Fine Chemicals and Highly Potent Active Pharmaceutical Ingredients
Highly Potent Active Pharmaceutical Ingredients (HPAPIs)
The definition of a HPAPI varies depending on the literature, but generally is defined as:
- 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-hour time-weighted average.
- A pharmacologically-active ingredient or intermediate with high sensitivity (i.e., ability to bind to specific enzymes) and/or with potential to cause cancer, mutations, developmental defects or reproductive toxicity at low doses.
- A novel compound of unknown potency and toxicity
The International Society of Pharmaceutical Engineering (ISPE) sought in RiskMaPP to engage with regulators and build an approach that would address the impreciseness of the classification approach and replace it with a clearly defined characteristic of active pharmaceutical materials, with the concept being that all manufacturers would demonstrate the adequacy of their controls.
Fine chemicals are complex, single, pure chemical substances, manufactured in limited quantities through multistep batch chemical or biotechnological procedures. They can be classified based on their added value into building blocks, advanced intermediates or active ingredients. Most of these fine chemicals are used as starting materials for specialty chemicals like pharmaceuticals, biopharmaceuticals, and even agrochemicals.
HPAPIs are generally small molecules with known therapeutic activity. They are being regarded as Active Pharmaceutical Ingredients that has an occupational exposure limit at or below 10 micrograms per cubic meter of air. Because of their strength, HPAPI compounds are known for their ability to target diseased cells more accurately and selectively compared with the usual APIs. Also, they are believed to be more highly effective at smaller doses.
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, ?/? 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 showers
- 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.
Key Consideration for HPAPI's containment system
"If an overall manufacturing facility consists of three components - pharmaceutical material, personnel, and the environment surrounding them - containment is the isolation of the first of these components from the other two" (ISPE).
In assessing the containment challenge, there are three levels of protection
- Primary containment - equipment targets isolation of the product from the operators and the environment. Equipment is normally equipped with Clean In Place (CIP) or Wash in Place (WIP) and may be supplemented by flexible single use element for interventions.
- Secondary containment - includes separate processing rooms.
- Tertiary containment - refers to facility design such as dedicated, segregated suite(s), security access controlled, HVAC single pass air (safe change in room), double HEPA exhaust, pressure cascade and fogging shower.