Considerations for Safe Handling of HPAPIs

Edition 1 / March 2021

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Key Systematic & Scientific Elements to Safely Handle Your Highly Potent API

Highly Potent compound manufacturing at CordenPharma Colorado & Boulder (US) is founded on a systematic & scientific approach to ensure safe handling.

Although regulatory agencies have yet to define what truly makes a compound highly potent, the pharmaceutical industry generally recognizes that a potent compound includes:

• >> Active Pharmaceutical Ingredients (APIs) with a daily therapeutic dose ≤10 mg
• >> An Occupational Exposure Limit (OEL) ≤10 µg/m³ (8 hr TWA)
• >> High selectivity to bind to specific receptors or inhibit specific enzymes and / or potential to cause mutations, development effects, or reproductive toxicity at low doses.

In order to safely handle potent and Highly Potent Active Pharmaceutical Ingredients (HPAPIs) and Drug Products, a systematic and scientific approach is needed. A complete containment concept includes hard elements such as engineering controls, and soft elements such as operating procedures and practices.

There is a significant need for quantitative industrial hygiene air & surface data to be developed over the entire time-period that potent compounds are handled, and to verify that the combination of these elements continues to minimize worker exposure & prevent product cross-contamination. This requires employing compound-specific data, in addition to surrogate data for verifying controls. The following demonstrates how CordenPharma Colorado and CordenPharma Boulder effectively applied potent compound safety elements into their business to meet growing demand for the safe manufacture of these potent APIs.

Basic Scientific Principles as Applied to Potent Compounds

The following section provides only a few of the basic principles around safe potent compound handling, and the ways in which CordenPharma Colorado & Boulder successfully implemented them.

Institute a Robust, Data-Driven Control Strategy

• >> The hazards of the material being handled should first be established, and then hazard information, along with exposure potential, analyzed to assess risk using robust, and where possible, quantitative risk assessment techniques.
• >> Risk management should provide a base range of controls designed to establish and maintain a safe working environment.
• >> Overall control should be established on a hierarchical basis, where in lieu of hazard elimination, the primary focus becomes engineering control at the source of emission, designed to prevent exposure at the top of the hierarchy.
• >> Secondary hierarchical elements include establishing written procedures, training and good techniques designed to prevent or minimize exposure potential.
• >> At the bottom of the hierarchy should be PPE (including Respiratory Protective Equipment [RPE]), which should be regarded as a redundant control.

Prior to bidding a new process into the CordenPharma Colorado facility, an evaluation is first performed with a qualitative & quantitative assessment of the product from an occupational health standpoint. CordenPharma regularly engages toxicology experts for these qualitative & quantitative assessments and training for new employees.

Engineering Controls

Engineering controls represent the hard element of the containment program. CordenPharma Colorado utilizes a variety of containment systems, including hard-sided and flexible isolators, drum containment systems with powder transfer systems, continuous liners, and local exhaust ventilation, among others.

Containment Culture, Process Development & Procedures

The soft aspects, such as a containment culture, are also vital to the success of the program. Individuals at all levels of the organization must understand their personal roles and responsibilities in safely containing HPAPIs. Executive management must also be committed to leading the program – this means ensuring that appropriate resources are provided for containment systems, from design and ongoing maintenance to monitoring, and that employees are accountable for themselves and their co-workers to ensure that containment systems are used properly. The end-user operators must also feel empowered to continuously identify and implement improvements to containment systems. Supporting this containment culture is a top-down process, where site-wide goals are set at the management level to maintain and improve containment and HPAPI handling capabilities, while at the operations level safety observations are openly discussed with management.

Conclusion

Based on the track record of success in CordenPharma Colorado and CordenPharma Boulder, a systemic and scientific approach is needed to safely handle HPAPIs and Drug Products. This combines hard elements (containment, engineering control) and soft elements (procedures, practices), which when integrated, prove to produce enhanced and repeatable containment for specific installations, and vital scientific principles for creating and maintaining a robust industrial hygiene program.

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