Tuesday, 16 July 2013

F3 Factory Case Study: Continuous Processing for Pharmaceuticals

This AstraZeneca led case study for in the F3 Factory project focused on the development of a proof of principle concept for the flexible, continuous production of pharmaceutical development materials for toxicological and clinical studies.  Working with academic partners KTH Institute of Technology, Denmark Technical University (DTU), Newcastle University and Karlsruhe Institute of Technology (KIT), as well as industrial partner Britest, the project developed and validated a new generic transformation methodology for the formation of pharmaceutical intermediates.

One of the biggest challenges facing the international pharmaceutical industry is the ability to offer a flexible response to the production of new materials for toxicological studies (both in vivo, in vitro).

The F³ Factory approach to providing a “one size fits most” process synthesis for the production of intermediates for ‘Campaign 2’ material offers an opportunity to build a faster and more flexible response to this requirement by:
  • reducing the cost of process development
  • increasing throughput and improving robustness
  • increasing manufacturing flexibility
Mindset barriers
New transformation methodology
  • development of a novel isolation technology (in conjunction with KIT) to isolate solid material, evaporate solvent and achieve uniform solid beads
  • development of a new continuous, micro-structured reactor (in conjunction with KIT - see image of a microstructured reactor plate below) capable of handling dispersed solid catalyst and a slurry feed, thus removing the need for fixed bed technology
Continuous manufacturing technologies for work-up in final stage active pharmaceutical ingredient synthesis are also of major interest to AstraZeneca.

A key barrier to overcome in this context was a mindset issue of “we’ve always done things this way, so why change” and/or “if it isn’t broke why fix it?” In recent years there has been some progress in this respect across the pharmaceutical industry but there is more progress to be made.

There are also Quality Assurance issues to overcome with regard to continuous processing versus batch manufacture – for example. how to define ‘in specification’ and ‘out of specification’ material.
Nitro reductions were selected to test the F3 Factory concept with transfer / catalytic hydrogenation identified as key options. A generic process and Substrate Adoption Methodology (SAM) were developed with DTU and Britest to enable more effective screening of molecules before they evaluated in the reactor.

A Risk Assessment Methodology (RAM) was also developed by the University of Newcastle to understand the value of the F³ Factory approach, not only in economic terms, but also in terms of reducing business risk in general.  For AstraZeneca, the RAM provided a structured approach and useful visualisation of risk assessment processes undertaken as a matter of routine.

Key technical features of this project included:

Project results
Reactions undertaken in AstraZeneca’s Large Scale Laboratory in the UK fully validated this new transformation methodology. A semi-modular production unit, with the ability to install different PEAs (process equipment assemblies) depending on the chemistry required, were installed successfully. AstraZeneca is now evaluating this new production unit for drug projects and obtaining better yields (mid 70% continuous versus 50% batch).

AstraZeneca recognises the value of collaborating in European Commission Framework projects as an important and practical means of supporting and enhancing its own internal research and development activities. It recognised at an early stage that the aims and objectives of the F³ Factory project aligned closely with its own research objectives and that the collaborative aspects of this large demonstrator project could lead to step-change process innovation in the development of new pharmaceutical compounds.

More information
For more information visit the F3 Factory Project website or contact Anil Mistry at AstraZeneca.

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