Sourcing of active pharmaceutical ingredients

DURING EARLY formulation development many pharmaceutical companies use single-sourced active APIs and typically only a small number of API batches. However, ICH Q8(R2)¹ indicates that, “at a minimum, those aspects of drug substances that are critical to product quality should be determined and control strategies justified”.

Additionally, APIs are often being developed in parallel to the drug products and consequently their critical quality attributes (CQAs) can change with time. Unfortunately, there is often too much focus on the chemical purity of the API; forgetting that changes in particle size, shape and bulk density can be equally important to the resultant drug product. The habit of an API can also be impacted by polymorphism; for example, orthorhombic paracetamol shows improved compression behaviour compared to the monoclinic form.

^{100% Delivery 99% Purity YK11 Powder CAS 1370003-76-1}

Leane, et al.³ recently developed a four‑box model for drug products, termed the manufacturing classification system (MCS), for oral solid dosage forms. MCS classifies products according to their manufacturing processes; ie, direct compression (DC – MCS 1), dry granulation (DG – MCS 2), wet granulation (WG – MCS 3) and other technologies (MCS 4). DC is cheaper, faster and much less complicated than DG or WG; however, DC is also likely to be the process that is most reliant on the initial API particle properties. The API mean particle size and distribution, together with particle shape, are particularly critical for DC as there are no additional processing steps to mitigate those unfavourable API properties. The dosage strength and API loading are important considerations. At low drug doses (ie, ≤1mg) or drug loadings (<2.0 percent) DC strategies can be challenging, particularly from the perspective of blend and content uniformity.³ As such, it is important to understand the consistency of physical attributes of the API as there can be large batch-to-batch variability.⁴ Some API physical properties can also change with time. Freshly milled metformin HCl contains appreciable levels of surface crystal defects, which are not present in aged samples. These in turn can cause differences in flowability of DC powder blends during drug product processing.⁵ Many companies often introduce “quarantine” periods post-milling or micronising to address such issues.

Unfortunately, those factors that influence API particle size and shape are not well understood and can be influenced by reactor size, shape, agitation speed and dryer type and configurations. They can also be vulnerable to scale up following the initial transfer into production.^7,8 In parallel, additional product demand and/or the need for supply chain flexibility often drives companies to assess dual-sourcing of their API. Ferreira, et al.⁹ recently highlighted an issue where a dryer at a second API site produced “denser, less porous material that leads to processability issues” in the drug product. Lastly, as the product enters the latter stages of its product lifecycle there can be economic considerations that underpin outsourcing the manufacture of the API and/or drug product to a third-party vendor. Here, the situation is often exacerbated as “institutional knowledge” underpinning the processing rationale for the product can typically be lost. Additionally, none of the major pharmacopoeias address physical properties as part of their API monographs. As such, it is not uncommon to encounter issues with the product/ process that can be attributed to subtle changes in the API affecting the drug product. Chan¹⁰ reported capping of metformin DC tablets arising from the introduction of a second source of API, which was attributed to different particle morphologies, ie, acicular versus plates. These potential issues highlight that the transfer and/or buyer specifications for second site sourcing of the API needs to focus on more than cost and chemical criteria; it should also encompass pharmacopoeial monographs and physical properties.