Taking up the challenge

The trend for the pharmaceutical industry to use isolator technology to minimise the risk of microbiological and particulate contamination, enhance the assurance of product integrity during product handling and minimise the direct human contact with toxic or hazardous compounds is well established. However the demands of performance, efficiency and reliability have lead to an increase in the progress of total containment where materials are isolated throughout the entire process. Leading the way in the design of contained process systems, Hosokawa Micron works in partnership with blue chip pharmaceutical manufacturers worldwide to develop unique processing solutions using equipment such as mills and dryers which challenge the traditional way we think about process containment. Traditional methods of process containment and operator protection centre around the use of a mixture of designated cleanroom and personnel protective equipment (PPE). By this method the entire room, in which any kind of process that might release material to atmosphere is taking place, is sealed off. Airlocks are used to maintain containment integrity as PPE-wearing operators enter or leave the room. These methods are employed not only during processing operations but also when equipment is opened for cleaning between batches and maintenance.

Weighing up the processes As all process engineers in the pharmaceutical industry will be aware that these methods are time consuming and expensive in operation with the inherent risk of human error if procedures are not correctly followed. Add to this the pressure to compress the 'time to market' for new pharmaceuticals and the process engineer's challenge is laid bare. The most perfect scenario must surely be that personnel operate equipment in regular clothing, without the need for restrictive PPE, that machines are cleaned in a contained environment without any areas being opened up to the atmosphere and that automated processing and cleaning operations minimise the risk of unfulfilled operating procedures due to human error. It is this scenario that major pharmaceutical manufactures aim to emulate in a practical, cost-effective and productive way, creating an increasingly demanding challenge as OELs decrease and materials become more complex and potent. The challenge can be illustrated by the complex chain of demands and the resulting search for production innovation and leading edge technology by a leading pharmaceutical manufacturer and pharmaceutical process system integrator. Astra Zeneca is one of the world's leading pharmaceutical companies, manufacturing a powerful range of products designed to fight disease in important areas of medical need: cancer, cardiovascular, central nervous system, gastrointestinal, infection, pain control and respiratory. Spending more than £7m each working day on research and development, AstraZeneca has a culture of product and technology innovation. Its commitment to the well-being of its employees is also of paramount importance to the company. AstraZeneca's John Sherwood, associate principal scientist, Product Development Pharmaceutical Analytical R&D at its Macclesfield site, comments: "We are always looking at the opportunities for product, process and environmental improvement with our personnel a key factor in the determination of new technology both in terms of technical input and health and safety. AstraZeneca has total commitment to meet or exceed legal requirements and international agreements in respect of Heath and Safety and Environment and to provide a safe and healthy work environment for all our employees." Hosokawa Micron is a specialist in powder and particle technology, providing equipment and process solutions to the pharmaceutical, chemical, mineral and food industries. "Hosokawa Micron has extensive experience and expertise in the design and build of equipment and complete powder processing systems for the pharmaceutical industry and has the full R&D and test resources of our worldwide group to ensure that customers' specifications are met. "Our philosophy is one of working in partnership with our customers to tailor solutions and develop new technologies as appropriate. In this particular case the brief was extremely demanding but opened up opportunities to further develop process technologies for tomorrow," says Andrew McLeish, pharmaceutical director, Powder and Particle Processing Division, Hosokawa Micron. "The challenge of contained micronisation of a potent compound to exacting particle size distribution while maintaining ultra low OELs meant a total rethink of existing equipment and radical redesign of substantial elements of that equipment to meet the demands of the customer," he adds.

The challenge 1. To micronise a highly potent pharmaceutical compound 2. Achieve a particle size distribution (PSD) of below 5µ 3. Maintain an OEL of 0.005mg/m3 during processing, cleaning and maintenance 4. To effect minimal post processing losses 5. To integrate the process equipment into a contained environment for optimal performance and space saving demands 6. Maintain continual real time analysis of particle size distribution (PSD), yield figures and material management for increased control of the plant and batch records 7. Provide a safe plant through pressure shock resistant, explosion protection equipment 8. Provide a safe/pleasant working environment 9. Atttain GMP standards.

"AstraZeneca is never satisfied with existing performance parameters and off-the-shelf solutions but is constantly seeking pioneering technology, which improves the process, the way our staff operate and their working environment. That often means going right back to square one or even thinking outside the square to make the step changes necessary that take us to the forefront of pharmaceutical production. Individually our demands are complex, but combined together, we appreciate that we are pushing back the boundaries of technology," says Sherwood. The project challenge required clear definition of all the customer demands with each demand being considered in isolation and also as part of the whole project as each criteria impacted down the demand chain. The creation of a single project team which brought together key engineers from Hosokawa Micron, Stott, Vitalair and Alpine together with engineers from AstraZeneca was instrumental in achieving accurate equipment specification, total redesign of key equipment, integrated systems and ergonomic designs to meet all criteria. 'The development partnership we created allowed an open exchange of information with all parties focused on achieving a practical solution to the demands of the project. This allowed for changing requirements and the opportunity to develop particular areas of the process line over and above our initial specification, creating a design for the future," says Sherwood. "There are so many totally innovative aspects to this process that it is difficult to define the step changes we have made. I think it would be fair to say that the interaction of AstraZeneca and Hosokawa has created a catalyst for truly innovative design and manufacture with many technological developments which we can take forward into other future installations," he adds.

Powder feeding Drums containing purified product are presented to a Hosokawa Stott four-chamber glove box for emptying into a hopper from which the powder is fed into a screw feeder. This discharges by way of a rotary valve into the AFG 200 fluid bed microniser, which is built to withstand a pressure shock of 10 bar for safety reasons. Milled product is collected by a reverse jet filter. The product stream is discharged from the reverse jet filter to a rotary valve with continuous product sampling taking place before product drops through into a double lined keg. Kegs are weighed on three separate scales for tare weight, full and gross weight. SCADA monitoring systems operate throughout the process ensuring complete and accurate control of the plant at all times with associated validation documentation prepared. From the chain of demands, six separate areas can be identified as critical in terms of containment levels. Evaluation of the design shows how these have been addressed and the success of each solution. 1. Drum emptying is protected by the quad cell drum tipping system. On entering chamber one the drum lid is removed and the drum automatically tipped to allow the bag to be placed into chamber two. Chamber two is sealed behind the bag. The door into chamber three is opened. The bag passes into the chamber where it is cut open and the contents fall into a feed hopper. The bag is discharged into chamber four for disposal.

Dust contained An internal air velocity of 0.5m/sec between each compartment and outer loading door was adopted, which assisted in maintaining containment of airborne dust and powder migration. A glove breach velocity of 0.7m/sec (one glove removed) was allowed for, and extraction for the unit was controlled via modulating pneumatic butterfly valves. The main compartment for liner opening had an internal extraction drawing air through an intake filter in the roof. This helped suppress any dust clouds and reduced powder covering the front viewing panel. The dust-laden air was pulled through a bag filter and collected. This bag filter was periodically shaken via a pneumatic unit to recover the product into the process. 2. Blockages can occur in feeding systems where cohesive pharmaceutical powders are handled, with the problems of leakage over a long campaign and cleaning difficulties also present. The feeder inlet and outlet rotary valves were therefore specially designed to operate within a glove box to provide a contained environment to meet all specifications. To ensure a practical and ergonomic design and smooth interface of equipment a complete wooden mock up was produced before production of equipment commenced. This enabled AstraZeneca personnel to thoroughly test the ergonomic design and recommend changes highlighted in the trial. 3. The critical requirement for the design of the equipment to provide for 8 hourTWA OELs below 0.005mg/m3 meant that the micronising system had to be totally contained. In order to create a practical, space saving containment solution the mill was redesigned to fit into an isolator rather than the isolator designed to fit round the mill. With high classifier rotor speeds creating their own challenges regarding noise, vibration and safety within the workspace combined with the actual 600kg weight of the monobloc design mill. The design solution demanded an innovative design of isolator too. 4. The filter was designed for wet-in-place cleaning. This reduced the airborne risk of contamination allowing personnel to operate with PPE. The filter incorporated a pneumatic vibrator on the conical bottom section to assist in dry cleaning and increase product recovery prior to WIP. 5. Both inlet and outlet rotary valves were totally redesigned in monobloc stainless steel to create defect free internals, crevice free construction and polished exterior to permit CIP and ensure low residence of product. Rotary valves incorporated specially designed shaft seals, which created a sound interface between mechanical and isolation equipment. Gas purge, leakage monitors and position indicators to check rotor pockets are empty before the valve is opened were all included in the new design. 6. Collection and sampling is undertaken within the specially designed, integrated isolator and downflow booth. Drums enter the Stott drum filling isolator on a roller track, which transfers them to the filling and weighing station. Designed as an integral part of the isolator, the Stott vacuum sealed filling head provides dust-free filling of the lined drums which are filled on a gain-in-weight scale base for accurate fill control. Within the sealing head an internal filter reduced product carry over into the extraction ducting. This filter was a reverse jet design allowing the product captured to be recovered into the next drum. An in-line retracting auto-sampler enables product monitoring without direct operator intervention. Once filled and tied the lined drums are transferred to the Vitalair downflow booth, which is joined to the side of the isolator, for lidding and wiping to remove any trace of toxic material before preparation for storage or transportation.

Partnership for success "Tests carried out when the plant was in full operation indicated operator exposure levels well below those of 0.005mg/m3, which was the target. Containment performance of this plant has exceeded our expectations," says Sherwood. McLeish concludes: "The containment demands of AstraZeneca for this plant have been achieved through a combination of traditional expertise in design and manufacture along with the innovative design capability, which is typical of Hosokawa Micron's commitment to powder and particle processing technology. "Both parties however agree that it is the unique partnership, between Hosokawa Micron and AstraZeneca, built on trust, which remains the defining or critical factor in the success of this installation."