Implementing Rapid Sterility Test Systems: A Guide from the Experts

PDA Journal recently released an article by pharmaceutical professionals sharing their comparison of two alternative microbial methods

Rapid sterility testing using ATP-bioluminescence is now a routine practice for pharmaceutical products on the market. Regulatory agencies approved validation packages for individual manufacturing sites confirming this alternative technology meets equivalency criteria compared to the compendial method. This recent article from the Parenteral Drug Association outlines how that’s possible, and how the test has been a beneficial integration into the laboratory.

In the paper, several key personnel from world-renowned pharmaceutical manufacturers, such as Pfizer, GlaxoSmithKline, Merck & Co., and Roche Diagnostics collaborated on an article for the PDA Journal of Pharmaceutical Science and Technology. This article, named “Rapid Sterility Test Systems in the Pharmaceutical Industry: Applying a Structured Approach to their Evaluation, Validation and Global Implementation”, outlines two case studies in validating an alternative microbial method for routine sterility testing.

What’s Included In the Paper

This paper is beneficial for QC professionals that understand the benefit of rapid sterility results but are unsure about regulatory acceptance and the steps needed to implement a system themselves. The paper features information regarding the overall implementation of any rapid system. The nine steps addressed in the paper are a helpful outline for organizations in the early stages of their buying journey.

• Step 1: Identify operational / business need
• Step 2: Define the application
• Step 3: Assess requirements
• Step 4: Compare options and technologies - landscaping and candidate(s) selection
• Step 5: Develop a business case: technical, quality and business evaluation and justification
• Step 6: Perform proof-of-concept studies / feasibility studies / pre-validation studies
• Step 7: Validate at pilot or primary site
• Step 8: Deploy global / company-wide qualification of additional laboratories
• Step 9: Define regulatory filings and implementation strategy

As soon as a site looking to expedite their operations completes step 1, they know that implementing a rapid method is a worthwhile project. According to the article “the extent of the development work . . . will depend on the maturity of the technology, data available from the vendor, and benchmarking information with the industry,” These projects have the best chance at success when supported by the vendor through completion.

The Technologies

The article discusses individual case studies for two different rapid method technologies, one based on Adenosine-TriPhosphate (ATP) bioluminescence, the other a cellular respiration-based test. Both technologies exploit natural behavior of viable organisms to detect their presence.

• ATP bioluminescence: All viable microorganisms produce ATP. The Celsis method extracts ATP from any microbes, if present, and uses an enzyme to react with ATP and generate light. The sterility result is considered positive if sufficient light is detected at the validated endpoint of the test.
• Respiration: All viable organisms undergo respiration. The respiration-based method uses media that changes pH in the presence of Microbial respiration. The sterility result is considered positive if a sufficient pH change is measured at the validated endpoint of the test.

As the article confirms, both methods can meet validation criteria to be considered statistically equivalent, or non-inferior, to the compendial method. The paper addresses multiple criteria comparing the methods in two tables occupying seven pages of the document. Some important differences are worth noting:

• The validated time to negative result was faster for the ATP-bioluminescence method (7 days) compared to the respiration-based method (8 days)
• The ATP bioluminescence method allows for membrane filtration testing. The respiration-based method can only be used with direct inoculation. Membrane filtration is the preferred sterility test compared to direct inoculation because it:

a. Allows for a larger test volume to meet sample size criteria outlined in USP <71>

b. Removes the majority of product residue, which could inhibit microbial detection

• The method comparison table states the respiration method “has issues detecting mold.” It’s notable the respiration case study included fewer species for the specificity test compared to the ATP-bioluminescence case study
• Incubation:

a. When using the respiration method, media incubation occurs on board the rapid method instrument. This allows for automated reads that could report positive results earlier than eight days.

b. When using ATP-bioluminescence, media incubation is performed in an off-board incubator. Therefore, capacity is not limited by the size of the unit and traditional intermediate reads can still be performed.

Conclusion

Rapid sterility methods are becoming more prevalent in QC laboratories. While there are many great test systems on the market today, it’s important to identify their differences to select the optimal method. Time to result, organism detection, and product flexibility are critical parameters to please both internal and regulatory stakeholders. Understanding these technologies, through sources like this PDA Journal article, is the first step in modernizing your laboratory.

The PDA journal article confirms the ATP-bioluminescence method is non-inferior to the compendial method for the identified intended use. As evidenced by the contributors to this article, the method is trusted among some of the most well-known pharmaceutical companies around the globe.

With assistance from the vendor to get validation testing through completion, any quality control laboratory can test their products safely, quickly, and with the utmost confidence in their data. QC microbiologists around the globe have already taken advantage of this technology, what are you waiting for (other than results using the traditional method)?

Read the full article from PDA.

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