Rapid microbiological methods (RMM’s) continue to grow in acceptance and significance in pharma, particularly for QA/QC testing. New rapid methods (see below) continue to flood the market, manufacturers test and validate them, and FDA continues to encourage their adoption. In its recently released (August 2011) strategic plan for the Advancement of Regulatory Science at FDA, the Agency emphasizes a need to reduce the risk of microbial contamination of products in the following manner:
a) Develop sensitive, rapid, high-throughput methods to detect, identify, and enumerate microbial contaminants and validate their utility in assessing product sterility;
b) Develop and evaluate methods for microbial inactivation/removal from pharmaceutical products that are not amenable to conventional methods of sterilization;
c) Evaluate the impact of specific manufacturing processes on microbial contamination; and
d) Develop reference materials for use by industry and academia to evaluate and validate novel methods for detecting microbial contamination.
The Agency has begun these activities on its own, following the testing and implementation already underway at major manufacturers. A recent CBER research document on sterility testing highlights the need to improve upon compendial methods in terms of time to results. It states that the compendial method “takes 14 days to provide results. 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.” Researchers in the Division of Product Quality (DPQ) in the Office of Compliance and Biologics Quality (OCBQ) are evaluating various rapid microbial methods. They have, for instance, favorably compared several rapid tests—EMD Millipore’s Milliflex, bioMerieux’s BacT/ALERT, and BD’s BACTEC—to compendial methods. Each exhibited “equivalent sensitivity” at detection of lowest spiked microorganism level, while requiring significantly less time.
With an increasingly strong regulatory blessing, solution providers continue to push forward with new rapid micro technologies that are accelerating, and improving, drug QA/QC. What follows are some moves and announcements that various companies have made lately:
This summer, FDA accepted a Drug Master File (DMF) from BioLumix entitled “Microbiological Rapid Method for the Detection and Enumeration of Microorganisms in Pharmaceutical Products.” The DMF provides specific technical and regulatory information for companies planning to use the company’s Rapid Microbiological System. The DMF includes information about the technology’s accuracy, limits of detection, robustness, and equivalence to USP methods. “It offers simplified single-platform testing for all assays with a 48-hour Automated Certificate of Analysis, while avoiding any product interference,” says Kevin LaBrecque, director of sales and marketing.
BD (Becton, Dickinson and Company) recently introduced the FACSMicroCount flow cytometry system. (It purchased the rights to the product, previously known as the Micro PRO Microbial Detection System, from Advanced Analytical Technologies.) FACSMicroCount screens for bacteria, yeast, mold, spirochetes, Mycoplasma, and parasite cysts. Microorganisms are labeled with fluorescent dyes for detection, enumeration, and differentiation between living and dead organisms and enumeration. The samples are then injected into the flow cell in which microbes pass under a laser, causing them to emit fluorescence and scattered laser light. The new system complements the company’s other media and PCR products, says BD Diagnostics president Tom Polen.
In addition to its Milliflex rapid system, EMD Millipore (recently purchased by Merck KGaA) is offering a new Steritest EZ sterility testing device—designed for easier use and improved ergonomics. The devices are double-packed, allowing operators to open the outer bag in a cleanroom and bring the inner package into a laminar flow hood or isolator. Tests performed include: fertility and retention; sterility and sterility efficiency; membrane bubble point and flow rate; burst pressure; and toxicity and pyrogenicity.
|EMD Millipore: Steritest EZ|
In August, Merck KGaA also purchased the microbiology business unit of Biotest AG. Reports say that Merck is positioning itself as a major player in the global microbiology marketplace.
Celsis Rapid Detection has added a Staphylococcus aureus kit to its ReACT family of rRNA-based microbial assays for the rapid detection of objectionable organisms.
ReACT is a secondary assay used as a follow-up to positive Celsis AMPiScreen results. The AMPiScreen assay confirms the absence of bacteria, yeast and mold in roughly 24 hours, enabling the rapid release of “in spec” product into distribution days faster than traditional microbiological methods. When results are positive, ReACT can provide information about the nature of the event in two hours, the company says.