Highly potent APIs (HPAPIs) are a rapidly growing segment of the global pharmaceutical industry—valued at >17 billion USD in 2020. Market estimates project close to 10% annual growth in this area. However, HPAPIs have strict handling requirements that require high capital investment and specialized personnel. As a result, many HPAPI investigators turn to CDMOs who have the facilities, equipment, and personnel in place to take their HPAPI project through development and manufacturing.

HPAPI product classification and the increased complexity regarding transfer and manufacturing compared with standard APIs is crucial for the success of bringing these medicines to patients in need.

 

An HPAPI is defined as:

›       Drug compound with an OEL ≤ 10 µg/m³

›       General therapeutic dose of ≤ 10 mg/d

›       1 mg/kg/d dose produces serious toxicity in laboratory animals

 

Why are HPAPIs so important in the market and so complex to manufacture? Over 25% of drugs under development are highly potent, as are > 60% of approved anti-cancer drugs. Manufacturing these products requires dedicated facilities to prevent cross-contamination of other products and protect personnel and equipment.

 

For risk management in an HPAPI production area, there are two key indicators: OEL and the permitted daily exposure (PDE).

 

OELs are health-based regulatory values that indicate levels of exposure for chemical substance in the air of a workplace. OELs determine the protection measures for the operator, and design of facilities and equipment. The OEL is the safe concentration of pharmaceutical substances (in µg/m3) present in the breathing zone under which all workers can be exposed for 8 h/d, 40 h/wk, 50 wk/y for a working lifetime of 40 y, generally without causing adverse health consequences.

 

On the other hand, the PDE pertains to patient safety. The PDE informs the acceptable level of patient exposure to harmful substances. Thus, the PDE helps prevent cross-contamination, and inform the corresponding need for separate production areas.

 

At Siegfried, we use the most appropriate protection measures for each product. Therefore, we carry out a comprehensive analysis to determine the optimal means of working with each substance: solid, powder, liquid, or gas-producing.

 

Traditionally, the OEL—set by toxicologists who factor in data from the literature, preclinical/clinical studies, and similar compounds (especially for new chemical entities)—is the basis for determining handling requirements. 

However, focusing only on the OEL value produces an conservative value. Regarding HPAPIs, additional factors also contribute to the hazard assessment.

 

A risk-based exposure evaluation process (REEP) measures the risk instead of simply the hazard of the substance. A REEP assessment considers e.g. the percentage of API in the formulation, physical state, and volume in addition to the OEL value.

 

Applying the REEP concept can reduce the cost and time required to introduce a new drug substance into your facilities. After the assessment one might conclude that the facilities/equipment and protection measures are insufficient for the necessary safety level.

 

We recommended splitting the manufacturing process into phases (i.e., dispensing, granulation, compression, coating, and bottling) and to analyze each phase in accordance with pre-defined criteria as well as pre-defined criticality. For example, a closed  process has fewer risks than an open process.

 

Accordingly, empirical tests must be conducted with the product and a manufacturing process must be delineated, in accordance with typical operating procedures. To render the REEP optimally representative, tests must be carried out with various operators to account for human variables.

 

A measurement point must be installed within the operator’s breathing zone. This measurement point consists of a small pump that acquires samples over the course of a workday. Sampling points can also be installed elsewhere within the same room. Samples must be taken to an accredited laboratory for analysis.

 

The test results are evaluated with statistical analysis software, which provides the assigned protection factor (APF). For example, the APF determines how well a respirator/filter combination protects an individual from external contaminants; considering the current process, type of machinery, and implemented operation.

 

Finally, as a result of this analysis, we can address the need for PPE, identify corrective actions to improve the process, or define new PPEs.

 

Some of the key points to consider in manufacturing HPAPI products include the following.

 

Facilities and equipment:

·      The entire area must have access control. Access should be limited to properly trained personnel in good health.

·      The area must be identified/labeled. All personnel must know what product is being handled, and the associated risks.

·      Ensure that there are alarms indicators, to increase the visibility of the safety alarms.

·      In accordance with the OEB, use equipment that has product leaks < 10 µg/m3.

·      Most of the equipment is completely closed. HPAPI management must not run on fully open equipment.

·      Product transfer between the various equipment must be closed. In addition, this equipment must have cleaning elements onsite, such as clean-in-place or wash-in-place.

·      Workers must have adequate protection measures.

Equipment:

·      Containment equipment such as weighting booths, closed pneumatic transfer, split valves, and isolators (flexible or rigid).

·       For OEB 4 compounds, closed systems, barriers, and procedures; for OEB 5 compounds, leak controls, automated processes, and remote operations.

·      HEPA filtration at the outlet is mandatory in HPAPI-handling areas (HEPA H13 or higher, preferably with a safe change system). Use 100% fresh air. Air recirculation is only permitted in specific situations and with assurances (e.g., prior double-HEPA filtering and only toward the same zone). We recommended HVAC systems that are dedicated to the area.

• Ensure complete technical and safety training for those who handle and manufacture HPAPI products.