(Part of Carlisle Process Systems)
Routine day-to-day pharmaceutical powder processing and production operations increasingly involve high-potency powders. To counter potential hazards to operators involved with these compounds, new strategies for powder handling are being developed, in addition to advances in the equipment used to contain the active or high-potency materials.
The term “containment” refers to the isolation of hazardous materials (high-potency) using engineering methods. Containment can protect the operator from the compound or protect the compound from operator-borne containment.
To quantify the scale of this problem, it is important to appreciate the growth in the use of high-potency compounds. Whereas in 1990 only about 5% of all pharmaceutical actives handled were considered potent, >30% of all active pharmaceutical ingredients (APIs) are currently classified as “potent” and therefore require special attention to protect the operator from the effects of coming into contact with them. High-potency compounds are classified according to the severity of acute (life-threatening) effects, acute warning symptoms and onset of warning, toxicity, sensitisation, likelihood and severity of chronic effects, reversibility and alteration of quality of life.
In addition to safety concerns, current good manufacturing practice (GMP), when applied to a pharmaceutical facility, includes “fitness for purpose”, which means that it must comply with regulatory standards and be consistent in the quality of material produced.
Without effective containment programmes in place, cross-contamination is a serious possibility that cannot be overlooked. Hence, the effective containment of potent compounds is one of the key factors to be considered to assure not only product quality but also employee safety.
Performance evaluation: containment devices
Appreciating the need for effective containment is one thing. How we select the right technology is another. Here the pyramid chart provides a useful guide (see Figure 1).
Containment strategy-based selection
Any containment issue should be evaluated not just as a means of controlling hazardous dust and vapours, but also as part of a well-thought-out containment strategy. To achieve this, the evaluation team will study the process (particularly the operator’s interface with the potent compounds to be handled) in detail. These potent compounds may be solids or liquids, but in any case it is crucial to appreciate how much interaction the operators will have with the materials and how dusty or volatile these materials are. In addition, the hazards created by these materials and their exposure limit, or “operator exposure limit” (OEL), must also be considered. Before looking at the different containment strategies available, it must be pointed out that a containment strategy is not merely the selection of a suitable device of a given type. A containment strategy must consider essential operator training, development of standard operating procedures, access and emergency training, in addition to maintenance and cleaning protocols that are needed to ensure that the containment device itself continues to operate satisfactorily and within its design parameters. Five key strategies have been identified by the British Institute of Chemical Engineers (see Box 1).
The differences between containment strategies 3 and 4 have been brought about by the realisation that the weakest links in any barrier isolation system are the inlet and outlet transfer doors/valves/ports. These could be, for example, “double porte de transfert entaché” (DPTE) ports or split-butterfly valves. When these ports are contaminated with the drug compound, some breakout of materials will inevitably occur due to poor maintenance or to ingress of the powdered material itself into the finely machined faces of these transfer ports, which constitutes an unacceptable risk of powder breakout. Containment strategy 4 eliminates this risk, as it requires that all powder transfers within the isolator body are fully contained. In this case, the isolator provides an outer layer of containment and an extra level of safety for operators.
Selecting the right approach to a containment project
The first step is to evaluate the operator’s exposure to dust or vapour for a specific operation. Exposure potential (EP) is the key factor that drives the risk associated with a specific operation. Figures that determine the quantities of material being handled in the specific process and their dustiness or volatility have been established. These figures drive users to an exposure potential, from EP1 (the lowest level of EP) to EP4 (highest level). In the case of solids, EP is dependent on two key factors: the dustiness of the material and the amount of material being handled. Tables 1 and 2 and Figure 1 show the relationship between these factors and the exposure potential. Establishing the EP constitutes the first step of a project evaluation. Once the EP is known, a pyramid chart (see Figure 1) simplistically enables cross-reference between the hazard and materials being used and the EP, which quickly leads to a recommended containment strategy. Overall, the pyramid presents a simple “yes” or “no” conclusion as to the suitability of a typical containment device within a few minutes of finding the facts and figures associated with the project.
Verification of containment strategy selection
At this point of containment strategy selection, it is crucial to cross-reference the final selection with health and safety professionals, the user group and the validation department. After receiving approval from the various user groups and other interested parties that the containment strategy selection is correct, it is possible to look at the various generic containment equipment types. For lower containment strategies, airflow containment as a means of control may be acceptable. However, for higher containment strategies, barrier isolation may be needed. The key design points of each design may be considered.
The best way of minimising exposure to risk is to reduce the operator’s interface with the powder, by adopting simple automation methods, such as “gain-in-weight” powder feed systems, drum tippers or post hoists.
Ease of operation: product flow
All containment devices, irrespective of their design or manufacture, place a burden on the operator’s ease of use. The more control is placed on the operator’s position and interface with the materials, the less easy systems are to operate. However, the benefit of reduced operator exposure leads to a reduced risk to their health. When designing the powder-handling area of a powder control booth, for example, the materials’ management and personnel flow should be given special attention. Inflowing materials are ideally entered to one side of the work zone, with weighed assemblies going into batch containers or batch cages at the opposite side. Removal of waste materials, particularly in areas of high-volume subdivision, is a serious issue that must not be overlooked. As the potency of the materials being handled increases, we will inevitably be driven into the area of barrier isolation technology to provide adequate levels of operator protection.
Airflow systems within the barrier isolation units vary greatly from vendor to vendor. Some isolator vendors claim that high-volume airflows within the isolator actually minimise contamination of the internal surfaces and reduce the cleaning burden at the end of the campaign; others favour minimal airflow regimes, irrespective of the airflow system used within the isolator. Some methods must be included in the design to permit decontamination of the isolator. The techniques chosen may include manual wiping with solvent solutions (manual washdown with handheld spray gun) or a fully automated washdown system clean-in-place (CIP).
In cases where CIP technology is required to decontaminate the isolator, it is difficult to predict accurately the cleaning potential of any spray ball systems at the design stage. Hence, a cleaning evaluation test should always be carried out during the factory acceptance test (FAT). Here, the isolator may be contaminated with a suitable marker compound before the CIP cycle, and the level of cleaning evaluated with swab testing.
Naturally, as the complexity of isolator solutions increases, so does the associated cost of manufacture. Thus, it is no surprise that containment of potent compounds is now drawing on new-technology ideas to permit easier and more cost-effective methods of containing materials handled during process operations. One example of this is the development of a split-butterfly valve system. The split-butterfly valve permits the docking of a precharged container onto a process vessel without the need for a second isolator.
Another growing area of interest in potent compound containment is the use of “disposable technology”, such as engineered glove bags and smart liners. The Doverpack bag (ILC Dover, USA) has been developed to permit virtually contamination-free discharge of process vessels and filter dryers without the need for a rigid glove box. Flexible glove bag technology provides low-cost localised containment for pilot-scale or laboratory operations, such as small-scale granulators and mixers. When using this technology, a prototype bag should be produced and tried with the user group to ensure that its operation will not hinder the process.
Many popular types of containment technology are currently available, ranging from disposable systems, glove bags or airsuit personal protective equipment (PPE) to the most sophisticated automated handling systems. Simple clean-air booths can often provide good levels of protection without the burden of investment and the difficult ergonomics of glove box isolator systems. Selection of the correct system can be made easier by the use of the pyramid chart, which provides a good insight into the containment strategy and type of device needed to get the most appropriate solution. One final thought: always seek performance guarantees from the equipment vendor. That way, your operators’ exposure to risk, as well as their exposure to APIs, is safeguarded.