It can be challenging to explain the complexity of oral solid dosage form design to the non-formulator. Many materials issues can stand in the way of successful manufacture of a tablet or capsule. Whilst particle properties of excipients are generally designed to facilitate manufacturability, those of the Active Pharmaceutical Ingredient (API) are generally not. Therefore, optimisation of API properties is a significant formulation challenge.
So, the big question when we start development of a new product is: How do we assess the properties of our API to get an estimate of how big a processing challenge it will be? There are some guideposts available, with the Biopharmaceutics Classification System (BCS) being one of the most widely used. Poorly soluble API will likely be more of a challenge as it frequently needs to be size reduced to facilitate bioavailability with ‘small’ API being more difficult to manufacture. Another guidepost is the likely human dose: high doses are more challenging as there is less opportunity to add additional excipients to overcome poor API properties due to constraints on acceptable maximum tablet or capsule size. In addition to these formal guideposts, formulators may also have more informal methods of assessment. My own personal strategy was to take that first sample from Discovery and look at it under my benchtop SEM. In general, the smaller and more needle-like the sample, the more of a formulation challenge, whereas larger and rounder particles were likely to be better behaved.
In 2013, following discussions with like-minded colleagues in the APS, we decided it would be worthwhile to formalise the criteria by which formulators made their processing decisions and thus the MCS was born. Borrowing from the BCS philosophy, this aimed to use properties of particles to form a new classification to aid drug product manufacturing. The aims of this initiative include to gain alignment on how to define ‘right particles’ and ‘best process’, to assist in particle engineering to provide targets for API properties, aid development and subsequent transfer to manufacturing and provide a common understanding of risk particularly when communicating with our colleagues outside of formulation. All this knowledge can potentially be used within QbD principles to obtain regulatory relief by demonstrating that the properties of the ingoing API and excipients are within established ranges for the process.
Our initial conference held under the auspices of the APS in Nottingham in 2013 reached an agreement on establishing an MCS based on processing route, with four distinct classes:
Class 1: Direct Compression
Class 2: Dry Granulation
Class 3: Wet Granulation
Class 4: Other Technologies
Moving from Class 1 to 4 progressively increases modifications to the original API properties, most typically by increasing API effective particle size, by combining it with excipients in a granulation process. In Class 4, even more extreme techniques such as API solubilisation can be used.
Although such techniques improve manufacturability by increasing process robustness to API variability, there are strong drivers to simplify processing routes wherever possible. A direct compression process has fewer steps reducing the energy footprint and costs and enabling higher efficiency. In addition, multiple processing steps needed for granulation introduce complexity increasing the changes of something going wrong and making it more difficult to identify a root cause of such issues. For example, the presence of water, heat, and shear, which are typical during a wet granulation process, can induce unwanted changes to API polymorphic form and stability. Therefore, our philosophy assumes a preference for simpler manufacturing routes with the ultimate aim of prediction from previous experience.
Since that initial conference, the initiative has expanded to be a major international industrial and academic collaboration via the MCS Working Group. We have presented at all major pharmaceutical science conferences in the United States, Europe, and Japan: APS, AAPS, PBP, and APSTJ. In addition, we have published three peer-reviewed papers outlining our philosophy.
Our first paper (Leane, Pitt et al. Citation2015) introduced the MCS concept and outlined our developability parameters for API, which are the ideal API properties for each processing route collated from pre-existing formulation knowledge. This paper has had wide impact, being cited over 200 times, and has been translated into Japanese.
As a follow-up to this first paper, the MCS Working Group circulated a questionnaire to establish which API properties were of most importance to manufacturability. Our second MCS paper reviewed this survey data and applied it to an analysis of publicly available filings to determine if there was a link between particle properties and choice of processing route (Leane, Pitt et al. Citation2018). This analysis confirmed that membership of a poorly soluble BCS Class (2 or 4) and higher doses required more complex processing routes. These two parameters by themselves could comprise a useful high-level MCS. This paper also provided different company cases studies to provide further context.
The third paper published in this issue reviews the literature citing the MCS over the last ten years in addition to extending the MCS concept to Continuous Manufacture (CM) (Leane, Pitt et al. Citation2024). The review structure follows the flow of drug product development focussing first on optimisation of API properties, moving to applications in formulation design, and finally discussing manufacturing process development. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. The CM MCS proposes a selection tool for deciding between batch and continuous processes alongside batch and continuous risk matrices. Continuous direct compression offers the prospect of processing a wider range of API properties compared to its batch equivalent.
The Working Group is currently planning another conference in early 2025 co-sponsored by the APS and APV which will perform a deeper dive into applications of the MCS as well as exploring how digital approaches may advance it further to an ‘MCS Plus’.
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References
- Leane M, Pitt K, Reynolds G, Tantuccio A, Moreton C, Crean A, Kleinebudde P, Carlin B, Gamble J, Gamlen M, et al. 2024. Ten years of the manufacturing classification system: a review of literature applications and an extension of the framework to continuous manufacture. Pharmaceut Develop Technol. 1–20. (Apr 15): doi:10.1080/10837450.2024.2342953.
- Leane M, Pitt K, Reynolds G, M. C. S. W. Group. 2015. A proposal for a drug product manufacturing classification system (MCS) for oral solid dosage forms. Pharmaceut Develop Technol. 20(1):12–21. doi:10.3109/10837450.2014.954728.
- Leane, M., K. Pitt, G. K. Reynolds, N. Dawson, I. Ziegler, A. Szepes, A. M. Crean, R. D. Agnol, B. Broegmann, S. T. Charlton, et al. and M. C. S. W. Grp (2018). “Manufacturing classification system in the real world: factors influencing manufacturing process choices for filed commercial oral solid dosage formulations, case studies from industry and considerations for continuous processing.” Pharmaceut Develop Technol. 23(10): 964–977. doi:10.1080/10837450.2018.1534863.