Media Fill Evaluations in Cellular Therapy Product Manufacturing: Three Possible Approaches. Doug Padley Mayo Clinic

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1 Media Fill Evaluations in Cellular Therapy Product Manufacturing: Three Possible Approaches Doug Padley Mayo Clinic

2 Media Fill Evaluation Process Simulation Manufacturing process performed using microbiological growth medium. Resultant product incubated to detect contamination Gives an estimate of the potential for real products to be contaminated during manufacture Sterile Drug Products Produced by Aseptic Processing

3 Media Fill Evaluations Analyze the process to be simulated Design MFE manufacturing process SOPs Packaging of media Sizes and container similar to real life Worst case scenarios Environmental Operator induced Set criteria for success Depends on how MFE are used

4 Media Fill Evaluations: Three Suggestions Required Training Ongoing Competency and/or Environmental Assessment Specific MFE for each new manufacturing process Technology transfer Multiple manufacturing sites

5 MFE for Training Goal is to assure new staff have adequate aseptic technique in a no risk environment Skills based rather than process based Should include the range of skills used in day to day manufacturing operations Include observation to coach and correct poor aseptic technique Requirement for X sterile media fill(s) before independent manufacturing Non-punitive

6 MFE for Competency/Environment Assessment Staff required to perform X MFE per year One for each process if multiple products manufactured In large facilities rotate MFE among BSC or clean rooms What to do with positive MFE Staff can t t process until sterile MFE? BSC or clean room out of service?

7 MFE for New Products or Technology Transfer MFE program and plan is created during product development MFE is specific for each new manufacturing process May be required for contract manufacturing or multi-center clinical trials with multiple manufacturing sites What to do with positive media fills Is manufacturing on hold until sterile media fills?

8 Case Study: MFE Use in a Large Cellular Therapy Laboratory >20 technical staff, 6 clean rooms, > 20 BSC Mix of 351 and 361 products Prior experience with MFE through contract manufacturing Implemented MFE across entire laboratory

9 MFE Program 2 MFE required for training At least one MFE per person per year Based on processes performed Two levels of MFE Level 1 modeled on PBPC processing Level 2 combined more open steps, complex processing, and overnight hold Surrogate for all complex manufacturing Goal was to rotate MFE throughout facility and BSCs

10 MFE Program Results March 06 July staff performed 30 MFE Level 1 n = 24 Level 2 n = 6 All MFE culture negative including 4 by trainees One Level 2 MFE performed with intentionally poor aseptic technique was culture positive

11 MFE Program Results Review of culture positive products during the same time period All culture positive products were associated with bacteremia or line infection in donor No evidence that lab process was introducing contaminants MFE program changed based on review of data Discontinued annual requirement Still required for initial training

12 A Risk Based Approach to MFE The main purpose of MFE is to help assess risk of product contamination during manufacture. MFE data by itself is not very useful Evaluate all aspects your manufacturing, including staff, raw materials/donors and post manufacturing activities Determine which are higher risk/higher impact Develop systems (MFE might be one of many) to address the high risk areas Continue to monitor systems for changing patterns and shifting of risk

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14 Conclusions MFE are a useful component of process control MFE can enhance aseptic technique training MFE data should be analyzed in conjunction with other laboratory data Product contamination rate and investigations of positives Environmental monitoring results Personnel monitoring HVAC/Facility performance