Flow Ready: How Pharma is moving biocatalysis toward continuous processing (ENG)

Introduction

Biocatalysis has become a core tool in pharmaceutical route design, driven by enzymes’ unmatched enantioselectivity and sustainability credentials. The pharmaceutical industry generates an estimated 10 billion kg of waste per year from active pharmaceutical ingredient (API) production, with E-factors (Environmental Factors, defined as kg waste per kg product) routinely exceeding 25, largely due to multi-step syntheses requiring stoichiometric chiral auxiliaries and heavy-metal catalysts [1].

Key enzyme classes driving these transformations include amine transaminases (ATAs), reductive aminases (RedAms), and lipases, each enabling highly selective chiral synthesis, yielding to high value enantiopure API building blocks under mild aqueous conditions. Importantly, their ability to perform such reactions without protecting-group chemistry or toxic metal residues, often translates into reduced waste and simplified downstream processing [1,2].

Two recent authoritative surveys confirm the maturity of industrial uptake: the Swiss Industrial Biocatalysis Consortium (SIBC) 20th-anniversary perspective [3], covering impactful industrial pharmaceutical syntheses, and a 2025 Angewandte Chemie update cataloguing the most recent large-scale enzymatic processes [2]. Both surveys document growing recognition that coupling bio-catalysis with continuous manufacturing is increasingly feasible. This momentum is reinforced by the regulatory landscape: the ICH Q13 guideline, adopted in November 2022 by all major regulatory agencies (FDA, EMA, PMDA), provides a harmonised framework for the development, implementation, and lifecycle management of continuous manufacturing processes, significantly reducing the regulatory uncertainty that previously limited industry adoption [4]. Compared to batch, continuous-flow reactors offer tighter parameter control, superior mass and heat transfer, and more predictable scale-up.

The logical endpoint of this convergence is flow biocatalysis: immobilising enzymes on a solid carrier, generally configured as packed-bed reactors (PBRs) able to run continuous operations (Figure 1), enables biocatalyst recycling, eliminates recovery steps, and unlocks significantly higher space-time yields (STY). This review aims to examine recent industrial case studies to assess where the transition from batch to continuous flow processing stands today.

Figure 1. General schematic of a biocatalytic continuous-flow process featuring immobilised enzymes on solid carriers in a packed-bed reactor (PBR). Reactant 1 (e.g. ketone, amino acceptor) and reactant 2 (e.g. amine donor) are pumped through the PBR where the enzymatic reaction occurs, followed by in-line sepa-ration of the product stream. Representative pharmaceutical examples produced via this approach are shown: (a) sitagliptin, (b) (S)-piperazine-2-carboxylic, precursor to linvencorvir, (c) cyrene amine, interme-diate for nemtabrutinib, and (d) L-phenylalanine analogue.”

 

Discussion

Commercial-Scale Enzymatic Processes in Batch Mode

Before assessing the transition to flow processing, it is instructive to recall how far enzymatic APIs synthesis has advanced in conventional batch mode. The biocatalytic synthesis of sitagliptin (Figure 1,a) is a landmark example: Merck–Codexis replaced a rhodium-catalysed asymmetric hydrogenation with an engi-neered ATA-117 transaminase, delivering the antidiabetic API at multi-ton scale with >99.95 % enantiomeric excess (ee) [5], thus demonstrating that free en-zymes in stirred-tank reactors can meet the most demanding pharmaceutical manufacturing targets. 

A decade later, Pfizer extended this precedent to reductive aminases: after three rounds of directed evolution yielding the variant SpRedAm-R3-V6, Pfizer produced multiple metric tons of the cis-cyclobutyl N-methylamine intermediate for the JAK1 inhibitor abrocitinib, with high space-time yield and selectivity [6]. Both processes use free enzymes in batch mode: the chemistry is commercially validated, however neither has yet exploited the productivity gains that immobilisation and continuous flow could deliver.

 

Roche: The Industrial Benchmark in Continuous Flow

The clearest current demonstration of continuous-flow enzymatic processing in pharmaceutical manufacturing comes from Roche, in collaboration with the University of Bern. In the synthesis of (S)-piperazine-2-carboxylic acid (Figure 1,b), a key precursor for Linvencorvir, a protein allosteric modulator, Roche combined Pd/C catalysed  hydrogenation with a kinetic resolution using a leucine aminopeptidase 2 (LAP2) [3,7]. 

Immobilisation of semi-purified L AP2 on a solid support enabled benchmarking across three configurations: conventional batch, SpinChem® rotating bed, and continuous PBRs. The results, summarised in Table 1, are compelling: a 20 mL PBR raised the ideal space-time yield from 2.9 to 50.4 g·L⁻¹·h⁻¹ and cut the E-factor from 14.5 to 3.6, reducing waste fourfold, while the immobilised catalyst retained full activity over multiple cycles [7].

Table 1. Productivity and sustainability metrics for different LAP2 process configurations (adapted from [3,7]).

 

Merck: From Batch to Flow at Kilogram Scale

A second fully documented batch-toflow translation comes from Merck & Co. An evolved transaminase (ATA-492), immobilised on an alkylamine-functionalised methacrylate resin (ECR8415), was used to transaminate the biobased solvent Cyrene™ in water-saturated 2-methyltetrahydrofuran (2-MeTHF), yielding cyrene amine (Figure 1,c) (a key intermediate for the inhibitor Nemtabrutinib) with a diastereomeric ratio (dr) > 50:1 [8]. 

Merck then translated this into a PBR, surveying kinetics under flow conditions before scaling to over one kilogram of product, with the enzyme retaining full activity for >100 h on-stream. Further scale-up to 26 kg of cyrene in the flow system improved diastereoselectivity to dr 200:1 [9]. These cases illustrate how industrial biocatalysis is evolving toward an integrated model that combines enzyme engineering, immobilisation, and continuous processing to enable scalable intensification.

 

Industry-Wide Enzymatic Processes at the Flow Threshold

Beyond these two implemented examples, a broader cohort of industrial processes has reached the enzyme configurations, substrate loadings, and catalyst stabilities compatible with packed-bed flow operation. The Novartis–University of Bern collaboration has already taken the flow step: phenylalanine analogues (Figure 1,d) are produced via an immobilised phenylalanine ammonia lyase (PAL) in a continuous PBR, achieving a threefold improvement in space-time yield over batch [10]. 

Johnson & Johnson also integrated an immobilised lipase in a batch chemo-enzymatic process combining a chiral Suzuki–Miyaura coupling with enzymatic acylation, yielding an MCL-1 inhibitor in high enantiopurity, without chiral chromatography [3,11]. Such robust, immobilised biocatalyst format is inherently compatible with subsequent implementation in continuous flow operation. The SIBC survey further documents processes at Lonza and Givaudan that combine high substrate loadings with in-situ product separation, collectively fulfilling key characteristics of flow-ready bio-catalysis [3].

The pharmaceutical industry now explicitly recognises this readiness: a 2020 pharma-industry perspective from Novartis and Roche scientists noted that enzyme immobilisation and flow chemistry were becoming standard design considerations in process development [12], a view echoed by the ACS GCI Pharmaceutical Roundtable, which identified continuous processing as a key lever for sustainability in API manufacturing [13].

While the case studies presented here demonstrate the industrial maturity of continuous flow biocatalysis, several practical challenges remain. The cost and commercial availability of appropriate immobilisation supports can be significant, particularly for novel enzyme–resin pairs that require functionalisation. Mass transfer limitations within densely packed beds can reduce effective enzyme utilisation and must be managed through careful reactor design and flow optimisation. 

Finally, the continuous-mode operation introduces additional complexity in process validation and regulatory filing compared to established batch protocols, although the ICH Q13 guideline now provides a harmonised framework to address these concerns [4]. Mitigation strategies increasingly employed in industry include the use of commercially available functionalised resins (e.g. Purolite ECR series), the adoption of dynamic flow platforms to survey residence times and kinetic parameters prior to scale-up [9], and the application of process analytical technology (PAT) for real-time in-line monitoring.

 

Conclusion

Continuous flow biocatalysis is transitioning from academic demonstration to industrial practice. Roche’s LAP2-PBR [3,7] and Merck’s ATA-492 PBR [8,9] are the two fully documented pharmaceutical examples where this transition has been executed and quantified, yielding significant gain in space-time yield and impressive reduction in waste generation. These flow benchmarks pave the way to the transition biocatalytic API manufacturing from batch to continuous flow. They are complemented by a growing number of industrial examples featuring immobilised enzyme, well suited to flow processing [3]. 

The technical toolkit including reactor design, enzyme immobilisation, and inline analytics, seems now sufficiently mature for broad implementation. With regulatory frameworks explicitly supporting continuous manufacturing [4, 12,13] and sustainability pressures intensifying, the question is no longer whether pharma will make the transition to flow biocatalysis, but at what scale and how
fast.

 

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H. Meersseman Arango holds a PhD in Industrial Biochemical Engineering from the Université catholique de Louvain (UCLouvain, Belgium). His doctoral research focused on continuous-flow transaminase reactions for the intensified production of chiral amines relevant to API synthesis, encompassing enzyme immobilisation, reactor engineering, and process intensification. He currently works as a project consultant at Strand Consulting.

At Strand, we support our partners through project staffing, project and service management, outsourcing solutions, and tailored training, helping them meet regulatory, operational, and business challenges efficiently. Feel free to get in touch to discuss how we can support your projects.

 

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