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:
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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
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Facility design: proper air pressurization, high number of air changes, single-pass air, restricted room access, airlocks, safe-change filters,
and misting showers
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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
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Personnel systems: training, written procedures/policies, education, and employee-health monitoring.
Nettleton (Cambrex): In pharmaceutical manufacturing, there are two primary objectives for containment: to protect product quality and prevent
worker exposure. There are underlying design principles that apply to all pharmaceutical manufacturing and analytical facilities
at Cambrex. The operational goal is to maintain process isolation using isolators, sealed process vessels, dedicated piping,
and single-pass, high-efficiency particulate air (HEPA)-filtered airflow. It also is crucial to design the ventilation system
so that potentially contaminated air will flow downstream and away from the process area. Ingress and egress also are controlled
to ensure both air and worker traffic moves in a single direction with minimal turbulence. Gowning/degowning vestibules, material
pass-throughs, and misting showers also are integrated into the flow. Upon ingress, disposable garments are donned, and upon
egress, workers are misted with water to tack particulates to disposable garments, which are then discarded before exiting.
Manufacturing chemist in personal protective equipment attaching a hose to the powder-transfer system below a glovebox on
a Nutsche filter dryer at SAFC's facility in Verona, Wisconsin.
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With respect to exposure prevention, in many instances, the design strategy for quality protection is the same as exposure
prevention. Process isolation using isolators, sealed reactors and dryers, and HEPA-filtered airflows all are important. In
some cases, however, pressure differentials that protect pharmaceutical quality may not be protective of worker exposure.
For example, when opening an isolator, positive pressure in the isolator will prevent cross-contamination, but the pressure
release will potentially expel particulate material toward the worker. In these cases, the engineering strategy may include
a bag in/out system. It also may be appropriate to include extra personal protective equipment when transferring toxic or
potent compounds.
Mockups, training, and verification also are key. Because all manufacturing processes are different, it is important to verify
that a given process design will function correctly and that operators are familiar with the process before a pharmaceutical
product is actually manufactured. At Cambrex, it is common for the manufacturing team to develop and conduct mock handling
exercises. These mock exercises may include the handling of surrogate pharmaceutical compounds followed by an assessment of
potential releases and cross-contamination using wipes, air sampling, and appropriate analytical detection. Naproxen is typically
used as a surrogate because it has an extremely low detection limit and is easy to clean. At completion, mock exercises will
demonstrate that process and containment equipment performs as expected, provide process ownership and training for operators,
and identify potential need for design modifications to prevent cross-contamination or worker exposure. Cambrex routinely
conducts equipment maintenance and equipment performance verification to ensure isolators, hoods, balance enclosures, airlocks,
and HEPA systems are working properly.
Müller (Carbogen Amcis): Carbogen Amcis has more than one site and has more than one production facility at its headquarters site in Bubendorf, Switzerland,
but the concepts pursued with regard to containment are governed by one common philosophy regarding the handling of HPAPIs:
the risks to be controlled regard the patient, the worker, and the environment. Therefore, we are analyzing the whole lifecycle
from the purchasing of raw materials (which may eventually be highly potent compounds) to the delivery of products and to
the creation of waste, the whole set of buildings and installations involved, and the whole series of applicable procedures
and measures.
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