A key challenge in high-potency manufacturing is to maintain the level of containment throughout the manufacturing process. Before examining how that is achieved operationally, what are the key considerations when designing a high-potency manufacturing facility and in equipment selection?
The concept of risk management was a major element of the facility design discussion at Metrics. The team (consisting of director-level managers from pharmaceutical development, environmental, health and safety, quality assurance, and operations as well as personnel from external engineering firms) considered the risks associated with locating a high-potency solid-oral dosage form facility adjacent to one designed for compounds with occupational exposure limits greater than 10 μg/m3 time weighted average. These risks were placed into two major categories. The first were risks associated with protecting the employee. The second were risks associated with protecting the drug product(s).
Interior of the multiuse isolator with a high-shear granulator, conical mill, and roller compactor installed. (IMAGE IS COURTESY OF METRICS)
To manage the risks of operator exposure, the team adopted the following tenets:
To manage the risks of a cross-contamination event, the team established the following requirements:
- Operators will not work with an unclassified compound.
- Operators will not work with a compound that cannot be suitably contained.
- The containment capabilities of equipment will be tested and quantified.
- Secondary protection will be available in the event of a containment breach.
- Engineered solutions (i.e., hard-wall isolators) were preferred to work-practice solutions (i.e., laminar-flow enclosures).
- Operators will be monitored for adverse health effects.
- Potent compounds will be processed under hard-wall isolation.
- Potent compounds would be processed in rooms discrete from other GMP manufacturing areas.
- Operators will not transit one GMP area to access another GMP area in which potent compounds are processed. Multiple airlocks (i.e., gray areas) will separate rooms in which potent compounds are processed from surrounding areas.
- Air handling and utilities will be separate; room pressurization will be such that dust is contained.
- Equipment used in the manufacture of potent products will not be used outside the potent facility.
- Equipment will be chemically tested for cleanliness by high-performance liquid chromatography and total organic carbon analysis after each processing event.
- Disposable accoutrements will be used where feasible.