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1.863 4.997 3.17 6.102 3.92.466.318.845.567 1.135.744.29.179.677.36 1.16.546.483.186.933.278 1.35.278h.026c.417 0 .867-.092 1.35-.278.483-.186.87-.367 1.16-.546.29-.177.67-.426 1.136-.744 1.39-.932 3.429-2.239 6.113-3.92z"></path></g></g></g></svg></a></li></ul></div></div><div class="w-full lg:w-2/3 px-4"><div class="articles"><h1 style="color:#732b90">Accelerating The Development of Viral Vector Manufacturing Processes</h1><div class="my-4"><p><span class="text-orange-500 font-bold cursor-pointer italic"><span href="/articles/topics/brammer-bio">Brammer Bio</span></span><span class="text-navy"> | </span><span class="text-orange-500 font-bold cursor-pointer italic"><span href="/articles/topics/cell-and-gene-therapy">Cell and Gene Therapy</span></span><span class="text-navy"> | </span><span class="text-orange-500 font-bold cursor-pointer italic"><span href="/articles/topics/q2-2019">Q2 2019</span></span><span class="text-navy"> | </span><span class="text-orange-500 font-bold cursor-pointer italic"><span href="/articles/topics/viral-vector">Viral Vector</span></span><span class="text-navy"> | </span><span class="text-orange-500 font-bold cursor-pointer italic"><span href="/articles/topics/viral-vector-manufacturing">Viral Vector Manufacturing</span></span></p></div><div></div></div></div><div class="w-full lg:w-1/4 px-4 flex flex-col"><ul class="px-8"><li class="mb-8"><div><div class="flex justify-center mb-4"><a href="/authors/richard-snyder-ph-d"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27211%27%20height=%27266%27/%3e"/></span><img alt="Richard Snyder, Ph.D. Headshot" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%"/><noscript><img alt="Richard Snyder, Ph.D. Headshot" srcSet="/_next/image?url=https%3A%2F%2Fthatsnice-testing3.com%2Fwp-content%2Fuploads%2FRichard%20Snyder_ThermoFisher_web_R.png&w=256&q=75 1x, /_next/image?url=https%3A%2F%2Fthatsnice-testing3.com%2Fwp-content%2Fuploads%2FRichard%20Snyder_ThermoFisher_web_R.png&w=640&q=75 2x" src="/_next/image?url=https%3A%2F%2Fthatsnice-testing3.com%2Fwp-content%2Fuploads%2FRichard%20Snyder_ThermoFisher_web_R.png&w=640&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%" loading="lazy"/></noscript></span></a></div><p class="text-navy font-bold cursor-pointer hover:text-orange-500">Richard Snyder, Ph.D.</p><p>Vice President, Science and Technology, Viral Vector Services Pharma Services<!-- -->,<!-- --> <span class="text-navy font-bold cursor-pointer hover:text-orange-500">Thermo Fisher Scientific</span></p><div class="flex justify-end mt-4 -mx-2"><a href="http://www.linkedin.com/in/richard-snyder-b0349a5?" target="_blank" class="px-2 grayscale hover:grayscale-0 transition"><svg xmlns="http://www.w3.org/2000/svg" width="44" height="44" viewBox="0 0 44 44"><g fill="none" fill-rule="evenodd" stroke="none" stroke-width="1"><g transform="translate(-1244 -1409)"><g transform="translate(1244 1409)"><path d="M0 0H44V44H0z"></path><circle cx="22" cy="22" r="22" fill="currentColor"></circle><path fill="#FFF" d="M12.504 18.413h3.899V32h-3.899V18.413zm1.85-1.7h-.028c-1.411 0-2.326-1.038-2.326-2.353 0-1.342.942-2.36 2.381-2.36 1.438 0 2.323 1.015 2.35 2.356 0 1.315-.912 2.358-2.377 2.358zM32 32h-4.42v-7.032c0-1.84-.692-3.095-2.212-3.095-1.163 0-1.81.847-2.11 1.665-.114.292-.096.7-.096 1.11V32h-4.38s.057-12.455 0-13.587h4.38v2.132c.259-.932 1.658-2.263 3.89-2.263 2.771 0 4.948 1.956 4.948 6.163V32z"></path></g></g></g></svg></a><a href="mailto:richard.snyder@brammerbio.com" target="_blank" class="px-2 text-navy hover:text-orange-500 transition"><svg xmlns="http://www.w3.org/2000/svg" width="44" height="44" viewBox="0 0 44 44"><g fill="none" fill-rule="evenodd" stroke="none" stroke-width="1"><g transform="translate(-146 -980)"><g transform="translate(146 980)"><path d="M0 0H44V44H0z"></path><circle cx="22" cy="22" r="22" class="fill-current"></circle><path fill="#FFF" d="M13.112 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1.39-.932 3.429-2.239 6.113-3.92z"></path></g></g></g></svg></a></div></div></li><li class="mb-8"><div><div class="flex justify-center mb-4"><a href="/authors/clive-glover-ph-d"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27211%27%20height=%27266%27/%3e"/></span><img alt="Clive Glover, Ph.D. Headshot" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%"/><noscript><img alt="Clive Glover, Ph.D. Headshot" srcSet="/_next/image?url=https%3A%2F%2Fthatsnice-testing3.com%2Fwp-content%2Fuploads%2FClive%20Glover_PallBiotech_web.png&w=256&q=75 1x, /_next/image?url=https%3A%2F%2Fthatsnice-testing3.com%2Fwp-content%2Fuploads%2FClive%20Glover_PallBiotech_web.png&w=640&q=75 2x" src="/_next/image?url=https%3A%2F%2Fthatsnice-testing3.com%2Fwp-content%2Fuploads%2FClive%20Glover_PallBiotech_web.png&w=640&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%" loading="lazy"/></noscript></span></a></div><p class="text-navy font-bold cursor-pointer hover:text-orange-500">Clive Glover, Ph.D.</p><p>Director, Cell & Gene Therapy<!-- -->,<!-- --> <span class="text-navy font-bold cursor-pointer hover:text-orange-500">Pall Corporation</span></p><div class="flex justify-end mt-4 -mx-2"><a href="https://www.linkedin.com/in/cliveglover/" target="_blank" class="px-2 grayscale hover:grayscale-0 transition"><svg xmlns="http://www.w3.org/2000/svg" width="44" height="44" viewBox="0 0 44 44"><g fill="none" fill-rule="evenodd" stroke="none" stroke-width="1"><g transform="translate(-1244 -1409)"><g transform="translate(1244 1409)"><path d="M0 0H44V44H0z"></path><circle cx="22" cy="22" r="22" fill="currentColor"></circle><path fill="#FFF" d="M12.504 18.413h3.899V32h-3.899V18.413zm1.85-1.7h-.028c-1.411 0-2.326-1.038-2.326-2.353 0-1.342.942-2.36 2.381-2.36 1.438 0 2.323 1.015 2.35 2.356 0 1.315-.912 2.358-2.377 2.358zM32 32h-4.42v-7.032c0-1.84-.692-3.095-2.212-3.095-1.163 0-1.81.847-2.11 1.665-.114.292-.096.7-.096 1.11V32h-4.38s.057-12.455 0-13.587h4.38v2.132c.259-.932 1.658-2.263 3.89-2.263 2.771 0 4.948 1.956 4.948 6.163V32z"></path></g></g></g></svg></a></div></div></li><li class="mb-8"><div><div class="flex justify-center mb-4"><a href="/authors/rajiv-vaidya-ph-d"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27211%27%20height=%27266%27/%3e"/></span><img alt="Rajiv Vaidya, Ph.D. Headshot" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%"/><noscript><img alt="Rajiv Vaidya, Ph.D. Headshot" srcSet="/_next/image?url=https%3A%2F%2Fthatsnice-testing3.com%2Fwp-content%2Fuploads%2FRajiv%20Vaidya_Brammer_web.png&w=256&q=75 1x, /_next/image?url=https%3A%2F%2Fthatsnice-testing3.com%2Fwp-content%2Fuploads%2FRajiv%20Vaidya_Brammer_web.png&w=640&q=75 2x" src="/_next/image?url=https%3A%2F%2Fthatsnice-testing3.com%2Fwp-content%2Fuploads%2FRajiv%20Vaidya_Brammer_web.png&w=640&q=75" decoding="async" data-nimg="intrinsic" style="position:absolute;top:0;left:0;bottom:0;right:0;box-sizing:border-box;padding:0;border:none;margin:auto;display:block;width:0;height:0;min-width:100%;max-width:100%;min-height:100%;max-height:100%" loading="lazy"/></noscript></span></a></div><p class="text-navy font-bold cursor-pointer hover:text-orange-500">Rajiv Vaidya, Ph.D.</p><p>Associate Director of Technical Operations<!-- -->,<!-- --> <span class="text-navy font-bold cursor-pointer hover:text-orange-500">Brammer Bio</span></p><div class="flex justify-end mt-4 -mx-2"><a href="https://www.linkedin.com/in/rajiv-vaidya-a20a204/" target="_blank" class="px-2 grayscale hover:grayscale-0 transition"><svg xmlns="http://www.w3.org/2000/svg" width="44" height="44" viewBox="0 0 44 44"><g fill="none" fill-rule="evenodd" stroke="none" stroke-width="1"><g transform="translate(-1244 -1409)"><g transform="translate(1244 1409)"><path d="M0 0H44V44H0z"></path><circle cx="22" cy="22" r="22" fill="currentColor"></circle><path fill="#FFF" d="M12.504 18.413h3.899V32h-3.899V18.413zm1.85-1.7h-.028c-1.411 0-2.326-1.038-2.326-2.353 0-1.342.942-2.36 2.381-2.36 1.438 0 2.323 1.015 2.35 2.356 0 1.315-.912 2.358-2.377 2.358zM32 32h-4.42v-7.032c0-1.84-.692-3.095-2.212-3.095-1.163 0-1.81.847-2.11 1.665-.114.292-.096.7-.096 1.11V32h-4.38s.057-12.455 0-13.587h4.38v2.132c.259-.932 1.658-2.263 3.89-2.263 2.771 0 4.948 1.956 4.948 6.163V32z"></path></g></g></g></svg></a></div></div></li><li class="mb-8"><div><div class="flex justify-center mb-4"><a href="/authors/matt-niloff"><span style="box-sizing:border-box;display:inline-block;overflow:hidden;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;position:relative;max-width:100%"><span style="box-sizing:border-box;display:block;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0;max-width:100%"><img style="display:block;max-width:100%;width:initial;height:initial;background:none;opacity:1;border:0;margin:0;padding:0" alt="" aria-hidden="true" src="data:image/svg+xml,%3csvg%20xmlns=%27http://www.w3.org/2000/svg%27%20version=%271.1%27%20width=%27211%27%20height=%27266%27/%3e"/></span><img alt="Matt Niloff Headshot" src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" 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hover:text-orange-500">Matt Niloff</p><p>Director, Biotech Integrated Solutions<!-- -->,<!-- --> <span class="text-navy font-bold cursor-pointer hover:text-orange-500">Pall Corporation</span></p><div class="flex justify-end mt-4 -mx-2"><a href="https://www.linkedin.com/in/mniloff/" target="_blank" class="px-2 grayscale hover:grayscale-0 transition"><svg xmlns="http://www.w3.org/2000/svg" width="44" height="44" viewBox="0 0 44 44"><g fill="none" fill-rule="evenodd" stroke="none" stroke-width="1"><g transform="translate(-1244 -1409)"><g transform="translate(1244 1409)"><path d="M0 0H44V44H0z"></path><circle cx="22" cy="22" r="22" fill="currentColor"></circle><path fill="#FFF" d="M12.504 18.413h3.899V32h-3.899V18.413zm1.85-1.7h-.028c-1.411 0-2.326-1.038-2.326-2.353 0-1.342.942-2.36 2.381-2.36 1.438 0 2.323 1.015 2.35 2.356 0 1.315-.912 2.358-2.377 2.358zM32 32h-4.42v-7.032c0-1.84-.692-3.095-2.212-3.095-1.163 0-1.81.847-2.11 1.665-.114.292-.096.7-.096 1.11V32h-4.38s.057-12.455 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Processes","slug":"articles-accelerating-the-development-of-viral-vector-manufacturing-processes","content":"\u003ch6\u003e\u003cspan style=\"color: #444444\"\u003e\u003cspan class=\"s1\"\u003e\u003cstrong\u003eINDUSTRY LEADER INSIGHT:\u0026nbsp;Viral Vector Manufacturing\u003c/strong\u003e\u003c/span\u003e\u003c/span\u003e\u003c/h6\u003e\n\u003ch3\u003e\u003cspan style=\"color: #f26722\"\u003eAs cell and gene therapies have the potential to rapidly advance through clinical trials to commercialization, there is increasing demand for practical manufacturing solutions for viral vectors that can be readily optimized and scaled. Through ongoing efforts, Brammer Bio and Pall Biotech are each developing and implementing state-of-the-art solutions designed to accelerate process development and scale-up for viral vector manufacturing.\u003c/span\u003e\u0026nbsp;\u003c/h3\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eNot Your Traditional mAb Process\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003eWhile lower molecular weight biologic drug substances are often produced via fermentation, larger recombinant proteins and monoclonal antibodies (mAbs), which account for the largest fraction of biologics on the market today, are generally manufactured using well-established platform processes. As a result, production equipment has been designed for mAb manufacturing, and this space is well serviced by equipment suppliers.\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eViral vectors are substantially more complex than recombinant proteins and mAbs, and very different biology is involved in their production. For instance, viruses often kill the cells that are used to produce them, which creates complications when scaling processes. Viruses are also substantially larger than recombinant proteins and mAbs, and are also highly charged.\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eConsequently, the equipment and reagents used for mAb manufacturing may not be optimal for the production of viral vectors. While some aspects of the technology have applicability, very different culture formats \u003c/span\u003e\u003cspan\u003e\u003ci\u003e–\u003c/i\u003e\u003c/span\u003e\u003cspan\u003e most notably adherent cell culture in plasticware \u003c/span\u003e\u003cspan\u003e\u003ci\u003e–\u003c/i\u003e\u003c/span\u003e\u003cspan\u003e have typically been employed for viral vector development and clinical trial material production.\u003c/span\u003e\u003c/p\u003e\n\u003cdiv class=\"callout\"\u003e\n\u003ch4 class=\"callout-title\"\u003e\u003cspan style=\"color: #f26722\"\u003eBrammer Bio has leveraged hardware technologies developed by Pall to provide enhanced services to its clients that require the scale-up of viral vector manufacturing processes\u003c/span\u003e\u003c/h4\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cspan\u003e\u003c!--more--\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eSuspension vs. Adherent Cell Culture\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003e\u003cspan\u003eIn suspension cell culture, the cells are free floating in the culture medium, while, in adherent cell culture, the cells are attached to a substrate in a monolayer. Adherent cell culture is used for certain cells, including cell lines used for viral vector production that must be anchored in some way to enable cell survival.\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eTraditionally, suspension cell culture has been performed in stirred-tank bioreactors, while adherent cell culture has been achieved using roller bottles, flasks and plastic flatware, such as Corning’s HYPERStack\u003csup\u003e®\u003c/sup\u003e or Nunc™ Cell Factory™ vessels. Indeed, the majority of viral vectors in the clinical pipeline were initially produced via adherent cell culture, and an extensive knowledge base has been developed around the optimized production of viruses in this manner.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eSuspension cell culture formats have been developed for the manufacture of adenovirus (AV), adeno-associated viral (AAV), retroviral (RV), and lentiviral (LV) vectors in HEK 293 cells and other cell types. Suspension culture using insect cell systems has also been applied to the production of AAV vectors (Figure 1).\u003csup\u003e1\u003c/sup\u003e While these processes are scalable, the level of process understanding can be limited.\u003c/span\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eFrom Plasticware to Bioreactors\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003e\u003cspan\u003eThe challenge with adherent cell culture is the lack of scalability afforded by these processes. Production of large quantities of viral vectors on plasticware requires scale-out (vs. the ability to scale-up). Cost scales directly with the addition of more flasks or trays and more plasticware also takes up a larger footprint in the plant. These processes are highly labor-intensive, and scaling-out introduces the need for multiple rounds of manipulations, which can lead to more risk.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eBioreactors — whether adherent or suspension — are closed systems with reduced risk for contamination, since they require fewer seeding, transfection and harvest unit operations. They are also available in multiple sizes. The largest single-use bioreactors for suspension cell culture scale to 2000 L.\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eAn example of the industrialization of adherent cell culture has been accomplished in the form of the Pall iCELLis\u003csup\u003e®\u003c/sup\u003e disposable fixed-bed bioreactor system, the largest of which is 500 m\u003csup\u003e2\u003c/sup\u003e. This area translates roughly to a volume greater than 1000 L for a suspension bioreactor and is equivalent to 794 10-layer cell stacks or 5,882 roller bottles at 850 cm\u003csup\u003e2\u003c/sup\u003e each \u003c/span\u003e\u003cspan\u003e\u003ci\u003e–\u003c/i\u003e\u003c/span\u003e\u003cspan\u003e \u003ci\u003ean order of magnitude increase in scale.\u003c/i\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eTimelines Drive Decision Making\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003e\u003cspan\u003eThe choice to manufacture viral vectors using an adherent or suspension cell culture system is based on several factors, though perhaps the most important driver is the timeline for the project. Regulatory authorities in many jurisdictions, including the United States, offer accelerated licensing approval pathways for cell and gene therapies, meaning that development and commercialization timelines can be shorter than those for traditional biologics.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eThe choice of culture system is driven by a number of factors, including the size of the product lot(s) needed in the clinic and marketplace, as well as the amount of time allotted for process development. Because adherent cell culture is familiar, and most viral vector processes are initially developed in flask-based systems, process development times, including scale-up in iCELLis\u003csup\u003e®\u003c/sup\u003e bioreactors, can be quicker. If scalability is more of a concern than a shorter timeline, then development of a robust suspension cell culture process might be preferred; however, it may require more time up front but it can, ultimately, pay dividends in terms of batch size.\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eOther factors that influence the choice between adherent and suspension cell culture production include the disease target, the dose for each patient, the size of the patient population and the expected market penetration. The platform that can best support production of the desired quantity of viral vector is a primary driver. For some gene therapies, clinical and commercial production in plasticware may be sufficient, while other indications require production in bioreactors for commercial supply.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eThere are challenges from timeline and technical perspectives when switching to a new production platform after clinical trials have been performed in humans, particularly the need to demonstrate comparability of the product manufactured using the original and replacement process. Consequently, some drug companies elect to invest the time up front to develop processes and analytical methods that can be readily scaled to a commercially viable process.\u003c/span\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eDownstream Processing\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003e\u003cspan\u003eThe upstream portion of viral vector manufacturing includes expanding the seed train, inoculating the terminal reactor and initiating production \u003c/span\u003e\u003cspan\u003e\u003ci\u003e–\u003c/i\u003e\u003c/span\u003e\u003cspan\u003e steps that can take 3–5 weeks, and that are followed by 1–2 days required for downstream processing. The downstream portion is very important too, as it is essential to purify viral vectors from impurities to ensure that the final product is suitable for therapeutic use.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eThere are many variations in downstream processing, but a process generally begins with clarification of the harvested virus to remove cellular debris and other, larger impurities. The clarified harvest is then subjected to tangential flow filtration (TFF) to concentrate the viral vector particles and achieve buffer exchange. Chromatography is then performed to remove other remaining impurities, such as host-cell proteins, host-cell and plasmid DNA, etc. Ultrafiltration/diafiltration (UF/DF) via TFF is again performed to formulate the vector in the final buffer, and the formulated bulk vector is then subjected to sterile filtration and ultimately filling/finishing.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eManufacturers of hardware and consumables provide options to support most downstream unit operations for viral vector processing. For example, Pall’s \u003ca href=\"https://shop.pall.com/us/en/biotech/single-use-solutions/automated-systems/zidhlieud7s\" rel=\"noopener\" target=\"_blank\"\u003eAllegro MVP\u003c/a\u003e system with fully disposable flowpaths and single-use sensors for control and monitoring of key parameters can be used to run most downstream processes, including TFF, buffer preparation, pH adjustment, membrane chromatography, UF/DF and filling. It provides control of fully automated process sequences for optimal operations, greater consistency in product quality, reduced labor costs and reduction of operator errors.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003e\u003cimg src=\"https://thatsnice-testing3.com/legacy/Q2%202019/Q2_IL_Brammer_sidebar.jpg\" alt=\"Q2_IL_Brammer_sidebar\" width=\"716\" style=\"width: 716px;margin-top: 0px;margin-bottom: 0px\"\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cdiv class=\"callout\"\u003e\n\u003ch4 class=\"callout-title\"\u003e\u003cspan style=\"color: #f26722\"\u003eBecause adherent cell culture is familiar, and most viral vector processes are initially developed in flask-based systems, process development times, including scale-up in iCELLis bioreactors, can be quicker.\u003c/span\u003e\u003c/h4\u003e\n\u003c/div\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eAnalytical Challenges\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003e\u003cspan\u003eThe complexity of viral vectors is much greater than traditional biologics. As a result, multiple orthogonal methods are employed to understand the physicochemical properties and quality of viral vector products. This multifaceted approach will continue unless breakthrough technologies are developed that enable the integration of the results from multiple analyses.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eDuring process development, the “noise” in cell-based assays can also create challenges for the evaluation of process improvements. To overcome this difficulty, trending is performed to develop confidence that an improvement has been achieved. Fortunately, most methods used to determine physical properties, such as polymerase chain reaction (PCR) techniques, have greater accuracy.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eBrammer Bio uses state-of-the-art technologies to verify the identity, strength and integrity of the genetic payload (e.g., vector genome), including digital droplet PCR\u003csup\u003e8\u003c/sup\u003e for quantification, which is crucial for proper dosing. Next-generation sequencing techniques help with understanding the nucleic acid impurities, while high-performance liquid chromatography (HPLC) methods have replaced gel electrophoresis for purity analyses.\u003c/span\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eEvolving Technology\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003eUntil recently, the systems used for viral vector production have largely comprised tools and technologies designed for other applications, particularly mAb production.\u003c/p\u003e\n\u003cp\u003eNewer analytical techniques are providing a better understanding of the critical quality attributes of the vectors that are monitored during process development and manufacturing. New resins \u003cspan\u003efor affinity chromatography of certain vectors (such as POROS AAVX resin from Thermo Fisher Scientific)\u003c/span\u003e have been introduced for purification, and filtration technologies that take into account the specific challenges posed by viral vectors are also under development.\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eProcess controls tailored for viral vector production systems, which can have different cell culture profiles than mAbs \u003cspan\u003eand other recombinant proteins, are leading to more consistent processes and higher-quality products. Progress is also being achieved in developing better cell substrates for viral vector production.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003eAdvances are being made on the drug product side as well, including formulation development, final product conditioning, fill/finish operations and labeling, storage and controlled transport\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003cspan\u003e \u003c/span\u003e\u003cspan\u003e\u003ci\u003e–\u003c/i\u003e\u003c/span\u003e\u003cspan\u003e \u003c/span\u003eall of which present unique challenges for viral vectors. The goal is to ensure that the product reaches the patient with the greatest possible potency and safety.\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eOutlook for the Future\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003eCompanies, including Pall, are working with viral vector manufacturers such as Brammer Bio to identify the needs for commercial viral vector production. They are actively investing in the development of new solutions and tools that are optimized specifically for viral vector upstream and downstream processing that will facilitate the manufacturing of these promising new treatments.\u003c/p\u003e\n\u003cp\u003eBrammer Bio has leveraged hardware technologies developed by Pall to provide enhanced services to its clients that require the scale-up of viral vector manufacturing processes. With a synergistic relationship, it is the patients who ultimately benefit from accelerating the development and commercialization of novel gene therapies.\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"https://thatsnice-testing3.com/legacy/Q2%202019/Q2_IL_Brammer_sidebar2.jpg\" alt=\"Q2_IL_Brammer_sidebar2\" width=\"600\" style=\"width: 600px;margin: 0px auto\"\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg src=\"https://thatsnice-testing3.com/legacy/Q2%202019/Q2_IL_Brammer_sidebar3.jpg\" alt=\"Q2_IL_Brammer_sidebar3\" width=\"600\" style=\"width: 600px;margin: 0px auto\"\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eScalable Adherent Production in the iCELLis Bioreactor\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003e\u003cspan\u003eThe PALL iCELLis\u003csup\u003e®\u003c/sup\u003e 500+ bioreactor is an automated, single-use, fixed-bed bioreactor that provides a large cell growth surface area within a small footprint. The compact fixed bed is filled with proprietary macrocarriers made of class VI polyester microfibers. Due to the cell-cell interactions within the 3D environment of the fixed bed, iCELLis bioreactors can be inoculated at very low densities (3,000 cells per cm\u003csup\u003e2\u003c/sup\u003e or less), allowing for streamlined and simplified seed trains, fewer manual operations and reduced costs.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eEvenly distributed media circulation is achieved by a built-in magnetic drive impeller, ensuring low shear stress and high cell viability. Media is pumped from the bottom through the packed bed and then cascades as a thin film down the outer walls, facilitating aeration and gas exchange. This unique waterfall oxygenation, together with gentle agitation and biomass immobilization, enables the compact iCELLis system to achieve and maintain high cell densities — achieving the productivity of much larger stirred-tank units. In addition, immobilization of the cells in the fixed bed combined with operation in perfusion/recirculation mode eliminates the need for centrifugation to harvest the cells, simplifying the downstream process.\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003ePall has investigated the production of various viral vectors using the iCELLis bioreactor and shown that it can enable the significant reduction of development timelines.\u003csup\u003e2–4\u003c/sup\u003e Other researchers have also demonstrated the use of the iCELLis fixed-bed bioreactor technology for large-scale production of AV,\u003csup\u003e5\u003c/sup\u003e AAV\u003csup\u003e6\u003c/sup\u003e and LV\u003csup\u003e7\u003c/sup\u003e vectors.\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan\u003eThe iCELLis 500 bioreactor is available in sizes ranging from 66 m\u003csup\u003e2\u003c/sup\u003e to 500 m\u003csup\u003e2\u003c/sup\u003e, and with a choice of packed beds with lower and higher densities. The iCELLis Nano system (up to 4 m\u003csup\u003e2\u003c/sup\u003e) is also available for process development work and small-scale production. Moving from the small to larger bioreactors involves increasing the cross-sectional area of the fixed bed while maintaining a constant bed height. As a result, cell seeding and nutrient and oxygen delivery throughout the fixed bed are comparable. Pall has demonstrated that processes optimized in the iCELLis Nano scale directly to the iCELLis 500+ bioreactor with little additional work required.\u003csup\u003e2\u003cbr /\u003e\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ch4\u003e\u003cspan style=\"color: #732b90\"\u003eFigure 1\u003c/span\u003e\u003c/h4\u003e\n\u003cp\u003eFigure 1. (A) Growth of insect cell line Sf9 in a Pall Allegro STR and cylindrical-vendor A* 200-L bioreactors. The cells were then co-infected with two baculovirus vectors to produce an rAAV5-GFP vector. \u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e(B) The ~3 μm diameter change in the cells is an indication of the progression of the infection in the Pall Allegro STR and cylindrical-vendor B* bioreactors. Clarified harvest: Pall Allegro STR 2.48×10\u003csup\u003e11\u003c/sup\u003e vg/ml, cylindrical-vendor A 2.50×10\u003csup\u003e11\u003c/sup\u003e vg/ml. *“A” and “B” signify two different cylindrical bioreactors.\u003cspan class=\"Apple-converted-space\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003ch6\u003e\u003cspan class=\"Apple-converted-space\" style=\"color: #444444\"\u003eAcknowledgement \u003c/span\u003e\u003c/h6\u003e\n\u003cp\u003e\u003cspan class=\"Apple-converted-space\"\u003eThe Brammer Bio process development, analytical development and manufacturing teams performed the work presented in Figure 1.\u003cbr /\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cdiv class=\"callout\"\u003e\n\u003ch4 class=\"callout-title\"\u003e\u003cspan style=\"color: #f26722\"\u003eProcess controls tailored for viral vector production systems, which can have different cell culture profiles than mAbs and other recombinant proteins, are leading to more consistent processes and higher-quality products. Progress is also being achieved in developing better cell substrates for viral vector production.\u003c/span\u003e\u003c/h4\u003e\n\u003c/div\u003e\n\u003ch4\u003eReferences\u003c/h4\u003e\n\u003col\u003e\n\u003cli\u003e\u003cstrong\u003eKotin, R.G. and R.O. Snyder,\u003c/strong\u003e “Manufacturing clinical grade recombinant adeno-associated virus using invertebrate cell lines.” \u003cem\u003eHuman Gene Therapy.\u003c/em\u003e 28:350-360 (2017).\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eKnowles, S., J.C. Drugmand and J. Castillo.\u003c/strong\u003e “Linear Scalability Of Virus Production in iCELLis\u003csup\u003e®\u003c/sup\u003e Single-Use, Fixed-Bed Bioreactors.” Pall Life Sciences. Sep. 2014. Web.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eLegmann, Rachel.\u003c/strong\u003e “Industrialization of adenoviral vector production in an iCellis\u003csup\u003e®\u003c/sup\u003e 500 fixed bed bioreactor for the creation of autologous insulin producing liver cells for the treatment of diabetes: From bench to clinical scale.” PhDISCT Presentation. 2 Oct. 2016. Web.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eLegmann, Rachel.\u003c/strong\u003e “Case study: Single-use platform for complete process development and scale-up of an Adenovirus” in \u003cem\u003eVaccine Technology VII,\u003c/em\u003e Amine Kamen, McGill University Tarit Mukhopadhyay, University College London Nathalie Garcon, Bioaster Charles Lutsch, Sanofi Pasteur Eds, ECI Symposium Series. 2018.\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eKarhinen, Minna, et al.\u003c/strong\u003e “Consistent Viral Vector Manufacturing for Phase III Using iCELLis(\u003csup\u003e®\u003c/sup\u003e) 500 Fixed-Bed Technology.” \u003cem\u003eVector and Cell Engineering/Manufacturing II.\u003c/em\u003e 24: S279 (2016).\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003ePowers AD, et al.\u003c/strong\u003e “Development and Optimization of AAV hFIX Particles by Transient Transfection in an iCELLis(®) Fixed-Bed Bioreactor.” \u003cem\u003eHum. Gene Ther. Methods.\u003c/em\u003e 27:112–21 (2016).\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eValkama, A. J., al.\u003c/strong\u003e “Optimization of lentiviral vector production for scale-up in fixed-bed bioreactor,” \u003cem\u003eGene Therapy.\u003c/em\u003e 25:39–46 (2018).\u003c/li\u003e\n\u003cli\u003e\u003cstrong\u003eSnyder, Richard, Diego Matayoshi, Susan D’costa, and Sushma Ogram.\u003c/strong\u003e “Digital Droplet PCR for Viral Vector Analysis.” \u003cem\u003ePharma’s Almanac.\u003c/em\u003e 12 Mar. 2019.\u003c/li\u003e\n\u003c/ol\u003e\n","date":"2019-05-24T13:00:00","dateGmt":"2019-05-24T17:00:00","roundtable":{"topic":null,"question":null,"roundtable":null},"featuredImage":{"node":{"sourceUrl":"https://thatsnice-testing3.com/wp-content/uploads/PA_Q219_Banner_IL_Brammer.jpg"}},"articleTags":{"edges":[{"node":{"name":"Brammer Bio","slug":"brammer-bio","id":"dGVybTo5MTI4"}},{"node":{"name":"Cell and Gene Therapy","slug":"cell-and-gene-therapy","id":"dGVybTo5MTcx"}},{"node":{"name":"Q2 2019","slug":"q2-2019","id":"dGVybToxMTM4NA=="}},{"node":{"name":"Viral Vector","slug":"viral-vector","id":"dGVybTo5MTg1"}},{"node":{"name":"Viral Vector Manufacturing","slug":"viral-vector-manufacturing","id":"dGVybToxMDI3Mw=="}}]},"mainTopic":{"mainTopic":"Viral Vector Manufacturing"},"articleFields":{"articleId":"PAP-Q2-2019-CL-009","accentColor":"#732b90","vimeoId":null,"associatedCompanies":[{"company":{"id":"cG9zdDo3NTg5Ng==","title":"Brammer Bio","slug":"brammer-bio"}}],"authors":[{"author":{"id":"cG9zdDo3OTc4NQ==","title":"Richard Snyder, Ph.D.","slug":"richard-snyder-ph-d","featuredImage":{"node":{"sourceUrl":"https://thatsnice-testing3.com/wp-content/uploads/Richard Snyder_ThermoFisher_web_R.png"}},"authorFields":{"bio":"\u003cp\u003eDr. Snyder was the founder of Florida Biologix, which was spun out\u003cbr /\u003e\nof the University of Florida in 2015 and merged to create Brammer\u003cbr /\u003e\nBio in 2016. Dr. Snyder has been investigating virus biology, vector\u003cbr /\u003e\ndevelopment, cGMP manufacturing and analytical technologies,\u003cbr /\u003e\nand viral vector–mediated gene transfer for over 32 years. Dr. Snyder\u003cbr /\u003e\nreceived his doctoral degree in microbiology from the State University\u003cbr /\u003e\nof New York at Stony Brook and obtained his BA in biology from\u003cbr /\u003e\nWashington University in St. Louis.\u003c/p\u003e\n","email":"richard.snyder@brammerbio.com","linkedin":"http://www.linkedin.com/in/richard-snyder-b0349a5?","title":"Vice President, Science and Technology, Viral Vector Services Pharma Services","company":{"id":"cG9zdDo3NjM1OA==","title":"Thermo Fisher Scientific","slug":"thermo-fisher-scientific"}}}},{"author":{"id":"cG9zdDo4MDEzMw==","title":"Clive Glover, Ph.D.","slug":"clive-glover-ph-d","featuredImage":{"node":{"sourceUrl":"https://thatsnice-testing3.com/wp-content/uploads/Clive Glover_PallBiotech_web.png"}},"authorFields":{"bio":"\u003cp\u003eDr. Clive Glover leads Pall Biotech’s cell and gene therapy strategy.\u003cbr /\u003e\nPreviously, he was responsible for driving product development efforts\u003cbr /\u003e\naround cell therapy at GE Healthcare and has also held positions in\u003cbr /\u003e\nmarketing and product management at STEMCELL Technologies.\u003cbr /\u003e\nClive holds a Ph.D. in Genetics from the University of British Columbia.\u003c/p\u003e\n","email":null,"linkedin":"https://www.linkedin.com/in/cliveglover/","title":"Director, Cell \u0026 Gene Therapy","company":{"id":"cG9zdDo3NjMyOA==","title":"Pall Corporation","slug":"pall-corporation"}}}},{"author":{"id":"cG9zdDo4MDEzMA==","title":"Rajiv Vaidya, Ph.D.","slug":"rajiv-vaidya-ph-d","featuredImage":{"node":{"sourceUrl":"https://thatsnice-testing3.com/wp-content/uploads/Rajiv Vaidya_Brammer_web.png"}},"authorFields":{"bio":"\u003cp\u003eDr. Rajiv Vaidya has over 10 years’ operational experience of upstream\u003cbr /\u003e\nand downstream of various biologics, including viruses, and has\u003cbr /\u003e\nbeen an integral part of Brammer Bio’s Technical Operations. Prior\u003cbr /\u003e\nto Brammer, he held the Assistant Director of Manufacturing role at\u003cbr /\u003e\nMeridian Life Science. He earned his Ph.D. and M.Sc. in microbiology\u003cbr /\u003e\nfrom the M.S. University of Baroda, India and a B.Sc. in microbiology\u003cbr /\u003e\nfrom the Veer Narmad South Gujarat University, India.\u003c/p\u003e\n","email":null,"linkedin":"https://www.linkedin.com/in/rajiv-vaidya-a20a204/","title":"Associate Director of Technical Operations","company":{"id":"cG9zdDo3NTg5Ng==","title":"Brammer Bio","slug":"brammer-bio"}}}},{"author":{"id":"cG9zdDo4MDE0OQ==","title":"Matt Niloff","slug":"matt-niloff","featuredImage":{"node":{"sourceUrl":"https://thatsnice-testing3.com/wp-content/uploads/Matt Niloff_Pall_web.png"}},"authorFields":{"bio":"\u003cp\u003eMatt Niloff heads up Pall Biotech’s Integrated Solutions Program in the\u003cbr /\u003e\nAmericas. He began his career at MIT working on The Human Genome\u003cbr /\u003e\nProject and went on to leading roles in the commercialization of singleuse\u003cbr /\u003e\ntechnologies at Millipore, Stedim, Xcellerex GE, and Pall. Matt holds a\u003cbr /\u003e\nMaster of Science degree in biology from McGill University in Montreal.\u003c/p\u003e\n","email":null,"linkedin":"https://www.linkedin.com/in/mniloff/","title":"Director, Biotech Integrated Solutions","company":{"id":"cG9zdDo3NjMyOA==","title":"Pall Corporation","slug":"pall-corporation"}}}}]}},"vimeoThumb":false},"__N_SSG":true},"page":"/articles/[slug]","query":{"slug":"articles-accelerating-the-development-of-viral-vector-manufacturing-processes"},"buildId":"3j1kwQFJR4bAVxAE0sM1B","isFallback":false,"gsp":true,"scriptLoader":[]}</script></body></html>