編者按：“讓天下沒有難做的藥，難治的病”，是初心，更是愿景。自成立以來，藥明康德步履不停：從一間實驗室，到覆蓋亞洲、歐洲和北美的全球網絡。從早期的化學合成服務，到貫穿研究（R）、開發（D）和生產（M）的一體化平臺。從第一位客戶，到全球三十多個國家的眾多合作伙伴。不斷發展的，是規模與能力；始終堅守的，是夢想與承諾。本系列文章將立足藥明康德一體化CRDMO平臺，系統講述公司不斷深化的能力和規模體系，以平臺承載信任，持續賦能客戶創新，共同推動更多突破性療法走向病患。

幾年前，藥明康德子公司合全藥業的酶催化團隊接到一項關鍵工藝優化任務。

彼時，某客戶正在推進一款創新藥的研發，其中一個關鍵手性中間體沿用傳統化學催化需要5步，總收率僅約為40%。隨著項目向臨床后期邁進，這條路線在效率與成本上的瓶頸日益凸現，優化迫在眉睫。

合全藥業團隊迅速行動，依托自有酶庫展開篩選與開發，成功構建出一條生物催化新路線。令人振奮的是，新路線將原本需要5步的合成過程簡化為1步，收率提高到76%，成本降低1/3。

但團隊并未止步于此。由于初始方案仍需三種酶與兩種輔酶協同作用，操作復雜度仍有優化空間。為此，團隊進一步引入高通量定向進化技術，在一個月內對酶進行兩輪定向進化。最終，反應體系被簡化為僅需一種酶與一種輔酶，合成時間縮短2周，收率躍升至90%，相較最初五步化學路線，總成本降低了70%以上，為這款藥物的商業化進程掃清了障礙。

從“五步收率40%”到“一步收率90%”，躍升的遠不止數字，更推動了客戶藥物分子的研發進程提速。這一案例，也成為多年來藥明康德酶催化平臺能力建設和賦能客戶的經典縮影。

耕耘十余載，酶催化一體化平臺賦能新藥工藝開發和生產

故事要從更早說起。

上世紀，工業界便開始探索將酶用于化合物合成催化。隨著酶催化及酶定向進化技術的跨越式發展，進入21世紀，這一技術成為制藥工藝開發領域的重要手段。

酶不僅能催化合成多種天然與非天然化合物，而且反應條件溫和，通常在近水相環境中進行，避免了傳統化學合成中常見的高溫、高壓條件。這使得酶催化技術被視為綠色化學的重要組成部分，正推動藥物合成朝著更高效、更可持續的方向變革。

作為全球醫藥創新的賦能者，藥明康德于2012年開始啟動酶催化技術的系統性布局。最初的工作樸實而扎實：收集天然酶和商業化酶，建立篩選酶庫，以支持原料藥工藝開發。

那時候，團隊沒有經驗，也沒有專業的實驗室，一切從零開始。團隊從市場上買酶，就放在幾臺冰箱里，一步一步摸索著往前走。

很快，團隊成功將酶催化工藝應用于一項商業化生產交付，邁出了從零到一的關鍵一步。隨著經驗不斷積累，客戶的需求也日益增多。

然而，行業需求持續攀升的同時，一個根本性瓶頸也逐漸顯現——天然酶在催化非天然化合物合成時，往往活性不佳，極大限制了其廣泛應用。

伴隨酶定向進化技術的日趨成熟，藥明康德敏銳把握這一趨勢，于2016年迅速籌建專用的酶進化實驗室，引入高通量篩選技術與半理性設計，構建起自主的酶定向進化能力，實現了從“被動選酶”到“主動進化酶”的關鍵躍升。

▲高通量酶進化設備

2017年，公司首個中試500L發酵罐投用，標志著酶發酵制備從實驗室規模邁入中試放大階段。隨著需求不斷增長，團隊持續擴建、提升酶產能，規模化生產能力顯著增強。與此同時，總面積近千平方米的兩個酶定向進化實驗中心也相繼投入運營，進一步增強了酶突變體篩選與功能評價的能力，為酶催化技術的系統化應用提供了堅實支撐。

經過十多年的持續投入，該平臺已建立起系統化的完整能力——一個覆蓋酶篩選、酶進化、酶發酵、酶工藝開發與放大的一體化平臺。

在酶篩選環節，自有酶庫涵蓋超過3500種生產用酶及超過20萬個優質突變體，可有力支持對目標化合物的快速篩選。平均兩周之內，團隊就能完成對一個化合物的酶篩選。

酶催化平臺同時能做40多個酶催化項目。若初始篩選獲得的酶在活性或選擇性上仍需提升，平臺通過高通量定向進化，快速開發出高選擇性、高反應效率的酶突變體。

目標酶確定后，平臺具備規模化制備酶粉的能力。發酵車間從實驗室規模到10,000 L反應釜實現無縫銜接，超20,000 L的總發酵容量可同時滿足從公斤級到噸級的酶快速交付，為處于不同階段的項目的工藝開發與生產提供支持。

十余年來，平臺已累計開發了650個酶催化工藝，并完成440個生產項目的交付，其中包括20項處于臨床III期及商業化階段的項目。據統計，平臺累計交付的關鍵手性中間體和原料藥已超過500噸。

在某個早期項目中，客戶面臨一道嚴峻的工藝瓶頸：原有的酶催化反應體系體積高達500V、酶用量需達3X（相比于底物量），轉化率卻僅為40%；而另一條化學合成路線雖可替代，但工藝復雜，難以支持公斤級原料藥的生產。

面對這一困局，接手項目后，酶催化團隊直擊源頭——對酶本身進行定向改造。經過五輪連續的定向進化，團隊獲得了性能顯著提升的新酶，并將新工藝的反應體積大幅縮減至80V，下降了超6倍；酶用量也顯著降低至0.1X。基于這一突破，團隊順利完成了數十公斤關鍵手性中間體的生產，為客戶臨床試驗的快速推進提供了堅實支持。

▲藥明康德酶發酵車間

酶催化：在新興藥物浪潮中破局

如今，藥明康德酶催化平臺正被用于應對不同分子類型所帶來的合成挑戰。

近年來，多肽與寡核苷酸藥物不斷拓展疾病治療的邊界，成為新藥研發領域的一股新浪潮。據統計，全球已有約100款多肽藥物獲批上市，超過40款多肽新藥是在過去十年間獲得FDA批準的。與此同時，寡核苷酸藥物的應用范圍也從罕見病逐步拓展至更廣泛的疾病領域。

這波浪潮對合成技術提出了新的挑戰：更長的序列、更復雜的修飾、更嚴格的質量控制，以及更緊迫的交付周期。

面對這一趨勢，藥明康德的酶催化一體化平臺已建立起針對性的解決方案。

在多肽領域，團隊針對各類新型非天然氨基酸進行酶催化方法開發，進一步優化合成路線，減少有機溶劑的使用，加速多肽藥物的研發和生產進程，同時實現綠色生產。

以某早期開發階段的多肽項目為例，采用傳統化學合成路線需經歷三十余步反應，總收率不足1%。當項目進入關鍵的工藝性能確認（PPQ）階段后，效率瓶頸亟待突破。在此背景下，酶催化方案被提上議程。團隊與客戶緊密合作，對整條合成路線進行系統性重構，定向進化了十余種酶，最終使合成步驟減少了十余步，總收率提升了數十倍，為該藥物的規模化生產提供了關鍵支持。

在寡核苷酸領域，長鏈RNA的制備一直是這類藥物開發中的技術難點，傳統固相合成在純度與收率方面均面臨挑戰。為解決這一問題，藥明康德酶催化團隊采用酶促連接策略：根據RNA的二級結構設計連接位點，開發高活性連接酶，將多個短鏈RNA片段拼接成長鏈。該方法精準高效地突破了長鏈RNA片段的制備瓶頸。基于此工藝，團隊已成功將其應用于復雜的雙鏈siRNA-GalNAc偶聯分子中，酶連接效率超過95%，粗品純度高達98%，且總體收率顯著提升。

如今，藥明康德的酶催化平臺正成為多肽和寡核苷酸等新興分子藥物研發的關鍵加速器之一，持續賦能客戶突破工藝開發和生產瓶頸，提升研發效率。酶催化與化學合成的協同效應，正在創新分子的浪潮中釋放出更大的賦能潛力。

與此同時，隨著酶定向進化技術與其他技術的不斷融合，酶分子的改造效率有望進一步提升，應用邊界也將持續拓寬。可以預見，這一技術未來將在更多類型的化學反應中得到應用，不僅助力提升藥物研發和生產效率，也為推動行業的綠色可持續發展提供重要支持。作為藥明康德的內部賦能平臺之一，酶催化代表了一條更高效、也更綠色的合成路徑。

從實驗室研究到用于商業化生產，從篩選單個酶分子到穩定交付數十噸關鍵原料，藥明康德酶催化平臺的能力不斷躍升，但那份初心始終未改——賦能客戶，加速項目進程，助力客戶將新療法更快惠及病患。

不止于酶：一體化平臺的技術網絡協同

在藥明康德一體化的CRDMO賦能平臺中，酶催化是眾多技術平臺中的一員，其發展是公司全面技術和能力不斷建設、優化迭代的重要體現。它與流動化學、金屬催化、結晶及顆粒工程等在內的各類技術能力互為補充，共同構成了一張精密協同的能力網絡，為客戶項目提供全面、多維度的工藝開發和生產解決方案。

例如，酶催化與流動化學常被譽為綠色化學的“兩大頂流”——一個用生物催化替代苛刻的化學條件，一個用連續化生產工藝提升效率與安全性。在藥明康德一體化平臺上，這些技術的協同應用，旨在為客戶提供從實驗室工藝開發到商業化生產交付的全鏈條支持。

而這張技術網絡的底層邏輯始終如一：把復雜的底層技術，轉化為可高效、高質量交付的賦能服務，持續支持全球創新者加速新藥研發進程。客戶不需要精通酶定向進化的計算邏輯，也不需要理解發酵罐的參數控制——他們只需要看到一個更高效、更穩定、更經濟的合成方案。

真正的賦能價值，往往藏在那些看不見的地方：藏在一輪又一輪的突變體篩選中，藏在完成酶蛋白合成的發酵罐中，藏在一次又一次的酶用量優化中，藏在不斷迭代優化的合成路線里。每一次按時交付、每一次工藝突破——它們或許不會出現在新藥獲批的新聞標題里，卻累積成藥明康德團隊可驗證的信譽，沉淀在每一款加速問世的創新藥物背后。

這或許正是賦能的意義：不站在聚光燈下，卻讓光更快地抵達需要的人。

From Five Steps to One: How WuXi AppTec's Biocatalysis Platform Enables Drug Innovation

Several years ago, WuXi STA, a subsidiary of WuXi AppTec, undertook a process optimization assignment for a client.

At the time, the client was advancing the development of an innovative drug candidate. A key chiral intermediate in the process required five steps using traditional chemical route, with an overall yield of approximately 40%. As the project moved toward later clinical stages, efficiency and cost constraints of this route became more evident, prompting a need for optimization.

WuXi STA’s biocatalysis team proposed an enzymatic route, condensing the original five-step synthesis into a single step, increasing the yield to 76%, and lowering costs by one-third.

The team did not stop there. The initial approach still required the coordinated action of three enzymes and two coenzymes, and operational complexity was an opportunity for improvement. To address this issue, the team leveraged high throughput directed evolution technology, targeting key regions and performing two rounds of directed evolution on the enzyme within a month.

Ultimately, the resulting reaction system was simplified to only one enzyme and one coenzyme.Synthesis time was reduced by two weeks, yield increased to 90%, and total cost was reduced by more than 70% compared to the original five-step chemical route – clearing a major hurdle for the drug's path toward commercialization.

From "five steps, 40% yield" to "one step, 90% yield", the leap was far more than a numerical – it accelerated the client's overall drug molecule development timeline. This case illustrates the capabilities of WuXi AppTec's biocatalysis platform and the value it has delivered to clients over the years.

Over a Decade of Cultivation: An Integrated Biocatalysis Platform Enables Drug Process Development and Manufacturing

The story begins earlier.

In the last century, the industry began exploring the use of enzymes to catalyze the synthesis of chemical compounds. With major advances in biocatalysis and directed evolution technology, by the 21st century this approach had become an important tool in pharmaceutical process development.

Enzymes can catalyze the synthesis of a wide range of both natural and unnatural compounds. They operate under mild conditions, typically in near-aqueous environments, avoiding the high temperatures and high pressures common in traditional chemical synthesis. As a result, biocatalysis is regarded as a cornerstone of green chemistry and is driving a shift toward more efficient and sustainable drug synthesis.

WuXi AppTec began systematically building its biocatalysis capabilities in 2012.The initial work was foundational: collecting natural and commercial enzymes to establish a screening enzyme library that would support active pharmaceutical ingredient (API) process development.

Back then, the team had no prior experience and no dedicated laboratory – and started from scratch. Buying enzymes from the market, the team stored them in a few refrigerators, and moved forward step by step.

Soon, the team successfully applied a biocatalysis process to a commercial manufacturing delivery — a crucial step from zero to one. As experience grew and expertise deepened, client demands grew steadily.

However, even as industry demand continued to rise, a fundamental bottleneck emerged: natural enzymes often exhibited poor activity when catalyzing the synthesis of unnatural compounds, severely limiting broader application.

With the increasing maturity of directed evolution technology, WuXi AppTec moved decisively.In 2016, it established a dedicated enzyme evolution laboratory, introducing high-throughput screening and semi-rational design to build in-house directed evolution capabilities. This marked a transition from passive enzyme screening to active enzyme engineering.

▲High Throughput Evolution Robot

In 2017, the company's first 500 L pilot-scale fermenter came online, signaling the transition of enzyme fermentation preparation from laboratory scale to pilot scale.

To meet steadily increasing demand, the team expanded and upgraded enzyme production capacity, significantly strengthening large-scale manufacturing capabilities. Meanwhile, two directed evolution laboratories spanning nearly a thousand square meters were put into operation, further enhancing the ability to screen enzyme variants and evaluate function, providing solid support for the systematic application of biocatalysis technology.

After more than a decade of sustained investment, the platform has established comprehensive, systematic capabilities – an integrated platform covering enzyme screening, enzyme evolution, enzyme fermentation, and enzyme process development and scale-up.

In enzyme screening, the in-house enzyme library contains over 3,500 manufacturing-grade enzymes and more than 200,000 optimized variants, enabling rapid screening against target compounds.On average, the team can complete enzyme screening for a compound within two weeks.

If the initially screened enzyme requires further improvement in activity or selectivity, the platform can run more than 40 enzyme evolution projects in parallel. Using the high-throughput screening laboratory, the team quickly identifies enzyme variants with high selectivity and reaction efficiency for each project.

Once the target enzyme is identified, the platform possesses the capability for large-scale enzyme powder manufacturing. The fermentation facility seamlessly connects laboratory-scale to 10,000-liter reactors, with total fermentation capacity exceeding 20,000 liters. This allows for rapid delivery of enzymes at scales ranging from kilograms to metric tons, fulfilling project requirements at every stage.

For more than a decade, our platform has developed 650 enzyme-catalyzed processes and completed delivery of 440 manufacturing projects, including 20 projects in Phase III clinical or commercial stages.To date, the platform has delivered over 500 metric tons of key chiral intermediates and APIs.

In one early-stage project, a client faced a severe process bottleneck: the existing enzyme-catalyzed reaction system required a volume of 500V and an enzyme loading of 3X (relative to the substrate) yet achieved only 40% conversion. An alternative chemical synthesis route existed, but its complexity made kilogram-scale API manufacturing impractical.

Confronted with this impasse, the team addressed the root cause – engineering the enzyme itself. After five consecutive rounds of directed evolution, the team obtained a new enzyme with significantly improved performance. The new process reduced the reaction volume to 80V, and enzyme loading was reduced to 0.1X. Based on these results, the team successfully manufactured dozens of kilograms of the key chiral intermediate, providing robust support for the client's rapid clinical trial advancement.

▲Fermentation Plantat WuXi AppTec

Biocatalysis: Navigating the Wave of Emerging Modalities

Today, WuXi AppTec's biocatalysis platform is being deployed to address synthesis challenges posed by diverse molecular modalities.

In recent years, peptide and oligonucleotide drugs have continuously expanded the frontiers of disease treatment, emerging as a new wave in drug innovation. Approximately 100 peptide drugs have been approved globally, with over 40 novel peptides approved by the FDA in the past decade alone. Meanwhile, the application scope of oligonucleotide drugs is expanding from rare diseases to broader therapeutic areas.

This wave presents new challenges for synthesis technology: longer sequences, more complex modifications, stricter quality control, and tighter delivery timelines. In response, WuXi AppTec's integrated biocatalysis platform has established targeted solutions.

In the peptide field, the team has been developing enzyme-catalyzed methods for various novel unnatural amino acids (UAAs) to optimize synthesis and reduce organic solvent usage and expedite manufacturing of UAAs and peptide drugs.

Take, for example, an early-stage peptide project where the traditional chemical synthesis route required over 30 steps, with a total yield below 1%. As the project entered the critical process performance qualification (PPQ) stage, overcoming this efficiency bottleneck became a priority.

A biocatalysis solution was proposed. Working closely with the client, the team systematically re-engineered the entire synthetic route and performed directed evolution on more than ten enzymes. The result: the number of synthetic steps was reduced by more than ten, and the overall yield increased by several dozen-fold, providing substantial support for the drug's large-scale manufacturing.

In the oligonucleotide field, the preparation of long-chain RNA has long been a major pain point in drug development, with traditional solid-phase synthesis facing challenges in both poor purity and low yield.

To address this, WuXi AppTec's biocatalysis team utilized an enzymatic ligation strategy to improve success rates in long RNA synthesis. They designed ligation sites based on RNA secondary structure, developed highly active ligases, and assembled multiple short RNA fragments into long chains. This approach addressed the key bottleneck in preparing long-chain RNA fragments.The team applied this process to a complex di siRNA–GalNAc conjugate, achieving enzymatic ligation efficiencies above 95%, crude product purity up to 98%, and a significantly improved final yield.

Today, the platform serves as one of the important accelerators for drug development of emerging modalities such as peptides and oligonucleotides, continuously enabling clients to overcome process development and manufacturing bottlenecks and improve efficiency. The synergy between biocatalysis and chemical synthesis is creating even greater enabling potential amid the wave of innovative molecules.

Meanwhile, as directed evolution technology increasingly integrates with other tools, the efficiency of enzyme engineering is expected to improve further, and the boundaries of application will continue to expand. This technology is expected to be applied to a broader range of chemical reactions in the future, supporting both drug development efficiency and the industry's progress toward greener and more sustainable practices. As one of WuXi AppTec's internal enabling platforms, biocatalysis represents a more efficient and greener synthetic pathway.

From laboratory research to commercial manufacturing, from screening a single enzyme molecule to stably delivering diverse fermentation products from kilograms to metric tons, the capabilities of WuXi AppTec's biocatalysis platform have grown steadily. Yet the founding purpose remains unchanged: to enable clients, accelerate project timelines, and help clients bring breakthrough therapies to patients faster.

Beyond Enzymes: Synergy Across an Integrated Platform

Within WuXi AppTec's integrated CRDMO enabling platform, biocatalysis is a key component of its broader network of technology platforms. Its development reflects the company's ongoing capability building and iterative optimization across comprehensive technologies. It complements various other technical capabilities – such as flow chemistry, metal catalysis, crystallization and particle engineering among others – all of which together form a coordinated capability network. This network provides clients with comprehensive, multi-dimensional process development and manufacturing solutions.

Biocatalysis and flow chemistry, for example, are often considered as two pillars of green chemistry: biocatalysis enables reactions under mild, near-aqueous conditions, while flow chemistry improves efficiency and safety through continuous manufacturing.On WuXi AppTec's integrated platform, the synergistic application of these technologies aims to provide clients with full-chain support from laboratory process development to commercial manufacturing delivery.

The underlying logic of this technology network remains consistent: turning complex foundational technologies into reliable enabling services that support global innovators in accelerating new drug development. Clients don't need to master the computational logic of directed evolution or understand the parameter control of a fermenter. They just need to see a more efficient, robust, and economical synthetic solution.

The true value of enablement often lies in the unseen details: in round after round of variant screening, in the enzyme synthesized within fermenters, and in continuously optimized synthetic routes. Every on-time delivery, every process breakthrough – these may not appear in the headlines announcing a new drug’s approval, but they accumulate into the trust for the WuXi AppTec team and are embedded in therapies that reach patients faster.

Perhaps this is the true meaning of enabling: not standing in the spotlight, but helping the light reach those in need faster.

免責聲明：本文僅作信息交流之目的，文中觀點不代表藥明康德立場，亦不代表藥明康德支持或反對文中觀點。本文也不是治療方案推薦。如需獲得治療方案指導，請前往正規醫院就診。

版權說明：歡迎個人轉發至朋友圈，謝絕媒體或機構未經授權以任何形式轉載至其他平臺。轉載授權請在「藥明康德」微信公眾號回復“轉載”，獲取轉載須知。