PFI:AIR - TT: Manufacturing of Pharmaceuticals by Fluidized Bed Impregnation of Active Pharmaceutical Ingredients onto Porous Carriers

该PFI：加速创新研究（AIR）技术转化（TT）项目的重点是转化流化床浸渍技术，以改善药品生产。这项技术很重要，因为药物片剂和胶囊主要是通过低效的工艺制造的，该工艺涉及将称为API（活性药物成分）的药物晶体与非活性填料粉末（称为赋形剂）混合。 然后将所得的粉末混合物进一步加工并进料至胶囊中或压缩以制备片剂。在混合过程中，很难确保正确量的API分布在整个赋形剂粉末中。在粉末混合物的后续加工过程中，保持混合物混合并防止赋形剂从API分离或流动到不同区域是具有挑战性的。这对于低剂量药物是一个特别的挑战。如果存在分离或混合不充分，则可能导致片剂或胶囊中含有过多或过少的原料药。然后必须丢弃所得的不合格片剂和胶囊。该项目将产生用于制药的流化床浸渍技术的原型。 该技术具有以下独特特征：用含有API的溶液浸渍多孔赋形剂，随后干燥以生产均匀浸渍有API的赋形剂。然后可以将浸渍有API的赋形剂进料到胶囊中或压制成片剂，而不用担心API和赋形剂的分层或分离，因为API现在存在于赋形剂的孔中。当与将API晶体与赋形剂共混以制备药物的常规方法相比时，这些特征提供了改善的产品质量和减少不合格产品的优点。 该项目解决了从研究发现到商业应用的以下技术差距：1）对于非常有效的药物，固体剂型中API的量可以从1重量%到0.1重量%不等。这些非常低的API载量给药品开发带来了最大的挑战之一：剂量均匀性的控制。低API含量变异性是高度期望的，并且由美国食品和药物管理局严格执行。2)产品开发中的另一个挑战是，大部分新发现的药物化合物溶解性差，这随后影响了它们的生物利用度。3)制药工艺开发的另一个重要方面是最终产品成本。随着制药公司努力开发更负担得起的药物，任何可能消除冗长和昂贵的单元操作都变得具有商业优势。 API在多孔辅料上的流化床浸渍可以通过改善剂量均匀性、提高生物利用度和减少生产步骤数量来解决原料药和产品开发中的所有上述挑战。此外，参与该项目的人员，研究生和本科生，将通过专门的培训获得创新和技术翻译经验，这些培训将涉及这些主题，并参与技术的商业化。

This PFI: Accelerating Innovation Research (AIR) Technology Translation (TT) project focuses on translating fluidized bed impregnation technology to improve manufacturing of pharmaceuticals. This technology is important because pharmaceutical tablets and capsules are manufactured primarily by an inefficient process, which involves blending drug crystals called the API (Active Pharmaceutical Ingredient) with inactive filler powders (called excipients). The resulting mixture of powders is then further processed and fed into capsules or compressed to make tablets. During blending, it is difficult to make sure that the correct amount of the API is distributed throughout the excipient powders. During subsequent processing of the powder mixture it is challenging to keep the mixture mixed and prevent the excipients from segregating or flowing to different regions from the API. This is a particular challenge for low dose pharmaceuticals. If there is segregation or inadequate blending, it can lead to tablets or capsules with too much or too little drug substance. The resulting out-of-spec tablets and capsules must then be discarded. This project will result in a prototype of fluidized bed impregnation technology for manufacturing of pharmaceuticals. This technology has the following unique features: the impregnation of porous excipients with a solution containing the API and subsequent drying to produce excipients uniformly impregnated with the API. The excipients impregnated with the API can then be fed into capsules or compressed into tablets without concern for de-mixing or segregation of the API and excipients since the API is now present in the pores of the excipients. These features provide advantages of improved product quality and reductions in out-of-spec product when compared to the usual method of blending API crystals with excipients for making pharmaceuticals. This project addresses the following technology gaps as it translates from research discovery toward commercial application: 1) For very potent drugs, the amount of API in the solid dosage form can vary from 1% to 0.1% by weight. These very low API loadings pose one of the biggest challenges in pharmaceutical product development: the control of dose uniformity. Low API content variability is highly desired and strictly enforced by the U.S. Food and Drug Administration. 2) Another challenge in product development is that a large fraction of newly discovered drug compounds have poor solubility which subsequently affects their bioavailability. 3) Another important aspect of pharmaceutical process development is the final product cost. As pharmaceutical companies strive to develop more affordable drugs, any possible elimination of lengthy and expensive unit operations becomes commercially advantageous. Fluidized bed impregnation of APIs onto porous excipients can potentially address all of the above challenges in drug substance and product development by improving dose uniformity, enhancing bioavailability and reducing the number of manufacturing steps. In addition, personnel involved in this project, graduate and undergraduate students, will receive innovation and technology translation experiences through specific training that will address these topics and by being involved with the commercialization of the technology.