Dr Mike Battrum, Aesica Pharmaceuticals describes the art of safely tableting potent APIs
Safe as houses: Employers are legally required to ensure that employees are not subjected to concentrations of substances above the occupational exposure limit
In recent years an increasing number of pharmaceuticals and intermediates have been developed that are classed as potent materials. As employers are legally required to ensure that employees are not subjected to concentrations of substances above the occupational exposure limit (OEL), the facilities, equipment and operational procedures for handling potent materials on a commercial scale must therefore, be designed, constructed and proven to be safe prior to manufacturing.
The fundamental basis of design is to provide primary protective equipment (PrPE) that is fully contained and prevents human contact with potent materials. It is then necessary to locate the equipment in a facility that provides secondary containment to ensure that airborne particles cannot reach the outside world should the equipment fail.
PrPE
The choice of contained system depends on a containment performance target, less than or equal to the OEL. This performance target must be given to an equipment vendor when specifying equipment.
The handling or manufacture of potent materials will centre around a piece of process equipment (for example, mills or tablet presses) in which dry powders are processed. Other types of equipment, such as coaters, can have a lower, but still quantifiable, risk.
During design, it is essential to examine how leak tight the equipment is and under what pressure it will operate. Technical advances such as inflatable door seals warrant serious consideration. Usually equipment should be operated under negative pressure.
The weak points of process equipment are the systems for transferring powder into and out of the unit. Barrier isolators are the most common equipment. Isolators can be stand-alone, fully enclosing the necessary production equipment or integrated with other process units.
Isolators can be fixed-wall or flexible-walled. Hard-walled isolators are convenient in API environments where potential damage is a factor. Flexible-walled isolators are frequently mobile stand-alone units, with stainless steel bases and tubular frames.
Both types can be operated either at atmospheric pressure or under negative pressure (at least -30 Pa). Negative pressure isolators deliver much better containment performance.
Split butterfly valves (SBVs) are another common method of transferring solids from a fixed contained unit to another mobile unit.
Alternatively, for processes that require the handling of less potent powders or tablets in the 0.5–10 kg range, the Hycoflex bag system is simple and easy to use and relies on the Hycoflex coupling — a plastic and metal device that can be docked and de-docked using a specialist tool. 1
The containment equipment must be designed so that the appropriate cleaning methodology can be performed. The main three stages of cleaning are wash-in-place (WIP), wiping down and dismantling.
An automatic clean-in-place (CIP) or WIP system is preferred as it should reduce gross contamination to an acceptably low level.
For wiping down it is important in the design phase to ensure that all surfaces can be reached using the glove ports though occasionally, specialist cleaning tools are required.
For dismantling in phase 3, it is sensible to do swab tests to confirm the cleanliness of equipment.
Secondary containment
PrPE is only part of the overall solution. Unfortunately, there is always a risk that the systems may fail or be operated incorrectly. Contamination at these low levels cannot be seen or detected and therefore it is essential that possible contamination cannot exit the building. This is known as secondary protection.
Facilities designed for the manufacture or handling of potent materials should follow clear guidelines, including, entry via an airlock that is at a higher pressure relative to the rest of the facility.
All facilities are different and may be subject to different influences based on the complexity of the process. This means that a number of factors should be considered such as how decontaminated PPE will be disposed of; and how materials will be made safe before they are removed from the area.
Performance testing
It is vital to prove the efficacy of containment equipment by testing with surrogate powders. A methodology for the testing is provided in the ISPE Good Practice Guide. Testing is usually performed over three runs of normal operation. Sample analysis can take as long as two weeks before results are available.
It is wise to ensure full training prior to testing as containment performance can often be operator dependent. Performance testing should be repeated after the first and second years of operation thus providing three data points against which to fully evaluate the containment performance of the PrPE systems.
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