The Growing Role of Biocatalysis in Industrial Synthesis
Dr Reuben Carr, Head of Chemical Biology, Ingenza Ltd
Chemical catalysis has driven organic synthesis and pharmaceutical manufacturing since the 19th century, enabling the mass production of key therapeutics. Despite this broad adoption and long history, traditional organic synthesis techniques are still limited by several unavoidable drawbacks, including high operational costs, environmental concerns and safety risks. Biocatalysis presents a promising alternative as it offers several advantages for pharmaceutical manufacturing, including improved resource efficiency, cost effectiveness and sustainability. This article explores the strengths of biocatalysis and the benefits of switching away from chemical synthesis in the development of active pharmaceutical ingredients.
Since the late 19th century, chemical catalysis has been a cornerstone of organic synthesis and pharmaceutical manufacturing, driving the development and mass production of key therapeutic molecules across multiple disease areas. Despite its broad adoption and long history, traditional organic synthesis techniques remain constrained by several unavoidable drawbacks. For instance, traditional chemical catalysis often suffers from low selectivity, requiring the use of protective groups to shield reactive sites on complex substrates. These temporary modifications must later be removed through de-protection, introducing extra steps into the process. As a result of this limited specificity, significant amounts of unwanted byproducts are typically formed, requiring extensive downstream purification that can affect the final product's quality. This added complexity leads to a high consumption of reagents and resources, driving up both the cost and duration of small molecule synthesis, while also contributing to the environmental burden of pharmaceutical production.
Chemical synthesis is also often highly energy intensive, frequently relying on extreme temperatures – either intense heating or cryogenic cooling – to drive reactions. This contributes to substantial energy usage, which not only raises operational costs but also increases environmental impact. Additionally, traditional synthesis methods commonly involve the use of harsh solvents, such as ethyl acetate, toluene and dichloromethane (DCM), which carry considerable ecological and safety concerns if not properly managed.
Another key challenge is achieving high levels of chiral purity, especially with traditional chemical catalysis. Chiral compounds consist of molecules that are non-superimposable mirror images of each other, and these subtle structural differences can lead to profound variations in a drug's biological activity, therapeutic effectiveness and potential side effects. Regulatory bodies such as the U.S. Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) require a typical minimum of 99 per cent enantiomeric excess for chiral drugs, recognising anything below this threshold as two distinct active substances that must be individually assessed for pharmacological effect. Chemical catalysis methods often struggle to reach this level of precision as they lack the necessary chiral control. As a result, substances typically require additional purification steps – such as recrystallisation – to isolate the desired enantiomer, leading to increased material waste, prolonged processing times and higher production costs.
A biological solution
Biocatalysis offers a compelling alternative to traditional chemical catalysis in pharmaceutical manufacturing, alleviating these challenges by providing advantages such as improved resource efficiency, enhanced cost effectiveness and greater sustainability. These strengths have led to its growing adoption as a preferred method for both developing new drug substances and redeveloping existing compounds. This is particularly true in applications involving the modification of natural products through non-cellular conversions.
In contrast to chemical synthesis, biocatalysis harnesses the innate high specificity of enzymes, which operate through a selective lock-and-key mechanism to recognise and bind to their target substrates. This precision reduces the reliance on protection and de-protection steps that are commonly required in traditional synthesis, simplifying workflows and minimising the formation of unwanted byproducts. As a result, biocatalytic processes tend to be cleaner and yield higher quality end products compared to multi-step chemical approaches.
An additional advantage of biocatalysis is that it can be performed under mild conditions, as enzymes typically operate efficiently at temperatures between 5 and 40 °C. This significantly reduces the energy requirements of pharmaceutical synthesis, offering considerable cost savings, especially in large-scale production. Lower energy consumption also supports manufacturers in reducing their carbon footprint and advancing sustainability efforts, contributing to a more environmentally friendly production process. Similarly, biocatalysis requires minimal solvent use, diminishing the reliance on hazardous chemicals. This contributes to greener and safer processes, with lower operational costs in comparison to chemical synthesis techniques.
Another notable strength of biocatalysis is its suitability for use in asymmetric conversions, which are necessary for manufacturing pharmaceutical products with more challenging stereoselectivity or regioselectivity demands, including chiral or diastereomeric molecules. Thanks to the inherent specificity of enzymes, biocatalytic methods can readily reach the 99 per cent enantiomeric excess benchmark for chiral compounds. This exceptional product purity streamlines downstream processing by reducing the need for extensive purification, ultimately lowering operational costs.
Application areas
This ability to carry out stereo- and regiocontrolled transformations with high precision makes biocatalysis particularly well suited to the synthesis of glycosylated products. Molecules such as glucose, for example, pose challenges in traditional chemical synthesis because of their multiple reactive hydroxyl groups and aldehyde functionality whereas enzymes, in contrast, offer remarkable selectivity, eliminating the need for extra protective strategies. One instance of this is glycosyltransferases, which enable the efficient and targeted attachment of sugar moieties, outperforming conventional chemical catalysts in both accuracy and efficiency.
Biocatalysis also holds significant promise in the production of amino acids for biopharmaceutical applications. These compounds are particularly valued as chiral synthons, and serve as cost-effective, biologically sourced building blocks in the assembly of complex drug molecules. While proteinogenic amino acids like alanine, phenylalanine and aspartic acid are readily available at scale and low cost, non-proteinogenic variants remain scarce and are typically supplied by only a few specialised contract research, development and manufacturing organisations (CRDMOs). Through precise chiral control, biocatalytic methods can efficiently generate a diverse array of non-proteinogenic amino acids, enabling the scalable synthesis of pharmaceutical compounds with high stereochemical purity.
Conclusion
Biocatalysis offers a number of compelling advantages over traditional chemical catalysis in a range of pharmaceutical applications, delivering high specificity and efficiency under mild, safer reaction conditions. Its reduced reliance on harsh reagents, solvents and energy-intensive processes also aligns well with the industry’s push toward greener, more sustainable practices. As the field continues to evolve with the discovery of novel enzymes and broader applicability to diverse organic molecules, biocatalysis is rapidly becoming an indispensable tool in the efficient and responsible synthesis of active pharmaceutical ingredients.
Dr Reuben Carr has over 25 years of experience in developing proprietary biocatalytic processes for fine chemical and pharmaceutical manufacturing. He specialises in using directed evolution to engineer natural enzymes to carry out novel chemical reactions, enabling the synthesis of challenging molecular targets for clients and customers.
