Brammer Bio

Cell and Gene Therapy

Q1 2018

Viral Vector

<h3 class="p1"><span style="color: #ff6600">Cell and gene therapies are rapidly advancing to late-stage clinical trials and commercialization. Brammer Bio has expanded its capabilities to meet the growing need for flexible, high-quality advanced viral vector development and manufacturing services with an emphasis on providing the highest level of patient safety and reliability.</span></h3>
<h4><span style="color: #45318a">Rapidly Growing Markets in Need of Viral Vectors</span></h4>
<p>Most gene and cell therapies, like the first two chimeric antigen receptor (CAR)-T cell therapies (KymriahTM and YescartaTM), and the first in vivo gene therapy (LuxturnaTM) approved by the FDA in late 2017, utilize viral vectors for transduction. Given the large number of cell and gene therapies in late-stage development/nearing commercialization, it is not surprising that demand for viral vectors is growing rapidly. According to Allied Market Research, the global viral vector and plasmid DNA manufacturing market (including viral and nonviral vectors and plasmid DNA) was valued at $262 million in 2016 and is expanding at a compound annual growth rate of 22.6% to reach $1.090 billion in 2023.<sup>1</sup> Viral vectors accounted for the largest segment.</p>
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<p>The rapid growth in demand for viral vectors is challenging the sector, however.<sup>2</sup> The production of viral vectors requires advanced manufacturing facilities and equipment, and highly skilled and experienced operators. There are a limited number of biopharmaceutical companies and contract development and manufacturing organizations (CDMOs) with the resources in place across all stages of the drug development cycle. Both academic laboratories providing early phase support, and most CDMOs providing clinical and commercial development and manufacturing services are running at full capacity, typically with wait lists that extend months to years.</p>
<h4><span style="color: #45318a">Expanding to Meet Development-Scale Needs</span></h4>
<p>Recognizing the growing need for viral vector production services on the development and commercial scale, Brammer Bio was formed as a highly specialized contract development manufacturing service organization focused solely on meeting the needs of the cell- and gene-therapy markets.</p>
<p class="p3"><span class="s2">In March 2016, Brammer merged with Florida Biologix, an Ampersand Capital Partners’ portfolio company based in Alachua, Florida that had a decade of experience and specialized expertise in the development and early clinical supply of all of the major viral gene transfer vector systems (Adeno-associated viral, Adenoviral, Herpesviral, Lentiviral and Retroviral). Brammer management had a strong track record of success supporting late-stage and commercial biologics manufacturing. </span></p>
<p class="p3"><span class="s2">In September 2017, Brammer completed the expansion of clinical capacity at the Florida site, doubling the site’s GMP manufacturing capacity supporting clients’ clinical cell and gene therapy trials. In addition to increasing capacity for adherent and suspension cell culture using mammalian and insect cell host systems up to the 1000L scale, additional unidirectional flow manufacturing suites were built and a state-of-the-art isolator and integrated fill line were installed for drug product manufacturing in a range of formats, including up to 2000 vials per day.</span></p>
<p class="p3"><span class="s2">Isolators are the most robust barrier systems available and provide a high level of assurance and reliability with respect to contamination control. Fill/finish is the last step in the manufacturing process, and the use of an isolator provides a high degree of safety for the drugs being produced. The new isolator system also meets tightening global regulatory requirements.</p>
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<h4 class="callout-title"><span style="color: #ff6600">The production of viral vectors requires advanced manufacturing facilities and equipment and highly skilled and experienced operators.</span></h4>
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<h4><span style="color: #45318a">Investing in Commercial Manufacturing</span></h4>
<p>The second step in the establishment of Brammer as a full-service cell and gene therapy CDMO was the acquisition on January 1, 2017, of Biogen’s biologics manufacturing and distribution facilities in Cambridge and Somerville, Massachusetts, including the on-boarding of an experienced team of 100 employees. The Cambridge facility was licensed by regulatory authorities to manufacture four commercial protein therapeutics.</p>
<p class="p3"><span class="s2">Following a FDA Type-C meeting to review the design plans for the Cambridge facility, Brammer began renovations to support late-stage development and commercial launch of gene therapy products. The project was completed in late November 2017, and the facility now houses state-of-the-art equipment in cleanroom suites specially designed to accommodate a broad range of gene therapy manufacturing process technologies.</span></p>
<p class="p3"><span class="s2">Multiple drug substance suites able to support small- to large-scale (up to 2000L) adherent and stirred-tank production, quality control laboratories and process establishment space were installed. The facility is also designed with an HVAC system for grade C clean rooms and unidirectional flow. A centralized vaporized hydrogen peroxide (VHP) system ensures suite sanitization. A fully automated version of the filling system at the Florida site that leverages similar isolator technology was also installed with capacity for nearly 10,000 vials per day to support late-stage and commercial gene therapy drug products.</span></p>
<p class="p3"><span class="s2">Brammer’s Cambridge facility also houses manufacturing science laboratories where processes can be run outside of GMP conditions, at or close to scale, in order to test them before moving to GMP production. In addition, it is important to note that beyond fill/finish operations, Brammer offers visual inspection and packaging and labeling services. The Somerville distribution center, which is located within one mile of the commercial manufacturing operations in Cambridge, is equipped for the storage of cell banks and viral banks, and labeling, storage and distribution of products as client needs dictate. In a separate project, Brammer plans to renovate a facility in Lexington, MA, increasing capacity to support late-stage clinical and commercial viral vector production. Construction is expected to start in early 2018 with capacity coming on line by year end.</span></p>
<h4><span style="color: #45318a">Focus on Flexibility, Transferability, Quality and Confidence in Patient Safety</span></h4>
<p>Cell and gene therapies are next-generation medicines that require novel manufacturing technologies. As with any new field, needs and capabilities are evolving rapidly. Flexibility in both drug substance and drug product manufacturing is essential for effective support of client projects. Efficient and simplified scale-up and transfer from early- to late-stage clinical and commercial manufacturing allow for shorter time to market for enhanced competitiveness. Ensuring quality and patient safety are absolute requirements and standards.</p>
<p class="p3"><span class="s2">The expansion projects in Florida and Massachusetts have enabled Brammer to evaluate state-of-the-art development and production systems. For instance, the Ambr<sup>®</sup> mini-bioreactor system from Sartorius, with the option for 24 or 48 single-use mini-bioreactors, allows high throughput scale-down modeling for efficient process characterization. Disposable technology has also been implemented at large scale in partnership with Pall Life Sciences. In addition to the new isolator systems, the implementation of </span>single-use product flow paths and the use of disposable technologies for drug product manufacturing provides significant flexibility with respect to the types of projects that can be completed and project scheduling, all while ensuring product quality.</p>
<p class="p3"><span class="s2">Brammer also purposely incorporated manufacturing capabilities for both large- and small-volume production of viral vectors. For instance, at both the Florida and Cambridge facilities, Brammer can accommodate filling volumes down to 250 microliters with a high degree of accuracy — also leveraging single-use technologies.</span></p>
<p class="p3">Given the fill/finish operation is the last step before the product reaches the patient, we made a significant investment into technology that provides confidence in the environmental control for drug product manufacturing. In addition, because similar fill/finish equipment is installed at the Florida and Cambridge sites, scale-up and transfer of projects between the sites can occur rapidly and seamlessly, Notably, the isolator system <span class="s2">at the Cambridge facility is equipped with a unique “L” flange design that enables rapid change out of different filling configurations (cartridges, syringes, closed vials, etc.) and the Florida site offers the same flexibility at clinical scales.</span></p>
<p class="p3"><span class="s2">Furthermore, with the ability to perform development, process scale-up and establishment, clinical and commercial drug substance manufacturing, fill/finish, visual inspection, labeling and packaging, storage and final product distribution, Brammer is an end to end service provider for companies in this specialized field. </span></p>
<h4><span style="color: #45318a">Unique Combination</span></h4>
<p class="p2"><span class="s2">Two key elements make Brammer unique as a cell and gene therapy CDMO. First is the deep level of expertise and experience we have in the development and production of viral vectors. Brammer’s process and analytics development capabilities and manufacturing track record are based on our team’s 11-plus years of experience gained through the successful execution of over 100 projects which have delivered over 150 clinical lots, many for first-in-human trials. Second is Brammer’s understanding of the technical aspects associated with the production of many different vectors using a variety of manufacturing platforms. At the Cambridge facility, Brammer’s team has successfully commercialized several biologic products, manufactured hundreds of product lots, and hosted numerous regulatory inspections.</p>
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<h4 class="callout-title"><span style="color: #ff6600">Cell and gene therapies are next-generation medicines that require novel manufacturing technologies.</span></h4>
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<h4><span style="color: #45318a">An Incredibly Important Role</span></h4>
<p>The cell- and gene-therapy sectors are booming, and demand for viral vectors has only increased as a result. With Brammer’s differentiating expertise in developing processes and analytics, and manufacturing of both drug substance and drug product, Brammer is positioned to catalyze the growth of the market. Brammer expects to rapidly fill our existing capacity and increase our staff; and we are already planning for additional expansions, as represented by the build-out of our Lexington facility.</p>
<p class="p3">Brammer’s Florida location is a center of excellence for process and analytical development and early-phase clinical manufacturing. It is fast becoming an industry hub for the development and qualification of products, processes and methods, and early-phase clinical manufacturing. Smooth transfer to Cambridge (or Lexington in the future) allows for rapid scale-up and commercial production. Final drug products are further supported by the capabilities at the Somerville distribution center.</p>
<p class="p3"><span class="s2">Perhaps most importantly, we recognize that the products we make at Brammer Bio are highly complex. We have great respect and humility for the fact that we are making viruses that are used to create unique and life-changing therapies. Our strategy is, in fact, underpinned by the recognition that we play an increasingly important role in advancing these new medicines with the goal of helping people.</span><span style="background-color: transparent">&nbsp;</span></p>
<h4>References</h4>
<ol>
<li class="p1"><strong>Onkar Sumant &amp; Sohail Shaikh.</strong><span class="s1"> “Viral Vector and Plasmid DNA Manufacturing Market by Product (Viral Vectors, Plasmid DNA, and Non-Viral Vectors) and Application (Cancer, Inherited Disorders, Viral Infections, and Others) &#8211; Global Opportunity Analysis and Industry Forecast, 2017-2023.”&nbsp;</span><span class="s2"><i>Allied Market Research</i></span></li>
<li class="p1"><strong>Gina Kolata.</strong><span class="s1"> “Gene Therapy Hits a Peculiar Roadblock: A Virus Shortage.”&nbsp;</span><span class="s2"><i>The New York Times</i></span><span class="s1">, 27 Nov. 2017, <a href="http://www.nytimes.com/2017/11/27/health/gene-therapy-virus-shortage.html">www.nytimes.com/2017/11/27/health/gene-therapy-virus-shortage.html</a>.</span></li>
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Ensuring Confidence in Viral Vector Manufacturing