Integration of Chemical Engineering Science into Pharmaceutical Process Research and Development
Multi-scale and/or multi-disciplinary approach to process-product innovation
Keynote Lectures: Theme-3
Keywords: Process development, Pharmaceutical industry, Chemical engineering
Introduction
Process development in the Pharmaceutical industry has been typically the domain of the process chemist with support provided by engineers only for asset development and modification. Increasingly however, process failures upon moving to commercial scale, the regulatory push for increased process understanding and increasing legislative constraints have demanded a different skill set to be brought into early development. Chemical engineering provides a blend of skills well suited to delivering the changes demanded by the industry, but working in rapidly changing environment of early process development brings a new set of challenges. Furthermore an understanding of the unit operations and the interaction of physical and chemical phenomena that occur within equipment is sufficient for the resolution of simple pilot plant related problems but potentially inadequate for process design. Bringing chemical engineers into early development is not straightforward but the rewards associated with successfully bringing chemical engineers and synthetic chemists together are high. What then must be done to mine the value at the chemistry – chemical engineering interface?
Role of Chemical Engineers in AstraZeneca Process Research and Development (PR&D)
PR&D is responsible for delivering drug substance for development activity and a manufacturing process suitable for commercial material requirements. The latter is typically achieved through the solution of problems that arise during development using chemistry solutions and scale up heuristics. Rarely are the demands of the commercial process considered until initial drug substance demands are required. The chemical engineer working in process development is therefore responsible for the development of a robust and scaleable manufacturing process through the application of experimental and theoretical process engineering science. Through this a long term view is brought to the process development strategy that ensures SHE issues are raised and resolved, bulk drug capacity requirements are achieved and the most appropriate innovative technologies exploited.
The above applies to the later stages of the development pipeline, where time, although important is determined more through success in the clinic than success in the laboratory and pilot plant. Furthermore the route has often been selected and the chemistry is not changing as rapidly or as frequently as it does very early in development. Speed is critical at this time, and during a very short period of time a final route may be selected and scaled up to deliver kilogram quantities for and opportunities to
To deliver this, much of the work of the chemical engineers must be done at the interface between chemistry and chemical engineering and at the time solutions are required. The concept of unit operations is still appropriate though a more detailed molecular level understanding is required, particularly in key areas including crystallisation, mixing and transport phenomena, solvent selection and physical property prediction and reaction engineering. Other areas that require the integration of chemical engineers into process development concern the implementation of alternative and potentially novel technologies and engineering solutions and the development of a predictive capability. Brief examples of the role of chemical engineers in these key areas will be used to illustrate the progress that has been made with respect to the integration of chemical engineers into process research and development.
Chemical Engineering Science and Alternative Technologies
Given the time pressures in Pharmaceutical Process development and the regulatory need to freeze synthesis and process development, there is a tendency to run technology lean. It is often the case that equipment selection does not take place given the number of alternatives available to be low. There are a number of good reasons for this, but introducing chemical engineers to early development allows alternative technologies to be considered on a timescale relevant to the development project. Further work is necessary to respond rapidly enough to ensure technology solutions rather than sub-optimal chemistry fixes.
The approach being taken by AstraZeneca with respect to the implementation of microreactors and other alternative reactor technologies (e.g. microwave) during the development of processes for API production will be presented to exemplify the approach being taken. The importance of understanding the characteristics of both the chemical reaction and the reaction device will be explained using AZ experiences and case studies. In particular, the types of synthetic chemistry commonly encountered in process development, which work optimally in novel reactor technologies rather than in stirred tank reactors will be highlighted. A methodology used to characterise the devices will be described together with experience gained from investigating the switch from batch to continuous for a potentially high tonnage compound using microreactors and process intensification.
Predictive Capability
One very simple example of a predictive capability provided by chemical engineers in PR&D is an appreciation of process throughput. The throughput of a process defines the amount of material (in grams, kilos or tonnes) that can be manufactured per unit time (seconds, hours or years). Key variables that influence throughput of a process include (i) the chemical yield (ii) the capacity and number of processing vessels and their availability (iii) the “cycle time” (iv) limiting concentrations of the various stages and (v) number of unit operations (linked to the number of chemical steps).
Throughput issues may not be identified until late in development, potentially only upon transfer to manufacturing. This is due firstly to the implicit influence of commercial scale plant considerations on throughput calculations, but secondly because development drug substance is delivered in campaigns that can be planned off the critical path of the development plan. However, consideration of throughput issues earlier than TT can benefit Process R&D in several ways. Increasing process throughput will potentially increase plant availability allowing more compounds to be processed. Identifying the volume or time limiting operations will allow optimisation work to be focused and directed to those operations that add most value. An understanding of throughput will improve the interaction and communication process at point of process transfer to manufacturing. Finally, the manufacture of the first GMP batch is typically on the critical path of the development process as no other work can start until material is available. Throughput will therefore critically affect delivery time and is therefore an important factor to consider.
An approach will be presented that allows throughput to be considered very early in development and then developed to determine the issues at commercial manufacturing scale. These issues and their resolution provide both focus and steer to the subsequent development.
Keynote Lecture
Presented Monday 17, 17:05 to 17:45, in session Keynote Lectures: Theme-3.
