What are the specific challenges associated with the purification and separation of HPAPIs?

Highly potent substances of category III and IV differ from other APIs in their dosages. For example, HPAPIs are more effective at a lower dosage; otherwise, their chemical behaviour is comparable to any other small molecule or chemical entity. Purification techniques typically used for highly potents span from crystallization to milling and preparative HPLC to simulated moving-bed chromatography, among others.

For antibody drug conjugates (ADCs), special techniques, such as tangential flow and size exclusion, are often employed. During the purification process of highly potents by preparative HPLC, the main issue is the handling of large amounts of contaminated solvent and stationary phase (silica). The Biotage system for large-scale purification utilises disposable cartridges at the stationary phase and, thus, limits the direct handling of toxic material. The high pressures used in the HPLC systems can also expose operators to traces of toxic substances. As such, our team performs a rigorous risk assessment before any operations commence and limits the use of HPLCs in engineer-controlled production areas dedicated to category III or IV compounds. Because of the containment issues associated with waste handling and the operational conditions (high pressure), the preferred purification system for highly HPAPIs is direct crystallization of the pure API followed by milling, and when possible, unitizing and wet-milling systems.

We expect to see a growing demand for highly potent APIs, including IARC (International Agency for Research on Cancer) Category I carcinogens, in the coming years because of an increasing elderly population. According to a study published by the University of Connecticut in 2008, more than 60% of cancer diagnoses in the US occur in people age 65 or older. This segment (36.8 million in 2008) is expected to double by the year 2030.

To satisfy this growing demand and allow market proximity to our customers, Carbogen Amcis and Dishman have invested more than 27.8 million euro in high potency to build two new engineered-controlled, high-potency facilities for the production of low dosage drugs in China and India, to complement the existing high-potency plant in Switzerland. The multi-tonne facility in Shanghai (China) supplies drug substances down to category III up to 50 metric-tonnes, whilst the multi-purpose facility in Ahmedabad (India) caters to both cytotoxics and cytostatics down to category IV, up to one metric-tonne per annum.

The Bubendorf plant is dedicated to niche manufacturing and provides a platform for pharma innovators to address the need for new cancer treatments. Even though cancer therapies have progressed significantly during the last decade, oncology remains the most significant area of unmet clinical need, as demonstrated by global revenues of 5.2 billion euro (at a compound annual growth rate of 12.6 %) for the highly-potent API market alone.

Reference

1. ISPE, "Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products," http://www.ispe.org/ (2010).