Why was the ICH Q5A R2 Especially Necessary for the Biopharmaceutical Market Now and How Does this Revision Impact the Viral Safety Strategy for Biologics?
Horst Ruppach,Executive Director Scientific and Portfolio Global Biologics, Charles River LaboratoriesRead on to watch the exclusive video and read the transcript
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Horst Ruppach, Executive Director Scientific and Portfolio Global Biologics, of Charles River Laboratories spoke with Brandy Fidler from Informa Connect Life Sciences about ICH Q5A R2.
The ICH Q5A guideline was revised to incorporate advancements in technology and product modalities over the past 25 years while maintaining the core viral safety principles for biologics.In the revised guideline, high throughput sequencing (HTS) is highlighted for its benefits in viral safety testing, offering broader detection capabilities and potential cost and time savings. However, its adoption is accompanied by challenges such as assay validation, data interpretation, and false positive results. In an interview with Brandy Fidler, Managing Editor, Digital Content, at Informa Connect Life Sciences, Horst Ruppach, Executive Director Scientific and Portfolio Global Biologics at Charles River Laboratories, further discusses why the ICH Q5A update was necessary and the importance of HTS as a replacement or supplemental technology for virus detection tools.
Why was the ICH Q5A R2 necessary, and how does this revision impact the viral safety strategy for biologics?
I should say the ICH Q5A is a leading guideline to address the viral safety aspects of biologics. The focus is a little bit on biologics derived from cell lines, but this guideline is also frequently referenced in other guidelines, which address other types of biologics.So one should know the guideline was released in 1997. There was a minor revision in 1999, so it’s now in the world for more than 25 years. And you can imagine since then there were many developments. So for instance, we have collected a lot of virus safety data over the last 25 years. New technologies emerged to address viral safety but also new product modalities emerged, you know cell therapy products, gene therapy products, etc. So all this forced the author of this guideline to revise the existing guideline and to bring in all these new developments into the new guideline.If the question is does it change the strategy? In principle, I would say no because the major principles, which were set into these guidelines 1997, are still the same — carefully sourcing, carefully testing, and doing viral clearance that are the major principles to ensure viral safety of biologics.So I just want to emphasize that the strategy definitely has not changed and emphasize and stresses how well this guideline was set up already in 1997 to ensure viral safety.
What challenges will be expected in viral clearance validation studies specifically because of this guideline adoption.
Viral clearance is a very important safety column in this safety program, but we have, as I said already, collected so many data within the last 25 years that this guideline decided to reflect this experience in the new version. And for well-established manufacturing process like Cho-derived recombinants, in fact, it leads to reduced study designs because you don’t need to repeat the investigation of the viral clearance capacity of a certain step again and again and again. While we have tons of data now showing that this step may provide a lot of safety to a manufacturing process. So just to give you an example, in the previous version, it was requested to analyze used resin of chromatography steps for its capability to remove viruses. But we have learned a lot that used resin is not a risk, and therefore, it’s no more requested in this new guideline.
Another example is virus filtration. We have learned from many data that virus filtration is a size-based removal of viruses. And why should we demonstrate the removal of a big virus like the murine leukemia virus compared to a small virus if the small virus can be effectively removed. That can also be regarded as a surrogate maker of all bigger viruses. So that is now implemented in these new guidelines.
I should however say, on the other hand, because we have new product modalities like gene vectors, viral vectors in the gene therapy area, but we also have new production modalities like continuous manufacturing. And this guideline also gives some lead and some information what needs to be considered for those new product modalities or if you apply continuous manufacturing.
Thank you, Horst. The guidelines stress high throughput sequencing or next-generation sequencing as an important technology to replace or supplement existing virus detection tools. What is the interpretation of this?
Yes, that’s really true that the guideline — I just counted — and the term next-generation sequencing of the abbreviation is mentioned 45 times in this guideline, which shows you how important this technology is regarded by regulatory bodies but also by the industry in applying this technology for viral safety testing.
There’s even a specific chapter about this technology.
What is the interpretation? What is said in this guideline about it? Yeah, this technology can replace the currently used and well-established methods for viral safety. Just to give you an example, right now if you do safety characterization of master cell banks, you use six up to nine methods, depends a little bit on the risk of the material. Different methods to address virus safety. And even these six to nine methods are not perfect.
There was a contamination case in Rotarix vaccine, which was detected in 2010 by using this technology, which was not detected by any of the methods applied at that time point. So it stresses the importance and the power of this technology. And by the way, this technology mid to long term will replace all these old assays.
So at the end you may end up with just using NGS for safety testing of master cell bank instead of using six to nine different methods. Of course, it will not happen immediately, so it will go step by step.
So I would say the in vivo assay will be replaced quite early and very soon because it also addresses the 3R principles in Europe but also in the U.S. But there are other reasons why it will replace those assays because it will reduce the cost for safety testing and also the turnaround times.
Could you summarize the opportunities and challenges of adoption of high throughput sequencing as a key technology for biologics testing for the biopharmaceutical market at large?
Yeah, I outlined already some opportunities in the previous questions: reducing cost [and] improving turnaround time.
But I should emphasize the most important aspect of these technologies is the potential to detect even unknown viruses and the breadth of detection, which is much wider than all the other assays. I mentioned the contamination case in these vaccines. Another benefit of this method is if this method detects a virus or contaminant, you get already some information about the nature of this contaminant. So you get the sequence information, so you have already an idea of what kind of contamination you have.That is frequently not the case with the existing assays, in vivo assay or the cell-based in vitro assay, which may give you positive results but at that time point you don't know what the contaminant is. So it will also speed up the investigation.
However, of course there are challenges with this technology. It’s a complex testing technology.It’s much more complex than like PCR or cell-based assays, and therefore, it’s very important that you address, you need to qualify, and validate these assays, this method, and to make it GMP compliant and that is very difficult for such a complex technology.
Just to give you some keywords here, how do you qualify the virus databank you use in order to identify viruses? How do you justify the filtering process? There is a filtering process of data in the bioinformatics pipeline, and you need to justify to ensure that you do not remove any relevant data.
And then I guess all people know the computer system validation is big topic for data integrity, and the bioinformatics uses different softwares in line, etc., and you have to make sure they all meet Part 11 compliancy.
However, maybe the most important challenge with this technology is the sensitivity of the technology, and most people are most afraid of that they get a false positive than false negative results. The question is if you get a false positive, how do you deal with it because you have to do further investigation, which can delay everything.So what is the way you can reduce the risk of false positives? And I just can say it’s really a challenge.
However, if you collaborate with an experienced partner in NGS, who has done a lot of studies already, they are able to put that into their bioinformatics pipeline, improving the pipeline, and they can eliminate false positive early on that they do not show up in the final certificate. That, however, requires strong expertise and experience with this technology.
Why is it important to offer GMP-certified NGS platform for biopharmaceuticals quality control and regulatory compliance, especially for the accelerated development and manufacturing of advanced therapies?
Viral safety is a very high-critical quality attribute, and you don’t want to have a virus introduced in your manufacturing process that it goes to the patient. So it’s very important, and therefore, GMP principles are essential in this process.
So if you analyze a master cell bank, which is used for production or if you’re using cell therapy products, etc., for some reason you need to demonstrate the virus safety, it needs to follow GMP principles, which means the method should be well-validated and qualified to ensure that any results which come out of it are reliable.
So, therefore, it’s very important that somebody’s offering this technology under GMP. Make sure that [you] take a look into the qualification and validation reports because that’s a huge effort for such a complex technology. I mentioned that already. I would say speed is certainly important not just for advanced product modalities. I would say NGS analytics, if well-established and robust, can provide virus safety information much faster and also at reduced costs. That’s certainly a benefit, which is relevant for all manufacturer of biologics. And there’s even the potential to further speed up these kinds of analytics for new developments in the NGS. Next generation sequencing technologies may offer turnaround time, which go down to maybe 24 hours using technologies like for instance Oxford Nanopore’s offering systems, which has, in principle, the potential to identify contamination within very short time.However, I just want to stress that the meaning of this technology is, specifically for these advanced therapy medicinal products, important because those products typically have a higher virus contamination risk than compared to the well-established Cho-derived recombinants.
It’s because of the start material — it can be donor cells, it can be iPSCs, etc., though these are primary materials. And there’s a higher risk that those materials are contaminated with viruses, and they are also more susceptible to contamination.
Also, the production process of such advanced therapy products is also a lot of manual handling still, and you are using still critical raw materials, which are by itself, can be of biological resource and be the risk that you introduce virus in the production process.
So I would say even for the advanced product modalities, next-generation sequencing is I would even say more a must than an option.
Thank you, Horst. Conclusively, in light of this key guideline adoption, can you please share how Charles River Laboratories is ready to support the industry in liaison with its NGS testing partner, PathoQuest?
As I emphasized previously, NGS is regarded as a powerful viral safety testing tool as it becomes clear from the ICH Q5A. So it’s really a technology, which provides [and] improves the safety testing of any kind of biologics. I outlined some challenges, which go along with validation, qualification, you know false positive, etc. So it’s important to run such analytics with an experienced partner who has all three: the technical, the bioinformatics, and what’s the most important the biology or the biological expertise.
So together with CRL’s experience in this field for over 25 years and our GMP expertise and our capabilities to provide still the conventional testing and along with VC, we provide pathogen safety testing together with PathoQuest in the most comprehensive manner.
So that enables us, PathoQuest and Charles River, together to assure a smooth transition from conventional virus safety programs to more advanced testing programs to address the principle outlined by the ICH Q5A.
Just as an indicator the power of this partnership is well-documented in a publication we released recently, I guess it was in late summer last year, which where we both performed a study where we compared next-generation sequencing with in vivo assay. So we took our capabilities, and PathoQuest took their capabilities; we created test material and compared it. And the study showed that NGS has a higher breadth of detection, it’s equally sensitive, if not sensitive, by this method.
Just want to show we were able as a partner to run such a big study and to share this information in a recent publication.
Well, thank you, Horst, very interesting discussion, and it was a pleasure speaking with you today.
Thank you.
