Chemoenzymatic API synthesis (biocatalytic small-molecule manufacturing)

01Overview and value chain

Markers: [EC: ICH Q11 + EDQM CEP / FDA DMF | OECD: Bio-pharma | Regulator: FDA (USA), EMA (European Union), NMPA (China)]

Chemoenzymatic API synthesis replaces one or more steps of a small-molecule active pharmaceutical ingredient (API) route with an engineered enzyme — a transaminase, ketoreductase, lipase or nitrilase — run either as an isolated biocatalyst or a whole-cell biotransformation, then rejoined to conventional chemical steps in a hybrid route. The approach cuts heavy-metal catalyst residues, lowers solvent and step count, and reaches stereochemistry that chemical catalysis struggles with; Codexis’s directed-evolution CodeEvolver platform (transferred to Merck for its own internal manufacturing use) supplied the engineered transaminase that replaced a rhodium-catalysed asymmetric hydrogenation step in sitagliptin (Januvia) manufacture, cutting total waste by roughly 19% and eliminating a heavy-metal catalyst — the field’s reference case. Almac runs immobilised-lipase (CALB) and cGMP flow-hydrogenation biocatalysis for late-stage API process development; Lonza folds biocatalysis into its global small-molecule and HPAPI (highly potent API) CDMO toolkit; and Asymchem and WuXi AppTec (WuXi STA) both offer biocatalysis-enabled green-chemistry platforms inside their broader Chinese CDMO operations serving global pharma sponsors.

The key directions of chemoenzymatic API synthesis are:

1. Engineered biocatalyst supply (Biocatalysis): directed-evolution or rational-design enzyme variants (transaminases, ketoreductases, imine reductases) sold or licensed as a manufacturing input — Codexis’s CodeEvolver is the reference platform.
2. Biocatalysis CDMO process development (Biocatalysis CDMO): contract development of a hybrid chemo-enzymatic route for a sponsor’s API, from route scouting through GMP scale-up — Almac, Lonza, Asymchem, WuXi AppTec.
3. Immobilised and continuous-flow biocatalysis (Immobilized Enzymes): enzymes fixed to solid supports or run in continuous-flow reactors for reuse across cycles and integration with flow chemistry — Almac’s flow-hydrogenation/CALB work.
4. Route replacement economics (Route Replacement): displacing metal-catalysed asymmetric synthesis or multi-step resolutions with a single enzymatic step, reducing heavy-metal residue, solvent volume and total step count.

Sectoral value chain

[enzyme discovery/engineering] ──> [route scouting & retrosynthesis] ──> [biocatalyst scale-up]
                                                    │
                                       (GMP chemoenzymatic manufacturing)
                                                    │
                                                    ▼
[API supply & lifecycle mgmt] <─── [purification & DMF/CEP filing] <─────┘

Value chain levels

Cross-cutting technologies of the sector:

• Directed evolution (Directed Evolution): iterative mutagenesis and high-throughput screening evolves an enzyme’s activity, stability and selectivity toward a non-natural pharmaceutical substrate — the basis of Codexis’s CodeEvolver.
• Enzyme engineering (Enzyme Engineering): rational, structure-guided redesign of enzyme active sites to accept API intermediates that the wild-type enzyme cannot process.
• Immobilised/continuous-flow biocatalysis (Immobilized Enzymes): fixing enzymes to solid supports enables reuse across reaction cycles and integration into continuous-flow manufacturing trains alongside chemical steps.

02US

The US anchors the reference chemoenzymatic-API platform business, led by Codexis’s engineered-enzyme licensing and supply model.

CodeEvolver, sitagliptin transaminase, FDA DMF

• Codexis CodeEvolver platform: a directed-evolution enzyme-engineering platform that has produced transaminases, ketoreductases and other biocatalysts for API manufacturing; Codexis completed the transfer of CodeEvolver technology to Merck for Merck’s own internal process-development use.
• Sitagliptin transaminase case: Codexis and Merck’s engineered transaminase route to sitagliptin (Januvia) replaced a rhodium-catalysed asymmetric hydrogenation, the reference case for chemoenzymatic API manufacturing cited across the industry; Codexis and Merck have since amended and extended their supply agreement for the enzyme.
• FDA DMF framework: chemoenzymatic API routes enter US supply chains under FDA Drug Master Files, with the enzymatic step documented alongside conventional chemical unit operations in the CMC package.

03CN

China hosts large-scale CDMO capacity offering biocatalysis-enabled green-chemistry routes alongside conventional chemical synthesis, led by Asymchem and WuXi AppTec (WuXi STA).

Asymchem, WuXi STA, NMPA

• Asymchem (凯莱英): a major Chinese CDMO whose biocatalysis-enabled green-chemistry platform sits alongside conventional chemical synthesis for global pharma API and intermediate manufacturing.
• WuXi AppTec / WuXi STA (药明康德): the small-molecule CDMO division WuXi STA offers a biotransformation/biocatalysis platform within its broader chemistry, manufacturing and controls (CMC) service line for global sponsors.
• Domestic cluster: China’s large-molecule and small-molecule CDMO base has progressively added enzymatic and biocatalytic route options to compete on cost and green-chemistry credentials for export-oriented API manufacturing.
• NMPA framework: chemoenzymatic API manufacturing for export runs under NMPA cGMP inspection, with dossiers filed in parallel for FDA/EDQM and other destination-market regulators.

04EU

Europe’s chemoenzymatic-API tier spans a UK biocatalysis specialist CDMO (Almac) and a Swiss global CDMO folding biocatalysis into a broader small-molecule and HPAPI toolkit (Lonza).

Almac, Lonza, EDQM

• Almac (Craigavon, UK): an API chemical-development CDMO running immobilised-lipase (CALB) biocatalysis and cGMP flow-hydrogenation capability for late-stage sponsor process development.
• Lonza (Visp, Switzerland): a global small-molecule and highly-potent-API (HPAPI) CDMO that includes biocatalysis among its process-development toolkit, expanding its Visp manufacturing capacity.
• EDQM CEP framework: chemoenzymatic API routes enter the EU supply chain under European Directorate for the Quality of Medicines (EDQM) Certificates of Suitability (CEP) and ICH Q11 development-and-manufacture guidance.

05Leading companies and research institutes

06Tech stack and innovations

The stack pairs directed-evolution and rational enzyme engineering with immobilisation/continuous-flow process engineering to insert a single high-selectivity biocatalytic step into an otherwise conventional chemical API route.

1. Directed evolution and enzyme engineering (Directed Evolution):
   • Iterative mutagenesis and high-throughput screening (Codexis’s CodeEvolver) evolves transaminases, ketoreductases and other enzymes to accept non-natural pharmaceutical intermediates, replacing metal-catalysed asymmetric steps.
2. Biocatalysis CDMO process development (Biocatalysis CDMO):
   • Almac, Lonza, Asymchem and WuXi STA scout a sponsor’s chemical route for a step an enzyme can replace, then scale the hybrid chemoenzymatic process to GMP.
3. Immobilised and continuous-flow biocatalysis (Immobilized Enzymes):
   • Almac’s immobilised-CALB and flow-hydrogenation work fixes the enzyme to a solid support or reactor, enabling reuse across cycles and direct integration with downstream chemical flow steps.
4. Route-replacement economics (Route Replacement):
   • A single enzymatic step can displace a multi-step chemical resolution or a heavy-metal-catalysed hydrogenation, cutting solvent volume, step count and catalyst-residue burden — the basis of the sitagliptin case’s reported waste reduction.

07Value chains and production pipelines

Industrial pipeline of a chemoenzymatic API route (ICH Q11 / EDQM CEP / FDA DMF)

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Enzyme discovery &     │ ───> │ 2. Route scouting &      │
│    engineering            │      │    retrosynthesis         │
└───────────────────────────┘      └───────────────────────────┘
                                                   │
                                                   ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. GMP chemoenzymatic     │ <─── │ 3. Biocatalyst scale-up  │
│    manufacturing          │      │                           │
└───────────────────────────┘      └───────────────────────────┘
              │
              ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. Purification &         │ ───> │ 6. Supply & lifecycle    │
│    regulatory filing      │      │    management             │
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Enzyme discovery and engineering

A wild-type enzyme (transaminase, ketoreductase, lipase or nitrilase) is identified against the target reaction, then evolved through directed mutagenesis or redesigned rationally until it accepts the pharmaceutical intermediate at manufacturing-relevant conversion and selectivity.

Stage 2: Route scouting and retrosynthesis

Process chemists map the sponsor’s existing (or new) chemical route to the API and identify which step — typically an asymmetric reduction, transamination or resolution — an engineered biocatalyst can replace or improve.

Stage 3: Biocatalyst scale-up

The engineered enzyme gene is expressed in a production host and fermented at scale, or the purified enzyme is immobilised on a solid support, to supply the manufacturing-scale biocatalyst.

Stage 4: GMP chemoenzymatic manufacturing

The enzymatic step is run in batch or continuous-flow mode and rejoined to the remaining conventional chemical steps under cGMP, producing the crude API with the metal-catalyst or multi-step-resolution burden of the original route removed.

Stage 5: Purification and regulatory filing

The API is crystallised and impurity-profiled, with the enzymatic step documented in the CMC package supporting an EDQM Certificate of Suitability (CEP) or FDA Drug Master File (DMF) under ICH Q11 development guidance.

Stage 6: Supply and lifecycle management

Sponsors manage tech transfer, second-sourcing and freedom-to-operate for the enzymatic step across the commercial life of the API, with the CDMO or enzyme supplier (Codexis, Almac, Lonza, Asymchem, WuXi STA) typically retaining the biocatalyst IP.