Contain the risks in powder dispensing

Powder and particle process technology expert Hosokawa Micron and AstraZeneca, one of the world’s leading pharmaceutical companies, have completed the installation and commissioning at one of its major manufacturing sites of an integrated powder dispensary for accurate weighing and blending of high volume drug formulations.

Anticipating growth in a number of its therapeutic products, AstraZeneca decided to look at developing a new approach to the automation of dispensing for dry ingredients going into tablet formulation. Active ingredient in the formulation is potent and would normally require use of Personal Protective Equipment (PPE) for a manual weighing activity.

The challenge addressed by the Hosokawa Micron design group, working in technical partnership with AstraZeneca, was to design a high accuracy dispensing system to a specified accuracy of ±1.0%, with full batch reconciliation for large volume pharmaceutical products, removing the previous restrictive practice of wearing PPE.

The completed dispensary has produced a considerable number of production batches and weighing accuracy is always better than 1.0% and generally around 0.3%. Operator exposure levels are regularly monitored, confirming the containment specifications have been achieved.

The control philosophy was to design an integrated control system that would allow operation of the plant using automatic sequencing, ensuring safe operation. During operation the system monitors, controls, records and displays critical machine and process conditions.

Where operator involvement is necessary, operator safety is paramount and the system has been designed with high levels of containment down to 5µg/m3 in areas of product handling such as drum tipping and the product discharge/fill/weigh.

Before any processing can begin, a recipe is selected. This writes the process values to the system unique to each recipe controlling feed rates, drive speeds and fill levels of the processing equipment and vessels. Once the recipe has been selected the system will assess the levels of the required excipients and will indicate the required quantities.

Charging of the excipients takes place within two Hosokawa containment down flow booths. Within each booth there are two conveying systems each dedicated to a single excipient. An excipient keg is presented for identification via a barcode reader.

The pneumatic conveying system can be operated only when the excipient has been successfully identified. Once this has been done the transfer route is automatically established and the powder is transferred via a dedicated suction lance, through a vacuum sifter, into the buffer storage hopper. A seal developed by the Hosokawa commissioning engineer in discussion with AstraZeneca replaced the original seals supplied by the manufacturer of the transfer system. This improved seal provided a clean surface flush with the internal circumference of the transfer lines, increasing cleaning efficiency.

A single blower acting as prime mover for the two conveying lines in each booth ensures that only one excipient can be charged from the down flow booth at any one time. In addition the buffer hoppers are sized to ensure that when material is requested by the system there is sufficient capacity to accept a full container. This ensures that no part drums are stored within the booth, a further safeguard against possible operational in-feed errors.

At the initial start-up a number of batches are transferred for dispensing. Charging of active ingredient to the dispensing system takes place inside a two compartment active isolator with a demonstrated containment level better than 5µg/m3.

Again, barcode reading of the product keg is required before the drum tipping system is allowed to proceed. The drum is placed into compartment one and the pneumatically actuated doors and inflatable seal ensure this compartment is isolated from the room environment. The inner door is then opened to allow access to the discharge compartment. The open drum is manipulated into the discharge position and the active removed from the drum within its enclosed liner. Interlocking between the compartment doors ensures reverse migration of powder is avoided.

Once the discharge compartment is sealed, material identification can be conducted. The system has the capability to use Near Infra-Red (NIR) in the future, as well as the current barcode for material identification. With the NIR recognition system a probe is inserted into the active within the isolator and a spectral analysis carried out.

Once the bar code information and the spectral analysis are in agreement, transfer of the active ingredient to the system is allowed to proceed. The active is discharged into the dispensary and the waste liner removed from the contaminated compartment through a used bag posting port. The integrity of the negative pressure isolator is monitored and the differential pressure between compartments maintained through the use of an inverter controlled variable speed fan.

In the unlikely event that the active spectrum is not recognised, the powder still contained within the liner is removed via a product rejection port. Containment levels are maintained during all operations.

Once the control system confirms that all ingredients are filled within the dispensary to the required levels and all system components are in place, automatic dispensing of the ingredients commences. A controlled percentage of the powders held in the buffer hopper is discharged into the loss-in-weight screw feeders.

Excipient discharge is controlled by a number of active loss-in-weight feeders, operating simultaneously, which dispense at a predetermined feed rate to achieve the target weight set by the recipe. The challenge of the high degree of accuracy required at this stage in the dispensary was achieved by a combination of level control, charging control and air balance across the feeders.

Active and an additional single excipient is dispensed through continuous loss-in-weight into the Hosokawa pharmaceutical mixer PM150, where combination and a degree of particle adhesion occurs. This ensures correct dispersion and consistent product flow.

This PM150 machine was extensively modified following trials with placebo materials and detailed design discussions with the AstraZeneca project manager. Purge seals were included to remove the possibility of leakage of ingredients into the surrounding areas. The intermediate orifice extrusion plates were removed from inside the machine and the rotor and static anvils redesigned to compensate and provide the necessary level of back mixing. The standard rotor shaft was replaced with a “fat shaft” design to reduce the mixing chamber capacity and as a result reduce the heel of material remaining within the body.

All products are then combined in a gravity stream before passing through a final stage cone mill. The cone mill serves to give a final stage agitation and blend of the products to guarantee homogeneity of the powder blend. Where the recipe dictates this final stage can be bypassed and the converging products dispensed directly into bulk containers.

Powder is collected into the bulk containers and the combined final weights monitored. Once these quantities have been attained the feeders are automatically stopped and the final bulk weight verified against the dispensed quantities.

Product enters the bulk container through a high containment split wafer valve equipped with vacuum purges. This again ensures that containment levels are maintained as the final blend is transferred to the next stage of the tabletting process.

Recharging of the excipients and active ingredients is allowed to take place only once the last batch of material has been charged into the feeders.

By using proven communications technology it was possible to reduce the field cabling and at the same time deliver more information to the point of use. This was displayed within the processing area on interactive touch screen operator interface panels located close to the excipient downflow booths and the active ingredients isolator. Each was connected to a PLC located together with the MCC control panel in a safe area technical space. Provision for a modem link to the SCADA and PLC gives the capability for remote technical support while maintaining a high level of security by removing the modem cable. When the processor is in run mode, access to carry out any changes by a remote user is inhibited.

The entire process has been designed for a full Clean In Place (CIP) using water and detergent washes. A complete CIP skid incorporating automated washing and drying cycles was provided; the system includes pressure-activated spray balls, which do not penetrate into the powder stream during normal operation. Key components are dismantleable for inspection and verification of cleanliness.

Again with safety as a priority, a dedicated control system to monitor the earthing of all removable parts of the dispensary was incorporated. This proprietary system continuously checks for consistent earth connections across the whole process. In addition to preventing the process start-up in the event of failure of the earthing integrity, it will indicate the location of any connections that do not give continuity of earth on reassembly. This method of monitoring proves that the path to earth is through the desired equipment and not, as is sometimes the case, through accidental and spurious earth against other plant items

Areas where operator safety could have been compromised by the quick removal of plant items were protected by the use of proprietary safety devices connected to high integrity safety relays through dedicated hard-wired safety circuits.

The plant has now achieved operational qualification, with Hosokawa and AstraZeneca having worked in close partnership from inception of the design through all stages to the fully commissioned process.