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Uniting to Transform Biotherapeutic Product Quality Control with NGS

October 30, 2022
Marie-Ange Kouassi

With the recent revision of ICH guidelines highlighting the demonstrated capabilities of NGS for the safety evaluation of biotechnology products, what better time than now to discuss this fast-evolving area and the important role NGS has in advancing drug development and manufacturing?

On the 13th of October 2022, Genedata hosted its 6th Industry Workshop on Biosafety and Product Quality Control in collaboration with Bristol Myers Squibb (BMS), featuring talks and an engaging panel involving representatives from Pfizer, Novartis, Sanofi, BMS, and Genedata. Many themes were discussed including applications of NGS in production cell line and gene therapy development, critical quality attribute (CQA) assessment and the challenges of implementing this successfully in a GMP-compliant environment. Participants also had the chance to see a live demonstration of the Genedata Selector® platform that enables biopharma companies to analyze NGS data easily and efficiently for a variety of applications such as product characterization and safety testing.

The event began with a welcome from Kitty Agarwal, Senior Principal Scientist in Biologics Process Development at BMS through which the attendees learned the motivation of BMS for pursuing NGS-based viral detection. They learned how the technique will enable scientists at BMS to expedite timelines allowing them to detect any contamination of the reference cell bank (RCB), Master Cell Bank (MCB), and Investigational New Drug (IND) substance release.

Providing insight into the evolution of genetic medicine over time, Lawrence Thompson, Associate Research Fellow of Medicinal Sciences and Biotherapeutics PharmSci, Analytical R&D, at Pfizer, presented how sequencing is applied and how crucial it is in supporting the company’s genetic medicine portfolio. Alongside pivotal discoveries that triggered breakthroughs in this field, Lawrence showed the development of sequencing technologies which have enabled a profound understanding of how changes in genetics can lead to disease. Lawrence then discussed the various applications of sequencing leveraged by Pfizer to characterize genetic medicine modalities such as DNA, RNA, and viral vectors, as well as plasmids, cell-free DNA starting materials, mRNA vaccines, and adenoviruses. Finally, he explained how his department has benefitted from the ability to assess product change-over processes for product carry-over, identify variants in plasmid DNA through spike-in studies, and profile and monitor the integrity of rAAVs to ensure consistency across product batches. 

Following Lawrence’s talk, Devon Ryan, Head of Scientific Consulting at Genedata, presented a use case on the automation of Adventitious Agent Detection and Critical Quality Assessment (CQA). He explained how the platform-agnostic solution Genedata Selector, supports a wide variety of NGS data analyses while connecting all data and results to samples for a unified overview. He presented the different steps involved in generating diverse results simultaneously using Genedata Selector for quality control checks such as plasmid contamination detection and AAV fusion detection. Devon showed how easy it is using Playbooks to generate multiple go/no-go signal readouts from the same samples to guide further manufacturing steps or look deeper into the genome to explore the source of contamination or reason for fusions detected in the AAV virus particles, the packaging product.  

Moving from gene therapy in the direction of cell line development and bio-similars, Matjaz Vogelsang, Associate Director of Science & Technology at Novartis delivered a presentation on ensuring clonally derived and contamination-free production cell lines. He explained two NGS-based applications currently being used at the technical R&D site of Novartis: monoclonality assurance of cell banks and the investigation of microbial contaminants. Matjaz then explained the reason why regulatory agencies request that drug manufacturers demonstrate the monoclonality of cell banks. He recommended a robust control strategy be put in place and documented in regulatory submissions when monoclonality is not identified. Upon sharing a standard cell line development workflow, he explained how single-cell derivation is assured and mentioned the use of Targeted Locus Amplification (TLA) to sequence transgenes. Focusing on microbial contamination investigation, Matjaz walked us through spike-in studies performed which confirmed that NGS was successful in identifying contaminants at even low concentrations. This allowed his team to identify the source of the contamination within a short time frame after detection, taking swift action to mitigate the cause. 

Speakers of the 6th Genedata Selector Industry Workshop

The open forum ended with an insightful panel discussion inviting all speakers and participants to ask any questions on the topic. This event featured a new guest panelist, Jarrod Dean, Associate Director, NGS Leader of the Genomic Medicine Unit CMC at Sanofi. Jarrod shared his impressions on the recently held International Alliance for Biological Standardization (IABS) conference. He mentioned that there was a strong regulatory presence providing insight into what is required to support regulatory submissions. He also shared that it is important to interact with regulatory agencies early in the R&D and manufacturing process. While many are looking to regulatory agencies for direction, Jarrod reminded all listeners that they need to be the drivers, setting the strategy to facilitate NGS adoption for biosafety testing.

Next, the discussion steered in the direction of the challenges of establishing NGS for product and quality control. During the interactive poll questionnaire, the majority of the participants voted that process validation was indeed the most challenging step and having a good validation strategy seemed to be mutually agreed as essential. Some also highlighted that another challenge is converting complex NGS data into easily interpretable information. Centralization of NGS, as well as omics data storage to form one source of truth, would also improve GMP-readiness.

Cell and gene therapy was mentioned as the first area where NGS may soon become the industry standard as it is an area that welcomes innovative, new approaches while requiring efficiency and comprehensive characterization. Other areas such as the biologics field will follow based on gained knowledge to replace traditional in vivo and in vitro assays. During the panel discussion, it was also emphasized that NGS is likely going to be the next multi-attribute method (MAM) like Mass Spectroscopy, allowing to substitute the use of multiple traditional methods with a single technique that addresses multiple aspects (identity, potency, safety) - drastically reducing time and costs. With the increasing therapeutic product demand and more and more drug modalities being developed, timelines are getting shorter, and resources are getting pushed to the limit. Biopharmaceutical companies and biotechnology companies can meet this demand by embracing digital technology purpose-built for this.

Genedata Selector was built with scientists in mind. The platform enables teams undertaking biotherapeutic product development, to easily analyze their NGS data to gain clear results that inform and guide the next R&D and manufacturing steps. This allows scientists to benefit from time savings and focus on the interpretation of findings. Besides the platform, Genedata offers scientific services to support companies looking to undertake specific projects or optimize NGS-based assay data analysis in-house.

In the future, we will continue to facilitate these discussions by hosting open forum events alternating between Biosafety, Cell Line Development, and Cell & Gene Therapy. Sign up to guarantee your place at the next event.