Byrn Stephen, Futran Maricio, Thomas Hayden, Jayjock Eric, Maron Nicola, Meyer Robert F, Myerson Allan S, Thien Michael P, Trout Bernhardt L
Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana.
J Pharm Sci. 2015 Mar;104(3):792-802. doi: 10.1002/jps.24247. Epub 2014 Dec 12.
We describe the key issues and possibilities for continuous final dosage formation, otherwise known as downstream processing or drug product manufacturing. A distinction is made between heterogeneous processing and homogeneous processing, the latter of which is expected to add more value to continuous manufacturing. We also give the key motivations for moving to continuous manufacturing, some of the exciting new technologies, and the barriers to implementation of continuous manufacturing. Continuous processing of heterogeneous blends is the natural first step in converting existing batch processes to continuous. In heterogeneous processing, there are discrete particles that can segregate, versus in homogeneous processing, components are blended and homogenized such that they do not segregate. Heterogeneous processing can incorporate technologies that are closer to existing technologies, where homogeneous processing necessitates the development and incorporation of new technologies. Homogeneous processing has the greatest potential for reaping the full rewards of continuous manufacturing, but it takes long-term vision and a more significant change in process development than heterogeneous processing. Heterogeneous processing has the detriment that, as the technologies are adopted rather than developed, there is a strong tendency to incorporate correction steps, what we call below "The Rube Goldberg Problem." Thus, although heterogeneous processing will likely play a major role in the near-term transformation of heterogeneous to continuous processing, it is expected that homogeneous processing is the next step that will follow. Specific action items for industry leaders are: Form precompetitive partnerships, including industry (pharmaceutical companies and equipment manufacturers), government, and universities. These precompetitive partnerships would develop case studies of continuous manufacturing and ideally perform joint-technology development, including development of small-scale equipment and processes. Develop ways to invest internally in continuous manufacturing. How best to do this will depend on the specifics of a given organization, in particular the current development projects. Upper managers will need to energize their process developers to incorporate continuous manufacturing in at least part of their processes to gain experience and demonstrate directly the benefits. Training of continuous manufacturing technologies, organizational approaches, and regulatory approaches is a key area that industrial leaders should pursue together.
我们阐述了连续最终剂型制备（也称为下游加工或药品制造）的关键问题和可能性。非均相加工和均相加工有所不同，预计后者能为连续制造带来更多价值。我们还给出了转向连续制造的关键动机、一些令人振奋的新技术以及连续制造实施过程中的障碍。对非均相混合物进行连续加工是将现有分批工艺转变为连续工艺的自然第一步。在非均相加工中，存在可分离的离散颗粒，而在均相加工中，各组分混合并均匀化，不会分离。非均相加工可以采用更接近现有技术的技术，而均相加工则需要开发和采用新技术。均相加工在充分收获连续制造的全部益处方面潜力最大，但与非均相加工相比，它需要长远的眼光以及在工艺开发方面有更重大的变革。非均相加工的弊端在于，由于采用而非开发这些技术，存在强烈的倾向去纳入校正步骤，我们在下文称之为“鲁布·戈德堡问题”。因此，尽管非均相加工可能在近期将非均相工艺转变为连续工艺中发挥主要作用，但预计均相加工将是接下来的下一步。行业领导者的具体行动事项包括：建立竞争前合作伙伴关系，包括行业（制药公司和设备制造商）、政府和大学。这些竞争前合作伙伴关系将开展连续制造的案例研究，并理想地进行联合技术开发，包括小规模设备和工艺的开发。制定内部投资连续制造的方法。如何最好地做到这一点将取决于特定组织的具体情况，特别是当前的开发项目。高层管理人员需要激励其工艺开发人员至少在部分工艺中纳入连续制造，以积累经验并直接展示其益处。对连续制造技术、组织方法和监管方法的培训是行业领导者应共同关注的关键领域。
