在显微镜下：高效的API和有毒有效载荷
威廉·桑德斯（William Sanders）博士讨论了高度有效的活性药物成分（HPAPIS）的开发和生产趋势和抗体药物缀合物（ADC）的有毒有效载荷。bob链接BOB体育客户端
最新的制药行业的变化如何影响合同制造组织（CMO），特别是关于BOB体育客户端HPAPIS的变化？
In the past 15 years, there has been a significant shift to focus on anti-cancer therapeutics. As a result, the proportion of HPAPIs and ADCs in the respective pipelines of most pharmaceutical companies has increased dramatically. This increase in the clinical pipeline of HPAPIs and ADCs has changed the demands on contract manufacturing partners and increased the need for high-potent handling capabilities. The result is a global shortage of production capacity, longer lead times to project initiation and longer delays in the progression of drug candidates through the clinical pipeline.
随着临床管道的扩大，对高度有效材料的毒理学的整个行业了解已呈指数增长。对更广泛的毒理学数据的获取和分析已导致更严格地分配了暴露限制，并实施了旨在提高工人安全的更严格的工业卫生实践。更多的HPAPI，对CMO行业中高度有效化合物的能力有限的能力有限的结合，强调CMO在满足其药物客户的供应期望方面的限制。
How does process development philosophy change as a result?
由于所研究化合物的效力，过程化学本身不会改变。反应优化，关键过程参数评估和过程鲁棒性研究与复合效力无关。在大多数情况下，商业HPAPI和ADC在高峰需求下需要相对少量的API。这种现实打开了多种处理技术，通常被认为是不兼容的（例如，色谱柱纯化），其商业生产更传统，更有效的API。尽管HPAPI的化学开发要求可能与传统API相似甚至更少的限制性，但对封闭系统生产技术和遏制技术的深入了解对于制造HPAPI是必不可少的。与典型的API制造相比，设施设计，隔离技术和一般生产实践在处理程序方面可能更加限制。仔细考虑材料和设备流必须是开发阶段不可或缺的一部分，并将其纳入生产计划中。此外，在开发阶段对新的遏制技术和技术的持续评估对于成功至关重要。
哪些关键技术对HPAPI生产很重要？
隔离器设计，实验室设计和遏制实践对于HPAPIS的安全生产至关重要。在20世纪末，CMO行业的遏制能力非常有限，当时采用的共同实践已得到改善，以基于不断发展的毒理学评估来遏制化合物。技术和专有技术的发展已经大大提高了工人的安全性，但这会导致设施设计，建筑和运营的成本相应增加。在2000年代初，默克©的SAFC只有一小部分®portfolio consisted of HPAPIs or toxic payloads. Today, a significant share of Merck©’s SAFC®投资组合需要HPAPI容器。这一趋势我s broadly applicable to the industry, resulting in significant investments in facility upgrades necessary for contract manufacturers seeking to compete in the HPAPI space. While adaptation of traditional processing techniques to maximise containment are a key focus in HPAPI manufacture, new technologies such as continuous flow manufacturing (CFM) are very promising, where closed systems can be utilised to improve upon traditional containment practices. CFM is highly attractive for HPAPI production and lends tremendous promise for
经验丰富的化学过程开发和工程小组，以设计更安全，更高效的未来过程。
What other implications of greater toxicities and increased focus on industrial hygiene practices are important to recognise?
The most significant implication is that HPAPI unit operations take longer. Many closed-system operations are restrictive and increase the time required compared to historical unit operations. Ultimately, this can lead to more expensive manufacturing processes. Regardless, worker safety always requires increased consideration and justification of costs. Pharma clients need to be aware of the possibility of longer lead times for HPAPI drug substance and ADC payloads. In the end, the promise of these new therapeutics, the increased efficacy, safety and better patient outcomes exceeds any extra expense derived from ensuring the safety of those tasked with producing the most promising medicines of the future.
威廉·桑德斯博士
Will is the Director of Process Development at Millipore Sigma’s Madison, WI SAFC®设施并直接参与了各种商业小分子HPAPI和ADC的有毒有效载荷的开发。他是培训的合成有机化学家，并拥有威斯康星大学的博士学位。他在药物和工艺化学方面拥有20多年的经验，过去14年在威斯康星州麦迪逊市的Milliporesigma和英国吉林汉姆（Gillingham）度过。他目前的兴趣包括在过程开发中实施自动开发平台，PAT和全面数据管理解决方案。
