Non-Scalable Parameter Justification

At some point in late-stage process development parameter justification becomes an important aspect in the overall control strategy of the drug product. Some effects of the non-scalable process parameters cannot be properly investigated by laboratory scale experimentation due to limitations in equipment. Therefore, at-scale parameter justification is typically required to properly address the adequacy of the non-scalable parameters and more importantly the operating limits. In most CMC development projects this type of experimentation is constrained by availability and cost of drug substance and the possibility to squeeze in batch productions in between the ongoing clinical and commercial productions in the GMP manufacturing facility. Ultimately it comes down to what data is needed to document process robustness and create comfort for the production unit for future routine productions.

Prior to designing the parameter justification studies a systematic CQA based process impact assessment should be conducted to create an overview on relevant process parameters, operating ranges and process controls. Out of this overview the relevant parameters should be selected for further investigation.

In below depiction, the parameter space shown covers the common compounding process parameters. As a minimum the hot spot illustrated with the red circle should be justified by at-scale experimentation. In biologics project this would represent the worst-case combination from a stability point of view.

It should also be considered whether the purple parameter combination is relevant especially in biologics projects where molecular dynamics can be a key factor in stabilizing the molecule.