INTRODUCTION

Biocatalysis has emerged as a versatile tool for streamlining purification processes to replace lengthy, multi-step chemical pathways. The past decade has seen a notable rise in the use of biocatalysis for producing small-molecule drug substances, fueled by growing academic and industrial interest in harnessing en­zymes to transform chemical pathways. As the biocatalytic toolbox expands, chemists have gained access to a wider range of cat­alytic options, enabling improved stereo- and regioselectivity, sim­plified chemical synthesis routes, improved process mass intensity (PMI), reduced environmental impact and stronger process eco­nomics.

However, the adoption of this methodology is not without its hurdles. While biocatalysis is starting to make impressive inroads into manufacturing routes, its uptake in early discovery chemistry has been slower. Technical and operational barriers, including enzyme durability, the management of aqueous waste streams and a lack of change mindset, are challenging to more wide­spread implementation. Nonetheless, increased collaboration and greater access to enzyme resources are beginning to open opportunities for early discovery R&D. This article examines both the promise and the practical constraints of biocatalysis in mod­ern drug substance development, as well as the role of contract research, development and manufacturing organizations (CRD­MOs) in meeting the evolving demands of modern small mole­cule synthesis.

BENEFITS OF BIOCATALYSIS

Enzymes, the catalysts evolved by nature, are capable of guiding chemical reactions with a level of precision that is difficult to match using conventional methods.1 Their highly specific active sites confer exceptional control over regio-, chemo- and enan­tioselectivity, enabling reactions that might otherwise be challeng­ing or inefficient.2 Modern protein engineering has expanded this capability even further, producing enzymes customized for a growing variety of transformations. In drug substance synthesis, such precision can eliminate redundant purification steps, main­tain strict stereochemical standards and condense what would normally be multiple stages into a single streamlined operation.2 As a result, drug substance development becomes far more effi­cient and affordable than with traditional methods of small mol­ecule synthesis.

Biocatalysis is also considered more environmentally friendly than chemical synthesis, helping drug developers to reach sus­tainability targets. This enzyme-driven chemistry is able to pro­ceed under gentle, water-based conditions, avoiding the need for extreme temperatures and the hazards of harsh reagents.3 This gentler operating environment not only enhances worker safety and reduces energy requirements but also aligns with sustainable manufacturing practices by lowering solvent usage and removing the need for heavy metal catalysts.4 The resulting reduction in PMI represents both an environmental benefit and a tangible cost sav­ing. For these reasons, biocatalysis is fast becoming a central strategy for efficient, economical and environmentally responsible drug substance development.

 OVERCOMING STABILITY & PROCESS COMPATIBILITY CHALLENGES

The advantages of biocatalysis are clear, but its integration into drug substance manufacturing is far from straightforward without the right expertise. The ability of enzymes to function in aqueous environments feels like a benefit, however they also op­erate within very fine environmental margins, specifically evolved for nature – and not industrial processes.5 Industrial settings, however, often demand reaction conditions – such as organic sol­vents, high heat, or extreme acidity or al­kalinity – that can diminish enzyme stability or halt activity altogether.5 In some cases, drug substances or their intermediates may also prove unstable or behave unpre­dictably under enzyme-friendly conditions, restricting the scope of possible transfor­mations. These limitations become partic­ularly problematic in complex, multi-step syntheses, where alternating between aqueous and non-aqueous stages can dis­rupt process flow. Without well-matched reaction conditions, manufacturers risk lower yields, inconsistent results or the need for intricate downstream purification. At larger scales, even slight deviations in pH, temperature or solubility can under­mine process reliability and inflate produc­tion costs.

TAILORING BIOCATALYSTS FOR NON-NATURAL OR NOVEL REACTIONS

Another potential barrier to biocatal­ysis is that enzymes are not always suited for large-scale pharmaceutical produc­tion, particularly when dealing with syn­thetic substrates or entirely new reaction types. Engineering an enzyme to meet specific process needs – then fine-tuning traits like catalytic activity, thermal stability or binding specificity – typically involves re­peated cycles of mutagenesis, screening and refinement, whether through directed evolution, rational design or integrated approaches.6 These optimization pro­grams demand considerable technical in­frastructure and capacity, which not all organizations possess. Without this invest­ment, many developers revert to estab­lished synthetic chemistry routes, sacrific­ing the long-term process and sustainability benefits that biocatalysis could offer.

One of the most effective ways of avoiding this and accelerating the adop­tion of biocatalysis in drug development is to apply it where it has a clear edge over conventional chemistry. Natural products – and the small molecules derived from them – represent a prime example of where biocatalysis can be extremely ben­eficial. Many clinical candidates and ap­proved drugs retain features of their natural counterparts. Their complexity can make chemical synthesis challenging and costly, but biocatalysis offers a way around these obstacles by streamlining synthetic routes, enhancing stereocontrol and en­abling reactions to proceed under gentler, more environmentally friendly conditions – factors that together make large-scale manufacture far more practical.

Islatravir – a nucleoside analogue now in Phase 3 trials for HIV prevention and treatment – provides a compelling ex­ample of what biocatalysis can achieve. Instead of relying on lengthy chemical routes, its production uses a multi-enzyme cascade of engineered phosphorylases, ki­nases and oxidases to construct the chiral sugar and couple it to the nucleobase.7 This streamlined process not only cuts down the number of synthetic steps but also achieves high stereoselectivity while lowering the environmental burden. Simi­lar innovations have opened the door to large-scale production of other natural product-derived substances, including artemisinin-based antimalarials generated in engineered yeast,8 paclitaxel analogues developed through targeted enzymatic modification of plant precursors,9 and erythromycin derivatives synthesized using glycosyltransferase-mediated sugar tailor­ing.10

MANAGING OFF-TARGET REACTIVITY

High selectivity is another celebrated advantage of biocatalysis, yet enzymes are not immune to unintended activity.11 When a substrate contains multiple functional groups, there is a risk of catalyzing side re­actions that reduce yield, complicate purifi­cation or introduce safety concerns. Even minor structural modifications to a sub­strate can alter reactivity or shift enzyme se­lectivity in unexpected ways. Identifying and mitigating these off-target effects early is essential to maintain process efficiency and product quality, particularly in complex or multi-step syntheses.

INCREASING ADOPTION OF BIOCATALYSIS

Cultural attitudes can also limit the adoption of the wider use of biocatalysis in drug substance development. Many process development teams – particularly in start-ups and small companies – are deeply rooted in well-established chemical synthesis methods. This reliance on a more familiar method that is widely accepted and works well enough reduces the drive to look for more efficient methods, partic­ularly if establishing a new pathway re­quires time investment. For emerging companies, the pressure to move quickly with limited resources often reinforces chemical synthesis as the default, conser­vative approach. However, sticking with established chemistry can store up prob­lems for later, such as processes with lim­ited scalability, variable yields and increased development risks that might have been avoided with earlier adoption of biocatalytic strategies.

COMPREHENSIVE CRDMO CAPABILITIES

Many CRDMOs now offer biocatalysis as a platform service, combining enzyme discovery, optimization and process inte­gration under one roof. Platform-based CRDMOs offer an invaluable blend of technical expertise and scalable infrastruc­ture for companies seeking to integrate biocatalysis into drug substance develop­ment. These organizations bring together modular, end-to-end workflows designed to accelerate enzyme optimization and im­plementation. Their expertise spans the entire development cycle – from early fea­sibility studies that evaluate reaction per­formance and scale-up viability, through to host system engineering to maximize enzyme expression.12 By combining com­putational protein design,13 high through­put screening14 and techniques such as directed evolution,15 CRDMOs can streamline the cycle from designs to tests, enabling tailored biocatalysts to be de­ployed earlier in the development process. This early adoption reduces project risk, improves process robustness and in­creases the likelihood of successful inte­gration under real-world manufacturing pressures.

CRDMOs are also well-equipped to address common challenges such as en­zyme instability, process incompatibilities and off-target reactivity. Predictive model­ling tools, curated databases and ad­vanced analytical platforms allow them to anticipate and identify unwanted side re­actions before they compromise yields, safety or purification strategies. A broad screening approach means potential side products can be detected early, giving teams time to refine enzyme or process conditions proactively.

Importantly, these organizations are not only solving technical barriers but also helping companies overcome cultural re­luctance to adopt new approaches.

By de­livering fully integrated solutions that embed biocatalysis directly into route de­sign, CRDMOs make the transition less disruptive and more commercially viable. Validated workflows, enzyme expertise and early optimization strategies ensure drug substance developers gain greater confidence in adopting biocatalysis with­out jeopardizing timelines.

BIOCATALYSIS AS A CORNERSTONE OF FUTURE DRUG SUBSTANCE MANUFACTURING

Biocatalysis has become a powerful approach for complex small molecule syn­thesis, offering improved precision, sus­tainability and efficiency – particularly for stereochemically rich molecules, hetero­cyclic scaffolds and functionalized interme­diates. Yet, its full potential will only be realized when the remaining scientific, op­erational and cultural challenges are ad­dressed. Platform-based CRDMOs are driving this shift, bringing together ad­vanced enzyme engineering, process inte­gration and compliance expertise within a single framework. By bridging the gap be­tween innovative science and industrial-scale implementation, they are helping to make biocatalysis not just a viable alterna­tive, but a preferred strategy in modern drug substance manufacturing. As tech­nology continues to advance and collabo­ration between stakeholders grows, biocatalysis is poised to become a corner­stone of greener, more efficient drug sub­stance development.

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