Contract Services

Highly potent molecules: safe, effective processing

By David O’Connell, Director of Scientific Affairs at PCI Pharma Services

David O’Connell, Director of Scientific Affairs at PCI Pharma Services, shares insights of the company’s experience in the saf

David O’Connell, Director of Scientific Affairs at PCI Pharma Services, shares insights of the company’s experience in the safe and successful management of highly potent active pharmaceutical ingredients (HPAPIs).
The pharmaceutical landscape continues to evolve, with much R&D focusing on more specialized medicines. As the biological activity and specificity of the active pharmaceutical ingredient (API) increases, dosage strengths decrease – resulting in increased potency of the APIs in terms of occupational handling for drug product manufacture. The marketplace is seeing continued investment in R&D with a visible shift towards speciality/potent medicines. Oncology is a particularly intense area of focus for the global pharmaceutical sector.
Leaders in the development and manufacturing of potent molecules with specialist containment technology provide expertise in the safe and successful management of highly potent active pharmaceutical ingredients (HPAPIs).
What is a potent molecule?
Although there is no standard classification for HPAPIs, potent molecules can be defined as powerfully active materials requiring very small concentrations to have a biological effect. All substances are potential poisons, since no chemical is completely safe; it is the dosage that distinguishes a poison from a remedy, even ‘toxic’ chemicals deemed ‘safe’ if concentration is low enough.
PCI 2018-05 Figure 1.png

General potency definitions:
  • A pharmacologically active ingredient or intermediate with biological activity at approximately 15 µg per kg of body weight or below in humans, or a therapeutic daily dose of 1 mg or less per day
  • An API or intermediate with high selectivity and/or the potential to cause cancer, mutations, developmental effects or reproductive toxicity at low doses
  • A novel compound of unknown potency and toxicity.
Occupational exposure limits (OELs) or hazard bands may provide a scientific means of identifying hazards and risks to ensure exposure mitigation can be implemented. However even by employing hazard bands, it is evident that no real harmonization of the bands themselves exists (Figure 1) as systems often differ between companies.
PCI 2018-05 Figure 2.png

Alternative for potent molecule development
A common definition is to classify a molecule as potent if it demonstrates an OEL <10 µg/m3. Such APIs therefore require special considerations during processing activities.
As APIs move through the drug development programme from discovery to commercialization, further toxicology information becomes available building a comprehensive understanding of toxicity (Figure 2). Even though the commercial product may suggest an OEL >10 µg/m3, during early phases, the data may be limited. Therefore, the API would be deemed potent.

Assessment and management of HPAPIs
The number of contract development and manufacturing organizations (CDMOs) claiming to offer potent processing capabilities has increased in recent years, but they may not have invested in contained technology – meaning a heavy reliance on personal protective equipment (PPE).

Any CDMO working within drug product development should be aware of the level of toxicology data available and risk assessments to ensure workforce protection. Emphasis should be placed on an on-boarding process for suitable handling of the API.

CDMO project on-boarding
An example of one on-boarding process would be to use the philosophy of lean manufacturing which examines safety, quality, delivery and cost. A gating system would ensure a review of the molecule from each discipline to determine the best approach for the project.
A technical discussion should occur between the client and CDMO based on an initial questionnaire.  This should examine key information such as: safety data sheet and/or toxicology package, dosage form/strength, and the method of manufacture, where known. In the absence of an OEL, the CDMO should perform an internal calculation by qualified personnel. Only following this assessment should a CDMO enter into an agreement to continue with a potential project.

Further staff evaluation and training
When a project is awarded a detailed evaluation of the API should be undertaken. Within this, the on-boarding data and information gathered should be catalogued and peer-reviewed as the API moves through the facility as part of a continuous review.
Of critical importance is the training of different disciplines working with the products.  Training should focus on the molecule and its handling including: toxicology, OEL/banding systems and engineering solutions.  Within any CDMO, set modules should be assessed through examination. Any personnel working with HPAPIs should also be subject to annual health assessments.
Workforce safety best practice
To satisfactorily work with HPAPIs, best practice dictates that facilities should not rely on PPE alone. Guidance advises that manufacturing be performed within a specifically designed facility utilizing contained processing equipment. An example of a best practice user requirement specification (URS) within a multi-API facility is shown in Figure 3.
The URS includes primary protection from contained equipment, combined with facility design operating into primary processing rooms, clear personnel and material segregation, and PPE in the event of a breach.

As the market continues to evolve with increasing numbers of potent molecules in development, it is important to understand the requirements for the safe processing, the differing regulatory requirements across the world, and – above all – the safety of employees and the environment.
For pharmaceutical developers looking to outsource the development and manufacture of products containing HPAPIs, the challenge is finding a CDMO with the right technical capabilities, knowledge and experience to successfully manage the project through the entire cycle.
David O’Connell, Director of Scientific Affairs at PCI Pharma Services, Gwent, United Kingdom
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