High-potency manufacturing is a niche, but specialised area that requires proper facility design, equipment selection, production
processes and operator knowledge to safely handle and produce highly potent APIs (HPAPIs) and finished drug products containing
HPAPIs. Pharmaceutical Technology Europe conducted an industry roundtable to gain a perspective of these issues. Participating were: Joe Cascone, director of potent
product pharmaceutical development at Metrics; Joe Nettleton, vice-president and director of operations at Cambrex's Charles
City, Iowa (US), facility; Peter Müller, delegate of the Dishman board and member of the Carbogen Amcis management team; Theodore
Iliopoulos, chief scientific officer at Euticals; Paul Doherty, chemical engineer, Sigma Black Belt, and plant manager at
Ferro Pfanstiehl Laboratories; and David Bormett director of operations at SAFC.
Facility design and equipment selection
Q. PharmTech: A key challenge in high-potency manufacturing is to maintain the level of containment throughout the manufacturing process.
What are the key considerations in designing a high-potency manufacturing facility and in selecting equipment?
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Iliopoulos (Euticals): High-potency containment structures address both cross-contamination requirements targeting patient safety and, at the same
time, worker safety by maintaining occupational exposure limits (OELs) below 10 mcg (Band III) or 10 ng (Band IV) per cubic
meter of air for an eight-hour weighted average. Exposure to just a small quantity of a HPAPI or highly potent compound can
pose significant health risks.
The challenge in designing a high-potency containment facility is to find the appropriate level of containment that should
manage the exposure risk at a reasonable cost. It is also crucial that the operators and the production staff understand the
need and proper use of engineering controls. Enclosed reactors, centrifuges, dryers and highly dusty mills are key manufacturing
assets in an API production line and, together with product-transfer systems, are key elements in a high-containment design.
The most crucial issues in selecting the proper equipment are the containment of the process itself. In other words, one must
ensure that no airborne particles are released to the ambient air and that product remains in the process piping used. Equipment
and facility-engineering controls apply to all areas handling such compounds, not just manufacturing. It also refers to process-development
and quality-control laboratories.
Bormett (SAFC): Proper initial design and engineering of a potent-compound handling facility is crucial to achieve the desired levels of containment.
Consideration must be given for containment of the entire process, from weighing and charging of raw materials, to packaging
of the final material. Key facility-design criteria include single-pass heating, ventilation and air-conditioning (HVAC) systems,
controlled access to areas, airlocks around potent-compound handling rooms for segregated gowning/degowning, proper room-pressure
differentials for containment, degown misting showers, bag-in/bag-out filtration components, sufficient support utilities
(such as supplied air) and proper waste-handling capabilities.
SAFC uses an overall potent-compound handling system that incorporates five levels of cascading protection, with the first
two being the primary methods of material isolation/containment:
Process isolation: using closed-system glassware and reactors and alpha-beta/split butterfly valves.
Containment equipment: glovebox isolators, ventilated laminar-flow enclosures, rapid-transfer ports, local exhaust ventilation and closed-system
cleaning through clean-in-place (CIP) systems.
Facility design: proper air pressurisation, high number of air changes, single-pass air, restricted room access, airlocks, safe-change filters
and misting showers.
Personnel protective equipment: As a secondary precaution, Saranex coveralls and hoods, powered air respirators or supplied air, proper glove selection,
and chemical suits when needed for solvents/reagents.
Personnel systems: training, written procedures/policies, education and employee-health monitoring.
When designing and selecting equipment, it is important to partner with vendors that understand isolation/containment and
the requirements for potent-compound handling. In many cases, the equipment vendors can provide data from previous containment
testing conducted using surrogate products. The equipment selected should be fit-for-purpose and provide the necessary flexibility
to accommodate process changes, especially for multipurpose facilities.