Considerations when manufacturing OSDs containing high potency API

Karen Tyrrell, Quality Assurance Lead at Pfizer CentreOne discusses the key considerations around the classification and handling of active pharmaceutical ingredients.

New active pharmaceutical ingredients (APIs) are being designed for high selectivity with biological targets, ultimately resulting in new compounds becoming more potent. Consequently, the manufacture of potent active ingredients and their associated drug products requires appropriate processes and expertise to reduce exposure risk to operators and to prevent cross-contamination. 

Defining high potency API 

The definition of a high potency active pharmaceutical ingredient (HPAPI) varies depending on the literature, but generally is defined by one or more of the following statements:

• 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
• Sex hormones and certain other steroids
• A pharmacologically-active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental defects or reproductive toxicity at low doses 
• A novel compound of unknown potency and toxicity 

Occupational risk presented by compounds is based on the use of occupational exposure limits (OELs) or occupational exposure bands (OEBs)¹. Typically, OEB systems categorise compounds from low to high potency and define the handling/containment requirements dependent upon the OEB category. Banding systems are often used in cases where there is insufficient data available to define an OEL for a compound (e.g. new drug candidates at preclinical stage of development). An example of a typical potency classification system is given in Figure 1.

HPAPI handling and manufacturing considerations

For safe handling of highly potent materials, manufacturing practices have moved away from reliance on personal protective equipment (PPE) alone (e.g. air-line suits), with current practices focusing on “containment at source,” using isolator technologies, to prevent operator exposure to such compounds during processing². 

However, occupational exposure risks and OEL/OEB classifications are not necessarily an appropriate indicator of segregation requirements in a shared facility.

In the manufacture of these highly potent compounds, special consideration needs to be given to the technical and organisational controls that will assure both operator safety and control cross-contamination risks to an acceptable level. 

While the control strategy for a shared manufacturing facility is multi-factorial, some of the key points to consider in the manufacture of HPAPI products include the following:

Toxicological and Potency information

• Having access to both expertise and data for occupational safety and toxicology to inform the hazard presented by the compound to both staff and the patient.

Facility 

• Room pressure controls designed for containment, including monitoring and verification of effectiveness, within the main HPAPI-handling area (negatively pressured area to the surrounding rooms).
• Airlocks around the manufacturing and laboratory spaces must provide gowning and degowning area with proper pressure controls.
• Only trained employees must have access to the HPAPI-handling areas.
• Heating, ventilation, and air conditioning (HVAC) systems must be designed with risk-based consideration of the appropriate degree of AHU sharing and filtered recirculation or 100% fresh single pass air. 
• Safe-change filters inside isolators, ventilated enclosures, general HVAC exhaust system, etc., must be used in the filtration and capture of contaminants.

Equipment and processes

• Risk analysis to identify containment requirements to limit/eradicate exposure to staff and risk of cross-contamination.
• The ISPE’s Risk-Based Manufacture of Pharmaceutical Products process³ (Risk-MaPP) is being widely adopted to manage the risk of cross contamination in order to achieve and maintain an appropriate balance between product quality and operator safety.
• Containment strategies (e.g.  general ventilation, localised vacuum systems, manipulation into isolators with open or closed systems, Clean in Place) - guidelines published by the European Medicines Agency.⁴

People

• Ensure sufficient training for those responsible for the handling and manufacture of HPAPI products.
• Having an expert team that has many years' experience of handling and containment is important, as is access to toxicology expertise.

Applying the principles of Quality Risk Management, incorporating toxicological information, and evaluation of the modes of cross contamination and the vectors that may contribute to those modes will ensure a comprehensive cross contamination control plan.

Regulatory considerations

Special consideration should be given to the expectations of regulatory agencies when manufacturing HPAPI products, particularly regarding segregation of operations and cleaning validation. The “traditional approach” endorsed by regulatory authorities had been to segregate facilities and equipment for product manufacture according to compound class (i.e. sex hormones, immunosuppressants, sensitisers, etc. produced in separate areas). 

In recent years, the combination of Quality Risk Management and a “Health-based” approach^5,6 to shared manufacturing facilities introduced by the European Medicines Agency (EMA) has gained popularity. This approach is based on using toxicological data to inform the risk to the patient and determine relevant cleaning residue limits, combined with the adequate operational and technical measures to control the risk.    

However, segregation of facilities for materials where toxicology data cannot support a controllable risk (e.g. sensitising compounds such as β-lactam antibiotics) is an expectation for both approaches. Figure 2 illustrates how the two approaches compare.

In summary

The manufacture of highly potent drug substances and their products bring many challenges. However, the application of containment technologies, access to appropriate expertise and comprehensive technical and procedural controls can ensure the safe manufacture of high potency drug products in shared manufacturing facilities. It remains key to consider the regulatory agency expectations in different countries particularly regarding segregation of operations and cleaning validation.

^References

^{1. Farris, J.P., Ader, A.W. and Ku, R.H.  History, implementation and evolution of the pharmaceutical hazard categorization and control system.  Chem. Today (Apr. 2006), 24: 5-10.}

^{EudraLex ‘The Rules Governing Medicinal Products in the European Union Volume 4, chapters 3 & 5}

^{2. Bormett, D. High-Potency APIs: Containment and Handling Issues.  Pharm. Technol. (Sept. 2008)}

^{3. ISPE, ISPE Baseline Guide: Risk-based Manufacture of Pharmaceutical Products (Bethesda, MD, 2010).}

^{4. Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. EMA/CHMP/ CVMP/ SWP/169430/2012.}

^{5. EMA/CHMP/ CVMP/ SWP/169430/2012.} 

^{6. EMA/CHMP/CVMP/SWP/246844/2018}