Because the potency of these drugs is greater, the commercial quantities required are relatively small. Industry data suggest that around 20% of drugs in development pipelines may be classified as highly potent, up from about 5% in the 1990s (1). At the same time, high-volume manufacturing is shifting to lower-cost operations in India and the Far East, and Western manufacturers are refocusing their efforts by establishing high-potency manufacturing assets that provide multiple barriers to entry. Typically, these barriers are capital investment, production capabilities, technology, and regulatory compliance. Several Western producers of active pharmaceutical ingredients (APIs) have adopted this strategy by building or enhancing capabilities in manufacturing highly potent compounds (1). This shift is also occurring for secondary manufacturing of high-potency drugs (2).
Liquid and semisolid encapsulation using two-piece hard-shell capsules is an ideal oral drug-delivery approach for poorly water-soluble compounds, compounds that exhibit poor bioavailability, and for highly potent drugs. From a manufacturing perspective, the production of two-piece hard-shell capsules provides an environment in which containment is easier and operates at a comparatively lower safety risk compared with powder filling or tablet manufacture that typically generate dust particulates. The authors review the challenges involved in the secondary manufacture of high-potency drugs. From their own experience, they further provide insight in designing and constructing a new high-potency secondary manufacturing facility for liquid and semisolid APIs and their manufacture into two-piece hard-shell capsules.Classification of high-potency compounds
High-potency APIs are classed according to their inherent toxicity characteristics and pharmacological potency, which are translated into an occupational exposure limit (OEL). Typically, APIs with OELs at or below 10 micrograms per cubic meter (μg/m3 ) of air as an 8-h time-weighted average are considered potent from an occupational health perspective. There is no universally accepted system of categorization, although most seem to use a four-category system (see Table I). The four categories range from Category I, low-potency compounds requiring conventional good manufacturing practices (GMPs), to Category IV, for which a high degree of containment is required (3).
The quantification of OELs and category classification is typically defined by the end of Phase-II or during Phase-III clinical studies. This process, however, does not address the classification of preclinical and early-development compounds. For early-stage compounds, it is important to have all relevant toxicological or compound-comparative data available to ensure an appropriate analysis of the risk and level of containment required to maximize safety.
Approximately 28% of the drugs currently on the market are considered potent by these criteria, according to SafeBridge Consultants. The same firm estimates that approximately 40–45% of the OELs that have been set by the pharmaceutical industry are at 10 μg/m3 or less. Supporting data relating to drug-development pipelines confirm a substantial and growing market (4).
Market size and growth
Data published by management consultants Becker Associates suggest there are 300–400 highly potent compounds currently in production for either clinical evaluation or commercial manufacture (5).
Many high-potency molecules such as cytotoxics, hormones, steroids, potential mutagenics, or ingredients that may produce toxic intermediates are frequently assigned OELs of less than 1 μg/m3 . Working to these levels requires more planning and risk analysis to ensure that every stage of manufacture and waste disposal is safe for workers and the local environment (4).