High-Potency APIs: Containment and Handling Issues - Pharmaceutical Technology

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

High-Potency APIs: Containment and Handling Issues
The author explains the planning, equipment, and facility design requried for manufacturing HPAPIs and specialized requirements for handling these compounds.


Pharmaceutical Technology


Compound evaluation. 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.


Table I
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.

Handling HPAPIs. 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 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.


ADVERTISEMENT

blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
|Monthly
| Weekly

Survey
FDASIA was signed into law two years ago. Where has the most progress been made in implementation?
Reducing drug shortages
Breakthrough designations
Protecting the supply chain
Expedited reviews of drug submissions
More stakeholder involvement
Reducing drug shortages
32%
Breakthrough designations
11%
Protecting the supply chain
37%
Expedited reviews of drug submissions
11%
More stakeholder involvement
11%
View Results
Jim Miller Outsourcing Outlook Jim Miller Health Systems Raise the Bar on Reimbursing New Drugs
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerThe Mainstreaming of Continuous Flow API Synthesis
Jill Wechsler Regulatory Watch Jill Wechsler Industry Seeks Clearer Standards for Track and Trace
Siegfried Schmitt Ask the Expert Siegfried SchmittData Integrity
Sandoz Wins Biosimilar Filing Race
NIH Translational Research Partnership Yields Promising Therapy
Clusters set to benefit from improved funding climate but IP rights are even more critical
Supplier Audit Program Marks Progress
FDA, Drug Companies Struggle with Compassionate Use Requests
Source: Pharmaceutical Technology,
Click here