Genetic Engineering & Biotechnology News

DEC 2017

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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20 | DECEMBER 2017 | | Genetic Engineering & Biotechnology News terial, hydrophilic modified polyvinylidene fluoride, also has the strength and integrity to withstand steam-in-place operations. An advantage of hollow-fiber membranes is the capability to increase filtration capacity without requiring conformational changes in the filter cartridge. "Each of our filter types, in sizes spanning laboratory and manufac- turing scales, is available in the same basic form factor," Buesing noted. While connec- tion types differ among sizes, the effective surface area of the filter membrane is in- creased by increasing the length or number of the hollow fibers in the bundle rather than by changing the filter conformation. While Planova filters were designed for batch processing, nothing precludes their use in a continuous process. "Certainly, the oper- ational aspects of total loading volume, varia- tion in load solution parameters, and repre- senting this manufacturing strategy at vali- dation scale need to be considered, but these questions would need to be addressed for any candidate nanofilter prior to implementation in a continuous process," Buesing asserted. "Asahi is currently working with regulators to determine the best path forward to dem- onstrate the suitability of our filters for con- tinuous processing." Virus- and Cell-Based Products The production of vaccines, viral vectors, and cell-based therapies presents unique chal- lenges for virus safety. If the product itself is a virus or a living cell that is capable of harbor- ing viral infections, size exclusion and chemi- cal inactivation are inappropriate. Michael Cunningham, Ph.D., associate director, applications, mechanical system analysis/design tool (MSAT, MilliporeSigma, noted that contaminating viruses are as small as 20 nm, which is close to the limits of vi- rus filtration, which makes them difficult to separate. "Just one viral particle per liter of process fluid is enough to contaminate an en- tire process," he remarked. Given available technology, ensuring the total absence of contaminating viruses in starting materials is impossible, so the focus during biomanufacturing is on virus detec- tion and removal using standard methods. Well-characterized sourcing of raw materials can also reduce virus risk. Safety testing of cell and virus stocks can include detection of virus nucleic acid by the polymerase chain reaction, or detection/ quantitation of viruses using cell-based as- says. In vivo testing can also be utilized if the virus is a known entity in the testing system. Viral Safety Continued from page 18 Bioprocessing Insights Bioprocessing Cancer immunotherapy developer Mustang Bio has agreed to lease space within UMass Medicine Science Park in Worcester, MA, for a manufacturing facility in- tended to support the clinical development and com- mercialization of the company's chimeric antigen recep- tor T-cell (CAR-T) product candidates. Mustang Bio, a subsidiary of Fortress Biotech, will lease 27,043 square feet at the park through Novem- ber 2026, subject to two additional extensions for five years each at Mustang's option, the company stated in a regulatory filing. In the filing, Mustang Bio disclosed that its base rent over the lease term will total approximately $3.6 million, net of $0.6 million in abatements, on a triple-net basis in which the company agrees to pay all real estate taxes, building insurance, and maintenance. The new facility will be located within the research park's 93,000-square-foot Four Biotech office and labora- tory building, the Worcester Telegram & Gazette reported. The company said it initially expects to build cell-process- ing capabilities at the new facility, in order to support its two lead CAR-T product candidates, the glioblastoma multiforme treatment MB-101 and MB-102, which is be- ing developed for both acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm. MB-101 targets interleukin-13 receptor subunit alpha-2 (IL13Rα2), which according to Mustang has limited expres- sion in normal tissue but is overexpressed on the surface of greater than 50% of glioblastomas. The company's CAR-T cells are designed to express membrane-tethered IL-13 receptor ligand with high affinity for IL13Rα2 and reduced binding to IL13Rα1 in order to reduce healthy tissue targeting. MB-102 targets CD123, a subunit of the heterodimer- ic interleukin-3 receptor (IL-3R) that is widely expressed on human hematologic malignancies, including AML. Mustang says it is investigating CD123 as a target for adoptive cellular immunotherapy in AML, since high CD123 expression is associated with enhanced AML blast proliferation, increased resistance of blasts to apoptosis, and poor clinical prognosis. Both MB-101 and MB-102 are in ongoing Phase I trials being conducted at City of Hope National Medical Cen- ter. For both candidates, the company states on its web- site, "We will assess the T-cell persistence and determine the potential immunogenicity of the cells to determine a recommended Phase II dose." Mustang Bio said it expects the new facility to be operational for clinical production in mid-2018. n Mustang Bio Plans Manufacturing Facility in Worcester, MA Raw materials qualification is a critical part of overall process and product safety that intersects significantly with virus safety. Given the discrete inputs and outputs for raw materi- als, a risk-based strategy for qualification makes sense. According to Aurora Henry, raw materials specialist at CMC Biologics, the riskiest materials are those that are non- compendial and are used late in the process. A compendial material will often be manufactured to GMP standards, with suppliers incorporating controls for residual solvents, elemental impurities, and other contami- nants. "Compendial materials are produced with pharmaceu- tical manufacturing in mind and therefore avoid animal-de- rived components, genetically modified organisms, and al- lergens as much as possible," Henry said. "They are tested to standards based on typical manufacturing conditions in the manufacturing region, and so they are well characterized." Non-compendial materials do not incorporate the same controls. Suppliers will not provide as much information about their process and may not include enough testing to fully characterize their materials. "This means that they are inher- ently less controlled than compendial materials, which makes it more challenging to demonstrate suitability for use through testing," Henry added. "Lack of characterization by the supplier typically requires additional characterization internally." Given those realities, eliminating all risky materials is impossible. Media, for example, are often not well charac- terized, so non-compendial materials will always be part of processes. As a consequence, the strategy often is to elimi- nate or mitigate the risk rather than revise the process to remove the risky material. Raw Material Parameters At CMC Biologics, risk assessment examines a variety of raw material parameters that might affect the process such as sourcing, quality, and the potential to affect the process. Assessments are completed for each material/supplier used in the process with the support of a multifunction team consisting of process science, manufacturing, quality, supply chain, and others. The initial risk assessment is com- pleted internally, but mitigation often employs outsourced services such as contract testing or third-party storage. "As for supplier verification or qualification, I expect infor- mation on material sourcing, including their supplier, if they are a repackager," Henry explained. "I will also ask about the process itself to ensure that potential impurities are captured in the specification. I expect that their assays are validated and that they have stability data for the container and closures, and will request test methods and elemental impurity profiles." Qualification is more than a process to minimize the end user's test burden. "It's an ongoing process," Henry advised. "As materials are used long term in the commercial product, new issues will be discovered and additional controls may be required. As a consequence, risk assessments should be revisited periodically to ensure that the qualification of the materials included in the commercial process are still appro- priate and the initial reasoning is still valid." n Raw Material Qualification MilliporeSigma's Mobius FlexReady Solution for Virus Filtration features an optimized single-use flowpath to support parvovirus filtration needs. It accommodates Viresolve® Pro Modus devices, which are designed to combine high virus-retention assurance and fast and efficient processing.

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