When considering the manufacture of an HPAPI, there must be close evaluation of the compound for potential toxicity, potency,
and hazards. The Occupational Safety and Health Administration ensures that employees are provided a safe and healthful working
environment, but there is no official guidance about safely manufacturing potent APIs. As a result, the industry has begun
policing itself. There are currently two commonly used programs—a five-tiered system such as the one used by Merck & Co.,
and a more frequently used four-tiered system similar to the one developed by SafeBridge Consultants.
The compound is placed into a potency category based on the available data and evaluation process (see Table 1). The following
are attributes that may be considered for each category of compound using the SafeBridge rating system:
Category 1: Low potency, higher dosage levels, minimal reversible acute and chronic health effects, good warning properties, no "genic"
effects, not a sensitizer, slow absorption, no medical intervention required following exposure
Category 2: Moderate acute and chronic toxicity, reversible effects, weak sensitizer, fair warning properties, moderate absorption rate,
no "genic" effects, may require medical intervention
Category 3: Elevated potency, high acute and chronic toxicity, effects may not be reversible, moderate sensitizer, poor or no warning
properties, quick absorption rate, suspected or known "genic" effects, moderate to immediate medical intervention required
Category 4: High potency, extreme acute and chronic toxicity, irreversible effects, strong sensitizer, poor or no warning properties,
quick absorption rate, known "genic effects," higher degree of medical intervention required, may affect sensitive subpopulations.
This categorization system is referred to as performance-based exposure control limits, which link compound toxicity and potency
to procedures for safe handling practices (5). This system was set up in the late 1980s by pharmaceutical manufacturers for
handling development projects where insufficient data was available to establish OELs. SafeBridge recommends Category 3 as
the default categorization when very little or no information about a compound is available. This requires handling of the
material as a potent compound with sufficient engineering controls for containment.
Engineering controls should be used as the primary source for containment and isolation of potent compounds. Although PPE
is also used, it is secondary employee protection for exposure control. The category assigned to the compound defines proper
handling procedures as follows:
Category 1: General laboratory practices and gowning; open handling can be completed for ~ ≤ 1 kg, local ventilation for > 1 kg; no containment.
Category 2: General laboratory practices and gowning, open handling can be completed for ~ ≤ 100 g, local ventilation for > 100 g; containment
for high-energy, dust-generating operations (milling)
Category 3: Additional gowning and respiratory protection when handling powders; no open handling of powders, additional facility controls
for containment, closed-system solution transfers
Category 4: Full gowning and PAPR (powered air purifying respirator)/supplied-air respiratory protection, no open handling, full containment
of all solutions and powders, deactivation solutions for cleaning, specialized facilities.
Potent-compound handling systems should ideally incorporate five levels of cascading protection, the first two being the
primary methods of product isolation as follows:
Process isolation: closed-system glassware and reactors, α/β valves
Containment equipment: glove-box isolators, ventilated laminar flow enclosures, rapid-transfer ports, local exhaust ventilation, closed-system
cleaning via clean in place
Facility design: air pressurization, high number of air changes, single-pass air, restricted access, airlocks, safe-change filters, misting
PPE: Saranex coveralls and hoods, PAPR or supplied air, proper glove selection, chemical suits when needed for solvents and reagents
Personnel: training, procedures and policies, education, health monitoring.