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
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
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 (
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 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 University
of Newcastle 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:
Reactions undertaken in AstraZeneca’s Large Scale Laboratory in the
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.