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The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent. [ABSTRACT FROM AUTHOR]

The article discusses the challenges of designing oral solid dosage forms and the importance of assessing the properties of the Active Pharmaceutical Ingredient (API) to determine the processing challenges it may present. The article introduces the Manufacturing Classification System (MCS), which aims to formalize the criteria for processing decisions and aid drug product manufacturing. The MCS categorizes processing routes into four classes based on increasing modifications to the API properties. The article also highlights the preference for simpler manufacturing routes and the potential use of the MCS within Quality by Design principles. The MCS initiative has gained international collaboration and has been presented at major pharmaceutical science conferences. [Extracted from the article]

Following the first Manufacturing Classification System (MCS) paper, the team conducted surveys to establish which active pharmaceutical ingredient (API) properties were important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. The most commonly identified factors were (1) API particle size: small particle sizes are known to increase risk of processing issues; (2) Drug loading in the formulation: high drug loadings allow less opportunity to mitigate poor API properties through the use of excipients. The next step was to establish linkages with process decisions by identifying publicly-available proxies for these important parameters: dose (in place of drug loading) and BCS class (in place of particle size). Poorly-soluble API were seen as more likely to have controlled (smaller) particle size than more highly soluble API. Analysis of 435 regulatory filings revealed that higher doses and more poorly-soluble API was associated with more complex processing routes. Replacing the proxy factors with the original parameters should give the opportunity to demonstrate stronger trends. This assumption was tested by accessing a dataset relating to commercial tablet products. This showed that, for dry processes, a larger particle size was associated with higher achievable drug loading as determined by percolation threshold. [ABSTRACT FROM AUTHOR]

This paper proposes the development of a drug product Manufacturing Classification System (MCS) based on processing route. It summarizes conclusions from a dedicated APS conference and subsequent discussion within APS focus groups and the MCS working party. The MCS is intended as a tool for pharmaceutical scientists to rank the feasibility of different processing routes for the manufacture of oral solid dosage forms, based on selected properties of the API and the needs of the formulation. It has many applications in pharmaceutical development, in particular, it will provide a common understanding of risk by defining what the 'right particles' are, enable the selection of the best process, and aid subsequent transfer to manufacturing. The ultimate aim is one of prediction of product developability and processability based upon previous experience. This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. Feedback can be given by replying to our dedicated e-mail address (mcs@apsgb.org); completing the survey on our LinkedIn site; or by attending one of our planned conference roundtable sessions. [ABSTRACT FROM AUTHOR]

An analysis of the free acid form of the HIV-1 attachment inhibitor prodrug BMS-663068-01 revealed a reversible moisture sorption event in the 42%-46% relative humidity ( RH) range. An existing single-crystal analysis indicated that these observations were due to the formation of a nonstoichiometric channel hydrate. This effect was reproducible on repeated cycles, suggesting that the material's structural integrity was not compromised because of the interconversion process. Small, reversible, and predictable changes in the atomic structure were observed by solid-state nuclear magnetic resonance (ss NMR). Atomic force microscopy ( AFM) and environmental scanning electron microscopy (E SEM) could discern changes in surface topography as a function of RH. Surface cracks were visible at 25% RH, most of which disappeared at 60% RH. This change was reversible on reducing the RH, with cracks reappearing in the same locations. A reduction in surface roughness was seen at high humidity, which was consistent with the uptake of moisture causing surface swelling. The observations by AFM/ ESEM were consistent with the atomic alterations seen with ss NMR. Changes in unit cell dimensions are not uncommon with channel hydrates as the crystal lattice expands or contracts when the crystal structure absorbs/desorbs water, but concomitant, reversible surface morphology property changes have not been widely reported. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4375-4383, 2013 [ABSTRACT FROM AUTHOR]

Amorphous forms of poorly soluble drugs are more frequently being incorporated into solid dispersions for administration and extensive research has led to a reasonable understanding of how these dispersions, although still kinetically unstable, improve stability relative to the pure amorphous form. There remains however a paucity of literature describing the effects on such solid dispersions of subsequent processing into solid dosage forms such as tablets. This paper addresses this area by looking at the effects of the addition of common excipients and different manufacturing routes on the stability of a spray-dried dispersion (SDD) of the cannabinoid CB-1 antagonist, ibipinabant. A marked difference in physical stability of tablets was seen with the different fillers with microcrystalline cellulose (MCC) giving the best stability profile. It was found that minimising the number of compression steps led to improved formulation stability with a direct compression process giving the best results. Increased levels of crystallinity were seen in coated tablets most likely due to the exposure of the amorphous matrix to moisture and heat during the coating process. DSIMS analysis of the SDD particles indicated increased levels of polymer on the surface. [ABSTRACT FROM AUTHOR]

Abstract: Blending of active pharmaceutical ingredient (API) and excipients is a pre-requisite to the dry manufacture of solid dosage forms intended for oral use, whether or not granulation steps are employed prior to compaction. Excipients and API are known to be subject to tribo-electric charging, against each other and the materials in which the blends are manufactured (e.g. stainless steel 316). This study aimed to assess and compare the magnitude of tribo-electric charging of excipients and API using a material-sparing technique. Intra-sample variability in tribo-electric charging was found to be generally low. The results showed that excipients had lower charge levels and smaller variability as compared to the API materials. Some of the APIs tested charged extensively to the levels in excess of ±150nC/g. It was also found that the extent of particle adhesion to surfaces of the container walls for charged API was considerably greater compared to the excipients. These results suggest that the extent and variability of tribo-electric charging of APIs is the predominant contributor to variability in electrostatic charge of pharmaceutical blends and to any related formulation issues. It is therefore reasonable to conclude that, to control the electrostatic properties of a formulation, it is a priority to control the particle properties of the API. [Copyright &y& Elsevier]