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.
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.”
[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.]