Improving Laboratory Containment - by a factor of 10

by Martyn Ryder, Managing Director of Extract Technology, part of the Carlisle Life Sciences Group

High potency compounds in the form of APIs or HAPIs are a growing source of concern in today's pharmaceutical industry. In 1990 only around 5% of materials passing through drug development necessitated special containment measures. However, in 2001 at least 35% of compounds meet these criteria. Many health and safety professionals and facility managers are considering how to provide effective containment, and this paper sets out to demonstrate that a number of effective solutions do exist, without having resort to the unpopular personal protection equipment and air suit methods of operator protection. Factor of 10 improvement For many pharmaceutical research facilities that face the increased use of potent compounds or materials with an undocumented toxicity, guaranteeing a safe workplace is posing serious problems. With hazards approaching microgram level, how can effective hazard containment for technicians and scientists working in the laboratory environment be assured? If a company's corporate objective is to reduce operating exposure in the laboratory by a factor of 10, then the first step is to evaluate the risks and hazards involved using the illustrated pyramid chart. This user-friendly system permits a no-nonsense evaluation of the risks and hazards involved in any laboratory. The pyramid chart uses a generic control approach and is not sales orientated. The chart allows assessment of any given situation through combining the four key elements of handling hazardous material, namely:

Together these details generate a 'risk/hazard' profile for the specific tasks to be carried out. By referencing the combination of 'risk/hazard profiles' with 'frequency of use' on the pyramid chart, users will be steered to select one of the five industry-recognized containment strategies', which are :

Containing Large Scale Chemistry Rigs (Glassware) For many years laboratory fume hood design has concentrated on the enclosure of the glassware sets in a ventilated chamber. Exhaust airflow at the rear of the chamber induces an inward airflow at the front sash opening point, and this often generates turbulence as the static room air is accelerated to entrain vapour escape. Many engineers believe that the main shortcoming of almost all current fume cupboard designs is the reliance upon exhaust flow only. It is well established and documented that the supply air distribution around laboratory fume cupboards is critical to their operational success.

'Industrial Ventilation', the well respected guide published by the American Conference of Governmental Industrial Hygienists, makes specific comments about the importance of well-distributed supply air within fume hood applications. This sensitivity of the fume hood has led to research into more reliable containment solutions. Recent data has established that enclosing glass reactors and distillation columns inside a typical chemistry reaction enclosure can reduce operator exposure levels down to around 50 microgrammes/m³. This compares favourably with the documented exposure levels of a typical walk-in fume cupboard at between 500-1500 micrograms/m³. Understanding the behaviour of airflow around operators and laboratory equipment is the key factor in generating this substantial improvement in operator safety.

Airflow in Chemistry Reaction Enclosures Coming from a background of much larger scale industrial operations, where bulky items of process equipment, such as IBC bins, powder mixers or sieves need to be accommodated, industry engineers have developed a technique using large vertical laminar flow panels in connection with their vapour or dust containment systems. As long ago as 1986, it was demonstrated that technicians could be protected by a clean, vertical airflow directly above the operator position. During handling bulky equipment may have to be segregated into the exhaust area of the chamber, and it was this basic concept that led to the development in 1995 of a chemistry reaction enclosure system. It works by taking a typical pilot plant glassware skid, including glass reactors, distillation columns and head tanks, and then placing the entire skid within a stainless steel enclosure. This features a bonded base capable of retaining liquids and access doors along the entire width of the enclosure that control access to the reaction skid, where only one door at a time may be opened. This technique effectively minimises the openings through which any vapours or particulates may escape. Such chemistry reaction enclosures are now in use in many locations within the US pharmaceutical industry and have demonstrated a significant improvement in operator protection over traditional fume hood systems. Solids Additions to Large-scale Vessels: One key area, where operators face a high risk of exposure to the compound under development, is in the addition of solids into reactors or other large-scale pilot plant vessels. To this end a new system has been developed that utilises either low-cost moulded polyethylene containers or disposable charge bags. These transportation containers are connected to the process directly using any of the available split-butterfly valve systems. Such a system permits off- line sub-division of the potent compound via a specialised dispensing isolator containing a precision weigh-scale. This operation also permits batch additions to be pre-weighed ahead of the reaction operation. It is here, in the transfer of the material into the process vessel, that this design demonstrates its 'factor of 10' improvement over conventional split-butterfly valve technology. It has long been recognised that almost all split-butterfly valves can only provide containment of fine solids down to around the 10 microgram/m³ level. The weak link with all current split-butterfly valves lies in powder compaction and dust escape during valve separation, after the powder transfer has taken place. One option is to position a polybottle within a specialised enclosure before adding solids into the process. With such as system a carefully set up exhaust sweep can eliminate any migration of the compound outside the enclosure.

After the powder transfer into the vessel using the split-butterfly valve, the two valve faces are held a short distance apart whilst still in the exhaust sweep zone of the enclosure. A front opening permits any residual contamination on the valve faces to be manually wiped off using a solvent impregnated wipe.

This technique, combined with an effective exhaust sweep, guarantees operator exposure levels, whilst charging, will be below the 1.0 microgram/m³ level. Containing Vacuum Tray Drying Operations The flexibility afforded by vacuum tray driers suggests that these devices will be used in pilot plant applications for many years. The downside of the vacuum tray driers' processing flexibility is their relatively uncontained operational needs. Firstly, solvent-saturated material needs to be manually loaded onto the various trays, and then at the end of the drying cycle, the dried material needs to be recovered and transferred into drums. This tray-to-drum transfer operation can prove to be one of the highest exposure potential operations carried out by pilot plant technicians. The area required and the air movements generated by the operation can render conventional local exhaust containment ineffective. Therefore, a refined booth system has been developed over the past five years, which uses the down flow of air to improve operator dust exposure levels from around 150 micrograms/m³ in earlier units to around 15 micrograms/m³ using the latest workstation method.

The workstation concept uses a ridged barrier to control the operator's position by keeping the technician a safe distance from any dust sources. Air velocities behind this barrier, and in the immediate vicinity of the tray and receiving drum, are increased to minimise the possibility of dust escape. With good work practices, operator exposure levels in the range of 20-15 micrograms may be guaranteed using a workstation method. Small Scale Chemical Synthesis Operations As a general rule, the smaller the batch size under development, the more potent the compound is. Recognising this trend, a one-box solution has been developed that permits solids/liquids separation, vacuum drying, and even milling, all within a single isolator. Within any high containment device, the weakest links are the entry/exit ports. The pyramid chart rates isolators (with open powder handling/internal contamination) as a lower performance factor than isolators with contained transfer inside the enclosure. The reason for this performance differentiation is dust break out through the transfer ports. Even the most sophisticated rapid-transfer port technology - if contaminated with powders - will ultimately compact and track out the very material the isolator was designed to contain. Therefore, what is needed is a simple and cost-effective approach to guarantee that containment levels are maintained at below the microgram level. This should include the entry of material into the isolator via direct pipeline connections from the processing vessel (usually placed on the floor above), and a system to pipe the slurry from the processing vessel directly into a filter welded into the isolator base. One solution utilises a glove box structure where the solids and mother liquor can be separated by the application of a vacuum across the filtration membrane. Collected solids are recovered by manual scooping and placed onto stainless steel trays which are loaded into a vacuum shelf dryer constructed into the sidewall of the isolator chamber.The first two critical stages of solids/liquids separation are conducted without any transfer of materials from the isolator body. Dried compound from the vacuum shelf dryer may be passed through a sizing mill and weighed prior to being passed out. Another technique for contamination-free material exit from the isolator is to use over-bagging, and diligent bag and port recontamination, prior to removal of the rapid-transfer port flanged container. It has been suggested that such isolators are capable of processing batch sizes up to 2000 gr., whilst ensuring operator protection to low nanogram levels. Spray Drying & Other Specialist Processing Steps

Some manufacturers within the industry also provide a number of highly customised containment solutions in the field of small/laboratory scale batch processing. Spray dryers and cryogenic processing can all be set up within customised isolator layout to provide maximum levels of operator protection. Flexible Wall Containments & Glove Bags Unlike long-term production operations that place a high level of wear and tear on processing equipment and associated containment, pilot plant and development laboratory operations often use equipment in occasional campaigns. This low usage factor permits low cost flexible wall containments and glove bags to be considered for containing these operations. Glove bag solutions provide considerable cost savings over traditional ridged shell isolators. Ergonomic issues may be quickly designed out by the user group and bag fabricator evaluating directly around the machine, device or operation to be contained. Elimination of the need for engineering in this way not only reduces design costs but also dramatically reduces delivery time scales from months to weeks. Do Glove Bags Perform? Several drug development facilities, particularly in the USA, have proven low microgram/m³ levels of exposure whilst using glove bags to contain their processing operations. This has been endorsed in the UK where containment levels in the 5-1.0 microgram/m³ region are attainable with good operating practice. One new development, based on glove bag experience, has been to take down-flow booth operator protection levels almost to isolator levels. This utilises a flexible screen or barrier of glove bag material, with glove ports that permit the operation of manual tasks. The barrier is suspended from the ceiling of the booth and can be moved up and down to suit differing operator heights, and is found to be far less restrictive to work with than rigid workstations or plastic screens. Recent proving tests saw task exposure levels fall from 400+ micrograms to around 6 micrograms/m³, thus providing huge levels of operator protection improvement. Conclusion The overall conclusion of this study is that 'factor of 10' and, in some cases, much greater improvements can be made in the pilot plant or drug development laboratory. With the well-proven containment solutions documented in this paper the challenge of handling more potent compounds need not necessarily lead to laboratory technicians reaching for the air suit.