By Michael Fiske, M.S., director, Upstate Stem Cell cGMP Facility (USCGF)
CGMP regulations incorporate the concept of quality by design (QbD). This concept is used in conjunction with a quality management system (QMS) aimed at controlling the collection, processing, storage, and release of human medicinal products. “Control” is the most important concept underlying all aspects of a cGMP. A well-managed facility must have systems for each aspect of cGMP and for the documentation of that control. Good documentation practices include:
- procedures written and approved for all programs and policies
- SOPs for the operation and maintenance of all equipment, processes, and test methods
- production and testing records documenting the complete history of each production batch
- deviation documentation and investigation records.
All the factors, systems, and methods relevant to cGMP need to be considered and evaluated when the physical space is being designed. Control must be the foundation of every aspect of cGMP facilities. For example, if instruments and equipment are well-controlled (calibrated, validated, maintained, and monitored), then the processes they support, and in turn the products of those processes, are more likely to be uniform and of high quality. Critical utilities and equipment, as well as processes and test methods, all need to be validated and controlled appropriately.
DESIGN CHARACTERISTICS OF CELL-BASED CGMP FACILITIES
The design of a cell-based cGMP facility must support the manufacturing of cell-based medicinal products (CBMPs) that are safe, pure, and effective, while eliminating the risk of contamination, errors, or cross-contamination during production. The design must also ensure biosafety, minimizing the risk of employee contact with infectious agents and prevention of the release of infectious agents into the environment. Important aspects of designing a cGMP-compliant production facility include:
- design features that reduce the risk of microbial contamination as well as the risk of product cross contamination (e.g., segregated air handling systems for adjacent production areas as well as control of appropriate room pressure differentials to ensure maintenance of specific room classification)
- access control to the facility, restricted access to critical areas
- mandatory unidirectional traffic flow (for personnel, raw materials and supplies, equipment, CMBP, and waste)
- design features for ease of cleaning: seamless floors, walls and ceilings, minimal ledges, easy-to-clean materials (gelcoat polymers, epoxy paint, stainless steel), use of receptacle and light switch covers, and movable equipment and tables.
ENVIRONMENTAL MONITORING PROGRAM
Cell-based cGMP facilities are required to have a comprehensive environmental control program. Key components include systems for ongoing continuous environmental monitoring. Environmental monitoring ensures that controlled-environment manufacturing areas, as well as critical process and storage equipment, continuously comply with design intent and user requirements. These systems provide information about the performance of the equipment and the heating, ventilation and air-conditioning systems, as well as data on the effectiveness of aseptic practices and cleaning procedures.
QUALITY MANAGEMENT SYSTEM
Some basic but essential elements of the quality system for a cell-based cGMP facility include document-control and change-control systems, validation support, supplier qualification, inventory management of raw materials and CBMP, and preventive maintenance and calibration programs for all equipment. Oversight of routine quality control testing, CBMP release, and environmental monitoring are also included, in addition to personnel training programs and auditing.
Before any batch of CBMP is distributed, a high degree of assurance in the facility’s performance and the manufacturing and testing of CBMP must be attained.All aspects of the facility’s environmental control are validated as well as all manufacturing and analytical testing equipment. In addition, many of the analytical test methods used to characterize the final product are validated.
The validation program must address all the elements of the facility and operations, including:
- production equipment
- analytical testing equipment
- temperature-controlled chambers
- computer systems (equipment control, data acquisition, and monitoring systems)
- cleaning and sterilization procedures
- production processes
- analytical test methods
- shipping protocols.