Hello again! ICH Q5A revision 2 updates guidance for developers of biotechnological products and ATMPs

Regulatory-blog-image_100x100.jpgThis blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.


Preventing adventitious agent contamination has always been a major consideration for biological medicine developers, with the challenge increasing for newer product classes such as vector-based gene therapies. Consequently, ICH Q5A “Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin” is one of the International Council for Harmonisation’s (ICH) most important guidelines. In November 2023 the final version of revision 2 was adopted by the Regulatory Members of the ICH Assembly under Step 4. While manufacturing and analytical technology has evolved considerably since the initial version, dating back to 1998, revision 2 maintains the key principles of viral safety while introducing additional sections that reflect new knowledge, technology, and additional product classes that are amenable to viral clearance. 

ICH Q5A – significant updates

The inclusion of new product groups is one of the most significant updates, with guidance given for some advanced therapy medicinal products (ATMPs) and cell-based production platforms. Products covered include genetically engineered viral vectors and viral-vector-derived products used in gene therapies and as vaccines. These products are often more labile to traditional viral clearance approaches, while also introducing new risks of adventitious agent contamination e.g., in the form of helper viruses, revertant replication competent particles, etc. Recommendations on when and how to test master cell banks (MCBs), working cell banks (WCBs), seedstocks, and cells at the limit of in vitro cell age (LIVCAs) and bulk harvest are now included for the first time. Expectations for viral clearance steps where they do not compromise product efficacy are also described. There is now also clarity that for specific types of vectors, such as AAV, some viral clearance steps and demonstration of their effectiveness are increasingly expected.  

Taking their product characteristics into account, developers should have a clear strategy on how best to control adventitious viral contaminants from early development onwards and need to be able to justify their approach to regulators. 

Another new addition is the viral safety considerations for continuous manufacturing (CM) processes, an area that has seen growth in traditional biotechnology product manufacturing. ICH Q5A(R2) now addresses technical aspects of viral safety control that may need to differ for continuous processes compared to batch processes. Considerations for monitoring, detection, and removal of viruses in CM operations, given system dynamics and fluctuations in process parameters, are described. Advanced process controls and verification methods in the context of viral safety are also discussed. While the basic viral safety principles and expectations that have been established for batch manufacturing still apply to CM, in practice some unique aspects will also need to be considered for viral safety of CM processes. For example, for CM, specific approaches are required for material traceability if viruses are detected. Also, bioreactor runtimes for CM processes will likely be longer than for batch processes, and the viral safety risks of a long runtime therefore need to be specifically addressed. One example is the calculation of estimated particles per dose in line with ICHQ5A Annex 4, where a single unprocessed culture harvest bulk might not be used in CM. As per ICHQ13, alternatives to ICHQ5A recommendations can be proposed for CM if justified. 

These are just two of the new additions to ICH Q5A (R2). Others include prior knowledge approaches for viral safety strategies, NGS approaches to analytical testing and updated guidance on chromatography media and its viral-clearance capabilities. 

Overall, the updated ICH Q5A(R2) addresses the current state of viral safety testing and evaluation for biotechnological products, incorporating new scientific developments and accommodating novel approaches. The guideline emphasizes a multipronged approach to viral safety, including comprehensive cell substrate and raw material characterization, testing for adventitious and endogenous viruses, and well-designed viral-clearance studies. Many aspects of the guidance are new and cutting-edge, such as the demonstration of in-house experience in place of time-consuming and expensive viral clearance studies. 

Implications for biotechnological and cell and gene therapy manufacturers

These changes and new approaches pose complex and scientific challenges for biotechnological and cell and gene therapy manufacturers. For example, defining what aspects of in-house data need to be considered to ensure validity for new products. In the short term, companies need to fully understand how such data impacts their current portfolio while planning for long-term changes in product testing and validation strategies. In our experience, viral safety experts who understand and have helped craft these new approaches are vital to guide manufacturers through the highly complex technical and regulatory landscape.  

Approaching regulators with feasible solutions to testing and validation challenges is paramount, and Parexel experts have experience in both regulatory and scientific approaches. Our team includes experts with practical experience of progressing viral clearance technology in lab-based studies, where the publication record helped form the revision 2 of ICH Q5A – as well as ex-national regulators who understand the requirements from an agency perspective.  

Revision 2 is a much-needed update for this critical area of biotechnology manufacturing and will provide a good framework for current state-of-the-art approaches. We hope ICH will prioritize more frequent revisions in the future, to ensure this guideline continues to stay abreast of new developments. 

Interested to learn more? Read our full article on the topic, published in BioProcess International. To discuss the impact of ICH Q5A (R2) on your biotechnological products and ATMPs, please get in touch.

Return to Insights Center