High-potency active pharmaceutical ingredients (HPAPIs) are a niche but growing area for pharmaceutical manufacturers and contract manufacturing organizations (CMOs). Specialized considerations in facility design, equipment, operation, and process safety are needed to achieve the desired level of containment of the drug substance or finished-drug product. For drug-substance manufacturing, the HPAPI may be a small-molecule, biologic, or a hybrid of the two such as an antibody–drug conjugate, which links a cytotoxic small-molecule to a monoclonal antibody.
Patricia Van Arnum
The definition of an HPAPI varies depending on the literature, but generally is defined as (1):
- A pharmacologically active ingredient or intermediate with biological activity at approximately 150 µg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg)
- An API or intermediate with an occupational exposure limit (OEL) at or below 10 µg/m3 of air as an 8-h time-weighted average
- A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses
- A novel compound of unknown potency and toxicity.
The potency of HPAPIs is characterized by OELs in µg/m3. The lower the value, the more potent the compound, and the greater the level of containment required (1). OELs and related criteria such as toxicity and carcinogenicity are used in determining the performance-based exposure control limits, which link compound toxicity and potency to procedures for safe-handling of HPAPIs (1). The industry generally uses two rating programs that categorize compounds based on performance-based exposure limits, a five-tiered system or a four-tiered system, which is similar to the one developed by SafeBridge Consultants (Mountain, View, CA) (1).
IMAGES COURTESY OF SAFC
Facility design, equipment, engineering controls, and the proper operation of facilities and equipment are needed to achieve the desired level of containment in HPAPI manufacturing. Operator safety is also critical and involves the use of personal protection equipment, related training in handling HPAPIs, and implementation of safe-handling practices and current good manufacturing practices (CGMPs) to prevent operator exposure and contamination (1).