Manufacturing Classification System (MCS)

THERE ARE numerous four-box decision-making models employed within the pharmaceutical industry. Among the more common are the biopharmaceutical classification system (BCS),¹ biopharmaceutics drug disposition classification system (BDDCS)² and the developability classification system (DCS).³ These models either facilitate regulatory decision making (BCS, BDDCS) or support formulation decision making (DCS). Another four-box model facilitating formulation decision making is the drug-product 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), ie, liquid-filled capsules. These are designated MCS class 1-4, respectively. MCS should also simplify scale-up activities into the proposed commercial manufacturing facilities. “The MCS would help ensure that the chosen process is more robust by putting the process in the centre of the design space rather than at the edges”.⁵

MCS specifically addresses the particle properties of the API, which can change markedly, particularly during early clinical development of new molecular entities (NME). Differences can also arise when companies look to initiate a second or third API supplier as part of business continuity strategies for their existing marketed products or intend utilising new suppliers during generic development.⁶ While direct compression (DC) or direct encapsulation (DE) are the simplest, most cost-effective processes, they are the least robust and even small changes in API particle morphology or particle size distribution (PSD) can result in product failure. Thus, by pre-defining the desired API particle properties, MCS could guide API ‘particle engineering’; thus enabling the implementation of cost-effective simple direct-mixing processes. Initially, MCS identified the optimal API particle properties for solid oral dosage form manufacture based on literature precedent, together with those specific parameters for drug products manufactured via 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/tap density, particle hardness and yield pressure, cohesion/ adhesion, wettability, surface energy, surface roughness and hygroscopicity” were viewed as being important.⁶

To better understand the relationships between API particle properties and any subsequent process decisions undertaken for commercial formulations, the authors⁶ performed a retrospective review of European Public Assessment Reports (EPAR), filed with the European Medicines Agency (EMA) between 1996 and mid-2017, focusing on capsule (96) and tablet (339) products, ie, 435 products in total. APIs were categorised as either Category A – likely to have larger PSDs, or Category B – likely to have smaller PSDs. The 435 products assessed were evenly split between those two categories, ie, category A (148, ie, 34 percent) and category B (178, ie, 40.9 percent). WG (40 percent) was the most popular process choice for tablet formulations, with other processing choices being far fewer; ie, DC (16 percent), DG (12 percent) and OT (four percent). In contrast, capsule formulations demonstrated a roughly even split between WG (25 percent) and DE (30 percent), with a smaller percentage of DG (nine percent) formulations. In addition, there was a relatively large percentage (20 percent) of OT formulations, ie, mainly soft gels. Reassuringly, API sourced from different suppliers is typically subsequently manufactured via similar processes, but rare exceptions do occur. “Sildenafil is processed by DC (Teva), DG (Pfizer) and WG (other generic companies)”.⁶ However, this can sometimes occur because a company has invested heavily in a specialised technology, ie, DG and they will “force fit” all APIs down this route, irrespective of whether the particle properties of the API are aligned with other processes, ie, DC.

The authors highlighted that dose often has the biggest impact on process choice: for high doses (>100mg) DC was favoured for Category A compounds, whereas WG was favoured for Category B compounds. In contrast, there was a much higher percentage of DC formulations at lower strengths. Interestingly, BCS Class 2/4 compounds show a higher propensity for WG processes at medium and high doses.⁶

In conclusion, the designated commercial manufacturing processes are often more complicated than they would be if API properties had been improved. MCS should help address these deficiencies, resulting in simpler, more cost-effective robust manufacturing operations.⁶

References

1. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995, 12, 413–420.
2. Benet LZ. Predicting drug disposition via application of a biopharmaceutics drug disposition classification system. Basic Clin Pharmacol Toxicol. 2010, 106,162–167.
3. Butler JM, Dressman JB. The developability classification system: application of biopharmaceutics concepts to formulation development. J Pharm Sci. 2010, 99, 4940–4954.
4. Leane M, Pitt K, Reynolds G, et al. A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms. Pharm Dev Tech. 2015, 20, 12–21.
5. Markarian K. Choosing oral solid-dosage production processes: Could a classification system help? Pharm Tech. 2015, 39(4), 30.
6. Leane M, Pitt K, Reynolds G, et al. 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, Pharm Dev Tech. 2018, 23(10), 964-977. https://doi.org/10.1080/10837450.2018.1534863