USP Mulls Rapid Sterility Testing Standards For Cell Therapies, PET Drugs And Sterile Compounding

USP is looking to develop standards for rapid sterility tests for drugs and biologics. Existing growth-based compendial methods are too slow to obtain results before cell and gene therapies, positron emission tomography drugs and sterile compounded drugs must be used. Quicker methods would improve efficiency in the manufacture of other drugs as well. Detection limits could be orders of magnitude higher without compromising the ability to detect infectious levels of microbiological organisms.

The US Pharmacopeia is considering developing compendial standards for rapid microbiological methods that can check short-lived drug products for sterility before they must be administered such as cell and gene therapies, positron emission tomography (PET) drugs and compounded drugs.

Such methods also could help manufacturers produce conventional drugs more efficiently by avoiding the 14-day waiting period that goes with existing growth-based compendial methods.

USP representatives discussed progress toward developing a compendial standard for rapid methods on Oct. 17 at the Parenteral Drug Association’s annual microbiology meeting in Bethesda, Md. Also, an FDA official outlined the agency’s criteria for approving – as well as rejecting – proposals to use rapid microbiological methods in the absence of compendial standards.

FDA requires under 21 CFR 211.165 that parenteral biological products undergo testing using the compendial sterility testing method set forth in USP General Chapter <71> to ensure that products are safe when they reach the market. Sterility is considered a critical quality attribute for an injectable product.

Anthony Cundell, a consulting microbiologist and member of a USP working group developing the new standard, said, “it is widely recognized that the current growth-based sterility test with at least a 14-day incubation is not suitable for short-lived products that are frequently infused into patients before the completion of the test. This two‐week period can be a significant limiting factor in the timely release of biologicals, particularly for pandemic vaccines and products with short shelf lives.”

Cundell said that although many pharmaceutical companies have successfully validated and implemented rapid microbial methods as alternatives to the compendial tests, there are still some validation and regulatory hurdles in getting them approved. Also, there are advantages in using a compendial standard for testing sterility because it can be implemented without prior regulatory approval.

Cundell said that the unmet need for rapid sterility tests is especially acute in compounding pharmacies. A February 2016 survey on sterile drug compounding counts 68,900 pharmacies in the US, of which 36,600 perform compounding. Of those compounding pharmacies, 4,230 perform sterile compounding, including 70 that have applied for Section 503B registration as outsourcing facilities. Three quarters of the outsourcers conduct high-risk non-sterile to sterile compounding.

Michael Miller, president of Microbiology Consultants, also gave some case studies at the meeting showing how to select the right statistical approach for validating alternative and rapid microbiological methods.

Expert Panel Makes Recommendations

In the fall of 2015, the USP microbiology expert committee appointed an expert panel to begin work on developing a new generation of rapid compendial sterility tests. The 14-member panel consists of experts from the sterile compounding, cell therapy, pharmaceutical, microbiology equipment and contract testing industries and FDA. Cundell is a co-chair of the USP expert group.

A stimuli article based on the expert panel report was published in the September/October 2017 issue of the Pharmacopeial Forum. Cundell is one of the authors of the stimuli article.

The article calls for, among other things, allowing much higher detection limits for rapid methods. Growth-based methods can detect a single colony forming unit of microbiological contamination per milliliter of drug product. However, the stimuli article says there is little evidence 1 cfu/mL is clinically significant. Rather, studies show that much higher concentrations are required to cause infections. A detection threshold of 1,000 cfu/mL would suffice to identify 95% of all infectious cases and a 100 cfu/mL threshold would detect all infectious cases.

The expert panel recommended six analytical methods as candidates for rapid sterility tests: adenosine triphosphate bioluminescence, flow cytometry, isothermal microcalorimetry, nucleic acid amplification, respiration, and solid phase cytometry. It also suggests the type of advanced technology, the instrument name, and the vendors of these instruments and technologies.

The expert panel, called the USP Microbiology Expert Committee, is recruiting experts to write generic test methods for proof of concept studies. The selected technologies will be written up on a draft USP chapter and will be published for public comment.

FDA Agrees Rapid Tests Suit Some Products Better

FDA’s Bryan Riley agreed that rapid sterility tests are needed for products with short shelf lives and for in-process testing. Riley also acknowledged the limitations of the USP Chapter <71> sterility tests. These limitations include the large sample sizes required and the lag time for obtaining results.

The advantages of using the conventional method are that it is relatively easy to use, it detects only viable microorganisms, and it is accepted by regulators without the need for sponsors to do any additional testing.

Riley said that there is no formal guidance for rapid methods. To get them approved for a new drug or biologic, sponsors can submit them as part of their new drug, abbreviated new drug or biologics license applications. Or for marketed drug products, sponsors can submit a prior approval supplement or a comparability protocol.

Riley said that the comparability protocol is a useful mechanism for introducing rapid-method testing for multiple products.

Riley recommended that sponsors interested in using rapid microbiological methods consult PDA Technical Report No. 33 on validating and implementing RMM and alternative methods for guidance, or refer to USP Chapter <1223> on validating alternative methods – or follow the European Pharmacopeia Standard 5.1.5.

He gave two case studies of sponsors submitting applications for rapid testing, one showing the correct way, and the second one showing the incorrect way of validating these methods.

The first case study involved sterile lyophilized powders and sterile solutions. The rapid test was based on membrane filtration and fluorescent cell labeling. The applicant followed the lists of validation parameters set forth in USP Chapter <1223> and PDA Technical Report 33. The sponsor also used a variety of organisms for validation studies including slow growers and environmental isolates as well as “relevant” inoculation levels. The method was approved.

The second case study involved a sterile aqueous solution. The rapid method was based on carbon dioxide production used to detect colorimetric changes. It was not approved in the first review cycle because the sample incubation temperature was not defined, there was a limited set of microorganisms used in validation studies, there were no slow growers or stressed cells studied, and the limit of detection was too high.

He said that the deficiencies were not related to the chosen method but rather were due to deficiencies in the applicant’s method validation. The applicant addressed the deficiencies in the second submission and the change was approved.

From the editors of The Gold Sheet.