COMMENT
Catalytic future N
ew product route definition and commercialisation remain a largely subjective exercise in the pharmaceutical sector. This obvious difference from
aerospace, electronics, and even a consumer goods supply chain, has many underlying causes. It is widely believed that the requirement for the
validated launch of a drug substance with defined purity and physical form is the difference, but this is a gross oversimplification. Often, new products are forced to fit into existing internal and external supplier networks, influenced by tax and treasury, capital allocation and intellectual property. The prevailing theme is sufficiency rather than efficiency, with ‘file on time’ as the undertone. Many believe that supply chains will be opti-
mised over the life cycle of the product, and feel re- assured by the inability of marketers to accurately forecast the demand for the new product. The loss of revenue and reputation by a delayed launch or stocking out ensures conservative behaviour. Deci- sion makers sitting in R&D organisations remain insulated by high gross margins, and frequently project blame on a complex and bureaucratic regu- latory framework. Nobody is surprised by a supply chain that is long, complex and with an inventory turnover as low as one per year. How can pharma get better by making more sophisticated choices to meet ever increasing soci- etal, business and environmental needs? The cost and capacity advantages of emerging
markets are eroding and we can no longer extract significant value. We need to improve by an order of magnitude, defining routes that are fundamen- tally more efficient, sustainable and that produce less waste. Metrics, including life cycle analysis, need to become more transparent. Optimising the overall synthetic sequence from
commodity raw materials, ideally in a single unit operation, will drive invention and eliminate regu- latory complexity. Not surprisingly, this approach will remove cost but the incentives are misaligned and need to become more agile; experimenting with new chemistry principles rather than relying on the chemistry we know. This can only be achieved by a stronger emphasis on catalysis, which is currently only used in a small fraction of the steps in pharma manufacturing. Even more remarkably, ‘catalysis’ often doesn’t meet the definition that we learn as undergraduates. We need to move beyond the novitiate stage so the catalytic process becomes the accepted baseline of success. This change requires new thinking since we all
realise catalysis creates novel unique bond-forming reactions but we find implementation difficult. For example, in an emerging area of photo catalysis, new and elusive reactivity is being exploited by merging concepts usually employed in light har- vesting rather than pharmaceutical synthesis.
This merger of concepts makes new commodity
feedstocks available and allows for once complex structures to be readily accessed using light. Elec- trochemistry, already an environmentally sustain- able method for oxidation or reduction, provides an opportunity to design new catalytic processes via mediators to achieve indirect processes much like the use of photons. Adoption will require new skills and thinking, and a willingness to retrain or relearn. Biocatalysts are frequently hailed as the manu- facturing future and are predicted to displace con- ventional chemistry. We still need to address their overall efficiency after a grace period as a ‘green technology’ – the concepts of life cycle analysis, atom economy or energy utilisation should still inform our thinking. Nature has evolved control systems of ‘repair,
reuse and recycle’ to maintain overall efficiency in biological processes. An ability to fix errors by design gives the opportunity for catalysts to check work in progress through proof reading. Direct reversal of non-productive pathways, like damage repair, would eliminate the generation of impurities. We can harness similar approaches designing a
network or cascade that can convert commodities into high value pharmaceuticals in a single step. This will reduce processing and remove a regula- tory burden since purification always negatively impacts efficiency, speed, compliance and cost. Approaches to define novel catalytic routes via
high throughput experimentation, predictive science and data analysis are important. These have to become faster and reliable enough to support the regulatory validation. Significant opportunities will be captured by machine learning algorithms that optimise overall processes to predefined attributes rather than optimising individual chemical steps. Finally, ‘design for quality’ will be built in rather
than ‘testing for quality’, removing other inefficien- cies. By leveraging supplier or competitor networks for common or closely related materials, we can ex- ploit approaches routinely used in other industries. I recognise the narrative of reducing cost, sustainability, improving quality and supply chain velocity isn’t new. There are other concerns about return on investment, and catalysis will drive inven- tion there. At this end of the business, pharma will remain difficult to disrupt since we largely behave as a cottage industry in process R&D and academia. We need to advance an innovative future before
change is thrust upon us. We will be challenged to ensure reputable and responsible sourcing; social and environmental risks are growing. With new in- novators entering the pharmacy business, the pace of change will inevitably accelerate. We can inno- vate with a focus on catalysis, and we can positively impact business, society, the environment and human health. The routes to our medicines should be as innovative as the therapies themselves.
Ian W. Davies, consultant, Princeton, NJ, US
The cost and capacity advantages of emerging markets are eroding and we can no longer extract significant value
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