Clinical Manufacturing Facility (CMF)
The 9000 sq. ft. facility located on the main campus of Nationwide Children’s Hospital on the 3rd floor of Research Building III consists of 7500 sq feet for GMP production. 1200 sq feet is dedicated to Cell Based Therapies. The facility accommodates multiple simultaneous productions and is designed to be flexible and adaptable to new processes, equipment and technology. Designated spaces for Research productions and Quality Control testing are also included.
Clinical products suitable for Phase I and Phase II clinical studies produced in this aseptic processing facility are compliant with FDA regulations (CFR 21 Part 11, 210, and 211) and that will ensure the safety, identity, purity and strength of the manufactured biologic . Multiple clinical products have been successfully supported for Phase 1 IND’s and EU Clinical trials directly as an institution and indirectly as a Contract Manufacturing Organization (CMO). All vectors are manufactured using cGMPs and follow a linear flow of unit operations from scale-up of producer cells in single use Corning Cell Cubes or Stacks to manual/semi-automated final fill operations.
The CMF design allows for controlled access, achieved using an electronic card key system. Environmental control within the facility is achieved using dedicated HVAC units that provide an ISO class 7 clean-room environment through a cascading system of room pressure differentials that allow for room isolation to assure proper segregation is maintained.
CMF processes are directed by over 100 Standard operating procedures (SOPs), Job Aids (JA), and Master Batch Record (MBRs) documents. This regulatory compliant document structure ensures that management-approved procedures are followed to ensure the integrity, reproducibility, and quality of data. Approved procedures serve multipurpose functions: (i) they reduce the introduction of errors and variables by ensuring the consistent use of appropriate procedures; (i) communicate to the necessary people (e.g., client, project personnel) how work is to be conducted; (iii) increase the effectiveness of training by clearly and consistently communicating the approved method of performing a procedure, (iv) provide a historical record of technical procedures, and (v) provide a basis for data comparability. SOPs govern the use, maintenance, and calibration of equipment, analytical procedures, chain-of-custody procedures, data management and documentation procedures, and records management.
The QC Lab contains 750 ft2 of general laboratory space and an additional 100 ft2 of separate microbiology lab in a controlled access area on the 3rd floor of the Research III building. Major equipment includes 6 BSCs (Type A2) that are used for tissue culture, microbiology, and qPCR Master Mix Preparation. Sample storage and incubation capabilities include: 2 Thermo Forma Model 3110 Water Jacketed CO2 Incubators, 2 Forced-Air Incubators (22.5°C and 32.5°C), 2 Refrigerators, 1 -20°C Enzyme Freezer, and 1 Thermo Forma Ultra-low Temperature Freezer. Sample centrifugation equipment includes 2 refrigerated tabletop centrifuge (includes tissue culture plate adapters), 1 microcentrifuge, 1 PCR tube centrifuge, and 1 Sorvall Spin-Vap. Data acquisition and other general equipment include 3 ABI 7500 Real-Time Sequence Detection Systems, 1 Bio-Rad Chemidoc Touch imaging system, 1 Bio-Tek Synergy2 Plate Reader with UV/VIS and Fluorescence modules, 1 NanoDrop ND-1000 Spectrophotometer, Charles River Laboratories EndoSafe-PTS Endotoxin detection system, 2 PCR Thermocyclers, Malvern Zetasizer Nano-S particle sizer, Bio-Rad ddPCR system (Auto DG and QX200), MACSQuant flowcytometer, inverted tissue culture microscope, electrophoresis units and power supply, Life Technologies eGel, NuPage, Bolt, and iBlot Electrophoresis systems, orbital shaker, analytical balance, pH meter, filter integrity testing system, adjustable micropipettes, and water baths. Based on the equipment outlined above, the QC Lab has capabilities in qPCR, general tissue culture, viral infectivity assays, in-vitro potency / expression assays, protein and DNA electrophoresis, western blotting, host cell protein quantification, host cell DNA quantification, mycoplasma detection, ELISAs, filter integrity (bubble point) testing, incubation and analysis of microbiological environmental monitoring samples, bioburden testing, and sterility testing. Additional capabilities through partnerships with contract labs include analytical ultracentrifugation analysis, plasmid and viral DNA sequencing, bovine and porcine viral detection (CFR 9), detection of a wide range of viral agents (through qPCR and RT-qPCR), and in-vitro/vivo detection of adventitious agents.
The Quality Assurance (QA) team at NCH ensures that the products manufactured and tested at the Clinical Manufacturing Facility meet quality and regulatory standards. This is achieved through implementation and maintenance of an effective Quality Management System, and a constant emphasis on quality and process improvement initiatives. QA has oversight on all phases of manufacturing including materials management, document and records control, and Quality Control testing. QA is responsible for an overall review of production records before releasing the product to the client.
The QA team consists of QA Manager, QA Auditor and QA Specialists. This team brings over 60 years of combined industry experience in areas of AAV manufacturing and testing, licensed pharmaceuticals, auditing, document control, quality improvement and process monitoring. The QA unit has successfully facilitated numerous client audits including audits to endorse regulatory requirements for Health Canada and European Medicines Agency (EMA). Organizationally, the Quality Assurance team reports to the Director of Research Compliance, and functions independently of CMF Management.