The landscape of cell and gene therapies (CGT) is rapidly evolving, necessitating the development of new techniques to replace traditional quality control compendial methods. As these advanced therapies become more prevalent, the need for faster, more efficient microbial testing has become paramount. This shift is driven by the unique challenges posed by advanced therapy medicinal products (ATMPs), including short shelf lives, small batch sizes, and the critical need to quickly deliver treatments to patients. To overcome these challenges, quality control testing must combine speed, sensitivity, and specificity to drive quick decision making and efficiency from development to release.
Regulations and guidance are continually being updated to accommodate these new products and requirements, emphasizing the importance of rapid methods. One of the most significant advancements in microbial quality control for advanced therapies is the adoption of nucleic acid amplification (NAA) techniques, such as PCR. Regulatory agencies including the FDA and European Medicines Agency (EMA) allow for the use of PCR to replace culture methods for mycoplasma and sterility testing, which can take up to 28 and 14 days, respectively. The traditional, time-consuming culture methods are impractical for CGT therapies that require rapid administration. Even when timelines allow, delays or testing issues can jeopardize product manufacturing, availability, or delivery to patients.
The FDA, United States Pharmacopeia (USP), European Pharmacopoeia (EP), and Japanese Pharmacopoeia (JP) have published guidelines dedicated to the validation and use of alternative microbiological methods, and additional chapters and updates are in progress as the adoption of these new methods increases. It is important to recognize that rapid methods have been accepted for more than a decade. Nucleic acid amplification techniques for Mycoplasma testing have been accepted per EP Chapter 2.6.7 Mycoplasmas since 2007 and by the USP since the inception of Chapter <63> Mycoplasma Tests in 2010.
While adoption of PCR-based methods in CGT testing has historically been gradual, these approaches are now becoming mainstream with established trust and acceptance from regulatory agencies. Since the guidance was originally published, the technologies have advanced significantly, and pharmaceutical companies, laboratories, and regulatory agencies have gained substantial experience in their application and validation. As a result, adoption of PCR methods continues to increase, driven by their proven efficacy and the growing demand for faster, more efficient microbial quality control.
Perhaps the most exciting advancement associated with the benefit of NAA techniques is automation. Automated systems can be used for sample processing, nucleic acid extraction, amplification, and computerized analysis. The adoption of automation is transforming microbial quality control for advanced therapies by improving turnaround time, efficiency, and reproducibility of testing procedures while minimizing the risk of human error. These improvements contribute to cost savings and enhance overall quality. By enabling laboratories to generate fast, reliable, and consistent results, automation helps ensure the safety and efficacy of advanced therapeutic products.
The industry is also moving toward risk-based approaches, prioritizing testing based on the potential impact of the environment, manufacturing process, raw materials, human factors, and regulatory requirements. This approach commonly leads to the implementation of (1) in-house rapid methods for testing raw materials, environmental monitoring samples, and in-process samples to detect microbial contamination during production, and (2) outsourced PCR methods producing good manufacturing practices (GMP) results for release testing. Utilizing PCR, results can be obtained within a few hours or days, supporting faster, data-driven decisions and keeping development and manufacturing on track.
The successful implementation of regulatory compliant PCR methods requires thorough validation and documentation. Method validation is typically outsourced to laboratory service providers that are qualified for GMP studies, certified by agencies like the FDA and EMA, and capable of producing detailed documentation according to industry standards. The full scope of method validation typically demonstrates system suitability, specificity, and detection limit of the PCR methods. Additionally, it can include comparability studies demonstrating improved performance of the validated PCR methods over compendial culture methods. Experienced laboratory service providers, whether operating independently or as part of a contract research organization, can partner with clients to design validation studies aligned with regulatory expectations and product specific requirements. This strengthens submission readiness and reduces risk during regulatory review.
Collaboration between CGT companies and laboratory service providers, the implementation of rapid technologies and automation, and the adoption of risk-based testing strategies are quickly becoming industry standard. Advanced therapies demand this evolution, pushing rapid methods to the forefront of drug development and manufacturing. By adopting these strategies early in manufacturing and assay development, drug developers can stay ahead of regulatory and operational needs, streamline testing workflows, and ultimately accelerate the delivery of safe, effective therapies to patients who need them.
