The containment requirements are defined in view of the toxicological category (performance-based exposure control limit [PBCEL],
OEL, or acceptable daily exposure [ADE], respectively), whereby Carbogen Amcis is working with a four-categories approach,
and strict requirements are applied in case of Categories 3 and 4. They involve with regard to production separation of the
ventilation (room and/or reactor exhaust, i.e. systems), HEPA-filtration of exhaust air, separation of the room (airlocks),
pressure cascades, partial dedication of specific equipment to HPAPIs, completely closed processing, and separation of the
wastestreams. The focus is on avoiding carryover as well as contamination of the workers and the environment through production
equipment (cleaning), through space, and through infrastructure systems. The respective considerations are applied along the
whole sequence of activities (i.e., the lifecycle). The details cannot be outlined here, but it can be said in a summary that
they include gloveboxes or isolators, respectively, barrier isolation benches, laminar flows, and flexible containment with
all the activities subjected to their specific risk analysis. Personal protective equipment is eventually used as a safety
backup during critical operations.
Cascone (Metrics): The facility and equipment constitute the barriers between the high-potent active agents and their surroundings. A facility
designed with one-pass air and multiple airlocks with cascading negative pressure differentials will, in conjunction with
other controls, mitigate cross-contamination. Hard- and soft-wall isolation technology demonstrates sufficient containment
for the manufacture of solid-oral dosage forms containing compounds deemed to fall within an occupational exposure band of
10 mcg /m3 to 30 ng/m3 (TWA). These systems may be verified by recognized industrial hygiene practices, such as the ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment (1).
Enclosing a particular process or unit operation is reasonably well-established by most equipment manufacturers and isolation
specialists. A key challenge is linking the unit operations together with the proper conveyance technology. This is particularly
daunting if there is a wide variety of equipment makes and models. It is generally easy to contain powders within a bowl or
vessel. Charging and discharging those powders and transporting them to other pieces of equipment is more complex. Examples
of conveyance technology that may offer solutions include vacuum conveyance and continuous-liner 'bag-out' systems.
Another challenge related to isolation and containment centers on powder sampling. Process intermediates (e.g., blends and
granules) need to be sampled to characterize in-process attributes and/or comply with prescribed regulations. Access to the
product via properly designed and contained sample ports is essential.
Doherty (Ferro): First and foremost is the principle to not rely on 'moon suits' for the operators and instead have a strategy and philosophy
to use engineering controls to provide proper containment. The key considerations are the OEL of the substance to be handled
and, particularly for a CRO/CMO, the stage of the API and the scale of operation. The organization should have a system in
place that uses the OEL to establish the acceptable options available for facility design and equipment selection. For a CRO/CMO,
the best and most economical means to handle a potent substance depend significantly on the stage (preclinical, clinical,
or commercial) and scale. For example, the best means of producing a preclinical small-scale API might be a combination of
dedicated laboratory-scale equipment, disposables, and a small isolator. In contrast, a commercial product produced at a 50-kg
scale might require plant-scale equipment with validated cleaning procedures and test methods.
|
