改寫“不可能”的結(jié)局！藥明康德如何打通新藥研發(fā)的突圍之路 | Bilingual

如今，藥物研發(fā)的邊界正在被“看似不可能”的分子不斷推遠。這些結(jié)構(gòu)復(fù)雜的分子正不斷觸及曾被認(rèn)為“不可成藥”的靶點。但與此同時，它們也對工藝開發(fā)和生產(chǎn)能力提出了前所未有的挑戰(zhàn)。

多年前，一項幾乎“無解”的任務(wù)擺在了藥明康德團隊面前。

這是一個合成路線長達幾十步的復(fù)雜分子，其合成步驟包含了多個復(fù)雜結(jié)構(gòu)。更棘手的是，分子的初始收率僅為幾十個PPM（parts per million）。換句話說，目標(biāo)產(chǎn)物的產(chǎn)量僅有理論產(chǎn)量的幾萬分之一。

在當(dāng)時，這樣的分子幾乎“不可能成藥”。

基于長期合作建立起的信任，客戶將這項任務(wù)交給藥明康德，希望能夠交付用于毒理研究的原料藥。

回憶起這段經(jīng)歷，藥明康德執(zhí)行副總裁、合全藥業(yè)負(fù)責(zé)人傅小勇博士也坦言這是“從業(yè)幾十年來從未見過的化學(xué)挑戰(zhàn)”。

然而，真正的突破，往往始于直面不可能。面對這一難題，研發(fā)團隊選擇重新設(shè)計整條合成策略。

通過引入酶催化技術(shù)，并定制合成策略，團隊將合成步驟縮短了十多步，同時收率提升了近百倍。這不僅是數(shù)字上的優(yōu)化，更是“是否具備成藥可能性”的分水嶺。

不久之后，首批原料藥順利交付。這次“力挽狂瀾”，也為藥明康德鎖定了該項目的長期合作。

幾年后，隨著項目推進，客戶提出了更高要求：實現(xiàn)更大規(guī)模的穩(wěn)定生產(chǎn)，以支持后續(xù)臨床研究。面對新需求，藥明康德團隊進一步優(yōu)化并縮短合成路線，并利用結(jié)晶工藝平臺鎖定多個關(guān)鍵中間體和原料藥的穩(wěn)定晶型，實現(xiàn)了數(shù)百公斤原料藥的持續(xù)交付，為臨床推進奠定了堅實基礎(chǔ)。

直面挑戰(zhàn)：打通商業(yè)化生產(chǎn)路徑

隨著時間的推移，一個關(guān)鍵節(jié)點出現(xiàn)了。該分子在2期臨床試驗中展現(xiàn)出積極數(shù)據(jù)，商業(yè)化的曙光初現(xiàn)。但這也意味著，生產(chǎn)規(guī)模、工藝穩(wěn)定性與質(zhì)量控制，將面臨更嚴(yán)苛的考驗。

為了應(yīng)對潛在的商業(yè)化生產(chǎn)需求，藥明康德團隊聯(lián)合客戶再次對合成路線進行優(yōu)化，一條全新的合成路線誕生。

在這條路線中，酶催化成為核心技術(shù)。早在十多年前，藥明康德就已前瞻性布局酶催化技術(shù)平臺。如今，藥明康德已構(gòu)建起涵蓋酶篩選、酶進化、酶發(fā)酵、酶催化工藝開發(fā)及放大等全面能力的技術(shù)平臺，使其成為公司一體化賦能平臺的重要一環(huán)。

但天然酶并非“拿來即用”。它們在催化活性、穩(wěn)定性以及底物特異性方面，往往難以滿足工業(yè)化需求，需要經(jīng)過萬里挑一的“改造”，這正是酶進化的價值所在。

在這一項目中，團隊歷時兩年多，完成了超百輪酶進化，最終開發(fā)出十多種關(guān)鍵酶，將酶的平均催化活性提升近千倍。

進化出高性能的酶只是成功的第一步。如何穩(wěn)定、高質(zhì)量地供應(yīng)這些酶，同樣決定著整條路線的成敗。為此，團隊同步推進發(fā)酵工藝開發(fā)，解決了關(guān)鍵酶的生產(chǎn)穩(wěn)定性與雜質(zhì)控制難題，實現(xiàn)了發(fā)酵收率的成倍增長。同時，針對未來商業(yè)化需求，團隊提前擴建發(fā)酵車間產(chǎn)能，為大規(guī)模生產(chǎn)做好準(zhǔn)備。

除了酶催化，工藝開發(fā)中還面臨諸多挑戰(zhàn)。

例如，在一項關(guān)鍵反應(yīng)中，需要在高壓強酸條件下完成氫化反應(yīng)。傳統(tǒng)釜式反應(yīng)雖然成熟，但在此類極端條件下存在安全風(fēng)險。

為此，團隊?wèi)?yīng)用連續(xù)流氫化技術(shù)，讓反應(yīng)物料連續(xù)通過固定有催化劑的反應(yīng)器，在高壓條件下實現(xiàn)高效、穩(wěn)定的加氫轉(zhuǎn)化。這一突破不僅解決了當(dāng)前項目的難題，也讓藥明康德的連續(xù)氫化能力開始走向商業(yè)化生產(chǎn)應(yīng)用。

最終，通過一系列優(yōu)化，合成路線被縮短了超2倍，生產(chǎn)周期顯著縮短，整體效率大幅提升。這個曾經(jīng)“無法成藥”的分子，一步步走向商業(yè)化現(xiàn)實。

圖片來源：123RF

精益運營：讓速度與質(zhì)量并行

當(dāng)技術(shù)路徑逐漸清晰，如何讓這條路線“跑得更快”，成為藥明康德團隊面臨的新挑戰(zhàn)。

在藥物研發(fā)過程中，速度不僅關(guān)乎項目成敗，更直接關(guān)系到患者等待新藥的時間。藥明康德依托高效整合的一體化平臺，通過跨團隊協(xié)同與無縫銜接，構(gòu)建起驅(qū)動速度與質(zhì)量并行的核心能力。

在這場與時間賽跑的競速中，各團隊都將高效執(zhí)行貫穿于每一個環(huán)節(jié)。例如，分析團隊開啟“加速度”模式，在短時間內(nèi)成功開發(fā)大量符合商業(yè)化標(biāo)準(zhǔn)的分析方法，推進研發(fā)進程；項目早期與后期團隊緊密協(xié)作，實現(xiàn)了研發(fā)生產(chǎn)與工藝驗證的同步推進，在提高效率的同時實現(xiàn)“零偏差”的高質(zhì)量目標(biāo)；質(zhì)量保證（QA）團隊通過迭代管理模式，將工藝驗證周期縮短了7個月，在強化質(zhì)量體系的同時提升工藝驗證的速度……

與此同時，自動化系統(tǒng)為高質(zhì)量交付提供了有力支撐，大幅提升整體生產(chǎn)效率。工廠采用了先進的數(shù)字化系統(tǒng)，能夠精確、動態(tài)控制工藝參數(shù)，讓生產(chǎn)過程更加持續(xù)、穩(wěn)定。

從極低收率的“幾乎不可能成藥”分子，到支撐臨床階段用藥、再到走向商業(yè)化生產(chǎn)，藥明康德始終全力以赴賦能客戶，在一場歷時十年的分子攻堅戰(zhàn)中為患者點亮了治療曙光。

如今，這個分子的故事仍在繼續(xù)。與此同時，仍有無數(shù)被貼上“不可能”標(biāo)簽的分子，正在等待被重新定義；也有無數(shù)患者，在等待新的治療方案出現(xiàn)。

正因如此，藥明康德的一體化、端到端CRDMO賦能平臺也一直在支持全球眾多合作伙伴破解研發(fā)挑戰(zhàn)，加速新藥從分子走向臨床的過程。藥明康德也將秉持著“讓天下沒有難做的藥，難治的病”的愿景，持續(xù)將“不可能”變成可能，助力客戶造福全球患者。

Rewriting the “Impossible”: How WuXi AppTec Carved a Path for Drug Development

Today, the boundaries of drug discovery are being pushed ever further by molecules once deemed “impossible.”Increasingly complex in structure, these compounds are enabling scientists to engage targets long considered “undruggable.” Yet at the same time, they impose unprecedented demands on process development and manufacturing capabilities.

Years ago, WuXi AppTec was confronted with a seemingly insurmountable challenge.

The molecule required a synthetic route with dozens of steps, many of which involved highly complex structural elements. Even more daunting, the initial yield was only in the tens of parts per million (PPM). In other words, the amount of target product obtained was merely a few ten-thousandths of the theoretical yield.

At the time, such a molecule was widely regarded as “undruggable.”

Built on years of trust, the client tasked WuXi AppTec with the goal of delivering active pharmaceutical ingredient (API) material for toxicology studies.

Reflecting on this experience, Dr. Xiaoyong Fu, Executive Vice President, Head of STA at WuXi AppTec, described it as “something I’d never seen in decades of chemistry.”

Real progress, however, often begins with confronting the impossible. Faced with this challenge, teams at WuXi STA, a subsidiary of WuXi AppTec, opted to redesign the entire synthetic strategy from the ground up.

By introducing biocatalysis and adopting an innovative synthetic approach, the team reduced the total number of steps by more than ten while improving yield by nearly two orders of magnitude.This was not merely a numerical optimization. It marked a fundamental turning point in determining whether the molecule had genuine drug development potential.

Shortly thereafter, the first batch of API was successfully delivered. This critical turnaround not only rescued the project but also secured a long-term partnership with the client.

Several years later, as the program advanced, the client raised the bar further: larger-scale, consistent manufacturing was required to support clinical studies. In response, WuXi STA further optimized and shortened the synthetic route. Leveraging its crystallization platform, the team successfully identified and locked stable crystal forms of key intermediates and the API, enabling the continuous delivery of hundreds of kilograms of material and laying a solid foundation for clinical advancement.

Confronting Challenge: Enabling Commercial Manufacturing

With the smooth progress of the project, the molecule demonstrated promising results in Phase II clinical trials, signaling the potential for commercialization. However, this also meant that manufacturing scale, process robustness, and quality control would face far more stringent requirements.

To prepare for future commercial demand, WuXi STA’s team collaborated closely with the client to once again reengineer the synthetic route, resulting in an entirely new process.

At the core of this new route was biocatalysis. More than a decade earlier, WuXi AppTec had already made forward-looking investments in building a biocatalysis platform. Today, this platform encompasses enzyme screening, evolution, fermentation, as well as enzymatic process development and scale up, forming a key pillar of WuXi AppTec’s integrated enabling platform.

Yet natural enzymes are rarely “ready-to-use.” Their catalytic activity, stability, and substrate specificity often fall short of industrial requirements, necessitating extensive optimization through enzyme evolution.

In this project,the team conducted over 100 rounds of enzyme evolution across more than two years, ultimately developing a dozen critical enzymes and enhancing their average catalytic activity by nearly three orders of magnitude.

However, engineering high-performance enzymes was only the first step. Ensuring their stable and high-quality supply was equally critical for the entire process. To this end, the team advanced fermentation process development in parallel, overcoming challenges in process stability and impurity control, while achieving significant improvements in fermentation yield. At the same time, fermentation capacity was proactively expanded to meet anticipated commercial-scale demand.

Beyond biocatalysis, additional process challenges had to be addressed.

For instance, one key transformation required hydrogenation under high-pressure, strongly acidic conditions. While traditional batch reactors are well-established, they pose safety risks under such extreme conditions.

To overcome this, the team implemented continuous-flow hydrogenation technology. By enabling reaction materials to pass continuously through a catalyst-packed reactor, the process achieved efficient and stable hydrogenation under high pressure. This progress not only resolved a critical bottleneck in the project but also marked a key step toward commercial-scale application of WuXi AppTec's continuous hydrogenation capabilities.

Through these and other optimizations, the synthetic route was ultimately shortened by more than half, significantly shortening production timelines and greatly enhancing overall efficiency. What was once considered “undruggable” steadily progressed toward delivering tangible clinical benefit to patients.

Image source：123RF

Operational Excellence: Speed with Quality

As the technical pathway became clearer, a new challenge emerged: how to accelerate execution.

In drug development, speed is not merely a competitive advantage, it also directly impacts how quickly patients can access new therapies. Leveraging its highly integrated platform, WuXi AppTec has built core capabilities that provide customers with both speed and quality through seamless cross-functional collaboration.

In this race against time, every team operated with a focus on efficiency. The analytical team entered “acceleration mode,” rapidly developing many analytical methods that met commercial standards, thereby advancing the program. Early- and late-stage teams worked in close coordination, enabling parallel progress in process development, manufacturing, and validation, achieving high efficiency while maintaining a “zero-deviation” quality standard. Meanwhile, the Quality Assurance (QA) team adopted an iterative management approach that shortened process validation timelines by seven months, strengthening the quality system while accelerating validation...

Automation further underpinned high-quality delivery and significantly boosted overall production efficiency. The manufacturing facility deployed cutting-edge digital operation systems, ensuring dynamic control of process parameters, optimizing production consistency.

From a low-yield molecule once deemed “nearly impossible to develop”, to one supporting clinical-stage supply and advancing toward commercialization, WuXi AppTec has remained committed to enabling its clients worldwide. Over the course of a decade-long scientific endeavor, this journey has helped bring new hope to patients.

Today, the story of this molecule is still unfolding. At the same time,countless other molecules labeled “impossible” are waiting to be redefined, and countless patients are still waiting for new treatment options.

Driven by the urgent need, WuXi AppTec continues to leverage its integrated, end-to-end CRDMO platform to help global partners overcome R&D and manufacturing challenges and accelerate the journey from molecule to medicine. Guided by the vision of “every drug can be made, and every disease can be treated”, WuXi AppTec remains committed to enabling its customers to turn the impossible into reality and bring benefits to patients worldwide.

免責(zé)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(dǎo)，請前往正規(guī)醫(yī)院就診。

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