Rethinking API Manufacturing with Biocatalysis

Bringing increasingly complex active pharmaceutical ingredients (APIs) from development to commercial manufacture is placing growing pressure on traditional synthetic approaches. Molecular complexity adds reaction steps, isolations, purification stages and solvent-intensive operations.

A route suitable for early clinical supply may become harder to sustain as demand grows and a program moves toward larger-scale manufacturing. This is creating greater interest in strategies that go beyond incremental optimization and enable a more fundamental redesign of how complex molecules are made.

For nucleosides and other APIs requiring precise stereochemical control or multiple functional-group transformations, conventional stepwise routes can present significant manufacturing challenges. Additional synthetic steps require more raw materials, solvents, intermediate isolation and purification. These operations may increase process complexity and waste while reducing overall efficiency.

Pharma biocatalysis offers an alternative to stepwise synthesis. Engineered enzymes can provide high levels of selectivity under comparatively mild reaction conditions, creating opportunities to perform transformations that may otherwise require more complex chemical strategies. The potential of biocatalysis extends beyond replacing an individual chemical step. Advances in enzyme discovery and protein engineering are making it possible to consider process redesign at the pathway level.

One of the most significant developments in pharma biocatalysis is the ability to combine multiple enzymes within integrated reaction systems. Rather than performing each transformation independently and isolating each intermediate, multi-enzyme cascades can enable several transformations to occur sequentially within the same process stream. Integrated enzymatic cascades offer:

• Fewer intermediate handling steps: Integrated cascades can reduce repeated isolations, workups and purification stages, helping simplify the overall process.
• Reduced reliance on organic solvents: Enzymatic transformations can often be performed under aqueous or comparatively mild conditions, creating opportunities to improve the environmental profile of a route.
• Greater process integration: Linking enzymatic reactions can build molecular complexity within a more streamlined process rather than through a long sequence of discrete operations.
• New synthetic possibilities: Highly selective enzymatic transformations can be combined in ways that may be difficult to achieve through conventional chemistry alone.

Enzymes have to work reliably under manufacturing conditions and alongside other enzymes in the process. Their activity, selectivity and stability must support the performance of the overall pathway. Protein engineering makes this possible by tailoring enzymes to meet the specific needs of an industrial process.

For biocatalysis to deliver meaningful value in pharmaceutical manufacturing, enzyme development must be closely aligned with process development and scale-up requirements.

Designing a biocatalytic process for scale-up requires consideration of:

• Process-relevant performance: Enzymes must maintain the activity, selectivity and stability required for efficient manufacturing conditions.
• Integrated development: Close alignment between protein engineering and process development helps performance targets evolve alongside the wider manufacturing route.
• Manufacturing readiness: Enzyme production and supply must support the timelines and material requirements of late-stage development and larger-scale manufacturing.
• System-level optimization: In multi-enzyme processes, kinetics, compatibility and reaction conditions must be balanced across the overall cascade.

Combining process expertise with manufacturing capabilities can help teams identify challenges earlier and optimize the complete process rather than individual reactions in isolation.

Merck’s work on the investigational nucleoside analog islatravir offers a compelling example of how biocatalysis can enable a more efficient, scalable manufacturing route. Its original clinical supply route involved a lengthy chemical synthesis, creating challenges around process complexity, solvent use and scalability. Rather than incrementally optimizing that route, Merck pursued a different strategy based on an integrated biocatalytic process.

Working with Codexis, Merck developed a new manufacturing route that incorporates a multi-enzyme cascade designed to perform a sequence of transformations within a water-based process. The collaboration demonstrates how enzyme engineering, process development and manufacturing capabilities can be combined to tackle a complex pharmaceutical synthesis and support broader process redesign.

Biocatalysis is increasingly moving beyond its traditional role as a solution for individual difficult transformations. When considered early and applied strategically, it can reduce process complexity, improve environmental performance and develop manufacturing routes better suited to scale. For developers working with complex APIs, pharma biocatalysis can open up manufacturing routes that would be difficult to achieve through conventional chemistry alone.

Download the case study to discover how Codexis and Merck applied this approach to develop a new biocatalytic manufacturing route for islatravir, and explore the scale-up capabilities behind the program.