suitable modern sterility test methods and keep pace with advances in science and technology. Because we are proposing to expand potentially acceptable sterility test methods to include non-culture-based methods in addition to culture-based methods, we also propose to remove the definition of a lot of culture medium currently defined in § 610.12(e)(2)(i).
Section § 610.12(e)(2)(ii) stipulates the test organisms, strains, characteristics, identity, and verification to be used. We propose to eliminate the requirement to test culture media with specific test organisms and to eliminate the requirement regarding the number of organisms that must be used to demonstrate the growth-promoting qualities of the culture media. This flexibility would allow manufacturers to use sterility test methods that are either culture-based or non-culture-based, which may necessitate different verification activities. Thus, instead of specifying the number and type of test organisms, proposed § 610.12(b) would require the following: (1) Use of a sterility test method that is appropriate to the material being tested such that the material does not interfere with or otherwise hinder the test; (2) validation studies to demonstrate that the sterility test method used is capable of consistently detecting the presence of viable contaminating microorganisms; and (3) verification that the sterility test method and test components used can detect the presence of viable contaminating microorganisms.
Due to the variety of currently available and potential future sterility test methods, we propose to eliminate specified incubation conditions (time and temperature) and visual examination requirements currently prescribed in § 610.12.
Validation
USP General Chapter 1223, ‘‘Validation of Alternative Microbiological Methods,’’ states: ‘‘Validation of a microbiological method is the process by which it is experimentally established that the performance characteristics of the method meet the requirements for the intended application.’’ For sterility testing, this means that the test can consistently detect the presence of viable contaminating microorganisms.
We propose to eliminate the prescribed sterility test methods found in current § 610.12 and instead allow the use of sterility test methods that are validated in accordance with established protocols, to be capable of consistently detecting the presence of viable contaminating microorganisms. If an established USP compendial sterility test method is used, a manufacturer must verify that this established method is suitable for application to the specific product; however, FDA considers established USP compendial sterility test methods to already have been validated using an established validation protocol, so their accuracy, specificity, and reproducibility need not be re-established to fulfill the proposed validation requirement. In contrast, novel methods and any methods that deviate from the USP compendial sterility test methods would require the detailed validation discussed (below).
Proposed § 610.12 allows the use of a material sample that does not interfere with or otherwise hinder the sterility test from detecting viable contaminating microorganisms. This requirement is crucial, because the material itself or substances added to the material during formulation may make some sterility tests inappropriate for use. A validated sterility test method is a critical element in assuring the safety and quality of the product. USP General Chapter 1223, as well as the ICH Guideline for Industry (Text on Analytical Procedures), provide general descriptions of typical validation parameters, how they are determined, and which subset of each parameter is required to demonstrate validity, based on the method’s intended use.
In the context of reviewing sterility test methods as part of BLAs and BLA supplements, FDA may decide, as appropriate, to encourage the use of the compendial method as a benchmark or starting point for validation of novel methods and certain other methods. FDA is specifically seeking comments on whether the proposed requirements are sufficient to ensure adequate validation of novel sterility test methods or whether additional criteria or guidance is needed.
It is important to consider validation principles, such as limit of detection, specificity, ruggedness, and robustness, while developing the validation protocol and performing validation studies. These terms are defined as follows:
- The limit of detection reflects the lowest number of microorganisms that can be detected by the method in a sample matrix. This is necessary to define what is considered contaminated.
- Specificity is the ability of the test method to detect a range of organisms necessary for the method to be suitable for its intended use. This is demonstrated by challenging the sterility test with a panel of relevant organisms in the sample matrix.
- Ruggedness is the degree of reproducibility of results obtained by analysis of the same sample under a variety of normal test conditions, such as different analysts, different instruments, and different reagent lots.
- Robustness is the capacity of the test method to remain unaffected by small, but deliberate variations in method parameters, such as changes in reagent concentration or incubation temperatures.
For non-culture-based methods, the feasibility of identifying microorganisms from a contaminated sample should be evaluated during validation. If a method does not have the capability to identify microorganisms to the species level, the validation protocol should require that an additional method for species identification be utilized for investigation of detected contaminants.
The test organisms selected should reflect organisms that could be found in the product, process, or manufacturing environment.
The validation study design should contain the appropriate controls to evaluate the product sample’s potential to generate false positive and false negative results. Validation of the sterility test should be performed on all new products, and repeated whenever there are changes in the test method that could potentially inhibit or enhance detection of viable contaminating microorganisms.