穿越工艺与产能瓶颈：药明康德加速小核酸药物驶上“快车道” | Bilingual

过去十余年，核酸药物领域迎来了迅猛发展，以反义寡核苷酸（ASO）为代表的新分子正在不断拓展传统药物的作用边界，为罕见病、神经系统疾病、肝脏及代谢性疾病等领域带来新的治疗机遇。然而，从实验室的分子蓝图到惠及患者的可用新药，这类分子还需跨越一系列研发生产挑战。

几年前，一家生物科技公司正在推进一款处于临床2期的颇具潜力的反义寡核苷酸候选分子，该候选分子针对的疾病患者群体广泛但现有的治疗手段有限。因此，加快研发和生产进程、提供稳定的临床用制剂，对于满足患者的迫切需求至关重要。

但在这一关键节点，放大生产与工艺验证却遭遇困境。反义寡核苷酸分子结构复杂，且对杂质控制要求高，原有工艺收率有限，导致其放大生产面临挑战。雪上加霜的是，原合作方也无法支持从小规模供应到商业化规模生产的无缝过渡。随着项目进入后期开发阶段，供应连续性中断风险将越来越大，甚至可能导致项目整体进度延误。

时间不等人，为保障项目按计划推进，该生物科技公司亟需找到一家新的合作伙伴——既能够在三年内实现快速放大、工艺验证、申报资料撰写以及PAI（批准前检查）准备，同时需要尽早建立具有成本效益的工艺，以支持未来数吨级的需求。

几经评估，他们将希望寄托于药明康德旗下专注于寡核苷酸和多肽疗法的WuXi TIDES。

直面挑战，建立稳健、可商业化放大的原料药和制剂工艺

客户的选择并非偶然，其背后是药明康德二十多年来在化学能力方面积累的深厚经验，以及WuXi TIDES平台在寡核苷酸等新分子领域进行的长期能力建设。

如今，WuXi TIDES已建立起包括原料药及制剂，覆盖从药物发现到商业化阶段的寡核苷酸药物开发和生产需求。近年来，该平台还在寡核苷酸领域不断建设新能力，如固相与液相合成，酶促合成等，进一步提升合成复杂序列的效率；在下游纯化分离方面，采用切向流过滤、连续流色谱等创新技术，优化下游处理流程、减少工艺步骤。

接手项目后，WuXi TIDES迅速组建了一支涵盖原料药和制剂工艺开发与生产等覆盖项目全流程的项目团队。

原料药方面，项目团队依托成熟的寡核苷酸技术平台和工艺开发专长，系统优化了原料药工艺，将粗品纯度从不到70%提升至88%。更高的粗品纯度不仅让整体收率显著提升，还将纯化步骤由两步简化为一步，使原料药生产周期缩短25%。同时，工艺优化后，原料消耗减少，又进一步改善了工艺的经济性。

得益于这些改进以及稳健的放大策略，优化后的原料药工艺运行稳定，团队在4.5个月内交付了多个PPQ（工艺性能验证）批次，超过25公斤原料药，且不同批次质量高度一致。原料药工艺在稳健性、高效性与成本效益方面形成了综合优势，为加速后期开发和未来商业化生产奠定了坚实基础。

在制剂方面，制剂团队专注于如何减少高价值原料药损失，提高总体收率。为此，项目团队重新优化了无菌转移和灌装工艺流程：使用无菌的一次性转移系统，并按批次定制一次性装配组件，显著降低了原料药损失率，将灌装废品率降低16%。得益于有效减少了生产过程中的物料损失，使得制剂收率超过95%，成效明显。

团队始终如一的稳健供应和规模放大能力，为PPQ批次的高效推进按下了加速键。团队仅用6.5个月，就完成了行业内平均10~12个月才能达到的多个PPQ批次交付量。

图片来源：123RF

一体化平台能力为未来商业化生产铺路

能够如此高效推动项目进程，不仅源于WuXi TIDES解决复杂问题的能力，更得益于药明康德一体化CRDMO模式所带来的协同优势。在一体化平台和统一的质量体系下，原料药到制剂的无缝衔接，以及工艺研发、分析方法开发和验证及生产等关键环节能够高效并行推进。

在这一模式下，各团队无需等待当前环节结束再启动下一环节，也无需担心跨环节衔接问题。例如当原料药团队交付临床批次原料药时，制剂团队同步开启工艺优化，并无缝启动了制剂生产；当原料药团队交付PPQ批次原料药时，制剂团队已做好制剂PPQ批次准备和生产。这样紧密的协作模式，使得团队能够快速突破工艺与产能瓶颈，加速项目推进，满足客户需求。此外，由于工艺、分析方法及质量体系的一致性，从工艺放大到分析方法转移的各环节均大幅提高了成功率，有效减少了方法转移过程中的偏差与重复验证工作，并有助于增强CMC资料的一致性与监管接受度。同时，公司原料药与制剂生产基地空间距离较近，也为实现高质量、快速的项目交付奠定了重要基础。

最终，WuXi TIDES团队在短短两年半时间内，实现了将该项目从临床2期，快速推进至后期工艺验证完成，加速了这款反义寡核苷酸药物的上市进程。

这项合作不仅印证了药明康德在处理复杂寡核苷酸分子从后期开发到未来商业化生产的一体化平台能力，更是公司赋能全球客户，突破研发瓶颈，加速新药上市进程的生动脚注。作为医药创新的赋能者，药明康德始终遵循“质量源于设计（Quality by Design）”的理念，从源头到过程中的每个环节，都恪守高质量标准，并将继续依托一体化、端到端的CRDMO平台，以其积累的丰富经验，助力客户更高效地推进研发项目，让更多新药早日惠及患者。

How Does WuXi AppTec Accelerate Late-Stage Development and Commercial Readiness for Innovative Oligonucleotide Medicines?

WuXi TIDES, an integral part of WuXi AppTec that provides solutions for oligonucleotides, peptides and related synthetic conjugates, accelerated late-stage development and commercial readiness of an innovative oligonucleotide medicine through process robustness, Quality by Design (QbD), and cost efficiency. WuXi AppTec ensured a seamless handoff from drug substance to drug product, while parallel execution of workflows across active pharmaceutical ingredient (API), analytical, production, and drug product teams reduced the overall timeline. 

Nucleic acid therapeutics have made significant strides over the past decade. New modalities such as antisense oligonucleotides (ASO) are expanding the boundaries of traditional therapies, offering new treatment options for rare diseases, neurological disorders, metabolic disorders, and other conditions. However, these molecules still face a series of development and manufacturing challenges.

Scale-up and validation hurdles: A race to get a biotech’s ASO therapeutic to market

Several years ago, a biotech company was preparing to advance a promising ASO candidate into late-stage development. This program addressed a condition affecting a broad patient population that had few effective treatment options, making it essential to achieve rapid development and dependable availability to meet urgent patient needs.

At this stage, however, production scale-up and process validation faced significant hurdles. The molecule’s complex structure, combined with stringent impurity control requirements, resulted in low yields under the initial process. This constrained the process’s scalability and created uncertainty around its readiness for late-stage development. Compounding the issue, the previous vendor was unable to support a smooth scale-up from development to commercial manufacturing. As the project progressed into later stages, the risk of availability disruption increased, potentially delaying the project timeline.

To keep the project on track, the biotech company needed to find a new partner capable of rapid scale-up, process validation, CMC dossier preparation and pre-approval inspection (PAI) readiness within 3 years, while also establishing a cost-effective process early on to support future multiton-scale demand.

Ultimately, they turned to WuXi TIDES.

Immediately following project handover, WuXi TIDES quickly assembled a project team that covered the entire project lifecycle to address both API and drug product process development and manufacturing.

To overcome the limitations of the initial API process, the WuXi TIDES drug substance team utilized its established oligonucleotide technical platform and process development expertise to systematically optimize the process. This approach increased crude purity from less than 70% to 88%. The higher crude purity also simplified the purification process from two steps to one, shortening the process time by 25% and improving manufacturing efficiency. In addition, the optimized process improved overall cost-effectiveness without compromising product quality or yield.

Owing to these advancements and a robust scale-up strategy, the optimized API process performed reliably, enabling the team to deliver multiple process performance qualification (PPQ) batches totaling over 25 kg of ASO in 4.5 months with consistent quality.

The API process demonstrated robustness, high efficiency, and cost‑effectiveness, laying a solid foundation for accelerated late-stage development and future commercial manufacturing. 

On the drug product side, the team focused on minimizing high-value API loss and maximizing overall yield during manufacturing.

They achieved a 16% reduction in filling waste by implementing sterile single-use distribution systems and designing batch-tailored single-use assemblies. As a result, the final drug product yield exceeded 95%.

The team also efficiently delivered PPQ batches through effectivepreparation and manufacturing, demonstrating reliable supply and scale up capabilities in 6.5 months, compared to the industry average of 10–12 months.

Image source: 123RF

Integrated Platform Accelerates Late-Stage Development Timelines and Commercial Readiness

Project timelines were accelerated by both WuXi TIDES’ problem‑solving expertise and the synergistic advantages of WuXi AppTec’s integrated CRDMO platform. Under a unified quality system, the platform enables seamless drug substance to drug product handover and parallel execution of activities such as process development, analytical development, and manufacturing.

In this model, each team has a comprehensive view of the timeline, enabling parallel execution without idle waiting or coordination gaps. For instance, while the drug substance team was producing late-stage batches, the drug product team advanced formulation optimization and process development. By the time PPQ batches of drug substance became available, the drug product team had already prepared for PPQ readiness and manufacturing. This collaboration enables the teams to tackle process and capacity constraints, accelerating project timelines and meeting client expectations. 

Built on an integrated platform with consistent processes, analytical methods, and quality systems, this approach increases success rates, minimizes deviations and repetitive re-validation. The close proximity of drug substance and drug product sites, together with a unified quality system, provides a strong foundation for high quality, rapid project delivery.

Ultimately, the program advanced from Phase II to PPQ completion in 2.5 years, enabling an accelerated path to NDA submission and laying a strong foundation for future commercial manufacturing. 

Establishing Robust, Commercially Scalable Processes for API and Drug Product

Today, WuXi TIDES offers comprehensive support for oligonucleotide drugs, from discovery to development and commercial manufacturing. In the realm of oligonucleotides, WuXi TIDES has been enhancing its capabilities through innovations such as solid-phase and liquid-phase synthesis, biocatalytic fragment ligation, and other techniques that foster the efficient construction of complex sequences. Downstream, innovative technologies such as thin-film evaporation and continuous flow chromatography are utilized to streamline workflows and simplify processing steps. 

WuXi TIDES leverages a Quality by Design (QbD) approach and upholds high-quality standards at each stage of development, as it continues to leverage its integrated, end-to-end CRDMO platform and extensive experience to enable clients to accelerate the research, development, and manufacturing of new drugs to bring benefit to patients globally.

Key Takeaways：

1. WuXi TIDES, a CRDMO platform that is an integral part of WuXi AppTec, is capable of rapid scale-up, process validation, and pre-approval inspection (PAI) readiness for an ASO drug, while also establishing a cost-effective process early to support future multi-ton demand.

2. WuXi TIDES has established capabilities spanning API and drug product, supporting oligonucleotide drugs from discovery to commercial manufacturing.

3. In the oligonucleotide field, WuXi TIDES has been advancing its capabilities in recent years through innovations such as solid-phase and liquid-phase synthesis, biocatalytic fragment ligation, and techniques that improve the efficiency of constructing complex sequences. 

4. Under a unified quality system, WuXi AppTec’s integrated CRDMO platform enables seamless drug substance to drug product handover and parallel execution of process development, analytical development and manufacturing.

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