All biopharmaceutical manufacturers have a legal obligation to monitor the microorganisms that are found in their plant. Regulations require that the microbiological quality of biologic medicines – for efficacy and safety reasons – is assured through analysis and the application of quality risk management approaches.
BioPhorum’s Microbial Control workstream has recently published its peer-reviewed perspective on a challenging aspect of this testing, highlighting a range of approaches through case studies. The paper offers options to industry to the potential risks of anaerobic contamination.
The manufacture of biologic medicines requires cell culture or fermentation to facilitate production of a clinically relevant molecule. These processes commonly need subsequent purification stages to separate the molecule from the remnants of the microorganisms employed to create them. Importantly, the same conditions that allow cell culture or fermentation, may also allow the growth of microbiological contaminants.
Microbiological testing commonly looks for the presence of aerobic microorganisms: those that require oxygen to survive and proliferate. The conditions required for the growth of the microorganisms that produce the biological molecules that are used in medicine commonly feature a warm temperature (for example, between 30 and 37°C), a nutrient-rich medium, and relatively low oxygen levels. These same conditions are often well suited to the proliferation of microbiological contaminants. The separation and purification of medicines from these cells is well understood and testing for contamination by such aerobic microorganisms is long-established and relatively clear and aligned across the industry. Ordinarily, the risk of contamination with unwanted microbes is well controlled as companies have contamination control strategies, which put in place strong barriers to extrinsic contamination in these systems. It is possible, though, for contamination to develop if those barriers breakdown.
By contrast anaerobes (microorganisms that can grow without the need for oxygen but can still often tolerate its presence) are tested for less frequently, with little consensus across the industry on testing practices and procedures. In some cases, anaerobes can go undetected if a facility uses unoptimized test procedures.
Elaine Spiers, facilitator of BioPhorum’s microbial control workstream added, “Living in the absence of oxygen, normal testing methods might not find anaerobes, and contamination can come as a surprise.”
It is possible to capture anaerobic contamination through regular test methods, but those methods, unoptimized for anaerobes – bring with them a degree of uncertainty. The real risk to industry sits with the significant disruption of production that in-depth investigations can bring, to say nothing of the risk to a company’s reputation. It’s vital to the industry that regulatory authorities can have absolute confidence in biopharmaceutical manufacturers.
Adopting a broader approach of including appropriate test procedures covering contamination by both aerobic and anaerobic microorganisms would result in both improved product quality and enhanced patient safety.
“The importance of aerotolerant anaerobic bioburden testing has been undervalued in the pharmaceutical industry,” Kate Young of BMS, and one of the paper’s lead authors said, underscoring the value of the team’s work. “Case studies within this paper support that contaminations have previously gone undetected using traditional aerobic bioburden test methods, impacting product quality. This paper outlines test methods, which companies can start implementing immediately.”
Detection of Cutibacterium Acnes, a high-risk aerotolerant anaerobe recovered in the biopharmaceutical industry, presents not a single recommendation, but several case studies that outline different methods and approaches that industry can adopt for anaerobic contamination testing. The paper highlights examples case studies and contributions from six global pharmaceutical companies, with the recommendations scrutinized through an independent and blinded peer-review process involving other leading industry experts.