Establishing Standard Operating Procedures
One of the first steps any cell processing facility should take is to establish standardized operating procedures (SOPs) for all workflows and processes. Having clear, written SOPs that all employees can refer to helps promote consistency in techniques and reduces errors. It is important that SOPs outline equipment specifications and settings, reagent amounts and storage conditions, thawing and passaging methods, quality control checkpoints, and documentation requirements. Regular training and competency assessments can help ensure all team members are following the established SOPs correctly. A company should review their SOPs at least annually and update them as needed based on process improvements or new equipment/reagents.
Automating Repetitive Tasks
Many cell processing tasks such as centrifugation, dispensing of media and reagents, and freezing of cell banks involve repetitive manual labor that is prone to human error. Automating these processes can help boost efficiency and consistency. For example, automated liquid handlers and centrifuges reduce the chance of mix-ups compared to manual pipetting and improve throughput.
Closed Cell Processing systems that integrate all workflow steps in controlled environments offer full digitization and traceability of processes. While automation equipment requires an up-front investment, reducing human error and hastening workflows through automation can significantly lower overall processing costs in the long run.
Implementing Quality Management Systems
Adopting formal quality management systems helps demonstrate process and product quality to regulators and gives operations structure and oversight. Systems such as cGMP, ISO 13485, and 21 CFR Part 11 compliance incorporate elements like document control, supplier management, corrective and preventive action management, change control protocols, and electronic record-keeping. Regular audits and management reviews ensure continued adherence to such standards. Microbial monitoring plans, process validations, and analytical testing provide scientifically-sound methods for evaluating product safety, identity, purity and potency. Having a robust quality system instills confidence in cell therapy developers and regulators about a facility’s ability to consistently produce high-quality cell products.
Streamlining Freezing and Thawing
The freezing and thawing of cell products and cell banks is a critical operation that requires careful optimization. Having SOPs detailing appropriate cooling rates, controlled-rate freezers, and validated thawing methods helps ensure cell viability is retained. Some procedures that can improve these processes include development of consistent cell formulations for freezing with optimized cryoprotectant concentrations, use of automated data-logging freezers and thawing devices, implementation of barcode tracking of cell containers, and use of controlled-rate freezing containers that hold multiple samples. Facilities should validate that post-thaw cell viability and other quality attributes consistently meet acceptance criteria following their standardized freezing and thawing processes.
Inventory and Distribution Tracking
Robust inventory management systems allow for full traceability of cell products from receipt of starting materials through processing, storage, release, and distribution. Features like lot numbering, expiration date assignment, barcode scanning, and electronic product records facilitate quality inventory tracking. Ensuring accurate stock levels of raw materials and finished goods is critical for maintaining production schedules. Implementing just-in-time production planning aligned with customer demand can help avoid excess inventory holding costs. Appropriate storage conditions must be maintained and monitored for cell therapy starting materials, work-in-progress, and final products. Distributions should incorporate validated shipping methods along with electronic chain of custody documentation to ensure product quality and compliance with regulations.
Lean Manufacturing Principles
Adapting lean manufacturing principles from the automotive industry can optimize cell processing workflows. Methods like value stream mapping identify non-value-added activities that can be eliminated through process improvements. The 5S methodology (Sort, Set in Order, Shine, Standardize, and Sustain) promotes well-organized facilities and standardized work areas. Systems like one-piece flow processing and pull production signaling triggered by downstream demand requirements rather than bulk batch production can reduce waste. Cell processing facilities should always be examining ways to cut down non-value-added tasks, motion, waiting time, defects and overburden through implementation of lean concepts. Such initiatives usually require changes in facility layout, equipment, procedures and company culture. However, they have proven effective at substantially increasing productivity and throughput.
Quality by Design Approach
Adopting a “Quality by Design” mindset from the earliest stages of process development lays the foundation for robust, reproducible manufacturing. At the research stage, applying risk assessment tools to methodically evaluate critical process parameters and sources of variability allows their impact on cell product quality to be understood. Design of Experiments testing then aids in process optimization. Developing processes with appropriate in-process controls and real-time monitoring further ensures consistent performance as operations expand to larger commercial scale. Ongoing technology transfer qualification between labs, manufacturing sites and contract providers is also fundamental. Thorough process characterization, validation, and continuous improvement based on product and process data collection deliver a firm state of control that regulatory bodies expect to see for advanced therapy approval and ongoing compliance.
implementing strategies for standardization, automation, quality management, lean principals and quality by design enables cell processing facilities to maximize productivity, efficiency and regulatory compliance for advanced therapies. Adopting these types of continuous improvement philosophies helps optimize operations and ensure consistent, high-quality cell products are delivered to patients.
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