改写“不可能”的结局！药明康德如何打通新药研发的突围之路 | Bilingual

如今，药物研发的边界正在被“看似不可能”的分子不断推远。这些结构复杂的分子正不断触及曾被认为“不可成药”的靶点。但与此同时，它们也对工艺开发和生产能力提出了前所未有的挑战。

多年前，一项几乎“无解”的任务摆在了药明康德团队面前。

这是一个合成路线长达几十步的复杂分子，其合成步骤包含了多个复杂结构。更棘手的是，分子的初始收率仅为几十个PPM（parts per million）。换句话说，目标产物的产量仅有理论产量的几万分之一。

在当时，这样的分子几乎“不可能成药”。

基于长期合作建立起的信任，客户将这项任务交给药明康德，希望能够交付用于毒理研究的原料药。

回忆起这段经历，药明康德执行副总裁、合全药业负责人傅小勇博士也坦言这是“从业几十年来从未见过的化学挑战”。

然而，真正的突破，往往始于直面不可能。面对这一难题，研发团队选择重新设计整条合成策略。

通过引入酶催化技术，并定制合成策略，团队将合成步骤缩短了十多步，同时收率提升了近百倍。这不仅是数字上的优化，更是“是否具备成药可能性”的分水岭。

不久之后，首批原料药顺利交付。这次“力挽狂澜”，也为药明康德锁定了该项目的长期合作。

几年后，随着项目推进，客户提出了更高要求：实现更大规模的稳定生产，以支持后续临床研究。面对新需求，药明康德团队进一步优化并缩短合成路线，并利用结晶工艺平台锁定多个关键中间体和原料药的稳定晶型，实现了数百公斤原料药的持续交付，为临床推进奠定了坚实基础。

直面挑战：打通商业化生产路径

随着时间的推移，一个关键节点出现了。该分子在2期临床试验中展现出积极数据，商业化的曙光初现。但这也意味着，生产规模、工艺稳定性与质量控制，将面临更严苛的考验。

为了应对潜在的商业化生产需求，药明康德团队联合客户再次对合成路线进行优化，一条全新的合成路线诞生。

在这条路线中，酶催化成为核心技术。早在十多年前，药明康德就已前瞻性布局酶催化技术平台。如今，药明康德已构建起涵盖酶筛选、酶进化、酶发酵、酶催化工艺开发及放大等全面能力的技术平台，使其成为公司一体化赋能平台的重要一环。

但天然酶并非“拿来即用”。它们在催化活性、稳定性以及底物特异性方面，往往难以满足工业化需求，需要经过万里挑一的“改造”，这正是酶进化的价值所在。

在这一项目中，团队历时两年多，完成了超百轮酶进化，最终开发出十多种关键酶，将酶的平均催化活性提升近千倍。

进化出高性能的酶只是成功的第一步。如何稳定、高质量地供应这些酶，同样决定着整条路线的成败。为此，团队同步推进发酵工艺开发，解决了关键酶的生产稳定性与杂质控制难题，实现了发酵收率的成倍增长。同时，针对未来商业化需求，团队提前扩建发酵车间产能，为大规模生产做好准备。

除了酶催化，工艺开发中还面临诸多挑战。

例如，在一项关键反应中，需要在高压强酸条件下完成氢化反应。传统釜式反应虽然成熟，但在此类极端条件下存在安全风险。

为此，团队应用连续流氢化技术，让反应物料连续通过固定有催化剂的反应器，在高压条件下实现高效、稳定的加氢转化。这一突破不仅解决了当前项目的难题，也让药明康德的连续氢化能力开始走向商业化生产应用。

最终，通过一系列优化，合成路线被缩短了超2倍，生产周期显著缩短，整体效率大幅提升。这个曾经“无法成药”的分子，一步步走向商业化现实。

图片来源：123RF

精益运营：让速度与质量并行

当技术路径逐渐清晰，如何让这条路线“跑得更快”，成为药明康德团队面临的新挑战。

在药物研发过程中，速度不仅关乎项目成败，更直接关系到患者等待新药的时间。药明康德依托高效整合的一体化平台，通过跨团队协同与无缝衔接，构建起驱动速度与质量并行的核心能力。

在这场与时间赛跑的竞速中，各团队都将高效执行贯穿于每一个环节。例如，分析团队开启“加速度”模式，在短时间内成功开发大量符合商业化标准的分析方法，推进研发进程；项目早期与后期团队紧密协作，实现了研发生产与工艺验证的同步推进，在提高效率的同时实现“零偏差”的高质量目标；质量保证（QA）团队通过迭代管理模式，将工艺验证周期缩短了7个月，在强化质量体系的同时提升工艺验证的速度……

与此同时，自动化系统为高质量交付提供了有力支撑，大幅提升整体生产效率。工厂采用了先进的数字化系统，能够精确、动态控制工艺参数，让生产过程更加持续、稳定。

从极低收率的“几乎不可能成药”分子，到支撑临床阶段用药、再到走向商业化生产，药明康德始终全力以赴赋能客户，在一场历时十年的分子攻坚战中为患者点亮了治疗曙光。

如今，这个分子的故事仍在继续。与此同时，仍有无数被贴上“不可能”标签的分子，正在等待被重新定义；也有无数患者，在等待新的治疗方案出现。

正因如此，药明康德的一体化、端到端CRDMO赋能平台也一直在支持全球众多合作伙伴破解研发挑战，加速新药从分子走向临床的过程。药明康德也将秉持着“让天下没有难做的药，难治的病”的愿景，持续将“不可能”变成可能，助力客户造福全球患者。

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.

免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

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