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14 BioPharm International eBook May 2021 www.biopharminternational.com expertise, convenience, and a sense of reliability that push the industry to outsource this rather critical service. Simplistic beliefs about viruses It is striking that many old beliefs in the behavior of viruses continue to persist today. For example, "if a virus comes into contact with any cell it will infect it and replicate." Likewise, "all infected cells will show signs of infec- tion." The reality is far more complex. In the presence of a human pathogenic virus, human cells may not necessar- ily show signs of infection or die and may continue to grow normally. In addition, a specific virus may not be able to replicate in vitro, only in vivo. Limited knowledge of virolog y and simplistic beliefs about virus replica- tion have led to misconceptions in the interpretation and, by default, effec- tiveness of legacy viral safety tests. BEST PRACTICES IN VIRAL SAFETY TESTING: WHAT TO DO, WHAT TO EXPECT Extending the biomanufacturer's capabilities If mutual trust, open discussion, and deep understanding are an obvious star ting point, historica l ly, a v ira l safety service company would develop a generic assay that could be used broadly by the industry to meet a spe- cif ic regulator y expectation. Rarely were the assays customized to meet the specif ic needs of a given man- u f a c t u r e r. T h i s l a c k of c u s tom- ization became a "one-size-f its-all " approach that left the manufacturer largely missing from the discussion. For compendial tests, this remains the case to this day. However, the evo- lution of biologics using new plat- forms and methodologies also requires an evolution of the guidance docu- ments and, by default, testing strate- gies. Collectively, viral safety testing is evolving to be more bespoke with a greater understanding that deeper interactions between the service pro- vider, the agencies, and the manu- facturer are needed. We are shifting from a prescriptive approach to full- r isk assessment a nd bespoke v ira l safety testing plan design. The viral safety supplier now positions itself as an extension of the biomanufactur- er's capabilities and facilities. It is a continuum of bioproduction activ- it y w it h sea m less commu n icat ion between the two. Qualifying a subcontractor through a technical audit The selection of a service provider can be a complex one. In the selection pro- cess of the service provider, a quality audit may be carried out. However, this audit often boils down to an audit of the quality system and metrics. It is strongly advisable to complete such a quality audit with a technical audit, for example, with a virologist review- ing the scientific rationale of the sub- contractor's assays and processes, or with a bioinformatics expert inquir- ing how hits from the NGS analysis will be processed. Several manufac- turers have understood this and now work with skilled resources to take this technical and scientif ic aspect into account when selecting their viral safety service provider. Actionable viral safety data Ultimately, the results of a viral safety test should have biological relevance to the test sample and be action- able. For example, NGS-based assays are meaningless if the raw sequence data cannot be interpreted and put into the context of the test system or f inal application. Likewise, without a robust quality system or assurance of compliance to the regulations, the signif icance of those results may be further challenged. There should be a fundamental expectation of exper- tise throughout the entire viral safety testing process, from laboratory execu- tion through data analysis and biolog- ical interpretation by qualified subject matter experts, to regulatory affairs to ensure full compliance and assurance of safety to the patient. NGS-based approaches also enable virus identi- f ication, which makes it possible to track it throughout the bioproduction process with standard molecular tests. Knowledge is power As alluded to earlier, the f irst step to ensure viral safety is knowledge—a f undamenta l understanding of the nature of the product and its man- ufact uring process is critical. This enables a qua lit y-by-design (QbD) t e s t i n g s t r at e g y for w h ic h NG S is wel l su ited. NGS-based testing approaches empower the manufac- turer to better understand their own biomanufacturing processes and the risks that may be encountered. NGS testing strategies to assess t he sa fet y and conta minat ion r isk can be applied to materials through- out the development and manufac- t u r ing process, f rom raw mater ia l to the f ina l dr ug product. Idea l ly, t h is shou ld prov ide t he ma nu fac- turer avenues to both optimize and s i mpl i f y t h e i r biom a nu f a c t u r i n g proce s se s , a nd more i mp or ta nt ly, m it i g ate t he r isk of a d v ent it iou s a gent conta m i nat ion. T h is is t he underly ing principle of QbD: that the risk of adventitious agent con- ta m i nat ion is pre vented or m i n i- m i z e d t h rou gh s m a r t biopro c e s s design (11,12). In turn, the gains or savings in process eff iciency, time, costs , a nd overa l l sensit iv it y a nd assurance of safet y can be substan- tial to the manufacturer. Partnerships for Outsourcing Analytics The viral safety supplier now positions itself as an extension of the biomanufacturer.