ee ee NCTC Saran ay 1 N TERN ATION AL Teen § CELL THERAPIES Process Strategies for Regenerative MedicineThe Finesse solution Anything’s possible Today's bioprocessing challenge: demand smarter solutions. Finesse solutions are built to work with your systems — not the other way around. Finesse offers state-of-the-art equipment, intelligent control software, and ‘custom integration services to optimize your bioprocessing unit operations, » universal control and automation platform compatible with all leading suppliers » Service, automation, and integration expertise ‘to harmonize old and new equipment » Addition of new sensors and peripherals without software modifications » Configurations fom prelinical through praduction scale www.Finesse.com @Finesse Learn more about Finesse Solutions: SmartFactory” cGMP facilites Universal contollers with “TruBio® software Trufluor* single-use sensors SmartGlass™ and SmartVessel” bioreactorsPharma&Biotech LONZa Your Trusted Partner in Cell and Gene Therapy =. — Tissue Acquisition = Aseptic Fill and Finish Process Development ~ Bioassay Services — cGMP Custom Manufacturing = GMP Storage and Distribution by Hae wotlonza.comBioProcess ‘Quantum coll expansion systems from TerumoBCT In use at contract manufacturer MaSTherCel in Gosseles, Belgium Gene and cell therapies have become intertwined under swssnici= cows the rubric of regenerative medicine. Gene theraples have evolved beyond early approaches based on delivering genetic material directly to patients into potential applications in modifying cells with viral vectors for immunotherapy. Product characteristics, technology ‘avoilability, and target market can influence decisions ‘made when companies design manufacturing processes for cell therapies. Commercialization will be enabled by adoption of a Q6D approach to manufacturing bioprocess development as well as cost efficiencies, process analytical technologies (PAT), and smart scale-up planning, Progress Toward Commercial Scale and Efficiency in Cel Therapy Bioprocessing 8 David Orchard Webb Manufacturing Plasmid DNA: Ensuring Adequate = Supplies for Gene and Cell Therapies R “] Tony Hitchcock id Innovative Downstream Purification Solutions for Viral Vectors: Enabling Platform Approaches to Advance Gene Therapies. . . Orjana Terova, Shelly Parra, Remko Clasen, and Pim Hermans @ 20 ® Designing the Optimal Manufacturing Strategy for an Adherent Allogeneic Cell Therapy... 24 Tania D. Pereira Chilima, Thierry Bovy, and Suzanne S.Fatid 10 Box 70, Dexter 08 97481 ne esearch Dive Ste 408 Product and Geos Mange Soicrecess Westborough, ha sise! GanevoveMcarhy 2122002752 — fasnguret nee Bs cen Peers eerste Ehone Montgomery Publster Ban Calne 13086141443 Deca of usness Operations drnongemenpoboprecessnlcom eaineebeproceantcam tr Audenes Derdofrem erties sede ttisher ere cas Senior Technical Editor Semege mann Contant (Ester NA) chert scot Gsopheohmaon. 108.18 25 Marketing and Dig Content Suategst Seatitoprocssin100 L. Modularization: Industrialization of autologous and allogeneic cell therapies is facilitated by modula manufacturing facilities. Genentec Lilly, and Merck all use such facilities (14), Single-use equipm: flexibility in a traditional facility; however, modular systems combined with single-use systems could be ideal for CMOs specializing in ‘medicine with different volumes and processes for individual clients. Single- shorten turnover time and Process Scale. it lacks some increase « company's flexibility in production planning, If capacity demands change, then a CMO can add or subtract some cleanroom areas. Prefabricated cleanroom pods ean be designed and built off site. Once assembled into a facility, pods are linked for access through aie locks “These pods can be used for an entire process or just a single step (14). Tais cons 2016 4 concept is potentially suitable for expanding autologous therapy ‘manufacturing across hospital locations. Improve Your CHANCES oF Success Commercialization of cell and gene therapies can be enabled by adopting a QHD approach to manufacturing bioprocess development. Cost efficiencies can be realized with single-use bioreactors integrated into ‘multiproduct pipeline automated ‘modular facilities. Seale-up ean be facilitated by Q6D planning, considering serum sources and shipping logistics. Use of innovative PAT such as inline, real-time, Flow cytometry apoptosis assays in bioreactors at a range of volumes can facilitate process development and ‘monitoring of batch-to-batch comparability. Currently, 20 regenerative medicine therapies have been approved. As has been seen with Dendreon’s Provenge experience, regulatory market approval does not guarantee commercial success. ‘Adopting the approaches outlined herein, however, can mitigate risk, Rererences 1 Lanphier E, Program Inracton and Industry Update, Regeneration Meine & Advanced Therapie Stat ofthe Edt Bring. Reepifalisncerm orgevent! redicine-tate-indutey-riefing. srpeon By Cecearlli J. Factories of the Future: Can Patient Specific Cell Therapies Get Thee from Here? BioProcu In 114) 2016 S4-S7; wow bioprocesitl com! p-vontent/epload/2016/04/14-4-p- Hampson. 3. Lipste VV, Timmins NE, Zander PW. Quality Cell Therapy Manuficturiag by Design. Natare Bitch 34(8) 2016: 395 400; do 10.1038/nbe 3525, 4 Joslin L, eta. Quality by Design: A CMO’ Perspective on Gaining Knowledge Faster and Better, Pharmacea. Teco February 2014 supplement; www aharmtech, ‘com/qalty-design-cmor-perspectve-gsining enowedge-fasterand-hetter0. 5. Sacoypke Mark, et a. Single-Use Bioreactor and Mirocariet: Sealable Techpology for Cell Based Therapies BisPraces In. 12) 2014) SS4-S68; www. biaprocestntl com /wp-content/cplondebp- content/BPL_A_161203ARO7_O_ 231760 pd 6 Prong A, etal. Paradigan Shife or Vaccine Manufacturing Fults The Next ation of Flexible, Modular Fecilit Continued on page 19C19 eal) GENE THERAPIES Manufacturing Plasmid DNA Ensuring Adequate Supplies for Gene and Cell Therapies Tony Hitchcock he concept of gene therapy is far from new, with initial studies performed over 20 years ago (1). However, in the past few years an explosion of interest in this area has gone beyond initial regenerative approaches using viral vectors. Interest is now moving. increasingly into potential use of T cells modified using recombinant viral ‘veetors for immunotherapy applications, Such therapies are based on using either adenoassociated virus (AAV) or lentivirus (1), both vectors being frequently generated through transient expression routes based on plasmid DNA as a starting material ‘The viral vectors are generated using two, three, or four plastid constructs for exch vector with two or three structural/helper genes and a single therapeutic transgene. These are then used to generate the viral vector of choice (Figure 1). tis widely recognized that manufacturing modified TT cells atthe scales needed for large patient numbers raises many challenges from a scientific, technical, and cost-of- goods perspective. Processes for these products take biomanufacturing t0 a new level of complexity — exemplified by the number of biological entities required to be produced, themselves manufactured through recombinant routes (Figure 2). ‘With improving levels of clinical success and the progression of. products into late-phase clinical studies, the industry will see an inevitable need for increased amounts 12 BloProcers Internationa! 48% cron 2016 Figure 1: Mancfacturing overview fr viral vectors and mad fed Tce: NCS = master cela of plasmid DNA to be made at larger manufacturing scales, Alongside that, it s reasonable to expect greater regulatory scrutiny of manufacturing processes as more patients are exposed to these types of products. Looking farther forward, as these types of clinical approaches continue to show postive clinical outputs, drug developers will need to increasingly “plan for success” and develop long- term manufacturing strategies that can be carried through into later clinical phases and in-market supply. ‘A number of companies are recognizing a need for significant changes in manufactaring approaches for producing the cell therapies themselves, and to a large degree for viral vector mannfacturing processes to meet the requirements for late-phase clinical trials and in-market demands for successful products. Technical solutions are needed to enable these changes. I do not doubs that the need to manufacture greater amounts of plasmid DNA will increase. ‘To meet rising demand, production platforms will need to be scaled up significantly Te may be possible to meet the demands for niche therapies of «10,000 patients with small-scale production platforms making <10g/batch. But a reasonable prediction is that 100-1,000 g/year will be required for each plasmid vector for a marketed produ ‘The implication of this increased need for material is that road maps must be created to guide processPlasmid DNA is the starting material for many gene and cell therapy applications. Our industry-leading plasmid experts can make DNA for you at any quality level — preclinical, GMP-Source™, and GMP. How can we help with your next biotech breakthrough? \ taldevron.com/ breakthrough Plasmids meeting DF Protein design and asp Antibodies directly all quality stendards monufocture from DNAFigure: immunoatnity chromatography Enrichment Activation B= e Gene transfer Guossary Modified T Cells: programed lymphocytes that target cancer- specific abnormalities so that malignant cells can be targeted and attacked throughout the body: wnwvicityofhope. orgiblogiadoptive-t-cel-fight-cancer. ‘Adeno Associated Virus (AAV): the parvovirus family of small viruses with a genome of single stranded DNA; they ‘can insert genetic material at a specifi site on chromosome 19 with near 1008 certainty; www. genetherapynetcom/ viralvector/adeno-associated-viruses. hue. Lentivirus: Retroviuses with long incubation periods; they can cause chronic, progressive, often fatal diseases in humans and other animals; www. sgenetherapynet.com/viral-vector/ lentiviruses html McB: master cell bank TeX and HIC: ion-exchange ‘chromatography and hydrophobic interaction chromatography HPLC and CE: high pressure liquid ‘chromatography and capilary ‘electrophoresis changes for manufacturing viral vectors and plasmid DNA. Those guides aso need to demonstrate comparability with regards to safety 3d functionality Taking this a stage further, as produets progress through clinieal phases, their developers mast build robust supply chains. Good manufacturing practice (GMP) guidelines suggest establishing back- up suppliers to make critical materials ing mateal for modied Tce preducton RNA Expansion Baka substance for late phase and in-mas Q. Tf this is the case for plasmid DNA, then it may well involve not only sourcing materials from different suppliers and facilities, but also incorporating different manufacturing processes ReGuLaTorY PERSPECTIVE OF Ptasmip DNA Propuction "The responsibility for supply-chain management clearly falls on drug developers and trial sponsors who are ultimately responsible for the quality of their products. Those groups are requited to provide materials for early stage clinical evaluation and to establish @ road map for supplying materials for late-stage clinical studies and in-market needs ‘When we look at the approaches taken to supply plasmid for early stage clinical trials, it is clear that many companies are using high- quality plasmid DNA. The 2005 EMEA guideline on “Development and Manufacture of Lentiviral Vectors” (3) cites the need for using high-quality DNA in production of lentiviral vectors and a requirement to provide full gene sequences for each plasmid and trans package. However, no real guidelines exist to describe quality systems or manufacturing approaches for thes high-quality products. Many of ther do not fit within the principles of GMP. Suppliers including my company offer services in this area, each with its own approach to levels of traceability of raw materials and consumables, environmental control, vector and final-product sequence integrity. ‘High-quality plasmids are currently used only in early stage “proof of principle” studies on very small patient numbers (<20). But how the approach will progress with suceessful produets and increased patient numbers has not been widely discussed. The issue is complicated by references to “quality, nonclinical, and clinical aspects of gene the ‘medicinal products” (), among other products mentioned, for which plasmid DNA is deemed to be a GMP level “starting material” and is required to be produced under the “principles of GMP” from the cell bank onward. However, as with the terminology of “high quality,” the phrase “principles of GMP" is open to differing interpretations, as is the alignment of the two requirements. It is clear that some larger companies have taken the approach that GMP standards are applied throughout, even for the supply of phase 1-28 clinical materials, with other product development groups taking a much less stringent approach. Iris also apparent that these more recent guidelines push further toward application of ICH guidelines for not only gene therapy products, but also ex vivo vital veetor modalities, Classifying plasmids as a starting ‘material is not surprising given that they provide the starting genetic code for protein elements that bring about a desired therapeutic benefit. Assessing the impact of coding errors is likely to be challenging in terms of patient safety and therapeutic impact. For starting materials, the MHRA 2015 guidelines suggest that a “level of supplier supervision should be proportionate to the risks posed by the individual material taking account of their source, ‘manufacturing process, supply chain complexity and the final use to which the material is put in the medicinal product” (3). Those guidelines may provide a useful starting point when determining quality approaches to plasmid production Applying increasing levels of GMP stringency based on clinical sting includingWhen it comes to creating breakthrough cell therapies with the power to cure the incurable, nobody has allthe answers. That's why Corning remains committed to helping you orchestrate groundbreaking discoveries in the lab ~ and quickly turn up the volume to, production. As a leader in cll culture, Corning provides platforms that scale predictably and with ease. Our advanced cell culture surfaces, vessels, media, and closed systems work in harmony to ensure cell viability, reproducibility, and regulatory compliance. Working in concert, our applications team can help guide you through process design, product customization, and protocol development. Together we can fuel the future of cell therapy and unleash its full potential ~ without missing a best. To learn more, please visit www.corning.com/celitherapy, call 800.492.1910, or contact your local Corning representative. £8 2016ornng incorporated ‘Ags servedFigure 3: Outline o plasmid DNA orodvetion avocess ‘alba % Supercoiled plasmid > 80% Endotoxin << 40 Eu/mg, Host DNA, <1% Host protein <1% phase is not unprecedented. PDA ‘Technical Report 56, “Application of Phase Appropriate Quality Systems and CGMP to the Development of Therapeutic Protein Drug Substance,” provides guidance for more conventional biologics and for drug developers (2). That document cites four specific areas to be assessed: quality systems, facilities, equipment, and materials and laboratory, with the main differentiations made between approaches at phase 2 and those at phases 2 and 3. Because many cell and gene therapy products are unlikely to enter classical phase 1 safety studies, assessments need to be made based on patient numbers and associated risks, including those incurred by compassionate use. ‘The guidelines also recognize various organizational structures and capabilities with different levels of compliance for early phase studies: + Large pharmaceutical/ biotechnology companies that are likely to take products through to in-market supply -art-up organizations that will develop products to phase 1-2 and then transfer them to, or partner with larger organizations + Universities and grant-fanded bodies performing small trials for scientific publications To date, many gene therapy studies have been sponsored by university and hospital-based groups, but this is rapidly changing, [vaiog or iyophiatin to prose ardgsbstance It is therefore challenging to identify meaningful critical quality attributes for plasmids used for generating viral vectors. Clearly, this is going tobe ‘CRUCIAL going forward as manufacturing processes are developed to meet future potential needs. Lines are blurring as large pharmaceutical and well-funded start-up companies work alongside academic groups in early clinical evaluations. The approach to quality systems needs to be risk based and requires an understanding of the nature of the starting material, the manufacturing processes behind it, and the intended use of the product, In the case of plasmid DNA, manufacturing is invariably outsourced to specialist manufacturers using in-house platform processes. In such circumstances, limited (if any) development studies of the specific plasmid vector production are performed up front. Instead, sponsors rely on the knowledge and understanding the manufacturer has of its own production platform rather than knowledge gained for « specific plasmid product. Ie is apparent that, to date, the selection of suppliers is based as much on cost and availability as it is on risk. [Manuracturine Processes From a technic manufacturing processes used for the production of clinical-geade plasmid DNA are fairly similar (Figure 3) Plasmids and Cell Banks: Although regulators identify a cell bank as the starting point ofa GMP envelope, in terms of absolute starting points for plasmid DNA, an initial plasmid constructs used to generate ‘manofacturing cell banks. ‘The identity, integrity, and stability of the plasmid DNA is critical to the future ofa product and provide the foundation ofthe process used to manuficturean intended viral vector and achieve the intended therapeutic ben Usually the plasmid backbone is the starting material provided to DNA producers. Those plasmids themselves are generated in-house by the drug developers who transform them into K12-based E. ca production strains. From the initial work, clones are selected before fairly basic assessments and ahead of cell-bank generation. One requirement of the ICH QSD guidelines (11) on cell banks is to demonstrate plasmid stability — with regard to plasmid loss, segregational loss, and rearrangement — for extended generations under process conditions. Such events are not unheard of with viral vectors and may require reengineering the plasmids. When assessing plasmid constructs and cell banks specific to “principles of GMP,” you can find a number of FDA and EMEA guidelines on the requirements for their construction, manufacturing, and testing (6). Guidelines include recommendations on the usc of antibiotic marker genes such as avoiding the use of ampicillin; concerns have been raised by both the FDA and EMEA expressing an overall preference for antibiotic-free systems (7-5). Although some developers choose not to generate fally tested GMP cell banks for& CellGenix preclinical CMP ea al trials phase 1/11 IL From Research to ATMP Your Dedicated Partner in Cell Therapy eer Rune ese) SR Rea commercialization. Use the same product with tailored ADCF/serum-free policy, stability tests, proven batch to Pros a ene Mum uc emer TG aN eS * Comprehensive documentation FDA Drug Master Files, data sheets, CoA, on-site audits OTe ulm C ea cme aa Cee Pe ee eee oeearly clinical phases, the implications of needing to change cell banks must be considered as do approaches for generating GMP cell banks to support later stage clinical trials using existing research cell banks (7). Fermentation and Downst Purification: Fermentation processes, tend to be fairly similar and usually run in fed-batch mode. They ate likely to be antibiotic free and follow the industry practice of using chemically defined media, especially for later phase and large- seale processes. The cell paste generated from fermentation is harvested and the plasmid extracted from the cell paste by a process of alkaline lysis. This tends to be where process differences lie, with manufacturers using proprietary cell lysis technologies to extract plasmid DNA. Precisely how different approaches affect the quality and functionality of a product is difficult to assess and not reported in scientific literature Purification processes are usually a combination of ion-exchange (IEX) and hydrophobic- chromatography (IIIC) steps, and in some eases include gel- permeation (size-exclusion) chromatography as well. These processes use IEX to remove the endotoxin and residual RNA, and HIC to remove host DNA and critically separate out open- and closed-circle plasmid forms Processes also may inclu precipitation steps to remove host RNA levels. Analytical Testing and Specifications: Currently most drug development companies base their specifications on the FDA 2007 guidelines for injectable DNA vaccines (1) (see the FDA Guidelines box) although the expectation for closed-circle DNA level is usually 90% supercoiled rather than 80% as cited, Although analytical procedures do vary, fairly standard approaches are taken with regard to measuring residuals Different approaches are taken to the quantification of plasmid forms, with some groups favoring HPLC. based procedures and others preferring CE-based methods. ‘The one area that is not covered in those guidelines is measurement of potency and functionality. Although plasmid supercoiled levels often are seen as a surrogate measure of plasmid functionality and stability and of transfectability with regard to production of viral consistently supports this link. Tt is therefore challenging to identify meaningful critical quality attributes for plasmids used for generating viral vectors. Clearly, this is going to be crucial going forward as manufacturing processes are developed to meet future potential needs. Similarly, we also need to identify those attributes that are less critical Future POTENTIAL MANUFACTURING APPROACHES Understanding critical quali attributes is going to be increasingly important. The need for changes in plasmid production processes and scales increases as manufacturers seek to identify approaches that achieve the required manufacturing scales and process flexibilities while also achieving acceptable levels of cost of goods (CoG). For example, the current expectation is for material to be purified to the specifications for injectable products with regard to residual contaminants. This is contrary to the approach some companies are taking to lentivirus production for which only limited purification is performed to remove levels of host contaminants — justified by robust demonstration of clearance in the cell therapy product. Can similar approaches be taken for plasmid DNA to allow for simplification of purification processes? We also need to look at the design of manufacturing facilities. Do we need to produce these products in high-grade cleanrooms, or can much of the produetion be performed in lower classification suites relying on closed-system approaches, whether it be through fixed or single-use facilities? In terms of quality systems, we ‘may also want to look at aspects of process validation. If plasmi generated using platform-based approaches, including cleaning validation and the risk-assessment regarding extractable and leachables for single-use systems, can we validate the platform for production of multiple rather than single products? Looking further ahead, we consider alternative approaches to plasmid manufacturing. Syntheti manufacturing processes that are used to make smaller DNA fragments —such as those developed by Touchlight (www.touchlight. com) with its Doggybone DNA (€bDNA) platform — may be used to generate viral vectors, In very early stage development, they could potentially simplify manufacturing processes. This also suggests that such small DNA fragments might be regarded as chemical (rather than biological entities) that can be fully characterized. ‘Suppty CHains, Supply-chain management will be increasingly critical to support the potential requirement for manufacturing two to four plasmids for each viral vector and for each therapy going into trials and for in-market products. Also, with nearly all plasmid DNA manufacturing being outsourced to specialist manufacturers and CMOs, it is going to be incumbent oon drug developers to seek long-term solutions with such suppliers to plan for future market needs. This includes identifying appropriate risk-based ‘manufacturing approaches and supporting both the development of and investment into required capability and manufacturing capacity. It also will require flexible approaches that are not necessarily fixed upon any single platform, especially for in-market produets, to ensure supply integrity. The future may well hold alternativeapproaches to meeting plasmid requirements, allowing reduction in CoG. BRINGING Promises To REALITY ‘We are in very interesting times with the increasing emergence of _gene and cell therapy products. As companies seek to take them to market, manufacturing challenges are being identified and solutions sought. Itis clear that we need to reawaken industry investment in plasmid production platforms, including novel approaches. Additionally, greater clarity is required for the quality systems in place to support and direct the investments and developments required to accelerate production of these life-changing new therapies. REFERENCES 1 Roots mabiz. Gone Therapy Marie 2015-2025; woww.sootsasalyss com/eepotal view documentgene-therspy= sarker-2015-2025/85 he. 2 Bylath A, etal, PDA Tecical Report No. 56 Appheatn of Phase Appropriate Quality Syrtemt and COMP tote Development of Therapenti Pratin Drug Substance, wor. pafbookstore com, 3. European Medicines Agency, (Commitee for Medicinal Produce for Homan Use. Gude om Development and Manafcare of Lemicval Vators (CUMP/BWP/2858/03), wwwemsearops.eufocs/en_GBMocument rary/Scentie guideline! 2009/10/ '500005984-p “4. European Medicines Agency. Quai, [Non-Clinical and Chal pet of Gene Therapy Motcnal Produss (Draft Guideline, EMAJCAT/80183/2014); wwwema europe.cu/ Aoexlen, GBidocument brany/Scientifc suldeline/2015/05/WCS00187020 pa. 5) Medicines and Healtheare Products Regulatory Agency. Rus and Guidance for Pharmaccatiel Manufacturers and Distribtort, (Grange Guide, 2015): hep harps con/produet/9 780857117157 onangeguide 6 Inecnatonal Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Haman Use. Quay of Bisebneogal Prodacte dbs ofthe Expresion Contract in Cl Used for Production sf R-DNA Derived Protin Products (CPMP/ICH/139/95), Noverser 1995; ww. ‘chorg/Aleadmin/Public Web. Sie/ICH_ Product/Gsideline/uslity/Q5B/Step/ (Q5B Guideline pa? 7 US Food and Drug Administration, Gaiden for FDA Recker and Sponsors Contnt and Review of Chemistry, Mansfistaring, and Contrl (CMC) Informaticn for Haran we Somatic Ql Therapy Investigational New Drag Applications (IND, Spit 2008; wow gow! dovnload BiologisBloodViccines! GuidanceComplianceRegultorylotormtion! Guidances/Xenotrnsplantationuem092705. pe, 8 US Food and Deug Administration, CBER. Guidens for Industry: Guidance for Human Somatic Cell Therapy and Gene Tera, March 1998; wwe gnidownlouds! BiologiceBloodVsccines! GuidanceComplianceRegulatorylnorration/ (Guidances/CellaarandGene herapy! ucrn0 81670 ph 9 European Medicines Ageney, Commitee for Proprietary Mesicnal Product, Nuts fr Guidance an the Quality, Prcnical and (Chnal Aspect of Gene Trnfor Medicina Produces, Apxl 2001(CPMP/BW P/3088/99} worwemsearops-euflocsvenGBldocument [hyary/Sclentific- guideline/2009/10/ wcs00003987 pd 10 US Food and Drug Administration, (GuieneforTndasry: Considerations for Plasmid [DNA Vacines for Infetions Disease Indication, November 2007; wwwema.curops.culdocslen_ GBidocument_library/Scientifi suldeine/2009/10/WCS00003987 pd. 11 ternational Conference on Harmonisation of Technical Requirements fo Registration of Pharmaceuticals for Human Use. QSD: Quali of iorchmalegeal Product Derivation and Characterisation of Cll Substrates Used fr Production of Biotechnical Bieogical Produce (CPMPIICH/294/95), March 1998; wren emacuropa euAloclen_GBMocument_ [bary/Scentifie-guideline/200%/09/ WCS0000280 pd Supronrina Documents Tovrea Metis Agee Cuiencon uaty, Non Cina an Chal ef Mca Pru Conenng Gt Madpe Gts Chior 6 e200, Api 2012 wows susp sudnsen GB? decane tary fridele 201208 WCSC036896 pat uooean Mens Agency. afin apron Gi, Nom Cha ond Chr Teas Relating pee eesti fe ‘esate Va Fes (CLINY GrWHise7807) Jane 200; wens turpeclioelen.Chiecunent lone Scena idle 2010077000945. ue Tony Hitchcock is technical director, Cobra Biologics, Stephenson Building, Keele Science Park Keele ST5 SSP UK; Tory. Hitcheock@cobrabio.com. Continued from page 11 ng Life Se 113) 2016) 244-53; dos10.1002/ ‘lee. 201400027. 7 Harnpion B. The Cost of Success Keeping Cost of Goods in Check for Patient- Specific Cel Therapies. Le Sei, Leader 12 ‘ay 2016; wwrlifexcienclesdercom/docthe- cont of success keeping cost of goods-in- checkfor-ptien-specii-cll-therapies-0001 8 Brindley DA, et al. Peak Serus: Implications of Serum Supply for Cell Therapy Mansfacturing. Regen Med. 70) 2012): 735, boit0.2217hme 11112 9 Stone E, Technological Advances Facilitate Autologous Cell Therapy Seale-Out Gen Brg Bitcinc News 25 August 2015; www gecengnews com/insighe-and- ‘neelligenceechnologial-advancee-fucilitate- sutlogour-cell-therpy-scle-out/77900S12, 10 Kamani NR, Kumar U, Standardizing Practices for Cellular Therapy Manufcturing BiaPharm Int 271) 2014; www. ‘opharminterationalcom/standardsing- prcties-celllartherspp-manfectuing. 11. Bauer I, SpichigerS,Spichiger-Kellr UE. Novel ingle-Use Sensors for Online Messurement of Glucose. BiaPrces In. 10(9) 2012: 56-60; wow presens de/hileedein/ se. ‘pload/producta Prew/2012_09 BPI Novel- Single Use-Sensore for Online- Measurement oF Glucose Bsucepde 12 Logan D. Te intradution of the Futur Bismatt Monto for Monitoring Concenionat and Dispesabe Bloeatr, Abe lesteurente ‘Aberystwyth, UK, July 2010; www. IUbiosystems deleadmin/Prodokt- PDFW197 her frara_biomass_monitor_ ju20%0 pale 18 Koystermans Darrin, Avesh M, AL-Rubeai M. Online Flow Cytometry for “Monitoring Apoptoris in Mammalian Cell Cultures Asan Application for Process Aaalytical Technology. Cyttechnel, 68(3) 2016 599-408; doi0.1007/10616-014-9791-3. 14 Hemander R. Modlar Manact Plaiosns fr Biologics. BisPharm I 28(5) 2015. @ ne David Orchard-Webb, PhO, isa bioscience consultant curently serving as a research assistant for Professor Amine Kamen in the Department of Bioengineering at ‘McGill University in Montreal, Quebec, Canada; biosciresourcesegmailcom: ups: /eioscirecom. For reprints, contact Rhonda Brown of Foster | Pring Serica, rhondabefesterprinangcom, "866 8793144188 For reprints, contact Rhonda Brown of Foster Printeg Service thondabotesterpriningcom, ase areata x94. conn 2016 a BlaProcessinterntional 19