仅0.03毫克，这个药物项目为什么反而更难做？| Bilingual

近年来，新药研发正朝着“更小剂量、更强疗效”的精准靶向方向持续演进。随着靶向蛋白降解剂、抗体偶联药物等新型分子不断涌现，药物活性持续提升，给药剂量则大幅下降。这一趋势在带来更强疗效的同时，也向研发与生产体系提出了远超常规药物的安全与质量控制要求。高活性化合物（high-potency compound），正是这一趋势下颇具代表性的“高门槛”领域。

某生物医药公司的一个分子胶降解剂项目，集中体现了该领域的典型挑战：OEB5最高职业暴露等级、长达12步的合成路线，以及仅0.03毫克的极低制剂规格。这些特点的叠加，使项目从一开始就充满挑战。

按照常规路径，类似复杂度的项目往往需要更长的开发周期。而药明康德子公司合全药业，依托其在高活性药物领域十余年的平台积累与一体化能力，在8个月内助力该客户完成了从PCC确认后的原料药（API）工艺优化到IND申报的整套CMC工作，实现了高质量交付。

高活化合物：“低”剂量背后的“高”门槛

高活性化合物，是指低剂量即具有极高药理活性的化合物。其微小的剂量即可达到非高活药物大剂量难以实现的效果。行业内通常将职业暴露限值（OEL）低于1 µg/m³的化合物定义为高活化合物（OEL指工作人员在特定时间内反复接触某种化学物质而不产生健康影响的空气浓度上限）。一般而言，传统非高活药物的生产规模常以吨计，而高活性药物的年需求量通常仅为几公斤到几十公斤。

高活性药物主要集中在抗肿瘤、细胞毒性及部分激素类药物领域。随着新分子类型不断发展，高活药物的应用边界持续拓展。例如，高活性药物可与小分子、多肽、核酸、糖类乃至生物大分子等偶联，通过精准递送实现对癌细胞或病毒目标的定点清除。再如，靶向蛋白降解剂的作用机制是通过诱导或稳定蛋白-蛋白相互作用，并由此具备催化特征——药物分子本身不被消耗，而是作为催化剂循环利用，反复诱导靶蛋白降解。这使得其在极低剂量下即可产生显著药效。因此，大多数此类分子在研发和生产中需按高活性化合物处理，以保障安全。

尽管前景备受期待，然而高活化合物因特殊药理活性与固有毒性，无论是原料药还是制剂，都对研发及生产条件提出了极为苛刻的要求——高度隔离密闭的硬件设施、扎实的工艺开发能力、专业的生产能力，以及贯穿全程的质量与安全管控体系。

药明康德子公司合全药业在高活领域已深耕10余年。自2012年起，公司就开始建设高活药物研发与生产技术平台，生产车间的密闭性能目标（Containment Performance Target，CPT）可满足OEL低至10 ng/m³化合物的控制要求，以满足行业与客户需求。目前，公司拥有一站式的高活原料药平台，配备高活研发实验室、公斤级实验室及商业化生产车间，覆盖从工艺开发到商业化生产的全链条服务。高活原料药平台还拥有流动化学、磨粉、氢化、制备级高效液相色谱、冻干等技术能力，满足从临床前到商业化不同阶段的各类项目需求。

除原料药服务外，合全药业还为高活制剂提供一体化CMC服务，覆盖口服及注射制剂。高活口服制剂车间具备湿法/干法制粒、压片、包衣以及胶囊填充等各类工艺，能够支持高活性成分片剂和胶囊等的生产。高活注射剂车间以业界领先的全隔离器灌装技术为核心，配备自动进出料系统，全流程自动化，最大程度减少人为干预，全方位避免交叉污染。

截至目前，公司已为超40个高活性项目提供原料药及制剂的一体化服务，成功生产及放行300余批临床批次。

此外，依托成熟的高活性药物一体化能力，合全药业可提供高活毒素小分子（payload）、连接子（linker）及payload-linker的工艺开发及生产全链条服务，并与药明康德WuXi TIDES平台形成协同，更好地赋能客户各类寡核苷酸及多肽偶联药物开发。

正是这些积累，为合全药业助力客户破解高活药物开发难题奠定了坚实基础。

▲合全药业高活原料药生产车间（图片来源：合全药业官网）

破解多维度技术困局

在本次项目中，该分子胶降解剂面临多重技术挑战。原料药环节，其职业暴露等级为OEB5——即行业内高活性化合物的最高管控等级，意味着需要专用的高活车间、配备经过专业培训的人员并执行严格安全规范；除此之外，该分子的合成路线长达十余步，涉及多次纯化，且终产物储存稳定性不佳。

制剂环节，低至0.03 mg的超低剂量规格使传统制剂和分析方法面临挑战：原料药易吸附于设备表面，既会造成物料损失，也易引发交叉污染风险。更关键的是，超低剂量对含量均匀度要求极为严苛，对高灵敏度分析方法的需求也进一步提升了项目复杂性。

针对上述难点，合全药业团队制定了系统性解决方案。

面对原料药工艺开发和生产的核心挑战，合全药业的工艺团队在OEB5工艺开发实验室首先通过系统的晶型筛选与结晶工艺优化，获得了一种稳定的晶型，有效防止了储存过程中的降解与晶型转变。得益于优化后的工艺，原料药GMP批次的总收率提升了超10%，纯度达到99%以上，且杂质控制良好。最终，团队仅用四个半月交付了数公斤原料药，为制剂开发提供了充足的物料保障。

制剂环节，合全药业团队依托高活制剂专属车间，采用流化床制粒及喷雾混悬技术，通过均匀分散和混悬液喷液，实现了活性成分在辅料中的高度均一分布。最终，有效成分含量均一性的相对标准偏差（Relative Standard Deviation，RSD）低于2.0%，显著优于美国药典/欧洲药典（USP/EP）标准中6.0%的要求。对超低剂量药物而言，RSD值越低意味着单剂药物含量一致性越好，是关乎药效与安全性的关键指标。

贯穿项目始终的另一个挑战是杂质控制。在高活项目中，产品接触材料评估是控制未知杂质的核心策略。合全药业团队使用填充辅料模拟生产批次，对设备进行预检，系统评估所有接触表面材料，确保杂质可控。此外，团队还开发了灵敏的高效液相色谱方法，可同时测定原料药含量与有关杂质，从而实现了超低规格下的精准质量控制。

8个月：一体化流程驱动的“加速”引擎

从项目启动到支持客户完成IND申报，整个项目仅用时8个月，为客户显著缩短了项目周期。这背后是药明康德一体化平台带来的系统性协同优势。

该项目中，原料药工艺开发和优化、生产尚在进行时，处方前研究和制剂开发已同步启动；同时，分析方法的开发、验证和放行也全程同步支持原料药和制剂的全流程研发，且所有操作均在OEB5实验室及GMP生产车间的密闭环境中开展。各环节不再是孤立串联的线性流程，而是并行推进，高效协同的有机整体。传统碎片化模式中常见的跨环节等待、方法反复交接、验证等效率损耗，被系统性压缩。

尤其针对高活化合物，一体化模式的优势更为突出：一方面，产品从工艺放大到生产的核心环节实现全链条密闭流转，避免了跨环节交接带来的交叉污染与暴露风险。另一方面，跨团队协同，同步优化高活分子的合成路线、特殊制剂工艺与密闭灌装设计等，真正实现了高活项目的“加速跑”。最终，项目不仅进度更快，质量稳定性也更有保障。

随着高活性药物的临床应用场景持续扩展，如何让更多具备治疗潜力的高活性分子更快、更高质量地进入临床，是整个产业努力的重要方向。药明康德也将继续与全球合作伙伴携手，通过一体化赋能平台，助力客户加速推动更多创新疗法从实验室走向临床，早日惠及患者。

Overcoming Multiple Challenges: How WuXi AppTec Helped a Client Complete an IND Submission for a High-Potency Molecule in 8 Months

In recent years, drug development has increasingly moved toward precisely targeted therapies that can deliver greater therapeutic effects at lower doses.As emerging modalities such as targeted protein degraders and antibody-drug conjugates continue to advance, drug potency is increasing while required doses are decreasing.Although this trend creates opportunities for more effective therapies, it also places safety and quality-control demands on drug development and manufacturing that go far beyond those associated with conventional drugs. High-potency (HP) compounds represent one such field where the technical bar is particularly high.

A molecular glue degrader project from a biopharmaceutical company illustrates many of these challenges. The molecule was classified as OEB5, the highest occupational exposure band, required a 12-step synthetic route and had an ultra-low drug product dosage strength of just 0.03 mg. Together, these characteristics made the project highly challenging from the outset.

Under a conventional development model, a project of this complexity would typically require a longer timeline. Drawing on more than a decade of experience and integrated capabilities in high-potency drug development,WuXi STA, a subsidiary of WuXi AppTec, helped the client complete the full CMC scope—from API process development through IND submission—in just 8 months, delivering a high-quality regulatory package.

High-Potency Compounds: The High Bar Behind Low Doses

High-potency compounds are characterized by strong pharmacological activity at very low doses. Minute quantities can produce effects that may require much larger doses of conventional, non-high-potency drugs. The industry generally defines compounds with an occupational exposure limit (OEL) below 1 µg/m³ as high-potency compounds. An OEL represents the maximum airborne concentration of a chemical to which workers can be repeatedly exposed over a specified period without expected adverse health effects. While conventional drugs may be manufactured on a metric-ton scale, annual demand for high-potency drugs is often only a few kilograms to several tens of kilograms.

High-potency drugs are commonly found in oncology, cytotoxic therapies, and certain hormone-based therapies. As new molecular modalities continue to emerge, their applications are expanding. For example, highly potent compounds can be conjugated to small molecules, peptides, nucleic acids, carbohydrates, or even biologics, enabling more precise delivery to cancer cells or viral targets.

Targeted protein degraders provide another example. By inducing or stabilizing protein-protein interactions, these molecules can exhibit catalytic behavior: rather than being consumed in the process, the drug molecule can repeatedly induce degradation of the target protein. This property enables some degraders to produce substantial pharmacological effects at very low doses. As a result, many such molecules need to be handled as high-potency compounds during development and manufacturing to help ensure safe operations.

Despite their therapeutic potential, the strong pharmacological activity and inherent toxicity of high-potency compounds impose stringent requirements on both development and manufacturing. Whether for APIs or drug products, these programs require highly contained facilities, robust process development capabilities, specialized manufacturing expertise, and comprehensive quality and safety management throughout the development lifecycle.

WuXi STA has been working in the high-potency pharmaceutical field for more than a decade. Since 2012, the company has continued to build its high-potency drug development and manufacturing platform in response to evolving industry and client needs. The facilities have a Containment Performance Target (CPT) designed to meet the control requirements for compounds with occupational exposure limits (OELs) as low as 10 ng/m³. Today, it is equipped with multiple high-potency process R&D labs, kilo labs, and plants along with various process technologies such as milling, flow chemistry, hydrogenation, preparative high-performance liquid chromatography (HPLC) and lyophilization, offering a one-stop high-potency API platform spanning process development through commercial manufacturing.

Beyond API services, WuXi STA provides integrated CMC services for high-potency drug products, including oral and injectable formulations. Its high-potency oral drug product manufacturing facilities support processes including wet and dry granulation, tablet compression, coating, and capsule filling, enabling the manufacture of both tablets and capsules. The high-potency injectable manufacturing facility utilizes fully enclosed isolation systems and automated filling machines. This design effectively minimizes human intervention, preventing cross-contamination and ensuring stringent quality assurance for sterile products.

To date, WuXi STA has supported more than 40 integrated high-potency projects covering drug substance and drug product and has released more than 300 clinical batches.

Leveraging its established integrated high-potency capabilities, WuXi STA also provides end-to-end process development and manufacturing services for highly potent small-molecule payloads, linkers, and payload-linker constructs. Through collaboration with WuXi TIDES, part of WuXi AppTec, these capabilities can further support clients developing a broad range of conjugated therapeutics.

This depth of experience provided the foundation for WuXi STA to address the challenges presented by high-potency drug development.

▲WuXi STA high-potency API plant (Image source: WuXi STA)

How WuXi AppTec Addresses Challenges Across Multiple Dimensions

The molecular glue degrader presented challenges across both API and drug product development.

On the API side, the compound was classified as OEB5—the highest occupational exposure band for high-potency compounds—requiring dedicated high-potency facilities, specially trained personnel, and rigorous safety protocols. In addition, the synthetic route involved twelve steps and multiple purification stages, while the final compound exhibited poor storage stability.

On the drug product side, the ultra-low dosage strength of just 0.03 mg created significant challenges for conventional formulation and analytical approaches. The API was prone to adsorption onto equipment surfaces, potentially resulting in both material loss and cross-contamination risks. More importantly, the ultra-low dose required exceptionally tight content uniformity, while the need for highly sensitive analytical methods further increased project complexity.

To address these challenges, the WuXi STA team developed a systematic solution.

For API process development and manufacturing, the process team conducted systematic solid-form screening and optimized the crystallization process in the OEB5 lab to identify a stable polymorph, effectively preventing degradation and polymorphic transformation during storage.Following process optimization, the overall yield under GMP manufacturing conditions increased by more than 10%, purity exceeded 99%, and impurities were well controlled. Within just four and a half months, the team delivered several kilograms of API, providing sufficient material for subsequent drug product development.

For the drug product, the team relied on the dedicated high-potency manufacturing facility and employed fluid bed granulation and suspension spraying techniques. Through multiple stages of uniform dispersion and liquid suspension spraying, the approach enabled highly homogeneous distribution of the active ingredient throughout the excipient matrix.

Ultimately, the relative standard deviation (RSD) for content uniformity was below 2.0%, well below the 6.0% criterion specified in USP/EP standards. For an ultra-low-dose drug product, a lower RSD indicates greater consistency in API content between individual dosage units—an important quality attribute related to both efficacy and safety.

Impurity control represented another challenge throughout the project. In high-potency programs, product contact material (PCM) assessment is an important strategy for controlling potential unknown impurities. WuXi STA used filler excipients to simulate manufacturing batches and pre-assess the equipment, systematically evaluating product-contact materials and surfaces to help ensure that potential impurities remained under control.

The team also developed a sensitive HPLC method capable of simultaneously measuring API content and related impurities, enabling reliable quality control even at the ultra-low dosage strength.

Eight Months to IND: How an Integrated Workflow Accelerated Development

From project initiation through support for the client's IND submission, the entire program was completed in just 8 months, significantly shortening the overall development timeline. This acceleration was enabled by the systematic coordination of WuXi AppTec's integrated platform.

Rather than waiting for API development to be completed before beginning subsequent activities, preformulation studies and drug product development were initiated while API process development, optimization, and manufacturing were still underway. In parallel, analytical method development, validation, and release testing supported both API and drug product development throughout the program. All operations were conducted in fully enclosed OEB5 labs and GMP plants to ensure containment.

As a result, individual stages no longer operated as isolated steps in a linear sequence. Instead, multiple activities progressed in parallel as part of a coordinated workflow. Inefficiencies commonly encountered in fragmented development models—including waiting between stages, repeated analytical method handover, and validation—were systematically reduced.

For high-potency compounds in particular, the benefits of this integrated model are especially apparent. From process scale-up through manufacturing, materials can be handled within a fully contained chain, reducing cross-contamination and occupational exposure risks associated with movements between different stages or facilities.

At the same time, cross-functional teams can work together to optimize the synthetic route, specialized formulation processes, and contained filling approaches in parallel, helping accelerate the overall program. In this project, the result was not only a shorter timeline but also greater assurance of consistent quality throughout development.

As the clinical applications of high-potency drugs continue to expand, enabling more high-potency molecules with therapeutic potential to reach the clinic faster and with robust quality remains an important priority for the industry.

WuXi AppTec will continue to collaborate with global partners, leveraging its integrated platform to help clients accelerate the advancement of innovative therapies from the laboratory to the clinic—and ultimately to the patients who need them.

Key Takeaways:

• With the emergence of new modalities such as molecular glues and proteolysis-targeting chimeras, the application landscape for high-potency drugs continues to expand. At the same time, advancing these molecules from the laboratory to the clinic places significantly greater demands on containment, process development, manufacturing, and quality control than conventional drugs.

• WuXi STA, a subsidiary of WuXi AppTec, has more than a decade of experience in the high-potency field. Its capabilities include a one-stop high-potency API platform spanning process development through commercial manufacturing, as well as integrated CMC services for APIs and drug products, including oral and injectable dosage forms.

• To date, WuXi STA has supported more than 40 integrated high-potency projects and released more than 300 clinical batches. Its capabilities span API manufacturing, oral solid dosage forms, injectable products, and automated material handling from charging through discharge and transport.

参考资料：

[1]小剂量，大疗效，这么好的药，如何加速研发？Retrieved September 28, 2026, from https://mp.weixin.qq.com/s/q98wTdmmiLEDX2iHzz4toQ

[2]合全药业官网. Retrieved September 28, 2026, from https://sta.wuxiapptec.com/cn/services-solutions/drug-substance/high-potency-api/

[3]走进CMC｜一体化系列：高活化合物的CMC关键点考量. Retrieved September 28, 2026, from https://mp.weixin.qq.com/s/fWa41WhsozYpIVWQS66QGw

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