Highly Potent; Highly Challenging?

Please can you provide an overview of some of the process, equipment and operational challenges associated with highly potent APIs?

The majority of oncologic therapeutic agents on the market and in the clinical phase, such as cytostatics and cytotoxics, are classified as highly potent compounds (category III and IV, according to our internal categorisation system). Highly potent APIs (HPAPIs) are effective at low dosages, but pose manufacturing challenges because their occupational exposure limit (OEL) is in the low nano-gram range. As such, their development and manufacturing requires containment facilities, extensive expertise and highly trained personnel.

The first publicly available guideline for the safe manufacture of highly potent compounds was issued in September 2010 by the International Society for Pharmaceutical Engineering (ISPE): the Risk-Based Manufacture of Pharmaceutical Products Guide (Risk-MaPP) (1). Before the Risk-MaPP, no official risk-based approach was available to regulate how manufacturing companies should manage the risk of cross contamination in multi-product facilities associated with the manufacture of category III and IV compounds. Carbogen Amcis has built a team of experts in toxicology, industrial hygiene and GMP manufacturing so as not to rely on external consultants. The environment, safety and health team is dedicated to risk assessment and management of HPAPIs, and determines the level of containment and cleaning limits based on ICH Q9. In addition, the team regularly monitors the plant to ensure its nano-level of containment.

How are pharmaceutical manufacturers approaching the high-potency challenge and what technologies/abilities are they requiring of service providers?

Nowadays, pharma innovators are faced with the complex management of a large number of suppliers for the outsourcing of intermediates, raw materials and API supply, either for clinical trials or commercial purposes, and research and development services.

As pharma innovators seek out global partnership solutions to simplify their supply network, the trend is to work with a single reliable partner for the sourcing of raw materials, API intermediates and final APIs, as well as custom research and manufacturing.

Dishman and Carbogen Amcis supply of GMP and non-GMP material (up to category IV) at multiple locations in Europe, India, and China, to support commercial manufacturing of drug substances. This global operational presence allows commercial supply at market proximity, supply chain risk management through multiple locations and life cycle management of drug products. In addition, pharma innovators are looking for reliable companies to outsource dosage form services for highly potent oral and injectable drug products. Therefore, in the past years, we have established a solid network of key trusted partners and recognised leaders in the high-potency pharma dosage form business for the outsourcing of final dosage products.

How has the industry’s emphasis on particle sizing affected HPAPI manufacturing?

Particle size distribution is one of the most requested technologies from companies outsourcing the development and manufacture of drug substances to contract research and manufacturing (CRAMS) companies. Control over particle size distribution of a drug is a key parameter, especially when the substance shows poor solubility. Finely ground powders increase the drug’s bioavailability by means of the increased specific surface area. For this reason, drug innovators find it useful to partner with companies that provide milling as a core particle-sizing technology.

Over the past two years, we have invested in several milling technologies, such as pin-milling and jet micronisation, for particle control from 1000 microns down to one micron. Nevertheless, the handling of dry powders poses some challenges to drug manufacturers. The exposure risk matrix for HPAPIs considers not only the duration of the task and the quantity of compound handled, but also its physical form—the risk for the operator is at its greatest when handling dry, dusty solids. To limit the risks associated with the handling of dry powders, it can be beneficial to use in-line wet milling (for particle size down to 20 microns) and flow-cell sonication milling (for particle size down to 10 microns).

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.

Do you think the demand for HPAPIs justifies the high investment associated with upgrading manufacturing equipment?

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," www.ispe.org (2010).