Working in isolation

With the need to rationalise costs, dedicated single product facilities are often regarded as something of a luxury, and companies are now looking towards highly flexible multipurpose plants that can process several high value products within one fully validated cleanroom.

It is with this design criterion in mind that Hosokawa Micron, a world leader in pharmaceutical manufacturing, has collaborated with companies to come up with solutions for various problems. The first was to produce a flexible ultra- fine grinding/micronising suite with high containment isolation to mill pharmaceutical products while maintaining a philosophy of no reliance upon personal protective equipment (PPE) within the processing area. The company wanted no special protective clothing to be worn during processing, but full CIP (clean in place) systems to ensure cleanliness between batches and operator safety during any dismantling operation. The ultra-fine grinding system consists of an enclosed drum-tipping section for the unloading of the primary coarse product; a state-of-the-art classifier milling unit, and a final fill/weigh packing system for the end milled product. Each of the drum-handling operations is carried out in special, purpose-designed negative pressure isolators where the requirements of the process equipment and operator activities were carefully considered. Each isolator unit was designed for optimum ergonomic accessibility for processing, cleaning and maintenance, and has its own internal CIP capability. Designed to maximise product manipulation while maintaining product isolation, the drum-tip unit is totally enclosed in a Stott isolator, achieving barrier containment levels down to 5µm3. Interlocked door access ensures that each compartment is secure during processing and that material from the drums is discharged into the next stage: the milling system.

Containment levels Working closely with the client engineers, Hosokawa Micron designed an integrated milling system with high containment Stott isolator units situated in a multi storey process area. System controls were integrated into existing control systems at their site, enabling monitoring of all critical process parameters for historic trend analysis. The containment philosophy allows operation in dual mode, with laminar flow achieving operator exposure levels of 10µm3, and full isolation achieving containment levels below 5µm3. Through close partnership with the end user, Hosokawa Micron engineered a flexible solution to meet their business demands, and this relationship continues as new products are brought into the manufacturing plant. The containment division of Hosokawa Micron supplied a high-tech Vitalair Downflow Booth to QinetiQ Nanomaterials, based in Farnborough, Hampshire. Installed in its nanopowder production facility, it is thought to be one of the first installations of its kind in this revolutionary field. Nanomaterial technology is an exciting field at the forefront of powder and particle science and has applications in fields as far apart as aero technology and medicine. The Downflow Booth forms part of the powder handling system for QinetiQ Nanomaterials, and according to Dr A J Shakesheff of QinetiQ Nanomaterials, "enables powders to be handled in a safe manner in a semi-enclosed environment and prevents release of powders into the rest of the production facility." The booth fully conforms to cGMP and FDA manufacturing standards, with flush internal and external panel construction designed to minimise crevices and facilitate easy cleaning. Designed in the downdraft, recirculating airflow format with vertical laminar airflow having approximately 600 air changes per hour, the Downflow Booth provides a safe operator environment; essential in nanomaterial production. To handle these particular powders, the booth layout was designed and engineered to have an external fan/filter plenum incorporating explosion relief venting.

Operational flexibility The Downflow Booth also contains a sink and static/mobile work benches with an overhead-mounted, sliding, clear poly-carbonate screen for additional operator protection while handling powders to very high containment level. "Our choice of supplier was heavily influenced by Hosokawa Micron's experience with powder handling, and expertise in the design of laminar flow booths," said Dr Shakesheff. Companies operating in the wet processing field of chemical synthesis now have access to innovative, specialist, wet processing, barrier containment systems when looking to safeguard personnel from potentially hazardous substances. Hosokawa Micron's containment division recently developed wet chemistry isolator technology in conjunction with a leading custom synthesis company. Designed to enclose a fully assembled and operational small-scale bulk active pharmaceutical manufacturing plant – including reaction vessel, crystallisation equipment and filtration vessels – the isolators give easy but contained operator access for product input, product removal, operational adjustment and maintenance. The new Stott isolator has been developed in response to health and safety concerns for personnel working directly with the liquid forms of increasingly concentrated active, toxic ingredients used in pharma production. For r&d projects or for companies manufacturing small product quantities of pharmaceutical or other potent products, the isolator offers flexibility of operation, product integrity and personnel protection of the highest level. The single chamber isolator offers two modes of operation: an isolator mode providing Operator Exposure Levels of <1mcg/m>= 8hr TWA; and an airflow mode to provide, by the use of inflow air velocity through the doors, an Operator Exposure Level of <200mcg/m>= 8hr TWA. As an additional safety feature, because solvents are used in the process, the isolator is designed to ensure that any solvent vapour concentration remains below the lower explosion limit (LEL) Within the isolator are shelves and dishes to retain small process components, cannisters, batch reagents or other products, which precludes the need for open door access for most operator process intervention. Plant equipment is assembled via the open front doors, and the picture shows a typical equipment arrangement. All process services are piped to the isolator and connected outside the isolator, which is fully equipped with spray balls and lance for complete CIP operation with the cleaning liquid fully discharged to drain. Custom and fine chemical specialist manufacturer Eastman Company (UK) Peboc Division, located in Anglesey, Wales, needed a flexible containment solution to cope with the varied and changeable demands in reactor charging operations; Hosokawa Containment was able to provide containment booths, purpose-built around the reactor charging vessels. Offering Eastman's customers a wide range of specialised organic intermediates and a confidential cGMP custom synthesis of substances for the pharmaceutical industry, the Anglesey site has the facilities for multipurpose pilot plant or batch production. It was therefore critical that any reactor charging containment system was suitable for handling a wide variety of substances and offered good levels of protection to the personnel, the product and the surrounding environment, in order to prevent potential cross contamination of products. The single pass booth was designed by Vitalair in conjuction with Eastman to fit around the charging vessel, creating a seal between the vessel and the wall of the booth. It was not necessary to contain the whole of the reactor vessel, but rather to contain the actual process of reactor charging, which meant that only the reactor opening needed to be within the containment area.

Associated problems Drums are transported into the reactor charging booth along a roller track, the height of which can be adjusted to accommodate containers of different sizes. The drums are manually lifted from the conveyor, opened and presented to the reactor vessel for tipping and emptying. To allow the operator to wash down personal protective suiting prior to leaving the contained area, thus preventing cross transfer of chemical products outside the booth, a safety shower is located within an adjoining cubicle and accessed through self-closing personnel doors. "Hosokawa's ability to work as part of a team and to work with changes was a key factor in choosing them as the preferred supplier for this particular installation," said Stephan Fell, principal chemical engineer at the Peboc Division of Eastman. Another isolator was initiated because of increased awareness of the potential long-term problems associated with respiratory sensitisation – caused by operator exposure to enzymes, proteins and dust within food manufacturing. This led Hosokawa Containment to develop a range of powder handling equipment, specifically designed to ensure personnel protection. Inhaled dust particles can cause an allergic reaction either in the nasal passages or lungs, resulting in respiratory sensitisation. For example, 'bakers' asthma' is a health hazard induced by wheat flour allergies, but the general growth in the use of enzymes and protein additives in food production is likely to increase the risk of exposure.

Exposure levels While all employers have a duty of care and responsibility for their personnel, many underestimate the dangers present in the handling of dry powders in the food industry. Powders that are safe to eat once processed may pose a respirable threat to personnel in their raw state. Exposure levels for some enzymes and flours/proteins are in fact already in place for food processors. Limited operator contact with particular powders, and personnel being moved from handling process to handling process to eliminate repeated exposure are becoming more common, often disrupting production. For powder handling applications where a minimum 99.997% filtration performance and very low exposure levels are required, Vitalair downflow recirculation booth systems can be supplied. Dust particles are captured by a downflow piston of air and pushed away from the person's breathing zone. They are then drawn through the three-stage filtration system before being recirculated into the booth.

Bespoke design Suitable for product dispensing, sampling, weighing and mixing, Big Bag stations and bulk powder discharge operations, Vitalair recirculation downflow facilities are available in both standard and non-standards layouts and sizes, can be designed to specific customer requirements, and can be fitted with ventilated benches, contained work zones, equipment cupboards and computer consoles. The need for a special contamination-free 'white area' to protect pharmaceutical formulations and staff at a key French development facility has been met by a purpose-built turnkey solution from Hosokawa Containment. Schering-Plough research centre in Dardilly, France, received an official recommendation from the French medicinal agency (Agence du Medicament), requiring raw material weighing operations to be carried out in a separate, purpose-designed weighing area. Hosokawa developed a self-contained stand-alone facility for location in Schering-Plough's warehouse. The innovative solution, developed in conjunction with the pharmaceutical group, centres on a high-specification vertical downflow recirculation booth – a high- containment working area where a sophisticated air recirculation system ensures that air flows from ceiling to floor – pushing any chemical dust downward, away from the operator's breathing zone. Purged air is then passed through primary and secondary filters before third stage filtration through an EU13 HEPA filter prior to recirculation. The system provides around 700 volume air changes per hour. Chiller and heater controls are incorporated in the design to provide a comfortable air-conditioned working environment for staff, who are required to wear full cleanroom protective workwear. The non-standard installation is unusual in having two entry airlocks – one for personnel changing and one for raw material de-dusting – providing a further guard against cross-contamination as well as safeguarding the health and safety of staff. The air in the entry airlock undergoes separate two-stage filtration, passing through a primary filter and HEPA filter before recirculation. The bespoke design of the isolator and airlocks was developed to a brief from Schering-Plough detailing scope of work, required work surfaces, working practices and cross-contamination concerns. Schering-Plough specified a white epoxy finish for the airlocks, while brush-finished stainless steel was chosen for the interior of the booth. The unit has an exterior height of 2.7 metres with an inside working height of 2.0 metres and working area 2.6 metres wide by 1.8 metres deep. The Vitalair plug-and-go facility, which can be easily relocated, is used by 10 of the centre's 40 staff for raw material weighing by the formulation group, and for goods sampling by the quality control section. The development facility is involved in the manufacturing supply and packaging of clinical batches; formulation and process development; process improvement, and the production of stability batches. Throughout all processes, both staff and product require the optimum safeguards against contamination.

Successful trials Prior to commissioning, the installation was fully assembled for certification and warranty testing at Hosokawa's facility in Elland, West Yorkshire, UK, with Schering-Plough personnel present. After successful trials the installation was shipped to France for assembly by a Vitalair team and was followed by commissioning, which included further certification testing The pan-European contract for Hosokawa Containment followed earlier successful installations at several of Schering-Plough's facilities, including Mexico and Brazil.