DOSAGE FORMS

50 manufacturing chemist March 2016

Demand is growing steadilyworldwide for innovative forms of drugdelivery. Multiple unit pellet systems(MUPS) are a dosage form consisting ofcoated API pellets, which are mixed withmicrocrystalline cellulose and pressedinto tablets. Their main characteristic isthe controlled release of the activeingredient, which is achieved by applyinga functional coating to the pellets. Thedrug is absorbed in the intestine once thetablets have dissolved in the stomach.

Since the tiny pellets pass through thedigestive cavity rapidly and unhindered,MUPS tablets do not have to be taken onan empty stomach. They can also behalved without losing their therapeuticefficacy. Cutting the tablets in two doesnot damage the sustained-release coatingof the micropellets. All of these criteriahelp to improve patient compliance.

The demand for MUPS formulationshas risen steadily over the past few years.Swiss pharmaceutical manufacturerAcino, a specialist in the development

and production of complex galenicformulations with its headquarters inAesch, was among the first to recognisethis trend and position itself accordingly.

‘Acino specialised in the manufactureof MUPS tablets over a decade ago,’ saysChristophe Dohr, PharmaceuticalProduction Head at Acino Pharma’sLiesberg production facility, locatedsouth of Basel, surrounded by themountains of the Swiss Jura. ‘The highlycomplex production process has beencontinuously improved ever since andwe’re now in a comfortable situationwhere we can deliver premium quality atattractive unit costs.’

The manufacture of pharmaceuticalsolids with delayed API release is one ofthe Liesberg plant’s core competencies.Around 1.5 billion tablets and capsulescurrently leave the factory every year. ‘Inspite of this, our capacities here are notyet exhausted and our internationaltarget markets in Europe, the MiddleEast, Africa, Latin America, Russia and

the CIS are growing at exponentialrates,’ says Dohr. ‘That’s why we’replanning to double our volumes in themedium term.’

Acino Pharma employs some 110 staffin Liesberg, with production in threeshifts, five days a week. The majority ofthe output is destined for licensees inSwitzerland and worldwide. Acino’sportfolio at the Liesberg site comprisesoral drugs for treating cardiovasculardisorders and Parkinson’s disease, as wellas various narcotic substances. MUPStablets account for more than 90% of allpellet batches.

Before being pressed into tablets, thepellets undergo a two-stage coatingprocess. Neutral pellets made fromglucose are used as starter particles. Inthe first step, the APIs are applied onelayer at a time, followed by the sustained-release coating. This complex processtakes several days, during which thediameter of the pellets increases fromaround 300µm to 1,000µm.

Kai Koch, Engineering Manager, Romaco Innojet, discusses how the company’s Ventilusequipment has helped Swiss pharma manufacturer Acino grow its innovative dosage forms business

Taking control of coating technology

During the productionof multiple unit pelletsystems (MUPS)coated API pellets arebuilt up using air flowbed technology

DOSAGE FORMS

Since 2004, Acino has used the air flowbed technology originally developed andinternationally patented by Dr h.c.Herbert Hüttlin to build up these pellets.Five Romaco Innojet productionmachines in the Ventilus series areinstalled at the Liesberg facility togetherwith a pilot system of the same type,which is used for R&D. The productionscale machines have a capacity of 800litres and are designed to handle batchesweighing up to about 600kg.

Despite its physical size the technologysaves valuable space on the productionfloor. ‘The air flow bed unites all theprocesses which are necessary to build upAPI pellets and granulates in onesystem,’ says Michael Tewelde, TeamExpert Granulation, Acino Pharma.‘Alternative technologies would need amuch bigger footprint, not to mentionthe additional storage capacity.’

The process air used for the air flowbed is controlled by the special booster –an ingenious container bottom consistingof overlapping circular plates. Thehomogeneous flow conditions this createsresult in a spiral, orbital product flow.The process air causes the pellets tohover, so that gentle intermixing isguaranteed and particle collisions orfriction are avoided. The speed of thepellets and the distance travelled areclearly defined. The evaporation rate cantherefore be calculated precisely and thedose rate adapted to match.

The coating material is sprayed intothe product from below by a centralbottom spray nozzle. This nozzle isdesigned with a rotating spray head,which prevents the annular spraying gapfrom becoming blocked. The gap has anadjustable width, enabling the dropletsize to be varied. In addition, the sprayangle can be set exactly by means of thespraying and support air and there isvirtually no measurable spray loss.

The pellets pass through the liquid filmregularly. Before the next coating isapplied, they must be sufficiently dry forthe product not to be over-wetted. Thespray rate can be adjusted to rule outunwanted agglomeration due to thecarrier dissolving.

‘The Ventilus technology lets usregulate moisture extraction absolutelyaccurately; that way, the pellets are builtup homogeneously with only a very smallstandard deviation,’ Tewelde continues.‘They’re spot on in terms of quality andprocess efficiency.’ The selectiveapplication of the suspension has led to a10–15% reduction in Acino’sconsumption of raw materials andcoating, saving further time and money.

Acino has an in-house test laboratoryin Liesberg with air flow bed systems for

March 2016 manufacturing chemist 51

laboratory and pilot trials. Manycustomers take advantage of thisopportunity to test their formulationsduring the development phase. Scale-upsfrom pilot to production are a regularevent there on a Ventilus V 200.

Video cameras that show the productmovement directly on a screen areinstalled in all Innojet systems to permitthe coating processes to be monitored.The operator can thus keep a close watchon the batch process at all times andintervene immediately if necessary. Andfor interested customers, it is a uniquechance to see the MUPS coatingtechnology live in action.

CONTACTRomaco Group Am Heegwald 11 76227 Karlsruhe, Germany T +49 (0)721 4804 0 info@romaco.com www.romaco.com

Top right: RomacoInnojet Ventilus V 800processing machine inaction at Acino Pharmain Liesberg, Switzerland

Centre: The centralbottom spray nozzle andannular spraying gap

Bottom: The AcinoPharma productionfacility in Liesberg,Switzerland