Stefan Mix of Almac Group looks at how a once niche technology has gone mainstream
Genes to GMP : Biocatalysis in the pharmaceutical industry today
Stefan Mix of Almac Group looks at how a once niche technology has gone mainstream
Biocatalysis is no longer considered an emerging technology in the pharmaceutical industry ; it has taken a firm foothold in the form of numerous manufacturing processes , with applications ranging from preclinical development batches to commercial API manufacture . The rise of biocatalysis is inextricably linked to the ease of access to the enzymes it relies on .
The roots of pharmaceutical enzymatic chemistry can be traced back to the 1950s , when whole-cell microbes were used for steroid oxidation . 1 Since the 1970s , the industrialisation of detergent enzymes has led to a strong uptake of lipases , esterases and proteases as catalysts by organic chemists . The attraction to enzymes is largely because of their unrivalled selectivity and specificity of reaction product formation , and because there is no need to use costly protecting groups .
Early days
In its early days , biocatalysis was an exotic niche technology . Its true emergence as a versatile technology class came with recombinant expression and directed evolution in the 1990s . This coincided with the genetic mapping of the biosphere , enabling advances in information technology , but also new competition in the form of asymmetric transition metal catalysis .
The cost of new enzymes was still comparable to the cost of a new metal ligand system , confining biocatalysis to large-scale applications with sufficient investment backing .
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Figure 1 - Biocatalysis publication abundance & share in OPR & D
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Examples included bio-hydroxylation and bio-hydrocyanation processes developed and run by the likes of DSM and Degussa , who invested in either catalysis technology as appropriate . 2 , 3
This changed when a whole new supplier landscape was established to meet the needs of biotechnology – the falling cost of genes , increased database access , rapid and inexpensive sourcing of essential consumables , such as primers and restriction enzymes - enabling biocatalysis to flourish in among more than just a few big players .
From niche to first choice option
As most large pharma companies invested in dedicated biocatalysis laboratories their output multiplied by using provisions from specialised developers of enzymes instead of having to clone all enzymes themselves .
For example , carbonyl reductase ( CRED , also known as alcohol dehydrogenase ) technology began to outcompete rival metal catalysis systems . Their attraction was in the value of new stereocentres needed in new drugs . The abundance and
robust versatility of natural reductase enzymes meant finding a biocatalyst for an asymmetric reduction became much easier , quicker and cheaper than developing a metal ligand system .
The list of examples of their utility has been growing ever since . 4 Other enzyme classes were also developed and , where natural diversity does not offer industrialisation-ready enzymes , protein engineering can often add the missing performance features . 5
Abundance & diversity
It is not easy to find accurate statistics on numbers of biocatalysis applications in the pharmaceutical industry . The approach taken here was to use the number of biocatalysis publications in Organic Process Research & Development ( OPR & D ), an industrial organic chemistry journal mainly focused on pharmaceutical manufacturing and process development .
Figure 1 shows a snapshot of industrial biocatalysis R & D activity and tracker of application development . This demonstrates a sustained growth of numbers and total publication share . What
36 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981