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COVID-19 Vaccine Urgency Throws Spotlight on Next-Gen Sequencing for Virus Control

May 31st, 2020

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The urgency of delivering a vaccine for COVID-19 in previously unattainable timeframes and volumes is throwing the spotlight on the expanded role next-generation sequencing (NGS) needs to play to avoid the time delays and other limitations of in vivo/animal testing.  

The wave of COVID-19 vaccine development projects now underway is driving sponsors and regulators to further intensify their focus on how the full potential of NGS technology in assuring the safety and control of the vaccines can be realized.

Under review is how far the methodology has advanced over the past decade, how to best fill in and/or adjust to the knowledge and experience limitations that remain, and what needs to be communicated between sponsors and regulators to assure that the technology is performing its intended purpose.  

These pivotal issues were explored at a very timely session on “the use of next generation sequencing to characterize and detect adventitious viral agents in biological products” at the mid-May 2020 CASSS CMC Strategy Forum Europe.

The forum was originally scheduled to be held in Stockholm, Sweden, but was conducted virtually due to the pandemic. The conference agenda took shape in the latter part of 2019 before the pandemic was in view, making the choice of NGS as a topic of importance particularly prescient.

A session on “technologies related to viral safety” had been held at the December 2019 CASSS CMC strategy forum in Tokyo, Japan, in the wake of ICH’s release in November of a concept paper on updating its Q5A(R2) guideline on evaluating viral safety in biotech products (see Part IV).

The first session of the CASSS Europe forum, held on Monday May 11, included the traditional European Federation of Pharmaceutical Industry Associations (EFPIA) satellite session – formerly held under the “European Biopharmaceutical Enterprises” moniker. EBE has now been folded into EFPIA’s Manufacturing & Quality Experts Group (MQEG). The session covered the current CMC issues for polysorbates, antibody drug conjugates (ADCs), and adeno-associated viruses (AAVs).

On Tuesday, attention at the CASSS forum was on ICH developments regarding Q12, Q13, Q14, and Q2(R), before shifting later in the afternoon onto NGS. Wednesday sessions addressed bioassays for monoclonals and patient-centric quality standards, respectively.

Academic, Industry, and Regulator Perspectives Offered

In focus at the NGS session at the CASSS Europe forum was the expanding use of the methodology in qualifying vector and virus seed sequences and the absence of adventitious viral agents that may impact the quality and safety of cell-based products and vaccines.

Explored were the significant advantages NGS offers over the conventional in vivo methods, as well as the technical and regulatory challenges involved and the heightened urgency of addressing them in the COVID vaccine development context. Included was a review of the ongoing regulator/industry discussions regarding the validation of NGS assays, and what data should be submitted and in what format.

The session included insights on the NGS progress and technical/regulatory challenges from the academic, industry, and regulatory perspectives.

Introducing the speakers was EDQM European Pharmacopeia (Ph. Eur.) Division B Head Emmanuelle Charton, who co-chaired the session along with CBER Office of Vaccines Research and Review (OVVR) Division of Viral Products Deputy Director Robin Levis. Noting that falling under the “next generation” designation are “massive parallel,” “deep” and “high throughput” sequencing (HTS), Charton stressed that “if PCR revolutionized the world of molecular biology as first generation sequencing methods in the 20th century, NGS revolutionized this world in the 21st century.”

Throwing strong light on the technology’s potential, she explained, was its use in 2010 in detecting the unexpected presence of porcine circovirus (PCV) in a rotavirus vaccine. Since then, she pointed out, its development and use has expanded as a replacement for in vivo methods in identifying, characterizing, and controlling contaminants in biological raw materials and cell substrates.

The lead-off speaker was Ghent University researcher Sebastiaan Theuns, who explored the evolution in the sequencing technologies over the past decade and their expanded use by pharmaceutical manufacturers and veterinarians. Theuns heads a new Ghent University research spin-off company, PathoSense, that will serve industry in viral/bacterial detection with NGS.

Sanofi Pasteur Virology Analytical Expert Carine Logvinoff followed with a discussion of the evolving regulatory environment for HTS and the interactions Sanofi has had with health authorities – and particularly with FDA’s Center for Biologics Evaluation and Research (CBER) – regarding substituting HTS for in vivo tests in detecting adventitious viruses for its new viral vaccine candidates. [Logvinoff’s and Theuns’ presentations are reviewed in Part II.]

Italy National Center for the Control and Evaluation of Medicines Senior Researcher Domenico Genovese provided a European regulator’s perspective on the current regulatory landscape for evaluating the safety of vaccines and biological products and the challenges of balancing “regulation and innovation” in applying NGS to the task (see Part III) .

The Impact of the Wave of Coronavirus Vaccines Under Development

Session co-chair Levis then offered some highly valuable insights on CBER’s substantial engagement with NGS and the impact of the current pandemic.

She reviewed the research her Division of Viral Products has been doing under the leadership of Supervisory Microbiologist Arifa Kahn to expand virus reference resources – stressing the challenges and importance of the bioinformatics piece in particular – and highlighted the sponsor interactions with Sanofi and others through “technical working groups” that have led to the ability to use NGS in replacing in vivo testing.

She then brought the audience squarely into the present with the wave of coronavirus vaccines that her office is now involved with and the important discussions that are taking place on how to deploy NGS in assuring their safety in eclipsed development timelines where full validation is not an option.

COMMENTS BY CBER’S ROBIN LEVIS AT THE CASSS EUROPE NGS SESSION

I want to just spend two or three minutes talking about FDA interactions in the world of NGS. First, I am in the Division of Viral Products. We are a research division at the FDA.

Probably most of you who are involved in the field of NGS know Arifa Khan. A lot of her laboratory efforts are related to the work of the working group and contributions. So I just want to start out first to just kind of introduce some of her contributions to the world of NGS. She is kind of our pivot point at the FDA for interactions with sponsors.

Virus Reference Resources

One of the things she has been really involved in is the development of the reference panel of, I think, five or six viruses that have been used for looking at standardization and validation. I will say that initially a very limited number of vials of each virus was made and characterized. But Arifa has just gotten a nice grant to renew and remake the reference panel, and she will have thousands of vials of each. So, that can be a global resource that can be made available to academics, to industry, and to anybody who wants them now that we have a good supply.

In conjunction with that, I know NIBSC [UK’s National Institute for Biological Standards and Control] is working on making a reference panel that is much more extensive, I think up to 25 viruses. But that work is really ongoing, and that panel will not be available for some time. But that is also in the works, just so people know.

The other thing that Arifa and our division have been involved in is the development and modernization of the virus-specific database. And that is just one database. I know that certain sponsors have their own databases, and I think that is kind of one of the discussions for downstream. I do not know if we will have that discussion today. ​

I think one of the things that needs to be addressed is the bioinformatics part of this whole thing. It scares most of us who do not really understand how that works. I think it really is a critical piece – how we utilize the bioinformatics and how we kind of harmonize that across all of the different people who are utilizing these technologies and potentially are using common databases versus ​having​ their own moderated databases. From a regulatory point of view, I think that is a really important question about how we use that data, and I will speak to that in a minute.

Sponsor Interactions

So the second thing I wanted to mention is kind of what our sponsor interactions have been. Carine gave a really nice introduction to that. I want to thank Carine and the Sanofi team, because we really have had what we call technical working group discussions, which are not regulatory meetings. They are just scientists who are engaged in the problem-solving as it pertains to the CMC development of a product. 

We have really had some fruitful and important and successful dialogues, which has led to Sanofi really moving the field forward with respect to the use of NGS ​for characterizing ​testing samples for use in product development. As Carine said, these kind of started out with the use of NGS to complement existing strategies. Now we have moved to where NGS can actually replace or substitute for those in vivo strategies and be the sole testing. Some of the PCR assays and things can be supplemented or replaced using the NGS. We have moved forward with the acceptance of that.

Applications for COVID-19

You can well imagine that in the days of coronavirus vaccine development, we have many, many vaccines coming across our doorstep to analyze and get into clinical trial. And, how do we effectively evaluate these vaccines, ensure they are safe, and get them into the clinic when our traditional pathway for entry into phase I of a trial is showing on the sponsor’s behalf that it is safe to go into first-in-humans?

Part of that is a complete adventitious agent set of assays done both on all raw materials of biological origin, such as in cell substrates, such as the virus seed banks. With an in vivo test taking up to four to five weeks, how do we move these products into trial in a way that​ we still ​know they are safe?

So, we have been engaging with a lot of sponsors about fast-forwarding the use of NGS to test these new products and the new raw material substrates, in terms of cell substrate and virus banks using NGS. It has been a little bit of a challenge for us because, given the breadth and number of sponsors we have, they do not all have the expertise that Sanofi has in terms of how to develop these assays.

And really, nobody has time to actually validate the assay. So how well qualified does it have to be? These are some of the issues that we are kind of just working through in terms of​ this short notice in this really critical situation where it is important to get these vaccines into the clinic. How are we going to utilize and rely on NGS data? ​That is something that is really foremost for us. 

Data Sets Needed for Submissions

Another thing I wanted to touch on, which is a little bit more technical – I just will say this quickly maybe for possibly this year’s discussion or next year – but how do regulators interact with the actual NGS data?

In the Division of Viral Products, we have made the decision that we are not going to reanalyze the data sets and do our own bioinformatics analysis. We just don’t have the computing capacity yet. We have the intellectual capacity kind of. But we would essentially have to set up a bioinformatics lab or division, and we just do not have those resources at this time. So, we have not been asking sponsors to submit the original data sets.

What we have been asking sponsors to do is to retain the data set – and as the libraries become updated, that potentially they reanalyze data to keep the data current. Like I said, those I think are discussions for a little bit farther downstream, when we get more experience with that.

Keeping Up with the Science

The final thing I want to say before we get to our discussion and questions is ​that​ I really appreciate and wanted to thank Domenico for the comments on really the limitations on our current assays. At any one point in time, we develop assays based on the existing technology. The assays that have been in use for some decades to ensure the safety of our products with respect to bioburden and adventitious agents were all developed at a time when what we could do is look in animals, what we could do is look in tissue culture. What we could do when PCR came around was to look at specific things by PCR.

Really now, all of that can be supplanted with this new technology as it moves forward. I just wanted to end my comments on saying we really should always use​ the current science to move ​both our​ product development from a sponsor’s point of view ​and product review from a regulatory point of view. Also, for the researchers who are developing all of these assays and how to use them, it is really important for us to stay current with the technologies.

 

Levis and Charton Stress the Harmonization Opportunity

Levis then moderated the panel discussion that followed (see Part II for a review of the full panel discussion). At its conclusion, she stressed that the introduction of NGS presents a “real opportunity” for harmonization between industry and regulators across the human and veterinary arenas and for sharing in the effort to maximize NGS’s effectiveness.

EDQM’s Charton agreed on the harmonization opportunity and benefits. Levis asked her fellow session moderator about the potential benefit of a pharmacopeial monograph for NGS.

Charton responded that in view of how quickly the technologies evolve, she did not envision having product-specific tests, but “maybe more guidance on how to validate the techniques” and how to demonstrate equivalence. She noted that how to further the use of these technologies was under active discussion at EDQM and that “there is lots to work on.”

She pointed to the appreciation for the NGS references in Ph. Eur. expressed by stakeholders at the major International Alliance for Biological Standardization (IABS) conference on “NGS for adventitious virus detection in human and veterinary biologics” held at the University of Ghent in November 2019.

“Of course, it is always a question of what to write and what not to write,” she commented, “because if we write too much, then you could be seen as preventing innovation. That is surely not what we want to do, but to continue to encourage the use of these techniques for the characterization or the identification of adventitious agents in biological medicines.”

[See next page for Part II. Highlights of the 2019 IABS meeting were provided by CBER’s Khan as part of her presentation on NGS in viral detection at the CASSS Japan Strategy Forum in December 2019, which is reviewed in Part III.]

 

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