How to Run a Large GMP Facility GMP Manufacturing in Texas – Where Bigger is expected to be Better! Adrian Gee Center for Cell & Gene Therapy Baylor College of Medicine Houston, Texas Plan • Introduction to CAGT & its History • The challenges of growth – Space – Staff – Workload – Documentation – Budget – Regulatory • Advice Center for Cell & Gene Therapy CAGT History • Formed in 1998 as a partnership between Baylor, The Methodist Hospital and Texas Children’s Hospital to share cost & avoid duplication • Dr Malcolm Brenner recruited as Director from St. Jude’s Children’s Research Hospital, Memphis, TN • Important to cover the spectrum from basic research to Phase I – II clinical trials • Total staff (including nursing etc.) ~400 ( ~ 40 Faculty) The Start • • • • • • • ~ 50 stem cell transplants per year 3 INDs for virus-directed cytotoxic T cells Newly built GMP Facility 2 cell processors ~3 IND cell technicians 2 QC technicians QA Manager • 9 Clean Rooms • Flow cytometry in clean area • Cell storage in clean area • Adjacent QC Laboratory The Change • 2009 – added 8 floors • Offered to build new GMP • 16th floor • Opportunity to redesign • 19,000 sq ft including offices The New Facility • • • • • • • • • • 22 Clean Rooms (Class 10,000, ISO 7) 12 – Cell Processing 7 – Vector Production 3 Swing Rooms Centralized Materials area 2 LN2 Banking Areas 1200sq ft QC lab Flow Cytometry Lab. QA Space Filing space Cell Processing Main Vector Production Facility Special Processing Receiving & Storage Cell Banks Quality Assurance & Control Offices & Administration HVAC Systems Cell Processing Facility 20-30 air changes per hour 50% recirculated air CPF Flow path Cell Processing Facility Single corridor design HVAC Systems Vector Production Facility 60 air changes per hour 100% exhausted air VPF Flow path Vector Production Facility Clean & dirty corridors Quality Control Quality Control Cell Processing Released Supplies Quality Assurance Freezer Storage Flow Cytometry Gowning Administration Vector Production Pass-through Cell Storage Materials Management Traffic Pattern Cell Processing Gowning Flow Supplies Materials Management Offices & Administration “Swing” Suites Supplies Gowning QA Vector Production QA Challenges – New Space Issues – What are you going to make & for whom? – How much space will really be needed? – Ongoing expense • Initial and ongoing qualification – Equipment – HVAC • Cleaning – Validation – how to do it? – Single- or-unidirectional flow? – Who will clean? • Environmental monitoring – Staff, equipment and expense Challenges – Staff – New staff • Recruitment • Exempt or non-exempt • Training time • Work existing staff to death! Particularly QC • Exempt (no overtime) staff – difficult to manage fairly • Initial emphasis on QC training then expanded manufacturing Challenges – Workload – New Protocols and Products • Space should be available • Need a controlled method to introduce new studies ~50 INDs + Transplant products Challenges – Workload – New Protocols and Products • Space must be available • Need a controlled method to introduce new studies ~50 INDs + Transplant products Cells Produced Products Manufactured Hematopoietic Progenitor Cells (HPC) Products Manufactured Cytotoxic T cells (CTLS) HPC, Marrow, Unmanipulated CTLs – EBV directed HPC, Marrow, Red cell depleted CTLs – LMP2 directed HPC, Marrow, Plasma depleted CTLs – LMP1/LMP2-directed HPC, Marrow, CD34 selected CTLs – Adenovirus directed HPC, Apheresis, Plasma depleted CTLs – tri-virus directed Marrow mononuclear cells (MNC) – cardiac repair CTL – EBV/Neuroblastoma directed Marrow CD34-selected – cardiac repair Marrow MNC – traumatic brain injury Marrow MNC – stroke patients HPC - Cord blood CD34-selected, ex vivo expanded For hearing loss & brain injury Lymphoblastoid Cell Lines Donor leukocytes (DLI) CTL- Genetically modified (TGFβ etc) Genetically-modified allodepleted donor T lymphocytes Lymphoblastoid cell lines +/- genetic modification – Intermediate product Tumor vaccines +/- genetic modification TV – autologous – neuroblastoma-directed TV- allogeneic – neuroblastoma-directed TV- autologous – CLL-directed Hepatic progenitor cells Mesenchymal stem/progenitor cells (MSC) Pancreatic islet cells – allogeneic Antigen presenting cells (APC) GMP-grade EBV NK Cells APC – dendritic cells – Intermediate product APC – monocytes – intermediate product APC – leukemic cell lines New Protocol Implementation • Binder includes –Manufacturing flowchart –Copy of Protocol –CMC section from IND –Presentation to staff –IRB Approval –SOP & worksheets –Certificate of Analysis –Product Label Workload - Documentation In order of frustration • • • • • • Staff training records Equipment records Environmental monitoring Standard Operating Procedures Validation & Qualification Audits – performance & documentation • Batch records Workload - Monitoring • Labor intense & expensive • How much, where & when? • Retrospective value of viable counts? • Correlation with product contamination? Challenges – Budget Money issues • Large facilities = large running cost – Staff, maintenance, calibration, monitoring etc. • Funding is tight • Many costs not covered by traditional grants • Helps to have high “internal” demand • Possible sources: contracts, space rental etc. Challenges – Compliance • Ongoing compliance is not an option! • Understand what is really required • Expectations for compliance in Phase 1 are different • Money for QA is often tight - but this is changing • “Good” QA people are hard to find • Option to close unused areas • Prioritize tasks • Deputize where possible Advice • Be realistic, not over-ambitious when planning • Set expectations with the administration • New staff, equipment, running costs etc. • Potential income/losses • Do not overbuild • Understand the regulations • Seek advice wherever it is available • Implement growth in phases Kia Ora!