No room for exposure

Currently some 5-10% of pharmaceutical drugs on the market, as well as an estimated 25% of the 6,500 medicines under development at the moment, contain highly potent compounds. As a result of this, a class of pharmaceutical manufacturing facilities, often referred to as Highly Active Pharmaceutical Ingredient (HAPI) facilities, need to be developed to meet the specific challenges associated with the handling of such compounds.

The handling of HAPI affects, in a much greater way than anticipated, the designs and "norms" that have been developed for API facilities. With the development of new drugs there has been a recognised trend of increased potency, which has resulted in the need to implement dramatic changes to plant design and operating procedures. Some 15 years ago, new plant design required 100mg/m³ operator exposure levels, while 5-10 years ago typical operator exposure levels had dropped to 10mg/m³. Today, the design of new plants requires operator exposure levels of the order of 0.1-1mg/m³ and, in the case of some compounds (e.g. hormones), operator exposure levels of 30ng/m³ can be the norm. Currently, 25% of new drugs under development will require operator exposure levels of less than 1mg/m³. Minimal intervention To maximise the achievable containment levels for any engineered solution, actual operator intervention in handling solids needs to be minimised as far as possible; after all, if no one has to get near the hazardous substance, then no one will be exposed to it. It is therefore important to spend an appropriate amount of time and money on the design of any equipment required to aid solids flow of the hazardous substances. Of course, as in many solids dispensing and container emptying applications, complete exclusion of manual intervention with the hazardous substance is not always possible. In such cases, a specialist containment engineer with significant relevant experience should be involved in the project. Containment engineers can be specialists from equipment manufacturers, consultants or engineering companies. Some larger pharmaceutical companies may have their own in-house personnel dedicated to addressing these types of issues. A good containment engineer should require only a minimum amount of initial information to successfully assess any particular project requirements and to make an initial proposal for possible containment strategies and potential solutions for any given issue. Of course, there should always be options presented for different philosophies – split butterfly valve technology, glovebox technology, personal protective equipment and bag technology (a selection of which are pictured). After an initial understanding of the processes involved (i.e. vessel charging, vessel unloading, dispensing, etc.), then for most solids containment applications, answers to the following questions should enable any experienced containment engineer to provide these initial strategies: • what containment level is required? • what quantities of solids are involved? • what is the frequency/time-scale of handling these solids? • what types and size of containers will the solids be handled in? • where do the containers come from and where will they go to? Following on from this initial, basic information being provided, a first list of possible containment strategies can be drawn up. It will then be necessary to look at specific issues for any individual application in more detail. This may involve special solvents being used, special atmospheric requirements, integration of special process equipment in the containment philosophy, weighing equipment accuracies required for dispensing and off-loading applications, and so on. Designing equipment or a process for contained handling of hazardous substances is not "rocket science" and does not always need to involve elaborate, costly and time-consuming design studies. Optimum solutions can be found reasonably quickly and without significant expenditure, in most cases by applying some common sense and by drawing from the experiences already gained in many similar applications from around the world. However, in some of the larger and more elaborate contain-ment projects it will be beneficial to employ a containment engineer to carry out a more involved design study of the problems in hand. Extraction booths extract high volumes of air with face velocities of 0.5-1m/sec at the booth entrance. This is not a suitable method for high containment, but can be very useful in applications where secondary containment is supporting primary containment equipment. Utilising airflow The downflow booth is an improved method of containment utilising airflow, where air is issued at 0.45m/sec (laminar) in a downward motion from the roof of the booth. Air is HEPA filtered and extracted at ground level at the rear of the booth. Some 90% of the air is recycled, with 10% being released to atmosphere, providing fresh air and helping to prevent heat build up. Due to air recycling, a downflow booth will utilise substantially lower volumes of room extraction and will typically achieve 100mg/m³ or less. However, the main weakness with this type of system is that direct product contact with operators and their protective clothing cannot be avoided, leaving potential for peak operator exposure level of up to 2,000mg/m³ for some operations. Continuous polyethylene tubing is another method that can be employed, using the "sausage-filling" principle to act as a successful form of primary containment with an extraction booth as secondary containment. This method is useful for drum filling and for the disposal of solids waste materials from containment enclosures. Containment levels of 25-50mg/m³ can be achieved with an extraction booth as secondary containment and less than 1mg/m³ can be achieved when using a glovebox. The split butterfly valve concept brings together two halves of a valve where a seal is formed between the two halves. When opened, the two halves operate as one, allowing powder to flow before the valve is shut. When the two halves are split, the surface contained between the halves is notionally clean. This method can typically achieve operator exposure levels of 10mg/m³, a figure that can be reduced to less than 1mg/m³ with secondary containment. The most common form of isolator is a glovebox run under a negative pressure of –100 to –250Pa in relation to room pressure, (for sterile applications normally +50Pa pressure with internal laminar flow). If gloveports do not provide sufficient reach, a quarter-suit window can be used to replace the gloveport window. A quarter-suit window is made from flexible PVC with integral gauntlets to which gloves are attached. No breathing air is required for this type of suit, unlike the half-suits frequently used in the past which required breathing air and substantially increased the physical size of the isolator. All isolator designs tend to use a minimum of legible extraction volumes. It may therefore be necessary to nitrogen purge the isolator due to the potential build-up of an explosive environment within a confined space. With good isolator design, containment to 20-30ng/m³ operator exposure levels can be achieved. Rapid transfer ports When rapid transfer ports are used they need to be utilised in conjunction with an isolator and are, therefore, not a containment method in their own right. The rapid transfer port has two halves that are joined together forming a door, which then opens as one and allows a sealed bag of powder to be taken out. The combination of rapid transfer port and isolator can normally achieve levels of less than 1mg/m³. Recently, there have been a number of projects involving the containment of entire small-scale processes and process equipment within isolators, and current trends point towards the emergence of more. Examples of these types of systems contained complete small-scale reactors, crystalliser vessels, rotary evaporators, Nutsche filters, tray dryers and filter dryers. But fully contained process isolators are not just confined to the primary (chemical) pharmaceutical world, they also extend into the secondary (formulation) side of pharmaceutical production, with equipment like tablet presses, granulators, mills and micronisers having been successfully contained to achieve occupation exposure levels in the ng/m³ region. One of the fundamental decisions regarding containment is the choice of handling method, a factor that will greatly influence system performance and design. For best system performance it is wise to keep all powder handling operations to an absolute minimum. Successful high containment can be achieved only if any solids flow is predictable without the operator having to access the system directly. Widespread changes in drug potency have also led to the requirement of smaller batch sizes, providing the potential for radical changes in production methods. Large-scale drug production has tended to have dedicated plant employing pneumatic conveying, mechanical feeders and storage hoppers. However, many new facilities are now designated multi-purpose and require greater levels of flexibility in addition to high levels of containment. Well-defined criteria The purchaser (end-user) of any containment equipment must also be clear about what is expected of the containment equipment in terms of usability, containment performance and its validation, as well as its cleanability. These performance criteria need to be defined at the outset of the specification process, as they may affect the design, leadtime and cost of any equipment being chosen. Appropriate containment performance validation and the way any results gained from such performance validation are expressed is much more of a contentious issue and has been the subject of much discussion in recent containment seminars and in the press. One example of how this can be tackled in the case of split butterfly valves is through the containment evaluation guidelines about to be published by the Standardised Measurement for Equipment Particulate Airborne Concentrations (SMEPAC) group of users, manufacturers and containment consultants. These guidelines aim to provide a common basis for manufacturers and users on how to perform the tests, how to analyse the results and how to present the results; it is likely that these guidelines will be adopted universally for the performance testing of split butterfly valves. Operative buy-in Containment and cleaning validation can be provided by most containment equipment manufacturers as part of their Factory Acceptance Testing (FAT) of the equipment, but this can rarely represent actual operating conditions on site and with the end-users of the equipment, which has to remain the ultimate performance verification for any such equipment. One aspect often overlooked by many companies is the early and detailed involvement of the eventual end-user of the containment equipment. These are the people who will be directly interfacing with the containment equipment, and they are the ones who can make either a complete success or complete failure of any containment solution selected. Where these operatives have been involved in the selection of the equipment (design meetings, reference visits, factory acceptance tests, etc.) from the start, a sense of ownership is instilled into the final solution, and most of the time they will do everything they can to ensure that the equipment is used as intended and that solutions are found to any eventual problems or failures of the equipment. Where the operatives have not been involved in the selection of the equipment, this usually fosters a sense of strong initial scepticism. The attitude is often one of, "well, we did not need this equipment before, why do we need it now", and every effort may be made to deliberately find faults with the systems and to find reasons for why it should not be used. Of course, this is not always the case, but it does happen.