Traditional microbiology testing creates a bottleneck in the release of sterile products which can cause various problems. For example, a vaccine manufacturer needs to release product as quickly as possible during a pandemic. A manufacturer of short-shelf-life radiopharmaceuticals must ship product immediately to avoid scrap costs.
The solution for both types of manufacturers and other companies wanting to avoid the lengthy delay needed for the traditional method is adoption of rapid methods, which have been available since the 1980s.
The U.S. FDA’s support of rapid microbiology methods is starting to be recognized, and many companies are investigating various technologies for different applications. The recently revised 21 CFR 610.12 allows manufacturers of biologics to use alternative methods for sterility testing, as long as the new method is fully validated and verified. Some companies are also looking at rapid methods to increase confidence in their overall quality since they can respond faster when a contamination is detected.
Developing a User Requirement Specification
There are quite a few issues to take into account when selecting a technology and application for a rapid method.
Several companies will initially utilize their R&D groups to evaluate new methods for a specific application. Raw materials, water and environmental monitoring represent categories of testing that may be an appropriate first application versus release tests like sterility or mycoplasma. Some may even choose a more specific application such as using rapid only for investigations or perhaps validations.
The application should be well defined at the very beginning of the project and included in a user requirement specification (URS). This document typically includes an objective and a purpose with as much background as possible. The URS should also include a list of “must haves” and “nice to haves.” The goal of the URS is to provide as much information as possible so that the expectations are clear to the project team members and potential suppliers. For example, expectations such as “system must be appropriate for filterable volumes over 200 ml” and “system must be able to handle 100 samples per day.” One should always ask the question “why?” after each specified requirement along with the cost impact, if necessary.
One of the most obvious requirements that will need to be listed in the URS is the time to result for specific applications; are results needed in hours or days? Many companies have other tests that may hold up release. For example, some companies wait until environmental monitoring plates are read before product release. The entire process for a specific application should be examined closely before deciding on a desired time to result.
A complete financial analysis should also be performed as the URS is being developed. Implementation of a new technology will take a significant amount of resources, and the necessary time, manpower, etc., should be estimated.
Lastly, a project team should be well defined. What areas (i.e., QC, QA, R&D) need to be represented? Unfortunately, when no project team is created and a system is purchased, the rate of success is very low.
Technical Issues to Consider
The risks of false negatives and false positives with various rapid systems needs to be considered. One should first examine the sample preparation and the risks of the analyst contaminating the test. Secondly, if the method is not growth-based, what is the risk of viable but nonculturable cells resulting in a false positive? The supplier or suppliers of the reagents, media and other consumables for the system should also show that their quality systems are superior so that contamination risks are low.
Sensitivity of the rapid method may actually be better than the current method. If the product or material has inhibitory properties, however, does the sample preparation allow for neutralization? Does the technology have published papers demonstrating efficacy on environmental isolates that are appropriate to your application? It is a regulatory expectation that one challenge rapid technologies with worst case organisms to show sensitivity. What is the required limit of detection for your application? The user must typically show that the rapid technology has a detection limit equivalent or better than the current method.
Depending on the application, it may be critical to identify the microorganisms in the event of an out-of-specification or a sterility test failure. If the technology is destructive to some of the organisms, how will it be addressed? The supplier should be able to show data on recovery of appropriate organisms.
Another important issue is the complexity of the system. How much training is required and what level of expertise is needed? Rapid technologies that have several steps can be very difficult to validate. If the system is highly automated, service and maintenance need to be readily available in the event of a breakdown. Does the supplier offer on-site service and what is the expected time to have a service technician on-site? Any system with a lot of moving parts will need routine maintenance as well as the availability of spare parts.
Choosing a Supplier
The history of the supplier in the pharmaceutical industry may also be relevant. If special reagents and supplies are required for the rapid system, what is the supplier’s ability to consistently supply quality products? An audit of the supplier’s manufacturing facility may be worth the time if the application is critical.
The supplier should offer some type of evaluation so that you can check the feasibility of the technology with your specific application and/or product. It is best to work closely with the supplier in generating an appropriate test plan so that all critical issues are addressed. Reviewing the supplier’s own internal validation data before developing the test plan may also be useful.
One of the most critical parts is the regulatory piece. If the rapid system is for a sterility application, how many other companies have received approval to use it? Regulatory agencies will evaluate technologies and often publish their findings.
In the United States, the current guidance for alternative methods is limited, and the compendial chapter for rapid sterility testing is years away from being published. Thus, it is best to have a very detailed strategy and project plan to gain approval.
With all this to consider, obtaining FDA approval should not be daunting if the project is implemented correctly. “New methods are approved and usually on the first review cycle, if validated appropriately and clearly described in the application,” said Jessica Cole, PhD, Microbiology Reviewer, FDA, at the recent PDA Aseptic Processing-Sterilization Conference (1).
While there may not be a rapid technology that meets every need yet, many companies have been successful in implementing and gaining approval. Companies often oppose changing methods because of all that is involved and required. Traditional microbiology methods, however, remain “crude and imprecise” (2).
Regulatory agencies are encouraging companies to improve their methods and their quality. Clinical microbiology has been using rapid testing since the 1980s while the food industry started to embrace it in the ‘90s. It is definitely time for rapid in the pharma industry.
[Editor’s Note: For more information about rapid methods, consider attending session A4: Innovative Technologies: Microbiology Testing Technologies, Oct. 21, 1:15 p.m. at the PDA 9th Annual Global Conference on Pharmaceutical Microbiology.]
- Cole, J. “A CDER Reviewer’s Perspective on Regulatory Submissions.” Presented at the 2014 PDA Aseptic Processing-Sterilization Conference, Chicago, June 2014.
- Hussong, D. “Regulatory Perspective on Testing and Microbiological Risk.” Presented at the 2013 USP Microbiology Workshop, Bethesda, March 2013.
About the Author
Claire Fritz Briglia is a Technology Specialist for EMD Millipore. She has trained many users in various pharmaceutical microbiology applications for over 15 years.