Here, David Elder explains the workings of the Manufacturing Classification System (MCS) used to guide the decision-making of drug formulators.
THERE ARE many four-box decision-making models used in the pharmaceutical industry. Among the most common are the Biopharmaceutical Classification System (BCS),1 Biopharmaceutical Drug Disposal Classification System (BDDCS)2 and the Developability Classification System (DCS).3 These models facilitate regulatory decision making (BCS, BDDCS) or support formulation decision making (DCS). Another four-box model that aids formulation decision-making is the Pharmaceutical Manufacturing Classification System (MCS).4 This model focuses on the preferred manufacturing route of the solid oral drug product based on input API particle characteristics, dose, stability, and cost considerations. The manufacturing technologies covered by MCS, in order of increasing complexity, are: direct compression (DC), dry granulation (DG), wet granulation (WG) and other technologies (OT), i.e. say the liquid-filled capsules. These are designated MCS class 1-4, respectively. MCS is also expected to simplify scale-up activities in proposed commercial manufacturing facilities. “The MCS would help ensure that the chosen process is more robust by placing the process in the center of the design space rather than at the edges.”5
MCS specifically addresses the properties of API particles, which can change significantly, especially during the early clinical development of new molecular entities (NMEs). Differences can also arise when companies seek to launch a second or third API provider as part of business continuity strategies for their existing marketed products or intend to use new providers during generic development.6 Although direct compression (DC) or direct encapsulation (DE) are the simplest and most cost effective processes, they are the least robust and even small changes in API particle morphology or particle size distribution (PSD) may cause product failure. Thus, by predefining the desired properties of API particles, MCS could guide API “particle engineering”; thus allowing the implementation of simple and economical direct mixing processes. Initially, MCS identified the optimal properties of API particles for the manufacture of solid oral dosage forms based on literature precedents, as well as the specific parameters for pharmaceutical products manufactured via the DC (or DE), DG and WG processes. .4 Based on a subsequent survey of interested parties, industry experts identified PSD and particle shape as the most important API parameters. In addition, other parameters, such as “elasticity/plasticity, hydrophobicity, electrostatics, bulk/cut density, particle hardness and flow pressure, cohesion/adhesion, wettability, surface energy, surface roughness and hygroscopicity” were considered important.6
To better understand the relationships between API particle properties and all subsequent process decisions made for commercial formulations, the authors6 carried out a retrospective review of the European Public Assessment Reports (EPAR), filed with the European Medicines Agency (EMA) between 1996 and mid-2017, relating to products in capsules (96) and tablets (339), i.e. 435 products in total. APIs were categorized as either Category A – likely to have larger DSPs, or Category B – likely to have smaller DSPs. The 435 products assessed were equally divided between these two categories, namely category A (148, or 34%) and category B (178, or 40.9%). WG (40%) was the most popular process choice for tablet formulations, with far fewer other process choices; i.e. DC (16%), DG (12%) and OT (4%). In contrast, capsule formulations showed a roughly equal split between WG (25%) and DE (30%), with a lower percentage of DG formulations (9%). In addition, there was a relatively large percentage (20%) of OT formulations, i.e. mainly soft gels. It’s reassuring that APIs from different vendors are usually subsequently manufactured through similar processes, but rare exceptions do occur. “Sildenafil is handled by DC (Teva), DG (Pfizer) and WG (other generic manufacturers)”.6 However, sometimes this can happen because a company has invested heavily in specialized technology, i.e. DG, and it will “force” all APIs down that path, that the particle properties of the API are aligned with other processes, i.e. CC.
The authors pointed out that dose often has the greatest impact on process choice: for high doses (>100 mg), DC was favored for Class A compounds, while WG was favored for category B compounds. In contrast, there was a much higher percentage of DC formulations at lower concentrations. Interestingly, class 2/4 BCS compounds show a higher propensity for WG processes at medium and high doses.6
In conclusion, designated commercial manufacturing processes are often more complicated than they would be if the API properties had been improved. MCS should help close these gaps, resulting in simpler and more cost-effective robust manufacturing operations.6
About the Author
David Elder has nearly 40 years of service in the pharmaceutical industry with Sterling, Syntext and GlaxoSmithKline. He is now an independent GMC consultant. He is a Visiting Professor at King’s College London and a Fellow of the British Pharmacopoeia. He is a member of the Joint Pharmaceutical Analysis Group (JPAG) and of the Analytical Division Council of the Royal Society of Chemistry.
- Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a classification of biopharmaceutical drugs: the correlation between in vitro dissolution of the drug product and in vivo bioavailability. PharmRes. 1995, 12, 413–420.
- Benet LZ. Predict drug elimination through the application of a biopharmaceutical drug elimination classification system. Basic Clin Pharmacol Toxicol. 2010, 106,162–167.
- Butler JM, Dressman JB. The developability classification system: application of biopharmaceutical concepts to formulation development. J Pharm Sci. 2010, 99, 4940–4954.
- Leane M, Pitt K, Reynolds G, et al. A proposal for a Pharmaceutical Manufacturing Classification System (MCS) for solid oral dosage forms. Pharm Dev Tech. 2015, 20, 12–21.
- Markarian K. Choice of solid oral dose production processes: could a classification system be useful? Pharmaceutical technology. 2015, 39(4), 30.
- Leane M, Pitt K, Reynolds G, et al. Real-world manufacturing classification system: factors influencing manufacturing process choices for proprietary commercial oral solid dosage formulations, industry case studies, and considerations for ongoing processing, Pharm Dev Tech. 2018, 23(10), 964-977. https://doi.org/10.1080/10837450.2018.1534863