Regulatory Considerations For Implementation Of Alternative Microbial Methods For Quality Control Testing

Biotherapeutic drugs are complex, and the use of living cells introduces variability inherent to biological systems into the manufacturing process. In addition to the complexity of the manufacturing process, raw and starting materials are complex and often less well defined, frequently made with materials of animal or human origin which have been shown to introduce microbial contaminants.

Monoclonal antibody, gene and cell therapies utilize mammalian or insect cells in the manufacturing process. These large-scale cell cultures provide a favorable environment for microorganisms to grow. A contamination event always has serious impacts on the process and product and eventually patient safety. To address this issue global regulatory guidance such as the International Council on Harmonization (ICH) Q5A, requires drug manufacturers to implement measures to prevent, remove and detect contaminants to ensure patient safety. This guidance requires manufacturers to address three areas; testing the starting materials, testing in-process samples and finally validating the steps used to inactivate or remove contaminants.

To address the viral safety of new therapeutic and vaccine modalities such as cell therapies and viral vector-based vaccines, development of sophisticated detection technologies, new manufacturing paradigms and to incorporate knowledge gained from decades of biologics development, the ICH Q5A guideline is being revised. It is expected that sensitive and specific molecular detection technologies such as polymerase chain reaction (PCR) and high throughput/next generation sequencing (HTS/NGS) will be discussed as alternatives to in vivo and possibly in vitro cell culture based detection, viral contamination detection for starting materials and in-process testing. The inclusion of these technologies in ICH Q5A revision indicates confidence in the utility of these technologies by both the regulators and the industry for biosafety assurance of biologics. As a result of this, it is highly likely there will be widespread adoption of molecular methods for the quality control during manufacturing of biologics.

This paper discusses the regulatory expectations for incorporation of alternative methods with a focus on comparability and strategies for easier substitution of current methods.