Demand is growing steadily worldwide for innovative forms of drug delivery. Multiple unit pellet systems (MUPS) are a dosage form consisting of coated API pellets, which are mixed with microcrystalline cellulose and pressed into tablets. Their main characteristic is the controlled release of the active ingredient, which is achieved by applying a functional coating to the pellets. The medication is absorbed in the intestine once the tablets have dissolved in the stomach.
Since the tiny pellets pass through the digestive cavity rapidly and unhindered, MUPS tablets do not necessarily have to be taken on an empty stomach. They can also be halved without losing their therapeutic efficacy. Cutting the tablets in two does not damage the sustained-release coating of the micropellets. All of these criteria help improve patient compliance.
The demand for MUPS formulations has risen steadily in the last few years. Swiss pharmaceutical manufacturer Acino, a specialist in the development and production of complex galenic formulations with its headquarters in Aesch, was among the first to recognise this trend and position itself accordingly.
'Acino specialised in the manufacture of MUPS tablets over a decade ago,' says Christophe Dohr, Pharmaceutical Production Head at Acino Pharma's Liesberg production facility, located about twenty miles south of Basel, surrounded by the breath-taking backdrop of the mountains of the Swiss Jura. 'The highly complex production process has been continuously improved ever since and we’re now in a comfortable situation where we can deliver premium quality at attractive unit costs.'
The manufacture of pharmaceutical solids with delayed API release is one of the Liesberg plant’s core competencies. Around 1.5 billion tablets and capsules currently leave the factory every year. 'In spite of this, our capacities here are not yet exhausted and our international target markets in Europe, the Middle East, Africa, Latin America, Russia and the CIS are growing at exponential rates,' says Dohr. 'That’s why we’re planning to double our volumes in the medium term.'
Acino Pharma presently employs some 110 staff in Liesberg, with production in three shifts, five days a week. The majority of the output is destined for licensees both in Switzerland and worldwide. Acino’s portfolio at the Liesberg site comprises oral drugs for treating cardiovascular disorders and Parkinson’s disease as well as various narcotic substances. MUPS tablets form the mainstay of its business, accounting for more than 90% of all pellet batches.
Before being pressed into tablets, the pellets undergo a two-stage coating process in which their weight is more than doubled. Neutral pellets made from glucose are used as starter particles. In the first step, the active pharmaceutical ingredients are applied one layer at a time, followed by the sustained-release coating. This complex process takes several days, during which the diameter of the pellets increases from approximately 300μm to 1000μm.
The pellets are built up using the air flow bed technology
Since 2004, Acino has used the air flow bed technology originally developed and internationally patented by Dr h.c. Herbert Hüttlin to build up these pellets. Five Romaco Innojet production machines in the Ventilus series are installed at the Liesberg facility together with a pilot system of the same type, which is used for research and development. The production scale machines have a capacity of 800 litres and are designed to handle batches weighing up to about 600kg.
Despite its physical size the technology saves valuable space on the production floor. 'The air flow bed unites all the processes which are necessary to build up API pellets and granulates in one system,' confirms Michael Tewelde, Team Expert Granulation, Acino Pharma. 'Alternative technologies would need a much bigger footprint, not to mention the additional storage capacity.'
The central bottom spray nozzle and annular spraying gap
The process air used for the air flow bed is controlled by the special booster – an ingenious container bottom consisting of overlapping circular plates. The homogeneous flow conditions that are created in this way result in a spiral, orbital product flow. The process air causes the pellets to hover, so that gentle intermixing is guaranteed and particle collisions or friction are avoided.
The speed of the pellets and the distance travelled are clearly defined. The evaporation rate can therefore be calculated precisely and the dose rate adapted to match.
The coating material is sprayed into the product from below by a central bottom spray nozzle. This nozzle is designed with a rotating spray head, which prevents the annular spraying gap from becoming blocked. The gap has an adjustable width, enabling the droplet size to be varied. In addition, the spray angle can be set exactly by means of the spraying and support air and there is virtually no measurable spray loss.
The pellets pass through the liquid film regularly. Before the next coating is applied, they must be sufficiently dry for the product not to be over-wetted. The spray rate can be adjusted to rule out unwanted agglomeration due to the carrier dissolving.
Romaco Innojet Ventilus V 200
'The Ventilus technology lets us regulate moisture extraction absolutely accurately; that way, the pellets are built up homogeneously with only a very small standard deviation,' Tewelde continues. 'They’re spot on in terms of quality and process efficiency.' The selective application of the suspension has led to a 10-15% reduction in Acino’s consumption of raw materials and coating, saving further time and money.
Acino has an in-house test laboratory in Liesberg with air flow bed systems for laboratory and pilot trials. Many customers take advantage of this opportunity to test their formulations during the development phase. Scale-ups from pilot to production are a regular event there on a Ventilus V 200. Video cameras that show the product movement directly on a screen are installed in all Innojet systems to permit the coating processes to be monitored. The operator can thus keep a close watch on the batch process at all times and intervene immediately if necessary. And for interested customers, it’s a unique chance to see the MUPS coating technology live in action.
