Process Analytical Technology (PAT) Tools for Pre-Clinical Pharmaceutical R&D

International Process Development Conference

Aug 20, 2008

Ben Littler (Vertex Pharmaceuticals, Inc., USA) reported on the use of Process Analytical Technology (PAT) in Pre-Clinical R&D to speed development and reduce time to market. The presented case studies illustrated the use of in situ FTIR reaction monitoring (ReactIR) and heat flow (MultiMax) to meet these objectivies.

ReactIR 45m with ConcIRT for real-time reaction monitoring

Ben Littler (Vertex Pharmaceuticals, Inc., USA) reported on the use of PAT in Pre-Clinical R&D to speed development and reduce resource needed to increase the number of compounds moving through pre-clinical and reducing time to market. Case studies illustrated the use of in situ FTIR reaction monitoring (ReactIR^TM) and heat flow (MultiMax^TM) to meet these objectives.

Background
Early pharmaceutical development was described as the period of research activity between lead identification and clinical proof-of-concept and/or proof-of-safety. In this period, there is a high risk of failure of any candidate drug molecule. General objectives included being able to deliver a process that can produce batches up to 25kg in quantity, to be able to do so rapidly and safely in multipurpose equipment. The advantages of achieving these objectives as quickly as possible were described as being favored by regulators by being first to file (NDA), significant financial advantage by having longer patent protection ($1.1M/day in revenue) and by having more time to develop additional candidate molecules.

Approach
Mid-IR analysis is considered a simple and intuitive tools for the organic chemist. Information is generated quickly and easily. Recent advances in hardware and software were highlighted as being key in their capability to implement ReactIR^TM technology. Most significant was the power of the ConcIRT^TM algorithm to automatically evaluate complex reaction data. Several case studies were presented. One example showed a "simple" reaction that exhibited unsafe thermal behavior when heat flow measurements were analyzed. Heat flow analysis proved the reaction was auto-catalytic, allowing them to develop a safe and scalable process.

Results and Conclusions
ReactIR^TM and the ConcIRT^TM algorithm were able to detect subtle changes in the spectra of a complex reaction allowing the precise detection of reaction endpoint. This resulted in the reduction of the reaction hold time from 18 hours to 4 hours. New software and hardware allows them to add mid-IR monitoring to a reaction in about 5 minutes. ReactIR^TM is used frequently to monitor reactions that are difficult to monitor by HPLC, such as Hydrogenations, reactions that are air sensitive, and reactions involving compounds that have poor UV absorptions.

Heat flow is simpler and faster to perform than full calorimetric studies. Even in pre-clinical R&D, it allows them to develop reasctions that are dose-controlled and readily scaled-up. It allows them to identify and avoid reactions that may be hazardous due to accumulation. Heat flow is described as a "classic fingerprint" that can be recorded in large vessels allowing them to effectively transfer the monitoring during scale-up ensuring that safe reaction conditions are maintained.

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