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).
