Process Optimisation Protocol

A useful approach to process optimisation is to identify all the critical process parameters that could potentially affect product quality or performance and prepare a Process Optimisation Protocol. Typically, data used to identify critical process parameters will be derived from laboratory or pilot-scale batches, and do not need to be confirmed on full-scale batches unless the control of the particular parameter can only be evaluated on a production scale. There is good incentive to use the production facilities at the earliest opportunity, drug availability permitting, to iron out any transfer difficulties. Manufacture of the stability batches to support Phase III studies, and also the Phase III clinical batches, at the final commercial site should minimise any questions from the FDA during PAI about possible differences between R D and Production process used. 

The Process Optimisation Protocol should outline the programme of work required to evaluate the effect of changes in the critical variables on product quality. This is in order to establish the working limits within which the process consistently produces product which meets specification. Critical parameters may include... 

One of the most attractive features of the IL/CO2 approach to homogeneous catalysis is the development of continuous processes [7]. Consequently it needs to be demonstrated that the combination of a suitable IL and compressed CO2 can offer more potential for process optimisation than just a simple protocol for batch-wise catalyst recycling. As an example we were able to activate, tune and immobilise Ni catalyst 13 in a continuous-flow system for the hydroviny-lation of styrene (Scheme 3). Styrene is co-dimerised with ethene yielding 3-substituted 1-butenes [26,27]. We could show that this powerful carbon-carbon bond-forming reaction can be achieved with high enantioselectivity in batch-wise operation and in continuous-flow systems. 

On completion of the work programme, a Process Optimisation Report should be written. This will summarise the results of the activities specified in the protocol and provide a rationale to define the operating limits for the process and the critical parameters affecting product quality or performance. The report should also conclude that the specifications for the raw active, excipients, components, in-process and product can be met. 

The second period corresponds to the quality period the quality process increasingly optimises the product, introduces the concept of feedback, rigorous procedures or protocols to satisfy customers it gradually eliminates the initial defects to optimise customer satisfaction. Regulatory constraints increase in parallel with this process. Hale et Swuste [5] identify rules at three levels which also represent three characteristics of risk management policies at this stage ... 

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