Cell and Gene Therapy GMP Manufacturing in the UK

Cell and Gene Therapy GMPManufacturing in the UK:Capability and Capacity Analysis August 2015

Contents1 Executive summary ........................................................................................................................ 62 Introduction and methodology ...................................................................................................... 83 Glossary of terms ............................................................................................................................ 94 High level summary of data .......................................................................................................... 10UK GMP cell therapy manufacture ....................................................................................... 104.1.1 High level summary........................................................................................................ 104.1.2 Classification of clean rooms ......................................................................................... 104.1.3 Summary of track record and experience ...................................................................... 12UK Gene Therapy Manufacture ............................................................................................. 144.2.1 High level summary........................................................................................................ 144.2.2 Summary of track record and experience ...................................................................... 15Geographic locations of cell therapy and gene therapy facilities ......................................... 175 Future Capacity and Expansion .................................................................................................... 18Expansion and transfer of existing sites ............................................................................... 18New sites ................................................................................................................................ 18Large-scale commercial supply capacity ............................................................................... 186 Manufacturing Organisations ...................................................................................................... 20Cancer Research UK Biotherapeutics Development Unit ................................................... 206.1.1 Details ............................................................................................................................ 206.1.2 Facility ............................................................................................................................ 206.1.3 Licence ............................................................................................................................ 216.1.4 Track record and experience .......................................................................................... 216.1.5 Personnel ....................................................................................................................... 226.1.6 Capacity .......................................................................................................................... 23Cellular Therapeutics Ltd (CTL)........................................................................................... 246.2.1 Details ............................................................................................................................ 246.2.2 Facility ............................................................................................................................ 246.2.3 Licence ........................................................................................................................... 256.2.4 Track record and experience ......................................................................................... 256.2.5 Personnel ....................................................................................................................... 256.2.6 Capacity .......................................................................................................................... 26Biomedical Research Centres (BRC) Clinical Research Facility (CRF) GMP Unit at Guy’sand St Thomas’ .................................................................................................................................. 276.3.1 Details ............................................................................................................................. 276.3.2 Facility ............................................................................................................................. 276.3.3 Licence ........................................................................................................................... 286.3.4 Track record and experience ......................................................................................... 286.3.5 Personnel ....................................................................................................................... 286.3.6 Capacity .......................................................................................................................... 29Imperial College London, John Goldman Centre for Cellular Therapy .............................. 306.4.1 Details ............................................................................................................................ 302

6.4.2 Facility ............................................................................................................................ 306.4.3 Licence ............................................................................................................................ 316.4.4 Track record and experience .......................................................................................... 316.4.5 Personnel ........................................................................................................................ 316.4.6 Capacity .......................................................................................................................... 32Rayne Cell Therapy Suite (RCTS) and The Wellcome Trust / BRC Clinical ResearchFacility and Cell Therapy Unit (CTU) at King’s College London .................................................... 336.5.1 Details ............................................................................................................................ 336.5.2 Facility ............................................................................................................................ 336.5.3 Licence ........................................................................................................................... 346.5.4 Track record and experience ......................................................................................... 346.5.5 Personnel ....................................................................................................................... 356.5.6 Capacity .......................................................................................................................... 36NHS Blood and Transplant (NHSBT)................................................................................... 376.6.1 Details ............................................................................................................................. 376.6.2 Facilities at Speke .......................................................................................................... 386.6.3 Licence ........................................................................................................................... 396.6.4 Track record and experience ......................................................................................... 396.6.5 Personnel ....................................................................................................................... 406.6.6 Capacity .......................................................................................................................... 406.6.7 Facilities at the Clinical Biotechnology Centre, Langford ............................................. 416.6.8 Licence ........................................................................................................................... 436.6.9 Track record and experience ......................................................................................... 436.6.10 Personnel ....................................................................................................................... 436.6.11 Capacity .......................................................................................................................... 43Roslin Cells Cellular Therapy Facility (Scottish Centre for Regenerative Medicine) ......... 446.7.1 Details ............................................................................................................................ 446.7.2 Facilities at Roslin Cells ................................................................................................ 446.7.3 Licence ........................................................................................................................... 466.7.4 Track record and Experience ........................................................................................ 466.7.5 Personnel ........................................................................................................................ 476.7.6 Capacity .......................................................................................................................... 48Scottish National Blood Transfusion Service (SNBTS) Cellular Therapy Facility (ScottishCentre for Regenerative Medicine) .................................................................................................. 496.8.1 Details ............................................................................................................................ 496.8.2 Facilities at SNBTS ........................................................................................................ 496.8.3 Licence ........................................................................................................................... 506.8.4 Track record and experience ......................................................................................... 506.8.5 Personnel ....................................................................................................................... 506.8.6 Capacity ........................................................................................................................... 51Cellular Therapies, Great Ormond Street Hospital ............................................................. 523

6.9.1 Details ............................................................................................................................ 526.9.2 Facility ............................................................................................................................ 526.9.3 Licence ........................................................................................................................... 536.9.4 Track record and experience ......................................................................................... 536.9.5 Personnel ....................................................................................................................... 546.9.6 Capacity .......................................................................................................................... 54Moorfields Eye Hospital, Cells for Sight Cell Research Unit ................................................ 556.10.1 Details ............................................................................................................................. 556.10.2 Facility ............................................................................................................................. 556.10.3 Licence ........................................................................................................................... 566.10.4 Track record and experience ......................................................................................... 566.10.5 Personnel ....................................................................................................................... 566.10.6 Capacity .......................................................................................................................... 56Newcastle Biomedicine Cellular Therapy Facility ................................................................ 576.11.1 Details ............................................................................................................................ 576.11.2 Facility ............................................................................................................................. 576.11.3 Licence ........................................................................................................................... 586.11.4 Track record and experience ......................................................................................... 586.11.5 Personnel ....................................................................................................................... 586.11.6 Capacity .......................................................................................................................... 59University of Oxford Clinical BioManufacturing Facility .................................................... 606.12.1 Details ........................................................................................................................... 606.12.2 Facility ............................................................................................................................ 606.12.3 Licence ............................................................................................................................ 616.12.4 Track record and experience .......................................................................................... 616.12.5 Personnel ........................................................................................................................ 616.12.6 Capacity .......................................................................................................................... 62Royal Free Hospital London, Centre for Cell and Gene Tissue Therapeutics .................... 636.13.1 Details ............................................................................................................................ 636.13.2 Facility ............................................................................................................................ 636.13.3 Licence ........................................................................................................................... 646.13.4 Track record and experience ......................................................................................... 646.13.5 Personnel ....................................................................................................................... 666.13.6 Capacity .......................................................................................................................... 66University of Birmingham, Cell Therapy Suite ..................................................................... 676.14.1 Details .......................................... 676.14.2 Facility ............................................................................................................................. 676.14.3 Licence ............................................................................................................................ 676.14.4 Track record and experience ......................................................................................... 686.14.5 Personnel ....................................................................................................................... 684

6.14.6 Capacity .......................................................................................................................... 68Cobra Biologics ..................................................................................................................... 706.15.1 Details ............................................................................................................................ 706.15.2 Facilities at Cobra Keele & Matfors .............................................................................. 706.15.3 Licence ............................................................................................................................ 716.15.4 Track record and experience .......................................................................................... 716.15.5 Personnel ........................................................................................................................ 726.15.6 Capacity ........................................................................................................................... 73Oxford BioMedica .................................................................................................................. 746.16.1 Details ............................................................................................................................. 746.16.2 Facilities at Oxford BioMedica ....................................................................................... 746.16.3 Licence ............................................................................................................................ 756.16.4 Track record and experience .......................................................................................... 756.16.5 Personnel ........................................................................................................................ 766.16.6 Capacity ........................................................................................................................... 767 Conclusions .................................................................................................................................... 775

1 Executive summaryAs recommended in the House of Lords 2013-14 Regenerative Medicine report, the Cell TherapyCatapult continues to review the status of MHRA MIA(IMP) licenced GMP manufacturing in the UKand publish on an annual basis. The first report was published in 2014. The review collectedevidenced-based information to provide an overall picture on the capability and capacity of MHRAlicencedcell therapy manufacture within the UK.The 13 MHRA-licenced facilities with cell therapy capacity analysed in the original 2014 report wereincluded in this update. In addition to these facilities, two additional cell therapy centres were addedto the list; the University of Birmingham, Cell Therapy Suite was a new facility, opening for 2015; theCCGTT centre at the Royal Free Hospital was in the process of an expansion project during the firstsurvey so was not listed, however the expansion is now complete so the facility was included in thisannual review. The addition of the Royal Free Hospital and the University of Birmingham to thisreview increased the number of facilities to 15, and was accompanied by a 16% growth in the numberof cleanrooms used for cell therapy manufacture.Additional insight into gene therapy production capability and capacity in the UK was also providedin the 2015 review. Both in vivo and ex vivo modification of cells currently requires the use of viralvectors and plasmid DNA, the supply of which is intrinsically linked to the success of cell therapies.This is especially pertinent to the current transduced immune cell therapies. Facilities previouslyassessed for cell therapy manufacture were further reviewed for their multifunctional gene therapycapabilities. Furthermore, MHRA-licenced facilities dedicated to the manufacture of gene therapieswere also taken into account, namely Cobra Biologics, Oxford Biomedica and NHSBT CBC Langford,increasing the overall number of centres assessed in the review to 18.A list categorising all the facilities analysed in this review can be found below, new additions for the2015 review are shown in bold:MHRA-licenced cell therapy manufacturers Cellular Therapeutics Ltd Guy’s & St Thomas’ Hospital, GMP Facility Imperial College London, John Goldman Centre for Cellular Therapy NHSBT – Speke Scottish Centre for Regenerative Medicine (Roslin Cells and SNBTS) University College London, Great Ormond Street Hospital Cellular Therapy Laboratories Moorfields Eye Hospital, Institute of Ophthalmology, Cells for Sight ATMP ManufacturingUnit Intercytex Ltd, Manchester (University of Manchester) University of Newcastle Biomanufacturing Facility Royal Free Hospital, CCGTT University of Birmingham, Cell Therapy SuiteMHRA-licenced multifunctional cell and gene therapy manufacturers University of Oxford, Clinical Biomanufacturing Facility Kings College London, Rayne Cell Therapy Suite 1 King’s College London Cell Therapy Unit, Clinical Research Facility 1 Cancer Research UK, Biotherapeutics Development UnitMHRA-licenced gene therapy manufacturers NHSBT – CBC Langford Cobra Biologics, Keele Oxford Biomedica, Oxford1 Combined for analysis in section 4 of this review6

Analysis of the technical capability of these facilities is very positive, showing that the UKmanufacturing sector covers the sphere of current cell and gene therapy manufacturingrequirements. Most of the facilities specialising in cell therapy manufacture are located in the NHSor UK academia. Cellular Therapeutics is a commercial organisation and Roslin Cells is a not forprofit commercial organisation offering contract manufacturing services. Intercytex Ltd is also acommercial organisation, but is currently in the process of transferring the IMP and specials licencesfor the manufacturing facility to the University of Manchester. The majority of these facilities havebeen established to enable the translation of academic research into clinical trials. This shows thatthe UK has a strong manufacturing base to facilitate the translation of early phase research into theclinic.Available cell therapy manufacturing capacity, which can be contracted out externally or utilised forinternal projects, decreased on average from 45% in 2014 to 26% in 2015 at the facilities. Thisstrongly highlights the increases in the number of cell therapies entering clinical translation and therequirement for GMP manufacture as a result. The implication of this data is that GMPmanufacturing capacity will need to continue to expand in line with clinical trial growth.The number of staff working in cell therapy manufacture within these MHRA-licenced facilities hasshown a strong increase over the year. The total number of staff working in the listed cell therapyfacilities has increased from 111 personnel to 157 from 2014 to 2015. The 46 additional positionsreported comprise 31 newly created posts and 15 existing positions at the CCGTC, Royal FreeHospital which were not included in the 2014 review. This represents a 25% increase in the numberof full time roles since April 2014. The rise in full time employment is reflected by a small decreasein part time roles.In contrast to cell therapy production, the manufacture of viral vectors and plasmid DNA for genemodification processes is driven by commercial organisations to a greater extent, including CobraBiologics and Oxford Biomedica. The workforce for these two dedicated commercial gene therapyfacilities alone is 158. There is also a well-respected gene therapy production network present in UKacademia and the NHS, further strengthening the health of the burgeoning industry. The four keyfacilities at King’s College London (RCTS and CTU), University of Oxford and Cancer Research UKcan also deploy an additional 54 people within their flexible cell and gene therapy manufacturingfacilities. In addition, NHSBT CBC Langford has 9 people dedicated to GMP plasmid supply alone.Overall the number of personnel employed across the cell and gene therapy manufacturers listed inthis review totals 324, with 103 positions dedicated to cell therapy facilities; 167 posts assigned togene therapy centres and 54 roles positioned within multifunctional cell and gene therapy facilities.The large-scale manufacturing centre that will be built and run by the Cell Therapy Catapult has notbeen included in this analysis. The funding for this facility was announced in the 2014 budget andthe plan is for it to be operational in 2017. This 7200m 2 manufacturing centre will provide a stepchange in large-scale and commercial cell and gene therapy manufacturing capability for the UK andcomplement the existing early phase network. This will complete the translational landscape in theUK allowing therapies to move from basic research, into the clinic and finally to commercialproduction.The combination of world leading research, the network of early phase clinical manufacturingcentres, substantial commercial gene therapy capacity and the large-scale Cell Therapy Catapultmanufacturing centre mean that the UK is well positioned within the global cell and gene therapyindustry. This situation will allow the growth of the industry within the UK and also the attraction ofinward investment.7

2 Introduction and methodologyThe Cell Therapy Catapult was established in 2012 as an independent centre of excellence to advancethe growth of the UK cell and gene therapy industry, by bridging the gap between scientific researchand full-scale commercialisation. The Cell Therapy Catapult works with Innovate UK.A key component is to ensure that the UK has a strong and competitive manufacturing base for celland gene therapies. With this in mind, the Cell Therapy Catapult performed a review of the currentcapacity and capability of this manufacturing base within the UK in April 2013. A report based onthe review was published in April 2014 and was subject to annual review in April 2015 as requestedin the House of Lords 2013-2014 Regenerative Medicine report.The aim of the report was to collect and summarise information on each of the MHRA-licencedmanufacturing sites in the UK with current spare GMP capacity. This overview comprises thetechnical and quality capabilities of each of these facilities as well as their spare capacity. Forexample:What types of cell and/or viral vector/plasmid DNA manufacturing processes does the sitehave experience with?What types of processing equipment does each site have available?What grade of clean rooms, MBSC and isolator technology does the site have?What Licences does the site have?How many different suites of clean rooms does the site have?How many staff does the site employ and what is the distribution between production, QCand QA?How many parallel projects and products can the site deal with?To conduct the 2015 annual review, all facilities listed in the 2014 report were contacted in March2015 and asked for updates with regards to their capability and capacity. In addition adverts werecommunicated via the Cell Therapy Catapult website and social media to gather information on anynew facilities with GMP cell therapy and/or gene therapy capability. A summary of the changes madeto the facility listings since April 2014 are documented in Table 1, including the addition of 2 newcell therapy and 2 new gene therapy sites.Table 1 Changes to facility listings for the 2015 UK GMP Manufacturing Capabilityand Capacity ReportOrganisation/facility nameContact name(s)New listing1Royal Free Hospital London, Centre for Cell and Gene Mark Lowdell andTissue Therapeutics (CCGTT)Owen Bain2 University of Birmingham, Cell Therapy Suite (CTS)Jane Steele andPhil Newsome3 Cobra Biologics, Keele Phil Ridley-Smith4 Oxford Biomedica James MiskinUndertransition1Intercytex Ltd – currently transferring MIA(IMP) andspecials licences to University of ManchesterPaul Kemp andJoan Benson8

3 Glossary of termsAAV – Adeno-associated virusCMO – Contract Manufacturing OrganisationCoG – Cost of GoodsHTA – Human Tissue AuthorityIMP – Investigational Medicinal ProductGMO – Genetically Modified OrganismGMP – Good Manufacturing PracticeMBSC – Microbiological Safety CabinetMHRA – Medicines and Healthcare Products Regulatory AgencyMIA(IMP) – MHRA manufacturing authorisation licence for Investigation MedicinalProductsQA – Quality AssuranceQC – Quality ControlAuto – Autologous, patient is treated with their own cells (i.e. each patient requires their ownproduct)Allo – Allogeneic, all patients are treated with cells derived from one donor (i.e. one productfor all patients)PE – Previous experience; meaning that key staff have experience in a particular techniqueor cell therapy manufacturing process but not at their current organisation.9

Table 3 Classification of clean roomsGrade of cleanroomGrade B Grade C Grade DIsolators withina classified areaNumberroomsof34 15 16 2211

UK Gene Therapy Manufacture4.2.1 High level summary4.2.1.1 Dedicated gene therapy production facilitiesA more detailed insight into the UK’s current capability and capacity for gene therapy, in addition tocell therapy manufacture, is presented in this annual review. MHRA-licenced biotechnology facilitiesspecialised in the manufacture of viral vectors and/or supporting plasmid DNA for in vivo and exvivo cell modification purposes have been included in the review. Both plasmid DNA and viralvectors can either be used as starting materials for further manufacture of gene modified therapiesor used directly as medicinal products. The organisations analysed were Cobra Biologics,manufacturers of both viral vector and plasmid DNA; Oxford Biomedica, specialists in viral vectorproduction; and NHSBT CBC Langford, plasmid DNA specialists. Summary data captured from thethree facilities are presented in Table 5. Facilities dedicated to the manufacture of gene therapies arepredominantly commercial organisations (Cobra Biologics and Oxford Biomedica). The nature of theorganisations supporting gene therapy manufacture is reflected by the high number of personnelemployed within the sector, with 158 staff employed across the 2 commercial organisations alone.This contrasts with the cell therapy sector, which is primarily located within UK academia and theNHS and employs 157 personnel across 14 facilities.Table 5 Summary data from dedicated gene therapy production facilities2015No. of facilities 3Manufacturing18cleanroomsFull time staff 1674.2.1.2 Multifunctional gene and cell therapy production facilitiesOf the facilities analysed in section 4.1.1 for cell therapy manufacture, 4 are multifunctional centreswith cell and gene therapy production capabilities. Summary data from the 4 facilities; CancerResearch UK, King’s College London RCTS, King’s College CTU and University of Oxford CBF areshown in Table 6. These facilities offer additional resources which can be deployed to gene therapyproduction and further strengthen the UK gene therapy industry. See sections 6.1, 6.5 and 6.12 ofthis report for more detailed information on these multifunctional facilities respectively. N.b King’sCollege RCTS and King’s College CTU are combined for analysis throughout this review and jointlydescribed within section 6.5.Table 6 Summary data from multifunctional gene and cell therapy productionfacilities2015No. of facilities 4Manufacturing23cleanroomsFull time staff 5414

4.2.2 Summary of track record and experienceFigure 2 shows a breakdown of the types of gene therapies and cell culture systems that the facilitieswith gene therapy capabilities are experienced in (includes dedicated and multifunctional genetherapy facilities). Analysis of the technical capability of these facilities is very encouraging. Themanufacture of GMP-grade lentivirus and gamma-retrovirus, two of the main viral vectors used incurrent ex vivo gene modification processes, are supported by a number of the facilities listed. Otherkey viral vectors: adenovirus, AAV, and the manufacture of supporting plasmid DNA are alsocovered.Figure 2 Gene therapy facility process experienceSummary of track record forUK manufacturing sitesPlasmid DNAAdeno‐virusGamma Retro‐virusLenti‐virusAAVAdherentSuspension0 1 2 3 4 5 6Number of sitesKey: Plasmid DNA – material used directly as IMPs and/or starting material used for transient infection to enable manufacture of viralvectors; Adenovirus/Gamma Retrovirus/Lentivirus/Adeno-associated virus (AAV) – key types of viral vectors used directly as IMPsand/or starting material used for transduction of cells ex vivo; Adherent – culture of anchorage dependent cells; Suspension – culture ofanchorage independent cells.Table 7 shows a summary of the capability and availability at all the gene therapy production centres.A number of the facilities have spare capacity for 2015 and beyond. In addition Oxford Biomedicaare currently undergoing an extensive expansion project, which will more than double processingspace at the site and further benefit prospective growth within the UK gene therapy sector.The opening of the UK Cell Therapy manufacturing centre in 2017 will further enhance the existingviral vector manufacturing network and facilitate the large scale manufacture and initial commercialsupply of gene therapies.15

Table 7 GMP Gene Therapy capability and availability summary at UK organisationsOrganisationCancer ResearchUKKings CollegeLondon, RCTS andCRFNHSBT – CBCLangfordParallelproductsSuspension Adherent AAVCapabilityLentivirusPlasmidDNAGammaretrovirusAdenovirusAvailability20151 0%4 30%2 40%Oxford Clinical BMF DoP 0%Cobra Biologics DoP 20%UnderOxford Biomedica DoP PEExpansionKey: DoP – dependent on process; PE – previous experience16

Geographic locations of cell therapy and gene therapy facilitiesThe map shown in Figure 3 highlights a diverse geographical spread of sites across the UK with aclear cluster around the Greater London area (6 facilities). Facilities specialising in cell therapymanufacture are shown by red markers; gene therapy manufacture by blue markers and both celland gene therapy manufacture by purple markers.Figure 3 Map showing locations of MHRA licenced cell and gene therapymanufacturing sites within the UKMap data ©2015 GeoBasis-DE/BKG (©2009), Google17

5 Future Capacity and ExpansionAnnual reviews of the data are important in order to identify facility expansions, increase in trackrecords and the opening of new facilities. They act as an annual stock-take of regenerative medicinemanufacturing capacity in the UK, as recommended by the House of Lords in the 2013-2014Regenerative Medicine report. The additional analysis of gene therapy facilities shall also continuein future reports.As a forward looking statement the following description of potential expansions of existing facilitiesor new sites has been drafted.Expansion and transfer of existing sitesWhen reviewed in 2015, Cellular Therapies at Great Ormond Street was operating close to maximumcapacity but has plans to expand in the future. This expansion will add significantly to the capacityat the centre and is due to be completed in 2018.Oxford Biomedica is currently undergoing an extensive expansion project and aim to more thandouble processing space at the facility by Q3 2015.As previously mentioned in section 4.1.1, the Intercytex Ltd facility has not been included in the 2015annual review data due to the movement of their CMO operations to University of Manchesterincluding the transfer of their MIA(IMP) and specials licences. An update of which will be providedin the 2016 annual review.New sitesNHSBT currently have one site Licenced to manufacture IMP cell therapies at Speke. Twoadditional sites in Birmingham and Filton (Bristol) are in the process of obtaining licences for celltherapy manufacture (IMP), further details will be provided when available in the 2016 review.To our knowledge no other new MHRA-licenced cell or gene therapy manufacturing sites are due tocome online in 2015/2016, however please contact gmp@ct.catapult.org.uk if you have anyinformation regarding new facilities that we are currently not aware of.Large-scale commercial supply capacityOne of the barriers to the growth of the cell therapy industry is the ability to grow cells reliably atscale. During 2013, the Cell Therapy Catapult, identified the lack of large-scale facilities as one ofthose obstacles to the translation of research into commercially viable products. The UK is stronglypositioned for early clinical phase manufacturing and the large scale capacity centre will help ingrowing a UK based global industry.In 2013, The House of Lords Science and Technology Committee, recommended the building ofmanufacturing facilities to support the scale-up of treatments in mid-to-late stage of development.The UK Government committed up to £55m to the creation of a world-leading manufacturing facilityin March 2014 to meet this business need.After a rigorous criteria-led selection process, Stevenage Bioscience Catalyst, was chosen as thelocation as it met all the essential criteria that included excellent UK and international logistics forshort-life medical products, available workforce and value for money.The manufacturing centre, which will be managed by the Cell Therapy Catapult and is due to openin 2017, will be used by companies for the manufacture of late phase clinical trial and initialcommercial supply of advanced therapeutic medicinal products including cell and gene therapies.The manufacturing centre is a unique global business proposition based in the UK that will providenational and international developers with a stepping-stone into the EU, US and other growinginternational markets. It will:18

Enable the growth of organisations by reducing/spreading the costs and risks of establishingand running a specialist manufacturing facility;Provide approx. 7200m 2 of space that will enable up to 12 firms to simultaneously, butseparately, manufacture different therapies within a secure, compliant facility, developed inclose relationship with the medicines regulator;The space will be used as a series of segregated modules, operating at Grade B downgradeableto D;The centre will also have warehousing, dispatch and QC facilities;Allow firms to make their products for pivotal clinical trials leading to further investment inUK manufacturing;Allow consistent and reliable transport of products into the EU within 24hrs, from a locationwith an established, cost effective pharmaceutical manufacturing workforce;Accelerate global expansion opportunities by reducing their cost and increasing speed ofexpansion using a flexible, replicable clean room design; andAccommodate multiple processing methodologies, including viral vectors, stem cells andtissue engineering within the same facility.The benefits to the UK include: Creation of up to 150 jobs directly and many more additional roles in the cluster that developsaround it – delivering health and wealth to the UK;Attracting inward investment to the UK and help address barriers to domestic growth,enabling high-quality UK-based manufacturing export of cell therapy and related productsto the global market;Building on existing UK capability for Phase I and Phase II manufacturing, the centre is forUK and global companies that are looking to scale-up to large-scaleFurther enhancement of the UK as an attractive place for SME biotech and life sciencescompanies; andSeeding the creation of a world leading cell and gene therapy manufacturing cluster.19

6 Manufacturing OrganisationsCancer Research UK Biotherapeutics Development Unit6.1.1 DetailsAddressClare Hall Laboratories,Blanche Lane,South Mimms,Potters Bar,Hertfordshire EN6 3LDContact: Heike Lentfer heike.lentfer@cancer.org.ukTel: 01707 625700Web: http://www.cancerresearchuk.org/science/research/drugdevelopment/scientists/manufacturing-other-capabilities/biotherapeutics-development-unit/6.1.2 FacilityManufacturing suites Two segregated manufacturing suites each with grade C clean rooms for closed processingand a separate 6-glove isolator for aseptic filling. Grade B clean room operation possible for one of the suites HVAC is fully segregated between suites allowing multi-product manufacture. Areas are alldesigned for cat II containment.Cell culture processing and analytical equipment Various Class II MBSC and Laminar Air Flow Cabinets Static and Shaking Incubator with CO 2 control, some with humidity control AppliFlex Bioreactor 20L and 50L (disposable) Single-use Bioreactor (SUB Hyclone) 50L, 100L, 250L NucleoCounter, Vi-Cell for automated cell counting CubiAnalyzer for metabolite analysisOther processing equipment Millipore Mobius Disposable Mixer System Disposable TFF System AKTA Explorer, AKTA Pilot and AKTA Ready (Disposable) Chromatography ControllerSterile filling equipment Flexicon FP50 Filling Machine Two 6-Glove Isolators20

Analytical equipment UV/VIS Spectrophotometers Plate Readers (visible light only - can be upgraded to bioluminescence or fluorescence) HPLC FTIR TOC Analyzer Q-PCR FACS Stability Cabinets Sterility Test IsolatorPhotos showing the finish of the clean rooms can be seen in Figure 4.Figure 4 Example photos of CR UK BDU facility6.1.3 LicenceMHRA licence for IMPs has been granted, currently does not cover cell therapy products, but theintention is to apply for a license amendment in 2015 and add cell therapy products.The site does not have an HTA licence.6.1.4 Track record and experienceThe main experience to date has been with biologics production (recombinant proteins, DNA andviruses etc.). Adherent and suspension cell cultures have therefore been used for this purpose (CHO,A549, various Hybridoma cell lines). Staff are currently being trained in the process of handlinghuman embryonic stem cells and a manufacturing process will be transferred in 2015 for scale-upand qualification. A summary of staff experience can be found in Table 8.The organisation has experience with manufacture of cell and virus banks and has established cellline development technology for generating high yielding, recombinant cell lines for antibody andprotein production using a commercial proprietary expression system.The organisation has experience of large (250L) scale stirred tank and rocking bioreactors. Thisapplies to both single use and CIP/SIP vessels.21

Table 8 Summary of experience for CR UK BDUSuspension Adherent 2D 3DAutoAllo Human ES CellTraining on-goingiPS CellCell isolation from donortissuePE6.1.5 PersonnelIn total there are 20 members of staff working within the facility. Staff are deployed where necessarybut strict controls are in place to prevent staff working on multiple different product streams. Mainareas of experience have been focused on production of biologics from various cellular expressionsystems.An organogram showing the organisation structure of the team can be found in Figure 5.Figure 5 CR UK BDU Organogram22

6.1.6 CapacityCR UK BDU indicated that they could run up to three projects per year on the assumption that eachwould require lengthy tech transfer activities prior to GMP manufacture. The multiple GMP suiteswith separate air handling, personnel, material and waste segregation would enable up to twosimultaneous production campaigns.The main bottleneck limiting further increases in capacity appear to be staff numbers. A secondbottleneck defined as space within process development labs to run through the process prior toGMP manufacture was also identified.Standard methodology to plan capacity and occupancy are used and updated monthly. Availablecapacity is described below.2015 – 0%2016 – 0%2017 – 50%2018 – 50%23

Cellular Therapeutics Ltd (CTL)6.2.1 DetailsAddressCellular Therapeutics Ltd48 Grafton StreetManchester M13 9XXContact: info@cellulartherapeutics.co.ukTel: 0161 606 7278Web: www.cellulartherapeutics.co.uk6.2.2 FacilityThis facility comprises of one large multiproduct manufacturing suite (grade D) with three isolators(grade A) and associated transfer hatches (grade B). Each open product is incubated within a productspecific secondary containment system to avoid cross contamination.Processing equipment Process development laboratory Environment Monitoring System to log parameters (particle count, pressures, temperatureetc) from the isolators, incubators and storage locations. CliniMACS – bench top platform enabling the separation of different cell types within aclosed system using magnetic bead conjugates. Automated closed system to aseptically concentrate and wash cells. Standard incubators for static cell culture Bag/closed vessel centrifuge and ‘bag squeezer’ (to remove supernatant). Perfusion bioreactors for actively managed cultures (10L scale)Analytical equipment Flow cytometer Microbiology QC GMP and process development assays24

Figure 6 Example of clean room at the Cellular Therapeutics Unit6.2.3 LicenceCTL holds MHRA Authorisation for Investigations Medicinal Products (IMPs) and ManufacturingSpecials (MS) (#44168). The facility does not have an HTA licence (at present).6.2.4 Track record and experienceCTL has experience of manufacturing both closed and open cell therapy products, manufacturinggene modified T cell (viral vectors) and Tumour Infiltrating Lymphocyte products: having completedtwo cell therapy trials; four trials ongoing; and further trails in the pipeline. A summary of theirexperience with cell therapies can be found in Table 9.Table 9 Summary of experience for Cell Therapeutics UnitSuspension Adherent 2D 3DAuto Allo Human ES CelliPS CellCell isolation from donortissue6.2.5 PersonnelAn organogram for CTL can be found in Figure 7. The unit operates under the CTL Board which isresponsible for determining the direction and oversight of products in the pipeline and in process.There are individual board members responsible for finance and contracts; production and qualityand process translation, scientific review; and GMP research and development. Within the facilitywe have access to consultant qualified personnel and dedicated product management and productionstaff.25

Figure 7 Organogram for Cellular Therapeutics6.2.6 CapacityCellular Therapeutics have the capability to manufacture six different products simultaneously witha current maximum of four open processes at any one time. This assumes a manufacturing cycle oftwo to three weeks per product.This allows us to manufacture between 60 and 100 complex ATMP products per year.Available capacity:2015 – 50%2016 – 40%2017 – 40%2018 – 40%26

Biomedical Research Centres (BRC) Clinical Research Facility (CRF) GMPUnit at Guy’s and St Thomas’6.3.1 DetailsAddressNIHR Guy’s and St Thomas’ Biomedical Research CentreGMP UnitClinical Research Facility15 th Floor, Tower WingGuy’s HospitalGreat Maze PondLondon SE1 9RTContact: Chris Fisher Christopher.fisher@gstt.nhs.ukContact: Drew Hope Andrew.hope@gstt.nhs.ukTel: 0207 188 7188 (ext 52362 or 52703)Web: http://www.guysandstthomasbrc.nihr.ac.uk/6.3.2 FacilityGuy’s and St Thomas’ Clinical Research Facility is a 125m 2 facility located on the 15 th floor of Guy’shospital tower wing. The main manufacturing area houses three grade D clean rooms which are intotal 95m 2 . Each clean room is equipped with an isolator for open processing. Closed processes canalso be accommodated.Processing equipment 3 x Rigid four-glove Grade A isolators Incubators Controlled rate freezer Rocking platforms Centrifuge CliniMACS Plus, CliniMACS Prodigy cell isolators Sepax and SynGenX1000 cell isolators MACS Quant Tyto FACS cell isolator Rocking BioreactorAnalytical equipment 1 x Countess cell counter 4 x Scepter cell counter 2 x Inverted microscopes 1 x ImageStreamX (Luminex) 1 x Cytoff Mas Spectrometer Flow cytometry (3 x FACS CANTO II, 1 x LSR, 1 x FORTESSA, 1 x INFLUX, 2 x ARIA) 1 x Luminex FlexMap3D27

Figure 8 Example of clean rooms at Guy’s and St Thomas’6.3.3 LicenceMHRA licence for IMPs. HTA licence for procurement and donor testing.6.3.4 Track record and experienceExperience with autologous T cells and autologous Treg cells at the facility. A summary of theexperience can be found in Table 10.Table 10 Summary of experience for Guy’s and St Thomas’AutoSuspension Adherent 2D 3DPEAllo PE PEHuman ES CelliPS CellCell isolation from donortissuePE PE PE6.3.5 PersonnelTwo members of staff are permanently employed in the CRF to oversee the quality managementsystem; a head of advanced therapy production and a head of advanced therapy quality. A contractQP s used for batch release. An advanced therapy production scientist is employed to assist withprojects being undertaken within the unit. Teams of up to four operators are recruited by theprinciple investigator and are then trained to work in production to comply with GMP regulations.28

Figure 9 Organogram of Guy’s and St Thomas’ CRFCluster 1ExperimentalMedicine &TherapeuticsCluster LeadBRC ChiefOperating OfficerPI’s for specificresearch projectsGMP QualifiedPersonAssistant ChiefPharmacistTechnicalServicesHead of QAGMP ProductionManagerGMP QualityManagerResearchers working in GMP facilityGMP FacilityCleanerPharmacy QCFlow CytometryQCExternal QCResponsible (Management) Accountable Research ResponsibilityProductionQuality6.3.6 CapacityGuy’s and St Thomas’ CRF has indicated that it would be possible for them run up to five open and10 closed projects per year. Forecasts of future spare capacity can be found below.2015 – 60%2016 – 50%2017 – 40%2018 – 40%29

Imperial College London, John Goldman Centre for Cellular Therapy6.4.1 DetailsAddressCatherine Lewis Building,Hammersmith Hospital,Ducane Road,LONDON W12 0HSContact: Anne Bradshaw anne.bradshaw@imperial.nhs.ukTel: 0203 313 2056Web: n/a6.4.2 FacilityThe centre is equipped with two independent clean room suites. Each suite has two grade B roomsfor processing and a grade C room for preparation. Class II MBSCs provide grade A environmentsfor open processing. One of the suites is designed to work with GMO level 2 material (for examplefor gene replacement work). Work with genetic modification would require an update to the IMPLicence however.Processing equipment Class II ducted cabinets Laminar airflow stations (LAF) Cell separators e.g. Cobe 2991, Cobe Spectra Immunoselection devices e.g. Miltenyi CliniMacs, Baxter Isolex 300i Tubing heat sealers Automated Cell washer – Baxter Cytomate Sterile Docker – Terumo SCDC Tissue Culture incubators Vacuum wrapping device Tissue Culture incubators Pharmacy grade fridge/freezer Controlled rate freezerAnalytical equipment Flow Cytometer Bench top centrifuges Pharmacy grade fridgeFigure 10 Example of clean room at John Goldman Centre for Cellular TherapyNo photographs provided.30

6.4.3 LicenceMHRA Licences to manufacture IMPs and Specials. HTA licences have also been awarded for variousoperations.6.4.4 Track record and experienceThe centre has a long history of experience immune-selection and separation (CD34+) using devicessuch as the CliniMACS. The centre has experience with Haematopoietic Progenitor Cells and Tlymphocytes for both autologous and allogeneic use. A summary of the centre’s experience can befound in Table 11.Table 11 Summary of experience for John Goldman Centre for Cellular TherapySuspension Adherent 2D 3DAuto Allo Human ES CelliPS CellCell isolation from donortissue6.4.5 PersonnelKey personnel at the centre include a head of operations and regulatory affairs, a medical director,consultant QP, head of processing and a head of quality. A description of the organisation of thecentre can be found in Figure 11.31

Figure 11 Organogram of John Goldman Centre for Cellular Therapy6.4.6 CapacityThe centre has two independent suites each with two grade B rooms enabling up to four simultaneousprojects. The spare capacity over the next few years is indicated below.2015 – 25%2016 – 25%2017 – 20%2018 – 20%32

Rayne Cell Therapy Suite (RCTS) and The Wellcome Trust / BRC ClinicalResearch Facility and Cell Therapy Unit (CTU) at King’s College London6.5.1 DetailsAddressKing’s College London,The Rayne Institute,123 Coldharbour Lane,London SE5 9NUContact: Farzin Farzaneh Farzin.farzaneh@kcl.ac.ukTel: 020 7848 5902/2900Web:http://www.kcl.ac.uk/lsm/research/divisions/cancer/research/sections/haematooncology/services/celltherapysuite.aspx6.5.2 FacilityThe RCTS premises contains 40m 2 of grade D clean rooms with two grade A isolators. This facilityhas operated as a GMP facility for the production of cell and gene therapy based investigationalmedicinal products since 2001.The CTU facility has a floor area of 420m 2 and is separated into three suites. The Cell and GeneTherapy (CGT) suite contains two independent grade D areas complete with isolators. Each area isdesigned to handle separate products. Production runs in The Cell and Gene Therapy Suite areconducted on a campaign basis with a “deep clean/decontamination” between the manufacture ofdifferent products. The Cell Isolation Suite has two grade C areas with Class II MBSC for initialisolation of the starting material from donor tissue. The final steps of processing are carried out inan isolator in the same grade C background. Although the grade C areas in this suite are declared assuch they are designed to function as grade B rooms.Processing equipment Cell culture incubators CO2 Incubators Centrifuges Cryovial filler/capper Controlled Rate Freezer 2 x Plasmatherm Micro-encapsulator 2 x CliniMACS cell processing systems Plasma expressor Sepax cell separation systemAnalytical equipment 4 x Microscope - inverted 2 x Microscope - fluorescent 5 x Microscope – normal Multi laser/coulour FACSCanto and LSR Fortesa Analysers FACSAria cell sorting33

Figure 12 Example of clean room at The Rayne Cell Therapy Suite6.5.3 LicenceThe RCTS facility holds MHRA licences for MIA(IMP) and Specials. In addition it also has an HTAlicence for the procurement, testing, processing, storage, distribution and/or import and export oftissues and/or cells intended for human applications. These licences cover the activities in both theRCTS and CGT facilities.6.5.4 Track record and experienceThe organisation has experience with dendritic cells for a variety of different indications, donor NKcells, mesenchymal stem cells and haematopoietic stem cells. They also have extensive experiencewith the manufacture of gene therapy products such as retrovirus and lentivirus vectors. Thisexperience includes the manufacture of the largest number of retro and lenti-virus based vectors for34

egulatory approved clinical trials I Europe and the manufacture of IMPs for a range of academicand industry sponsored Phase-I through to Phase-III clinical trials.Table 12 Summary of experience for the Rayne Cell Therapy Suite and the CellTherapy UnitAutoSuspension Adherent 2D 3DAllo Human ES CellIPS CellCell isolation from donortissue6.5.5 PersonnelThere are ten permanent members of staff at the RCTS and the Cell and Gene Therapy componentof the Cell Therapy Unit. The current list of staff include:Lucas Chan…………..Rebecca Pru…….……Joti Bhalla …….……..Lin Liu…………………Yuqian Ma………….…Sabine Domning…….Maeve McEnery……..Hedieh Shirazi……….David Darling…….….Wendy Collicott….….David Farrer…….……Farzin Farzaneh.….…Head of ATMP ManufactureHead of QualityQuality ManagerResearch FellowResearch FellowResearch FellowResearch AssistantResearch AssistantProcess DevelopmentQA/QC (Pharma-Resolution)External QP (Pharma-Resolution)Internal QP/DI/ Director35

Figure 13 Organogram of the Rayne Cell Therapy Suite6.5.6 CapacityThe RCTS and the CGT components of the CTU can handle four separate projects at any time. In thecurrent manufacturing campaigns the production of each batch of cell therapy product takes one totwo weeks and the manufacture of each batch of gamma retrovirus or lentiviral vectors between 2 to8 weeks.2015 – 30%2016 – 40%2017 – 50%2018 – 60%36

NHS Blood and Transplant (NHSBT)6.6.1 DetailsNHS Blood and Transplant (NHSBT) has two sites with MHRAManufacturer’s Authorisation for IMPs covering cellular andmolecular therapies. In addition, there are a further six laboratorysites with HTA licences (two of which have future plans to addMHRA licences).Site address oneNHS Blood and TransplantAdvanced Therapies Unit14 Estuary BanksEstuary Commerce ParkSpekeLiverpool L24 8RBContact: Dr Eric Austin, Head of Laboratory, eric.austin@nhsbt.nhs,ukTel: 0151 268 7200Site address twoNHS Blood and TransplantClinical Biotechnology CentreLangford HouseLower Langford, near Bristol BS40 5DUContact: Dr Paul Lloyd-Evans, Head of Laboratory, paul.lloyd-evans@nhsbt.nhs.ukTel: 0117 928 9388Additional contacts:Contact: Teresina Pinnington, Business Development Manager,teresina.pinnington@nhsbt.nhs.ukTel: 07889 304615Contact: Dr Jon Smythe, Head of Cellular and Molecular Therapies, jon.smythe@nhsbt.nhs.ukTel: 01865 38 7967Web: http://www.nhsbt.nhs.uk37

6.6.2 Facilities at SpekeThe NHSBT Speke facility has two grade B rooms with Class II MBSC dedicated to the manufactureof cell therapies. There is also an additional grade B room and a grade C room shared with the NHSBTTissue Services department. The department also has a dedicated QC laboratory.Processing equipment Class II cabinets CO 2 incubators Sterile connecting devices Controlled rate freezers Liquid nitrogen storage vessels Centrifuges Orbital shaker 4 o C storage pharmacy fridges Peristaltic pump Filter integrity tester Endosafe PTS Cytospin Line sealers Sepax 2 MicroscopesAnalytical equipment Haematology analyser Flow cytometer38

Figure 14 Example of clean room at NHSBT (Speke site)6.6.3 LicenceThe Speke site has a MHRA licence for IMPs and a HTA licence.6.6.4 Track record and experienceThe ATU has experience of the genetic manipulation of T cells, cell selection and depletion protocolsand broad cell culture knowledge. The unit also has experience of the isolation and culture ofmesenchymal stem cells from bone marrow and umbilical cord plus peripheral blood stem cells forclinical trials. The laboratory has prepared master and working cell banks under GMP.Table 13 Summary of experience for NHSBTSuspension Adherent 2D 3DAuto AlloHuman ES CellIPS CellCell isolation from donortissue39

6.6.5 PersonnelThe NHSBT site in Speke has six dedicated staff for IMP manufacture.Figure 15 Organogram of NHSBT, Speke site6.6.6 Capacity2015 – 10%2016 – 10%2017 – 10%40

6.6.7 Facilities at the Clinical Biotechnology Centre, LangfordThe NHSBT Clinical Biotechnology Centre has four grade D rooms and three grade C rooms. Onegrade C room is dedicated to the aseptic filling of products in a pharmaceutical grade positivepressure isolator with a state of the art closed-vial sterile filling station. Class II MBSC or laminarflow cabinets are present in the other rooms dedicated to the manufacture of gene therapy andbiotechnology products.Processing equipment HVAC System Class II cabinets / laminar flow hoods Pharmaceutical grade positive pressure isolator with BioQuell Clarus L-3 VHP generatorcapabilities Fermentation systems AKTA chromatography equipment Highly purified water plant Incubators and shaker incubators Freezers, fridges and storage areas including liquid nitrogen storage vessel Centrifuges Peristaltic pumps GMP grade Autoclave Laboratory grade dishwasher Emulsiflex high pressure homogeniser Aseptic Technologies Crystal M1 closed-vial sterile filling station for dispensing of productsAnalytical equipment UV / Visible spectrophotometer Filter integrity tester Endosafe PTS Microplate plate reader with fluorescence capability Osmometer pH & Conductivity meter Turbidity meter PCR equipment HPLC Electrophoresis equipment Gel analysis and documentation system Access to DNA capillary sequencer Environmental testing equipment41

Figure 16 Examples of clean rooms and equipment at NHSBT (CBC site)42

6.6.8 LicenceThe CBC site has a MHRA licence for the manufacture and importation of molecular IMPs.6.6.9 Track record and experienceThe facility has experience in the manufacture of plasmid DNA vectors as direct vaccines or for usein viral vector manufacture, production of recombinant proteins, production of monoclonalantibodies and the conjugation of antibodies for therapy. To date the facility has manufactured over50 plasmid DNA vectors, five recombinant proteins and been involved in over 14 clinical trials since2001 (with over 400 patients treated). The CBC has developed an expertise in the manufacturingand testing of patient-specific DNA vaccines to current regulatory requirements.6.6.10 PersonnelThe NHSBT site in Langford has ten dedicated staff for IMP manufacture.Figure 17 Organogram of CBC site6.6.11 CapacityCBC can process two products in parallel with a capacity of up to 15 to 20 products per year,depending upon scale. Current available capacity is shown below:2015 – 40%2016 – 80%2017 – 90%43

Roslin Cells Cellular Therapy Facility (Scottish Centre for RegenerativeMedicine)6.7.1 DetailsRoslin Cells is situated within the Scottish Centre forRegenerative Medicine (SCRM). Roslin Cells shares theCellular Therapy Facility with the Scottish NationalBlood Transfusion Service at SCRM.The facility was specifically designed for the development and manufacture of cellulartherapies/ATMPS and contains 3 separate suites served by a dedicated Air Handling Unit.AddressCellular Therapy FacilityScottish Centre for Regenerative Medicine5 Little France DriveEdinburgh BioQuarterEdinburghEH16 4UUandNine Edinburgh Bioquarter9 Little France RoadEdinburghEH16 4UXContactsJanet Downie, Chief Operating OfficerEmail: janet.downie@roslincells.comTel 0131 658 5182Ruth Sorbie, Head of GMP OperationsEmail: ruth.sorbie@roslincells.comTel 0131 658 5350Web: www.roslincells.com6.7.2 Facilities at Roslin CellsThe Roslin Cells processing area is divided throughout the 3 suites and consists of:Suite 1:1 Grade B processing room + 2 Grade A MBSCs1 Shared Grade C support room.Suite 2:1 Grade B processing room + 2 Grade A MBSCs1 Shared Grade C support room.44

Suite 3:1 Grade C processing room with CliniMACs and is awaiting fit out with a custom built Cell TherapyIsolator.Example cleanrooms at SCRM (for both Roslin Cells and SNBTS) are shown in Figure 18. RoslinCells also has technology transfer cell culture facilities within the SCRM. The Cell TherapyDevelopment team and the Process Development tissue culture facilities are based next door withinNine Edinburgh BioQuarter.Processing equipment:Cell culture incubatorsCentrifugesControlled rate freezer (Planers and Asymptote)Ohaus Analytical Balance / Precision BalanceClosed system cell processing – TSCD, Tube sealers, Transfer Bag centrifuges etc.CliniMACS plus cell selection systemPortable ice-free cooling systemsDry block heatersClosed filtration system for large-scale media productionAmaxa 4D NucleofectorAnalytical equipment:AB 7900 HT Real Time PCR system2720 Thermal CyclerFlow Cytometer (Guava EasyCyte)Biotek ELX808 Plate ReaderNanodrop ND1000 SpectrophotometerPall Flowstar Filter Integrity TesterRoslin Cells is located close to a number of MHRA licenced contract testing facilities who providea full range of testing capabilities.Cell/product storage:Statebourne Vapour Phase LN 2 Storage VesselsMechanical -150 °C Freezers45

Figure 18 Example of clean rooms at SCRM6.7.3 LicenceRoslin Cells holds an HTA licence, MHRA MIA (IMP) and Manufacturer’s Specials licences for thefacility.6.7.4 Track record and ExperienceRoslin Cells – Contract manufacturingThe team at Roslin Cells has extensive cell therapy expertise and a wealth of experience to ensureprojects proceeds in the right direction and the right standards from the very beginning, in a timelyand cost effective manner.The GMP team has many years’ experience in the production and testing of cell therapies/ATMPsand GMP pluripotent stem cell Banks. These include:Manufacturing drug substance cell banks for neuronal cell products.Manufacturing final product batches of pluripotent cell based products.Producing clinical grade cell banks for pluripotent stem cells.A range of adherent cell based productsThey are also experienced in the practicalities of technology transfer of cell therapy/ATMP processes.The team are also performing the manufacturing of some of the leading cell therapy clinical trialswithin the UK, including manufacturing for ReNeuron and Pfizer NeusentisThe Cell Therapy Development Team have many years’ experience of translating academic celltherapy protocols to GMP, process development and the associated documentation required forGMP manufacturing.46

Table 14 Summary of experience at Roslin CellsSuspension Adherent 2D 3DAllo Human ES CellIPS Cell Cell isolation from donortissue6.7.5 PersonnelRoslin Cells currently has 54 employees with 35 focused on our Cell Therapy Manufacturing andDevelopment Services based in Edinburgh. The core team are organised into 4 departments;Production, Quality Control, Quality Assurance and Cell Therapy Development. The Organogramfor Roslin Cells (April 2015) is shown in Figure 19.Figure 19 Organogram of Roslin Cells47

6.7.6 CapacityWe can run up to 4 open processes at one time excluding the capacity provided within the CellTherapy Isolator suite which comes on line beginning of 2016. The amount of spare capacitycurrently forecast can be seen below.2015 – 25%2016 – 25%2017 – 50%2018 – 75%48

Scottish National Blood Transfusion Service (SNBTS) Cellular TherapyFacility (Scottish Centre for Regenerative Medicine)6.8.1 DetailsSNBTS is situated within the Scottish Centre for Regenerative Medicine(SCRM). SNBTS shares the Cellular Therapy Facility with Roslin Cells at SCRM.The facility was specifically designed for the development and manufacture ofcellular therapies/ATMPS and contains 3 separate suites served by dedicatedAir Handling Units.AddressCellular Therapy FacilityScottish Centre for Regenerative Medicine5 Little France DriveEdinburgh BioQuarterEdinburghEH16 4UUContactsProf. John Campbell: Associate Director, Research, Development and InnovationEmail: johncampbell3@nhs.netTel:0131 314 5677Dr Neil McGowan: Cellular Therapy Project ManagerEmail: neil.mcgowan@nhs.netTel 0131 651 9572Web: http://www.scotblood.co.uk6.8.2 Facilities at SNBTSThe SNBTS processing area is divided into 2 suites consisting of:Suite 1 (Manufacture):2 grade B processing rooms + 2 Grade A MBSCs in each.1 Grade C clean room + 1 Grade A MBSC – tissues and closed processes1 Grade C shared support areaSuite 2 (Characterisation & QC):Controlled non classified GMP cell analysis room, including Flow Cytometry and Cell countingProcessing Equipment:1x GE Excellerex 10L bioreactor2x CliniMACS plus2x CliniMACS prodigy6x Cell culture incubatorsCentrifuges2x Controlled rate freezer (Planers)Closed system cell processing – TSCD, Tube sealers49

Analytical equipment:FACS Canto IISysmex haematology analyserEvos imaging microscope (x2 – 1 in grade C clean room)Cell/product storage:2x Statebourne Vapour Phase LN 2 Storage VesselsSee Figure 18 for images of example clean rooms at SNBTS (within the SCRM). SNBTS is locatedclose to a number of MHRA licenced contract testing facilities who provide a full range of testingcapabilities.6.8.3 LicenceSNBTS holds individual HTA licences, MHRA MIA (IMP) and Manufacturer’s Specials licences forthe facility.6.8.4 Track record and experienceSNBTS currently produces three different cellular therapy products, under appropriate HTA, MHRAspecials or MAI IMP licences. These are CD133+ autologous stem cells, EBV-specific Cytotoxic Tcells, and Corneal Epithelial Stem Cells. CD133+ stem cells and Corneal Epithelial Stem cells arecurrently produced at SCRM.SNBTS also has extensive cell therapy translational research laboratories at SCRM which areinvolved in the final translation of several other novel cell therapy products.Table 15 Summary of experience at SNBTSSuspension Adherent 2D 3DAllo Human ESCellIPS CellCell isolation from donortissue6.8.5 PersonnelSNBTS employs 10 full time team members and receives extensive R&D and QA support fromwider SNBTS. The organogram for SNBTS is shown in Figure 20.50

Figure 20 Organogram of SNBTS6.8.6 CapacityThe amount of spare capacity currently forecast at SNBTS is as follows2015 – 30%2016 – 10%2017 – 5%2018 – 5%51

Cellular Therapies, Great Ormond Street Hospital6.9.1 DetailsAddressCellular TherapiesGreat Ormond StreetLondon WC1N 3JHContact: Sue Swift s.swift@ucl.ac.ukTel: 0207 905 2830Web: n/a6.9.2 FacilityThere are two suites within Cellular Therapies. The first consists of a grade C clean room with a gradeA positive isolator for aseptic processing. The second suite has a grade C preparation room andaseptic processing with two grade A negative isolators. The facility is licenced for gene and celltherapy products by the MHRA (MIA (IMP) and MS 17328). There is an adjacent stem cell facilityfor routine cell manipulation licensed by the HTA.Processing equipment Centrifuges (various) Incubators (various) Plasmatherms Tube welders and sealer and bag sealers Dynal ClinExVivo (magnetic particle concentrators for removal of beads) CliniMACS cell separator Wave Bioreactors CliniMacs ProdigyAnalytical equipment Nikon stereoscopic and inverted microscopes52

Figure 21 Example of clean room at GOSH Cellular Therapies6.9.3 LicenceMHRA licence for IMP and specials. The facility is also licenced by the HTA.6.9.4 Track record and experienceThe facility has the experience of manufacturing gene and cell therapy products for Phase I / II trials.In total around 10 products have been manufactured for clinical trials and another 10 are in progress.Table 16 Summary of experience for GOSH Cellular TherapiesSuspension Adherent 2D 3DAuto Allo Human ES CellIPS CellCell isolation from donortissue53

6.9.5 PersonnelThe unit is organised under a chief pharmacist with an aseptic services manager, a quality assurancemanager and a contract QP.Figure 22 Organogram of Cell Therapies GOSH6.9.6 CapacityThe facility has indicated that it is capable of manufacturing up to 30 open or closed products peryear in the facility.2015 – 10%2016 – 10%2017 – 10%2018 – 30%54

Moorfields Eye Hospital, Cells for Sight Cell Research Unit6.10.1 DetailsAddressUCL Institute of Ophthalmology11-43 Bath StreetLondon, EC1V 9EL, UKContact: Julie Daniels j.daniels@ucl.ac.ukTel: 0207 608 6893Web: http://www.ucl.ac.uk/cells-for-sight/cell-therapy6.10.2 FacilityThe facility is split into two grade B manufacturing areas. The smaller area contains one MBSC andone CO 2 incubator. The larger area contains three MBSCs and three CO 2 incubators.Processing equipment 4 x Class II MBSCs 4 x CO 2 incubators Fridges and freezersAnalytical equipment 2 x Microscopes Microbiological incubatorsFigure 23 Example of clean room at Cells for Sight55

6.10.3 LicenceThe facility has an MHRA licence for IMP manufacture, a Specials licence and a HTA licence.6.10.4 Track record and experienceThe main area of experience involves both allogeneic and autologous manufacture of limbal stem cellcultivation on a scaffold. There is also manufacturing experience with retinal pigmented epithelialcells derived from human ES cells.Table 17 Summary of experience for Cells for SightSuspension Adherent 2D 3DAuto Allo Human ES CellIPS CellCell isolation from donortissue6.10.5 PersonnelThe facility employs production and quality managers a contract QP and one technician. Additionalstaff are supplied by the client/PI.Figure 24 Organogram of Cells for Sight6.10.6 CapacityThe organisation indicated that they were capable of running greater than 3 open process productsper year.2015 – 50%2016 – 50%2017 – 50%2018 – 50%56

Newcastle Biomedicine Cellular Therapy Facility6.11.1 DetailsAddressNewcastle Cellular Therapies FacilityNewcastle University3rd Floor, West WingBioscience CentreTimes SqNewcastle University NE1 4EPContact: Anne Dickinson anne.dickinson@ncl.ac.ukTel: 0191 2086794Web: www.ncl.ac.uk/ctf6.11.2 FacilityThe facility contains two suites one with four grade B clean rooms and a second with five grade Brooms. These processing labs are supported by two grade C preparation rooms that also provideaccess to the rooms.Processing equipment MBSC (Class II) CO 2 incubators Refrigerated centrifuges Caridion Cobe 2991 cell processing equipment Water baths Blood warmer CliniMACS Plus Miltenyi ProdigyAnalytical equipment Microscope FACS PCR ThermocyclerFigure 25 Example of clean room at Newcastle Biomedicine Cellular Therapy Facility57

6.11.3 LicenceMHRA licence for manufacture of IMPs and a specials licence. The facility also has a HTA licence.6.11.4 Track record and experienceThe facility has experience with stem cell cryopreservation using controlled rate freezing, cellmanipulation using COBE 2991 (separation of blood and bone marrow) and isolation of subpopulationsusing a CliniMACS. Development and culture of dendritic cells and mesenchymal stemcells, limbal stem cells and tolerogenic dendritic cells for ATMP clinical trials.Table 18 Summary of experience for Newcastle Biomedicine Cellular Therapy FacilitySuspension Adherent 2D 3DAuto Allo Human ES CellIPS CellCell isolation from donortissue6.11.5 PersonnelThe facility employs four staff in production and two QC analysts. An organogram for the companycan be found in Figure 26.Figure 26 Organogram of Newcastle Biomedicine Cellular Therapy Facility58

6.11.6 CapacityThe facility has nine separate clean rooms allowing it to run up to nine separate projects at any time.2015 – 60%2016 – 70%2017 – 80%2018 – 70%59

University of Oxford Clinical BioManufacturing Facility6.12.1 DetailsAddressClinical BioManufacturing FacilityUniversity of OxfordOld RdHeadingtonOxford OX3 7JTContact: Sarah Moyle sarah.moyle@ndm.ox.ac.ukTel: 01865 744845Web: http://www.cbf.ox.ac.uk/home6.12.2 FacilityManufacturing suites Three grade B suites; one large 51m 2 area with two MBSCs, 23m 2 room with one MBSC anda smaller room 10m 2 with an isolator. Two grade C suites; one 17.4m 2 with a 4 glove isolator for fill/finish but could also be usedfor manufacture and one 11m 2 with an MBSC One grade D area 22.9m 2 for preparation, staging and inspection and a through wallpharmaceutical autoclave.Processing equipment 2 x CO 2 shaking incubators 2 x static CO 2 incubators 4 x Class II MBSCs 4-glove isolator 2 glove isolator 2 ultracentrifuges 3 low speed centrifuges AKTA pilotAnalytical capabilities Endotoxin measurement Sterility check DNA and protein quantification Access to FACS analysis Molecular Biological Capabilities (QPCR, PCR, enzyme restriction analysis, sequencing) Analytical QC testing for viral vector applications Analytical QC testing for residuals Other QC testing can be outsourced60

Photos showing the finish of the clean rooms can be seen in Figure 27.Figure 27 Example photos of Oxford CBF facility6.12.3 LicenceAn MHRA MIA (IMP) licence has been granted which authorises cell therapy, gene therapy andmany additional manufacturing capabilities. The facility does not currently have an HTA licence butkey personnel have previous experience with HTA requirements and licensing. The CBF has priorexperience importing IMPs from outside the EU and certifying these to clinical trial in the EU.6.12.4 Track record and experienceThe facility has a great deal of experience with biologics production (recombinant proteins andviruses etc.). Adherent and suspension cell cultures have therefore been used for this purpose. Keystaff have experience during previous employment with cell therapy manufacture (including viraltransduction). A summary of their experience can be found in Table 19. Personnel at the Oxford CBFhave a large degree of experience with viral vector manufacture which is a key component of genemodified cell therapies.Table 19 Summary of experience for Oxford CBFSuspension Adherent 2D 3DAutoAllo Human ES CellIPS CellCell isolation from donortissuePE6.12.5 PersonnelIn total there are 16 members of staff are working within the facility. The site has one permanent QPonsite and 3 named contract QPs on their licence.61

Figure 28 University of Oxford CBF Organogram6.12.6 CapacityThe facility is currently working at capacity with respect to manufacturing work. The facility hasplans for future expansion which would mean a greater degree of capacity in the future.2015 – 0%2016 – 100-300%2017 – 300%62

Royal Free Hospital London, Centre for Cell and Gene Tissue Therapeutics6.13.1 DetailsSite addressRoyal Free HospitalPond StreetLondon NW3 2QGCentre for CellGene&Tissue TherapeuticsUCL Institute of Immunity & InfectionContact: Dr Mark Lowdell, Director of Cell Therapy & Qualified PersonTel: 020 7830 2183Additional contacts:Contact: Dr Owen Bain, Head of QCTel: 020 7794 0500 x331406.13.2 FacilityThe CCGTT is an ATMP manufacturing unit owned and operated by the Royal Free London NHS FTproviding a core facility for the manufacture and storage of all three types of ATMP to full GMPcompliance under licences from the MHRA (MIA IMP / MS) and the HTA. It consists of a suite of 10GMP laboratories with 5 associated support rooms (two Quarantine Goods stores, two ReleasedGoods stores and male/female changing rooms) on the lower ground floor at RFH plus two QualityControl labs, one GMP Process Development lab and three staff offices on the first floor, theRFH/UCL biobank cryogenic cell repository on the first floor and two offices on the second floor.The suite consists of 4 grade D laboratories (including a lab for in-process QC accessible from D andB labs), 1 large grade C laboratory for long-term “closed” cell expansion and 5 individually isolatedgrade B labs with individual grade B gowning compartments to prevent cross-contamination. One ofthe grade B labs is dedicated to handling GM products under negative pressure within a positivepressure background.Each B lab is maintained at +50Pa to atmospheric air pressure and there is a 10-15Pa air cascadethrough each grade of laboratory and there is no air recirculation; fresh air enters each laboratorythrough a terminal Hepa filter and is removed via a low level extract. Air change rates vary from 70AC/H in the B labs to 28 AC/H in the D labs. Continuous particle monitoring is provided in each ofthe class II microbiological safety cabinets and the QUBE isolator which provide the grade Aenvironments.Each laboratory can be completely isolated from the others for fumigation with vapourised hydrogenperoxide.The GMP manufacturing facility is shown in Figure 29.63

Figure 29 GMP Manufacturing facility at CCGTTGrade D QCGrade B GMGrade BGrade DGrade CReleasedStage 1changeReleasedStage2D6.13.3 LicenceMHRA MA(IMP) MS 11149 / HTA licence 110166.13.4 Track record and experienceThe CCGTT has the skills and resources to undertake GMP conversion of almost any process for anytype of ATMP and has taken multiple somatic cell therapies and now three tissue-engineered 3-Dstructures to clinical use. They have QA and QC skills and a QP in-house to release ATIMPs. Theycan draft IMPDs, IBs, PSFs, SOPs and BMRs and manage them within their in-house documentcontrol system. The CCGTT can train staff to work in a GMP compliant manner and have routinelydone so. These resources are largely provided by the core NHS staff and the facility currently has noexcess capacity.The CCGTT has successfully supported five commercial clinical trials and has a number undernegotiation at present.64

• Pre 2001-83-EC– Autologous IL-2 primed NK cells in AML– Autologous TIL in RCC– Autologous LAK in Ca Ova– Allogeneic NK in AML– DC primed sib allo CMV-specific T cells• Post 2001-83-EC– Sib allo CMV T cells by IfnG catch– DC-Vax in glioma– HuESC retinal epithelia – PhI commercial– Allogeneic NK cell therapy for AML – PhI/IIa PhII commercial– Two, matched allogeneic anti-viral T cell products - PhI/IIa commercial– Autologous stem cell seeded cadaveric tracheal tissue engineered products– Autologous stem cell-derived cell seeded biocompatible tissue structure tissueengineered products– Autologous stem cell seeded cadaveric laryngeal tissue engineered products– Large scale MCB and WCB of allogeneic MSC carrying a single gene insertion(lentiviral)– Autologous iPS cells– Autologous MSC for tendonopathyTable 20 Summary of experience at CCGTTSuspension Adherent 2D 3DAllo/Auto Human ES CelliPS CellCell isolation from donortissue65

6.13.5 PersonnelFigure 30 Organogram showing organisation structure at CCGTTDirectorDr Mark W LowdellQP (1) / HTA DIPAMedical AdvisorDr Adele FieldingHead of BiorepositoryQM / QADeputy Head ofBiorepositoryProduction / FacilitiesManagerBiorepositoryTechnicianQC Lead /QP (2)GMP Clinical ScientistLead scientist ProcessDevelopment (QC2)GMP PD Scientist /Production ScientistBiorepositoryTechnicianBiorepositoryTechnicianQC ScientistGMP Clinical ScientistGMP Lab Assistant6.13.6 CapacityThe amount of spare capacity currently forecast can be seen below.2015 – 25%2016 – 25%2017 – 25%2018 – 25%66

University of Birmingham, Cell Therapy Suite6.14.1 DetailsSite address:Cell Therapy SuiteAdvanced Therapies FacilityCollege of Medical and Dental SciencesUniversity of BirminghamEdgbastonBirmingham B15 2TTContact: Dr Jane SteeleEmail: j.c.steele@bham.ac.ukTel: 0121 414 7668Contact:Email:Professor Phil Newsomep.n.newsome@bham.ac.uk6.14.2 FacilityThe cleanroom suite includes 2 biological safety cabinets (BSC, Grade A), a processing laboratory(Grade B), change room (Grade B/C), preparation room (Grade C), change room (Grade C/D) andan unclassified store room, office, lobby and locker room. There is a separate QC laboratory, freezerroom and cryostore containing liquid nitrogen storage and a controlled rate freezer.The Cell Therapy Suite is joined onto the adjacent NIHR/Wellcome Trust Clinical Research Facility,under the governance of University Hospital Birmingham NHS Foundation Trust, wheremanufactured products can be administered to patients in an appropriately staffed and monitoredenvironment.Processing equipment Environment Monitoring System Cobe 2991 CliniMACS Prodigy 4 x standard CO2 incubators Tube sealers, centrifuge, microscopeAnalytical equipment MACSQuant analyser Microbiology QC GMP and process development assays6.14.3 LicenceMHRA licence for IMPs and an MS specials licence. The facility does not have an HTA licence (atpresent).67

6.14.4 Track record and experienceThe unit is a new facility and will commence production in September 2015. Initial projects at thefacility will include the production of the autologous dendritic cells, and process validation for thisproject is currently being performed at the unit. The previous experience of personnel employed atthe unit is shown in Table 21.Table 21 Summary of experience for University of BirminghamSuspension Adherent 2D 3DAuto Allo Human ES CellIPS CellCell isolation from donortissuePE6.14.5 PersonnelAn organogram can be seen in Figure 31. The facility is regulated by the Advanced Therapies FacilityManagement Committee which oversees the direction, management, governance and finances.There is a full time Production Manager, Quality Assurance Manager and technician on sitemaintaining the Cell Therapy Suite – further technical and production staff are employed on aproject by project basis as required. The unit sub contracts a Qualified Person for batch release.Figure 31 Organogram of organisation structure at University of Birmingham, CellTherapy Suite6.14.6 CapacityThe Cell Therapy Suite at the University of Birmingham has the capability to manufacture 2-3 differentproducts simultaneously depending upon the timings and complexities of manufacturing protocols.68

2015 – 25%2016 – 50%2017 – 50%2018 – 100%69

Cobra Biologics6.15.1 DetailsSite addressCobra BiologicsStephenson BuildingKeele Science ParkKeeleST5 5SPwww.cobrabio.comContact: Philip Ridley-Smith, Sales & Marketing DirectorTel: +44 208 246 5895Additional contacts:Contact: Steve Garland, Director of OperationsTel: +44 1782 714 1816.15.2 Facilities at Cobra Keele & MatforsCobra is a development and manufacturing organisation producing materials for pre-clinical,Phase I/II/III clinical trials and in-market products with over 220 employees. Cobra has acommercially licenced fill / finish and secondary manufacturing facility and supplies commercialproducts to Europe and the rest of the world. The company routinely produces a wide range of biotherapeuticsranging from plasmid DNA, viral products, microbial and mammalian proteins andhave been manufacturing GMP batches for over 15 years. Within Cobra there are three operatingfacilities, based at Keele UK, Södertälje, Sweden and Matfors, Sweden, which have been inspectedand found compliant on a regular basis by the relevant regulatory authorities in the UK andSweden.An example of a GMP cleanroom at Cobra Biologics is shown in Figure 32.70

Figure 32 Example GMP cleanroom at Cobra Biologics6.15.3 LicenceAll of Cobras’ facilities are cGMP licenced under the EU clinical trials directive and inspected on aregular basis; MHRA and MPA licence for IMPs for the respective country locations. Cobra has aQP employed at each of its three manufacturing sites.6.15.4 Track record and experienceCobra has 15 years of experience as a contract manufacturer providing services for gene therapy.In the UK the main gene therapy site is designed for BLS-2 handling. The company has workedwith over 50 customers and produced over 80 GMP batches for customers in Europe, NorthAmerica and Asia in Phase I to Phase III clinical trials.Over the last 15 years Cobra has developed a number of platform services key in helping their genetherapy customers:Platform process for GMP adenovirus productionPlatform process for GMP DNA production for Phase I-IIIPlatform process for the supply of small quantities of DNA requiring traceability for AAV andlentivirus productionAn AAV production process is currently being developed to meet the demands of the gene therapymarket.71

6.15.5 PersonnelKey personnel working in the gene therapy facility in Cobra Biologics, Keele, UK are shown in theorganograms belowFigure 33 Key production personnel at Cobra Biologics, Keele facilityFigure 34 Key analytical personnel at Cobra Biologics, Keele UK72

6.15.6 CapacityThe availability at the Keele facility for the next 4 years is listed below:2015 – 20%2016 – 60%2017 – 90%2018 – 100%73

Oxford BioMedica6.16.1 DetailsSite addressOxford BioMedica (UK) LimitedHarrow HouseTransport WayOxfordOX4 6LXContact: Peter Nolan enquiries@oxfordbiomedica.co.ukTel: +44 (0) 1865 785300Web: www.oxfordbiomedica.co.uk, www.oxbsolutions.co.uk6.16.2 Facilities at Oxford BioMedicaOxford BioMedica is a leading gene and cell focused biopharmaceutical company specialising inlentiviral based vectors for gene therapy and immunotherapy. Oxford BioMedica has a platform oftechnologies, intellectual property including know-how for underpinning the design, developmentand manufacture of unique gene-based medicines.Facilities at Oxford BioMedica provide the full range of GMP manufacturing services from preclinical,research and bioprocessing development through to GMP manufacture and supply ofclinical trial materials. The current fully-operational clean room area covers 390m 2 , and can beoperated as two specialist manufacturing suites in parallel. The clean rooms are supported by anadditional ~1100m 2 providing warehouse, QC, office, utilities and fallow space.Processing equipment:ÄKTA Ready liquid chromatography systemsMicrobiological Safety CabinetsCO 2 incubatorsCentrifuges-150°C, -80°C and -20°C freezersPeristaltic pumpsFilter integrity testersAnalytical equipmentHPLC SystemFlow cytometerMicro Plate ReaderAutomated nucleic acid extraction systemsqPCR instrumentsUVP Biospectrum 500 gel documentation systemClass II Biological Safety cabinetsUV/Vis Spectrophotometer74

Cell culture equipped containment level 3 laboratoriesCell countersMicroscopesCentrifuges (floor and bench-top)Temperature mapped CO 2 incubators4 o C storage pharmacy fridgeTemperature mapped -80 o C freezerspH meterElectrophoresis equipmentLAL endotoxin readerTOC analyserAn example cleanroom at Oxford BioMedica is shown in Figure 35.Figure 35 Example cleanroom at Oxford BioMedicaAn extensive expansion plan is currently underway at Oxford BioMedica; total clean room area uponcompletion in 2015/2016 will exceed 1900m 2 in upstream and downstream processing areas acrossmultiple independent suites and sites.6.16.3 LicenceOxford BioMedica is MHRA licensed for IMP manufacture6.16.4 Track record and experienceOxford BioMedica does not operate as a traditional contract manufacturing organisation (CMO).Instead Oxford BioMedica is a platform and product development company with a unique75

combination of technical expertise, vector-related intellectual property, a proprietary LentiVector ®platform coupled with process development and in-house GMP manufacturing/analytical testingservices and clinical & regulatory expertise. The facility allows for the production of lentiviral basedvector products for Phase I/II and Phase III clinical trials.Upon completion of the ongoing expansion plan, in addition to the current capacity, OxfordBioMedica’s facilities will be able to accommodate additional adherent 2D planar technologies suchas cell factories as well as scaled-up production in 3D packed bed technologies and 200L single-usestirred-tank bioreactors.A new GMP-compliant filling suite that has been designed for aseptic processing and semicontinuousvial-fill to support Phase I/II IMP clinical material supply will also be available in 2016.6.16.5 PersonnelThe manufacturing department currently consists of 32 biotechnologists who are supported by aprocess compliance team, warehouse, engineering, QC micro and MSAT functions. QC releasetesting is performed by the Analytical Service Group (ASG) overseen by the Chief Business Officer(CBO). Batch release is performed by the Qualified Person (QP) who also manages the QC microfunction and eight QA officers. An organogram for the facility is shown below in Figure 36.Figure 36 Organogram of key personnel at Oxford Biomedica6.16.6 CapacityCurrent capacity in 2015 is 390 m 2 of cleanroom processing space, with an additional 560 m 2coming online in Q3 2015. Details regarding spare capacity at the facility will be provided whenavailable in future annual reviews.76

7 ConclusionsThe UK has a strong research base in cell therapies and this is supported by a network of early phaseGMP manufacturing centres. In total 13 facilities were highlighted in 2014 and a further two centresspecialising in cell therapy manufacture opened in 2015, with the current capability and capacity tomanufacture cell therapies to licensed GMP. Gene therapy capabilities within the UK also existwithin a strong network of both academic and commercial organisations.The centres are highly experienced and their combined knowledge and track-record covers thesphere of current requirements for cell and gene therapy manufacture. A wide variety of equipmentis available at the sites to support this proficiency. Most experience centres around manufactureusing ‘open systems’ either in grade A/B environments or in isolators. Some facilities do haveexperience of working with ‘closed systems’.The facilities are spread fairly evenly across the UK (Oxford, Speke, Keele, Birmingham, Bristol,Manchester, Newcastle and Edinburgh), with a significant cluster in and around central London.Most of the cell therapy facilities are located in the NHS or UK academia; the exception being CellularTherapeutics and Roslin Cells, who are commercial organisations. In contrast, gene therapy facilitiesare predominantly commercial and operate a larger scale and capacity. Translational gene-therapyproduction is underpinned by a handful of academia-based facilities.Many of the centres report spare capacity over the next few years and so the manufacture of newproducts for early phase clinical trials can be supported within this network. Importantly, sparecapacity has dropped since 2014, so free capacity may become an impediment to clinical trialmanufacture in the medium term. This report will track capacity and will be a useful tool to helpmap future requirements, when used in combination with the annual Preclinical and ClinicalDatabases published by the Cell Therapy Catapult (https://ct.catapult.org.uk/preclinical-database;https://ct.catapult.org.uk/clinical-trials-database). In mitigation of the reduction of spare capacity,the opening of new facilities in 2015 increases overall cleanroom capability and current expansionprojects reflect the ever expanding nature of the UK cell and gene therapy manufacturing sector.The UK Cell Therapy Catapult Manufacturing Centre, which was announced in the 2014 budget bythe Chancellor of the Exchequer, will complement this existing network. This centre will provide astep change in capacity for cell and gene therapy manufacture in the UK. It will complete thetranslational picture thus allowing transfer from the research stage into the clinic and finally to laterphase trials and commercial manufacture.The combination of the high quality research taking place in UK academia, the network of early phasemanufacturing centres, substantial commercial viral vector capacity and the Cell Therapy Catapultlarge-scale manufacturing centre will mean that the UK is a very attractive location for the global celland gene therapy industry.77

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