BioPharm International - May 2021

BioPharm - Partnerships for Outsourcing - May 2021

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Page 13 of 39 May 2021 BioPharm International eBook 13 this new class of therapeutics requires not only continued innovation at the bench during development, but also during the critical testing phase. To this end, a whole new class of molecu- lar viral safety tests and tools—particu- larly those that utilize next-generation sequencing (NGS) as a platform—have emerged and are poised to supplant more traditional testing. To many, NGS is a revolutionary new tool. Yet in reality, it is a 20-year-old technology that is only starting to be widely accepted for use in the viral safety testing space. The push for broader acceptance has been two-fold. In 2010, a fortuitous discovery of a viral contam- inant in a vaccine using NGS brought that technology out of the shadows (2). More recently, its use has been pushed by the need to deliver vaccines faster in the setting of the COVID-19 pandemic. Pharmaceutical and biotech companies producing vaccines and advanced ther- apy medicinal products (ATMPs) have been early adopters of NGS-based viral safety testing solutions and are driv- ing the market today. NGS-based tests are paving the way for safer, faster, and cost-effective viral safety assays. As bio- logics become more and more sophisti- cated both intrinsically and in the way they are bioproduced, traditional viral safety approaches are being challenged, and, in parallel, the relationship between pharma and CROs is moving closer to a true partnership. This article details not only the typi- cal hurdles when outsourcing viral safety services, but also the best practices to select a service supplier, how to develop a fruitful partnership between the CRO and the industry, and, more critically, how NGS is positioned to bridge and meet these needs. VIRAL SAFETY TESTING: THE CHALLENGES The advent of sophisticated biologics Cases of vaccine contamination in the mid-1900s (3) revealed that the risk of viral contamination was quite real, with oversight by FDA and other agencies emerging shortly thereaf- ter. The Internationa l Council for Haromonisation's (ICH's) Q5A guide- line was adopted in 1997 for biotech- nological products as a lesson learned from the vaccine industry (4). From there, the risk of viral contaminations in bioproduction batches was relatively low and well mitigated by traditional testing approaches. With the advent of sophisticated biologics, such as cell and gene therapies, new risks of viral contaminations arose (5). As such, the past decade has witnessed a growing gap between the speed at which inno- vative biotherapeutic products derived from biotechnologies have emerged and the speed at which the means to prevent and detect adventitious agent contamination have evolved (5). Today, a collection of guidance docu- ments from different agencies around the world drive the nature and type of test ing requ irements to ensu re product safety. In general, guidance documents focus on ensuring safety while leaving the door open to the nature of the testing strategy (6). This has allowed new approaches such as NGS-based tests to make their way not only with vaccine development but across the entire biologics industry. Detection of a world of viruses One major concern with screening a biologic for adventitious viruses, the ta xon of greatest concern, is how broadly the method detects both known and unknown or unexpected viruses. Viruses represent the most diverse taxon in the world and they are con- tinuously evolving with implications on human health, as evidenced by the cur- rent COVID-19 pandemic. More than 6000 species of viruses have already been sequenced (7) and there is an esti- mation of 320,000 species of mamalian viruses awaiting to be discovered (8). A method to detect all viruses that could be introduced as a contaminant during the manufacturing process is quite challenging using traditional animal-, cell-, and PCR-based tests. Indeed, these tests require prior knowl- edge of the virus properties and/or its sequence to enable robust detection. Viral risk management in a reactive mode The problem of viral contamination has been a forced one. Historically, viral safety testing arose from the rare contamination event experienced by a few that temporarily rocked the indus- try and caused f inancially expensive pauses in the availability of therapeu- tics (5,9,10). The experience ref lected a reactionary culture of the times— addressing the issue only as it hap- pened. Simply put, minimal testing, as per the regulations, was the norm until a contamination event occurred. Only recently has this culture transi- tioned into quality- or safety-by-de- sign one, with the pharma industry, in general, taking greater steps to be pro- active about viral safety. The invest- ment in safet y is considerable and, because of this, many manufactur- ers have not invested significantly in in-house virus testing capabilities. One other challenge is the general lack of def ined methodologies and criteria (e.g., parameters such as lim- its of detection) in the guidance doc- uments. This in turn can make the selection of the appropriate tests and, by default, the ideal service provider somewhat challenging for those less versed in the requirements or expecta- tions. Ultimately, it is the investment, Partnerships for Outsourcing Analytics Simply put, minimal testing ... was the norm until a contamination event occurred.

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