Continuous Direct Compression of a High-dose Drug Evaluation of Process and Quality Attributes
Summary
Continuous production has now been adopted even in the pharmaceutical industry and is indispensable in current product developments. This study focuses on the process of continuous direct compression, with the aim of guaranteeing constant product quality over the whole production run. A production run over eight hours was carried out to manufacture a high-dose acetylsalicylic acid tablet. In-line, at-line and of-line analyses of the intermediate and final product were performed. Process and quality data were used to detect and analyze errors in the process and eliminate them from future processes. Specifc instances when the product quality was out of specifcation could be fully explained with the aid of the recorded data.
Introduction
The continuous manufacturing of medicinal products is now an indispensable, innovative process in the pharmaceutical industry. Many publications in this feld describe and claim a slow development from batch-based production to continuous production, but reality is very diferent. Alongside conferences taking place across the whole world on an almost monthly basis dealing with this subject area closely, as well as research consortia dedicated to this topic, there are now fve products which are manufactured continuously and which are approved by the FDA (Food and Drug Administration) and EMA (European Medicines Agency). Some companies which are highly active in the feld and have placed several plants for continuous production in their production facilities around the world, now even follow the maxim of producing each new product with a QbD (Quality by Design) approach over continuous processes. This shows that even the slow-to-modernize pharmaceutical industry is embracing these new, better and safer methods of production. Compared to batch-based manufacturing, the benefts of continuous production are diverse, and not every pharmaceutical production considers the same benefts as a top priority. In a nutshell, benefts range from the possibility of manufacturing higher quality and therefore safer products, to the possibility of substantial savings through smaller GMP areas with less transport and storage, all the way up to greater production fexibility in the life cycle of a product, to name just a few [1].
Similar to various manufacturing processes in the “batch-based world”, the continuous manufacturing of solid medicinal forms also provides various manufacturing methods. The most prominent routes are the manufacture of (flm-coated) tablets based on continuous dry granulation, continuous wet granulation and drying or continuous direct compression. Two of the products continuously manufactured and approved so far are produced via continuous direct compression, which provides the same benefts as batch production, i.e. lower costs through great savings, shorter process times and smaller required machine and therefore GmP areas. The formulation must naturally be suitable for this purpose and have sufcient fowability and compactibility. Due to the signifcant nature of the subject, this study presents the results of a continuous direct tabletting process which was performed over a production period of eight hours (one working shift). Alongside the simplicity of implementing a new formulation, it shows that a long process runtime is possible without signifcant problems. In-line and at-line process and product analyses measure the product quality in real time and allow a high degree of process control and adjustability. Of-line analyses performed later should confirm the consistent quality of manufactured medicinal forms. To understand this study, it is also important that this is a pure feasibility study without a product-relevant background. The formulation and the API (active pharmaceutical ingredient) concentration were chosen arbitrarily, and no discovery study for possible process parameters or even a design space was performed beforehand.
Materials
Acetylsalicylic acid was used as API in a direct compressible quality. It is a free-fowing powder, which contains 90% acetylsalicylic acid and 10% corn starch (abbreviation: ASS, Shandong Xinhua Pharmaceutical Co., Ltd, China). This was kindly provided in large quantities and had a total 78% ratio in the formulation. Microcrystalline cellulose (abbreviation: MCC, Vivapur 102, JRS, Germany) was used as a dry binder (21%) and sodium stearyl fumarate (PRUV, JRS, Germany) with 1% concentration was used as a lubricant for tabletting.
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Dr. Robin Meier, B.Sc. Andreas Teske, Diploma Engineer Daniel Bexte, Pharmacist Juliana Kotthof. Continuous Direct Compression of a High-dose Drug Evaluation of Process and Quality Attributes
Source: L.B. Bohle Maschinen + Verfahren GmbH