ICH’s viral safety guidelines catch up with the latest biotech innovations
More than 25 years after adopting the first version of the guideline on the viral safety of biotechnology products, the ICH has issued the draft of the revised ICH 5QA focused on products derived from cell lines of human or animal origin. The guideline is out for comments with plans to implement it in 2023, though that timeline will likely extend to 2024.
The ICH 5QA explores the testing and evaluation of the viral safety of biotechnology products, detailing the kinds of data that should be included in a marketing application and registration[i].
While the initial guideline has served the industry well, new technologies and therapeutic modalities have necessitated an update. One such development is what is commonly referred to as next generation sequencing, or deep sequencing. One of the huge advantages of NGS is that it opens the door to replacing animal testing, which is not only unreliable for detecting viruses but is also costly and highly unethical.
NGS presents some issues during routine use, where time is of the essence, but it is strongly recommended during the development phase of cell bank characterisation, where it has been found to be a useful method for excluding the presence of infectious viruses.
One concern with NGS is its potential to pick up reads, or sequences — a virus, bacterium, fungus, DNA or RNA sequence. While many of these reads don’t represent live viruses, they are sensitive, broad and agnostic, and companies will need to find a way to deal with these before releasing a batch. During routine production, there isn’t always the time to deal with these reads and find out what they mean, which is why companies have been hesitant to implement NGS in routine manufacturing until now.
Another key area is the issue of virus clearance validation and risk mitigation for advanced manufacturing, for example, continuous manufacturing. The FDA’s Center for Drug Evaluation (CDER) has sought to work collaboratively on best practices for the removal of viral particles during the manufacture of protein biologics using chromatographic, chemical inactivation, and filtration steps[ii]. However, a move toward continuous manufacturing, while offering huge potential for efficiency, does present some challenges.
The guideline notes that during perfusion of continuous manufacturing processes, unprocessed bulk test samples should be considered. “If unprocessed bulk is toxic in test cell cultures, initial partial processing (e.g., minimal sample dilution or alternative testing assays) can be considered,” The guideline states. Manufacturers should have a justified sampling strategy, for example every couple of days, to test what is present in the fermenter. Manufacturers can’t rely on testing at the start and again at the end as this won’t reflect what happens during the full process.
The guideline recommends having a strategy to segregate potentially contaminated material from the rest of the bulk and notes there may be differences with regards to virus safety in terms of detection, removal, traceability and validation. In particular, it raises questions as to how you validate a process with such different dynamics. One possible answer to that issue is to adopt batch style validation, where feasible.
Taking advantage of prior knowledge
Virus clearance studies are broadly and deeply explored in the guidelines. As the guidelines note, “A major issue in performing a viral clearance study is to determine which viruses should be used.” This is where prior knowledge should be leveraged. Typically, in virus clearance studies (VCS) done to support a marketing license a panel of four virus types is used. Those should represent a wide range with variable characteristics: enveloped viruses, non-enveloped viruses, DNA and RNA viruses. Drawing on virus filtration knowledge, study time and costs can be saved by simply focusing on the worst-case-scenario – parvoviruses, which are small non-enveloped studies. The data generated from these studies can be extrapolated to demonstrate removal of larger viruses as well.
Another key focus of the guideline is the function and regeneration of columns. The guideline notes, “Over time and after repeated use, the ability of chromatography columns and other devices used in the purification scheme to clear virus may vary … For protein A affinity capture chromatography, prior knowledge indicates that virus removal is not impacted or slightly increases for used (e.g., end-of-life) chromatography media/resin. Therefore product-specific studies with used resin are not expected.” This removes a significant burden from the validation process.
Prior knowledge is also relevant with Annex 5 calculation of estimated particles per dose, which is “applicable to viruses, such as endogenous retroviruses, for which an estimate of starting numbers can be made.” What this does is simplify some of the testing requirements and remove some of the burden from the validation process.
With Annex 6, the revision allows for a platform validation approach whereby different antibodies that are purified over the same process can take advantage of prior knowledge and in-house data to reduce product-specific validation.
New Therapeutic Modalities
One other key consideration from the revision is Annex 7, genetically engineered viral vectors and viral vector-derived products. This section mentions the implementation of virus removal process steps. However, if the implementation of such steps is not possible, as in larger and more fragile virus vectors, there is a strong recommendation for comprehensive testing strategies using Master Cell Banks and Master Virus Seeds and the selection of safe starting- and raw-materials.
Conclusion
The revision of the ICH 5QA is timely and well-considered. For innovator companies, it offers details on virus safety that is more appropriate to the types of products they are working with while providing good and thorough grounding in established components of virus safety: namely identifying potential contamination sources, implementation of robust clearance steps and using low-risk starting- and raw-materials.
About the author:
Sebastian Teitz, Ph.D., is a principal consultant at Biopharma Excellence, drawing on his knowledge and expertise in virus safety to support clients in the manufacture of biological therapeutics.
[i] ICH Q5A (R2) Guideline, https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-r2-viral-safety-evaluation-biotechnology-products-derived-cell-lines-human-animal-origin_en.pdf
[ii] Shifting Therapeutic Protein Drug Substance Manufacturing Paradigms, FDA, https://www.fda.gov/drugs/regulatory-science-action/impact-continuous-manufacturing-processes-viral-safety-therapeutic-proteins
