An innovative MUPS tablet production line has been developed that eliminates segregation and significantly increases process yield.

Producing Multiple Unit Pellet System Tablets

Producing Multiple Unit Pellet System (MUPS) tablets using conventional bin blending to feed a tablet press is reported by many pharmaceutical manufacturers to pose significant challenges regarding process yield, productivity and batch content uniformity. Because MUPS blends are susceptible to particle segregation, a new production system has been developed that eliminates these manufacturing inefficiencies and product quality risks.

What is MUPS?

MUPS is a pharmaceutical solid dosage form produced by compressing a mixture of drug-containing pellets and powder excipients (Figure 1). The pellets have a spherical core that contains or is coated with the active ingredient, and have one or more protective layers to control drug release. The powder phase typically comprises a pre-mix, containing components such as fillers, binders, lubricants and a disintegrant. The pellets in a MUPS formulation have a mass percentage from 20 to 70% and range in size from 300 to 2000 µm, whereas the excipients are typically smaller than 200 µm. Thus, MUPS formulations can behave very differently regarding flowability, compressibility and risk of segregation depending on the concentration and size of the pellets.

The MUPS Compression Challenge

The particle size of the powder phase excipients is typically between 50 and 200 µm. Moreover, the bulk density of the pellet phase is generally greater than 0.7 g/cm3, whereas the density of the excipient mixture is 0.4–0.6 g/cm3. These significant differences in average particle size and density make a MUPS mixture extremely sensitive to segregation. It is, therefore, vital to maintain blend uniformity during storage, transport and feeding of the MUPS formulation into the tablet press, right up to when the blend is fed into the dies for compression. If segregation occurs during transfer, tablets could be produced with an out-of-specification (OOS) pellet concentration and, hence, an OOS API content. The content uniformity of the produced batch would subsequently fail quality assurance checks and the batch would need to be rejected.

Classic Production Method

MUPS formulations are typically prepared by dry blending the pellets and excipients in a bin blender and discharging the mixture into a drum or IBC. The IBC is then transported to a storage area or immediately transferred to the compression room. The container is lifted above the tablet press and its outlet chute is connected to the inlet of the tablet press. During these procedures, percolation segregation and heap segregation might occur inside the container as a result of vibration and gravity. Therefore, blend uniformity inside the container cannot, in many cases, be guaranteed.

When the container discharge valve is opened, the MUPS formulation drops into the tablet press feed chute and paddle feeder. Elutriation segregation will occur during the descent and, furthermore, if the IBC is not properly vented, this type of segregation will also occur inside the IBC owing to air movement through the blend bed. These multiple occurrences of segregation often result in severe blend composition variations within the batch and, as a consequence, the pellet content of the resulting tablets will vary significantly. This means that during the compression process, large quantities of OOS tablets are produced (mainly, but not limited to, the beginning and the end of the batch).

Unfortunately, during the compression process, it is not possible to detect whether the pellet content of a tablet is within specification or not. This means that OOS tablets cannot be identified and rejected by the tablet press. Historically, these limitations have been dealt with by

  • rejecting a fixed amount of tablets at the beginning and end of the batch — up to 15% in some cases
  • more frequent tablet sampling and API analysis to assess batch uniformity. If too many tablets fail the analysis, the entire batch is rejected.

Clearly, this is a wasteful production method that results in poor productivity and poor yields. Moreover, there is a significant quality risk linked to releasing OOS batches.

An Innovative Solution

To increase process yield and guarantee tablet quality, an innovative new MUPS production method — a continuous dosing, blending and compression system — has been developed that eliminates these production inefficiencies and product quality risks. Segregation is kept to an absolute minimum and online process monitoring detects OOS tablets.

Two loss-in-weight screw feeders, either gravimetric or vacuum fed, are installed above the tablet press; one feeds the pellets and the other feeds the premixed excipients. The type and configuration of the feeders can be adapted to the characteristics of the pellet or powder phase and fine-tuned for particular applications. Both the pellets and excipients are continuously fed via drop chutes into a conical ribbon blender above the tablet press, which mixes the two product streams into one uniform MUPS formulation stream that feeds the tablet press. The fill level of the blender is accurately controlled as it determines the residence time in the blender and hence the blending time.

The conical blender is installed directly above the tablet press inlet to minimize the transfer distance between blending and compression and reduce the risk of segregation to an absolute minimum. The transfer tube  from the blender to the tablet press feed frame measures approximately 60 cm and could induce segregation if it was directly connected to the paddle feeder. To avoid this, a special valve was developed to ensure “plug flow” via a vertical powder feed tube: the powder dosing valve or PDV. The PDV is mounted just above the paddle feeder inlet and driven by a separate electromotor. Finally, the design of the feeder base plate and paddle wheel has been modified to avoid segregation, as well as pellet damage, in the feed frame.

Enhanced Process Yield and Content Uniformity

The continuous dosing-blending-compression system has been developed, built and extensively tested in collaboration with a leading pharmaceutical company. The results were significant:

  • stable content uniformity throughout the entire batch, decreasing the risk of batch rejection
  • start-up losses were reduced by a factor of 3 (from 15% down to 5%), and further reduction possibilities have been identified
  • process stop and restart without any product losses
  • accurately controlled end-of-batch with minimal product loss
  • the GEA Dual Control system detects and rejects tablets with an increased risk of OOS pellet content.

The system is further enhanced with an integrated “Dual Control” system that measures two quality parameters for each tablet (thickness variations under constant pre-compression force and peak force at main compression) as opposed to a single parameter (peak force at main compression) in conventional presses. By measuring and combining these two signals, tablets with a deviating pellet concentration can be detected. The system can’t actually predict the pellet concentration, but it can detect tablets with an increased risk of OOS pellet content. Such tablets can then be rejected, which significantly reduces the risk of producing a batch that does not meet content uniformity criteria. The continuous dosing-blending-compression system is now available at GEA’s test facilities in Belgium, for customer product trials.