With the FMEA completed and the process parameters identified, the next step is to qualify the scale down model. One question that I've been considering is, "does the qualification lend itself to phase appropriate strategies?"
During efforts that carry a program from a research molecule to IND, there will most likely be a limited number of lots manufactured that lead to a limited process experience. Further, for biologics the process can be expected to evolve under the pressures of cell culture optimization. With such a dynamic process in place, a classic strategy for the purification team would be to leverage the knowledge from 1.5 cm and 10 cm column performance for establishing the scale-down model. At these scales, the drug substance being generated is typically for pre-clinical research and is completed within the development lab. As a result, the team has a clear picture of the scale comparability. For example, the tubing type, plumbing length, pumps, on-line meters, etc., can all be evaluated along with the change in column scale (a 44x scale-up in this case). When combined with the chromatographic performance and process performance (elution volume, recovery, etc) at each scale, the team can document the starting point of the process development history. This also presents an opportunity to leverage process knowledge from the literature into the scale-down documentation and create a foundational document for future process development activities.
As the program moves into pivotal phase 2 status, the push is to deliver material to the clinic in sufficient quantities to support the clinical program. With a bit of luck and great planning, the cell culture process has been completed to the point that they can be scaled-up. For companies working with their CMOs, the path to scale-up becomes a bit more challenging as the purification equipment to support an 80 cm column is much different than that of the earlier models: the scale difference is 2844 between an 80 cm and 1.5 cm column. The plumbing becomes stainless steel, the hold up volumes increase, water quality, and the differences continue and all will need to be documented. Looping back to a previous post, the qualification of the laboratory-scale model presents a good opportunity to initiate (or revisit) the FMEA to prioritize the scale differences with the greatest potential to impact the process and product quality attributes. To bridge the scale performance back to the early phase results, data from the 80 cm columns has to be compared with data from the laboratory-scale models. To maximize the opportunity for success, the ideal situation would be to use process eluate retains from the clinical manufacturing scale in the laboratory-scale models whose process parameters are run as close as possible to those at clinical manufacturing scale. An important point to consider is that there are relatively few raw material lots being used in the cell culture process during this stage of the program. Consequently, the anticipated variation in the product quality will be relatively modest and this will need to be included in the discussion of the scale-dependent, or independent, process performance or product quality differences.
What are the metrics establishing the scale down model? Based upon the above discussion, the argument can be made that these metrics will change, and become more robust, with the phase of the program (see links at the start of this entry). Documenting, and providing scientific justification, through the drug development stages will establish the basis of the QbD program because the laboratory-scale model qualification links the design space knowledge to the manufacturing scale. The importance of this link cannot be under appreciated when the time comes to file the commercial process because the sponsor will have to provide a scientifically sound justification that the results obtained in laboratory-scale models are predictive of the process at manufacturing scale.
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