Anticipation of scale up issues in pharmaceutical development
Chemical Product Design and Engineering (CPD&E)
Chemical Product Design & Development - IV (CPD&E - 4)
Keywords: Batch Process, Process Development, Scale up, Risk
Anticipation of scale up issues in pharmaceutical development
Frans Muller, John Latimer (AstraZeneca)
The pharmaceutical industry is currently expanding the role of process engineers from their traditional roles in chemical manufacturing and capital projects. Significant process engineering populations can now be found in process development, which has typically been the domain of the process chemist. Some drivers for this trend are the regulatory push for increased process understanding, and the frequency at which scale up issues occur in processes moving to commercial scale (Sherlock & Brewis 2006). This paper is focussed on identifying scale up issues in batch processes early in development.
Hulshof (2000) demonstrates that scale up problems lead mainly to loss of yield, productivity or quality. An additional issue in the pharmaceutical industry is the high cost of any delay in the drug reaching the market. Hulshof identified the main cause of scale up problems to be related to mass transfer and mixing, followed by longer processing times and heat transfer.
The basis of a batch process is the process recipe. A typically recipe is often 30 to 50 operations to convert raw materials and intermediates in to the next intermediate or final product. The paper reviews the nature of the operations, and concludes that most batch processes have a multiphase aspect. One can infer that the chance of encountering a scale up issue in batch process development is thus high.
In this paper we present a Scale Up Risk Evaluation (SURE) tool that is developed to anticipate scale up issues early on in the development of a new compound. The principal of SURE is based on that of a hazard and operability study (HazOp) for each operation in a process recipe various scale up/down scenarios are identified. A scenario represents an unplanned change in conditions from those specified in the recipe. The potential impact of a scenario on the process is qualitatively assessed and identified as a “threat” or an “opportunity”. The scale up scenario is then scored on:
(i) The likelihood process conditions change with scale
(ii) The likelihood the operation affects the product quality or process operability.
A number of examples from SURE studies will illustrate the use of the tool.
The output of a SURE study is risk matrix, and a prioritised list of the threats and opportunities that provide development drivers for the development team. We conclude with an analysis of the data generated by SURE studies in AstraZeneca that demonstrates how risk changes as processes move through the stages of development.
Sherlock J.P., Brewis N, 2006. AIChemE Process Development, Symposium, June 11-14 , 2006, Palm Spring, CA, USA
Hulshof L.A, 2000. Organic Process Research and Development, July 10-12 2000, Montreal, Canada.
See the full pdf manuscript of the abstract.
Presented Thursday 20, 11:54 to 12:12, in session Chemical Product Design & Development - IV (CPD&E - 4).
