The global market for drug products containing highly potent active pharmaceutical ingredients (HPAPIs) is currently on a growth fast track. Data indicates a Compound Annual Growth Rate (CAGR) of 8.7% to 2032, with oncology a major driver, capturing a market share of 76% in 2022.1 Additionally, even though biologic dosage forms are experiencing significant growth, the shift from intravenous (IV) dosing towards solid oral dosing is likely to gain momentum; the main driver for this is patient experience, as taking solid oral dosage forms is far less stressful than spending days or weeks in hospital receiving chemotherapy infusions.

Therefore, the role of CDMOs that can develop, manufacture and package drug products containing HPAPIs is more vital than ever. There should be a robust approach to all stages of the process, including containment strategies, formulation development, scalable manufacture and potent packaging operations.

Containment Strategies

Throughout the pharmaceutical industry, there is a lack of consistency regarding the assignment of Occupational Exposure Limits (OELs) to specific bands. It is therefore critical to have a unified understanding of all relevant definitions, as described below.

• PDE (Permitted Daily Exposure), also known as ADE (Acceptable Daily Exposure), represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.
• NOEL (No Observed Effect Level) is the highest tested dose at which no “critical” effect is observed. If the critical effect is observed in several animal studies, the associated NOEL should be used to calculate the PDE value.
• OEL (Occupational Exposure Limit) is the average concentration load of an airborne active pharmaceutical

ingredient (API) in μg/m3 that’s acceptable during an 8-hour time-weighted average with no negative impact on workers/environment.

• OEB (Occupational Exposure Band) is the banding of OEL into ranges for which appropriate measures to protect workers and facilities/equipment can be defined in common for APIs with different OELs within this band.

• COSHH (Control of Substances Hazardous to Health) assessment.

Table 1 below illustrates the difference in banding applied by two pharmaceutical companies, demonstrating that there is a significant lack of common terminology, and therefore true understanding, of potent classification.

When developing and manufacturing highly potent drug products, there should always be an OEL monitoring program at each stage of the process. Strict cross-

contamination controls are essential, with a risk assessment performed in accordance with four principle modes:

• Airborne;
• Mechanical;
• Personnel transfer;
• Retention of product on contact

surfaces.

With traditional, non-potent drug products, avoiding contamination from personnel involved in the production process is, of course, critical. However, when manufacturing drug products containing HPAPIs, processes carried out under negative pressure process rooms aren’t enough. High-grade specialised containment equipment is also required in order to protect employees from the API

itself, and to ensure drug product integrity in a multi-product facility.

Understanding the levels of containment is important when determining the

appropriate handling of highly potent compounds (Figure 1).

Designing a safe and compliant high-potent containment facility is a demanding process. Primary containment requires the use of suitable equipment that runs under negative pressure and effectively serves as a “cleanroom” in its own right, with secondary containment being the facility itself. The appropriate solution depends on the product potency and batch size being handled, as different solutions may need to be considered for laboratory, small- and commercial-scale use. Containment must therefore address the potency of the product with careful consideration being given to dust extraction (heating, ventilation and air- conditioning systems [HVAC] and central dust collection) and breach control procedures. HVAC systems should be controlled using a building management system (BMS), which must be suitably designed with terminal high-efficiency particulate air (HEPA) filters (H14 grade).

Additional safeguarding measures such as single-pass air ensure a full room evaluation of any potential loss of containment, suitable automatic equipment cleaning and waste disposal systems. In addition to the room pressure differentials, airlocks adjacent to the manufacturing area are necessary for high-risk activities such as API dispensing, along with utilities such as purified water and effluent treatment capabilities. Restricted access is also a requirement, ensuring that only essential staff can access the HPAPI processing areas, with cleaning and decontamination areas provided for employees.

It is therefore clear that containment is a technology in its own right, and for CDMOs working with HPAPIs, it is just as important as granulation, compression, or roller compaction technologies. A sound understanding of what containment really means is therefore essential for CDMOs operating in the high potency development and manufacturing space.

High Potent Development and Manufacture

A noticeable trend in the high potent formulation development space is the use of a Design of Experiment (DoE)/Quality by Design (QbD) approach at earlier stages of the product lifecycle. DoE is a systematic, statistical approach with the aim of optimising the product and the process by understanding the relationship between various factors (input variables) and responses (output

variables). This method helps identify the most influential factors, determine their optimal levels, and establish robust and efficient processes while minimising the number of experimental runs.

During formulation development, multiple factors can influence the quality, safety, and efficacy of the final drug product, such as the choice of excipients, API concentration, processing conditions, and manufacturing equipment. Traditional trial-and-error methods can be time-consuming, and resource-intensive, and may not identify the best combination of factors to produce a high-quality drug product.