Direct Compression Learn More About Direct Compression
The unmistakable trend towards the Conti process in pharmaceutical solid dosage production requires intelligent approaches. Continuous direct compression with Glatt’s Modcos system fulfills every wish for an economic and stable process. Continuous Direct Compression is a lean, effective and economic process.
Continuous technologies have started to gain widespread acceptance in pharmaceutical production since the FDA published their GMP Initiative for the 21st century in 2003.
The approaches for improving quality in pharmaceutical production propagated by both the FDA and the EMA encourage continuous manufacturing, particularly of solid dosage forms, where the advantages of this approach become clearly visible: reproducible quality, great versatility, high throughput and compact design. Pharmaceutical companies embarking on a journey towards continuous production are currently faced with a choice between three technological processes:
- continuous direct compression
- continuous roll compacting, and
- continuous wet granulation.
Glatt’s experience also shows a definite trend towards this production method: pharmaceutical companies currently favor continuous process solutions, particularly for new active substances. However, the suitability of a formulation must be precisely assessed before the choice for one of the three technical solutions is made. None of the listed processes can be seen as a panacea which prevents the manufacturer from encountering any of the possible difficulties of classical batch processing.
Continuous direct compression — lean, effective and economic process
However, the continuous process does offer verifiable advantages over the batch process in many cases. One particularly good example is the production of MUPS (Multiple Unit Pellet System) tablets — an innovative, controlled-release dosage form in which active substance pellets are mixed with excipients and compressed into tablets. Producing MUPS tablets in a conventional batch process is often fraught with problems, since the concentrations of premixes fluctuate due to the differing particle sizes of powder and pellets.
Trials carried out by Glatt prove that continuous direct compression has become a stable alternative to batch processing. Furthermore, continuous direct compression is considered to be a lean, effective and economic process, since it requires fewer steps than the often-used continuous wet granulation, which, for instance, requires an energy-intensive drying step.
Modular design creates advantages
Glatt’s Modcos Direct Compression System was developed to be a smart solution which is modularly configurable according to customer requirements. Starting with the dosing unit, the various powdered active substances and excipients are continuously and gravimetrically fed into one or several parallel mixers for subsequent continuous homogenization. The dosing units work according to the loss-in-weight principle, as this method compensates for any potential deviations in bulk density.
The dosing units’ storage containers, which are limited in size, are refilled with the help of automatic feeding stations, container loading systems or vacuum conveyor systems. A special control system compensates for any inaccuracies during the short refilling procedure and consequently guarantees that the feed rate always remains constant. A highly accurate dosing unit is vital to the reproducibility of the process. This is especially true for formulations with very low active substance content and active substances which are difficult to dose.
This is why Glatt has joined forces with Coperion K-Tron, a specialist in gravimetrical dosing technology with the required expertise. Requests are often made for between three and six different dosing units, specified for each excipient or active substance and according to the properties and feed rate of the product. Glatt has even developed concepts for special cases where up to ten dosing units synchronously feed two mixers in parallel.
Proven Mixer Quality
The Modcos Direct Compression concept required Glatt to develop an innovative mixer which was tested by Rutgers University, USA and found to be outstanding. The mixer allows for a variable positioning of the dosing devices, which provides greater flexibility to feeding. Additionally, the device can be modularly extended in two different directions, which allows a higher variability in the retention time for the powder to be mixed.
A specially-designed connection between the mixer discharge chute, the filling shoe and the tablet press prevents product segregation after the mixer discharge. The installation of an additional NIR controlling function directly in the tablet press, such as the functions offered by Glatt’s strategic partner Fette Compacting, is still nonetheless possible today.
PAT Technology for Reproducibility
Since the use of PAT technology is another prerequisite for the reproducibility of a process, an inline NIR sensor is installed in the mixer to continually measure the homogeneity and composition of the powder mix. By virtue of the plant’s short start-up and shutdown times, the product is automatically removed from the process before it reaches the tablet press until the specified degree of homogeneity has been achieved.
Only then is the quality product led directly to the tablet press. This means that even segregation effects can be recognized in a timely manner, since homogeneity is monitored continuously during the process and any potential “out of spec” mixtures are removed. In most cases, however, provided the dosing and the rotational speed of the mixing process are accurate and constant, a homogenous mixture is guaranteed. Consequently, inline measurement is normally only used for quality assurance purposes.
If specially requested, inline measurement can be used as a critical process parameter to not only monitor the process but to also control it. However, the core of the Modcos concept is the process control system which amalgamates, monitors and controls all processes as a superordinate unit. Each raw material can be followed exactly as it passes through the system, due to the use of a retention time model.
Modcos also Available as an Upgrade
The entire process sequence is fully documented with all events. Glatt View Conti measures the mass flow and operating conditions, calculates the set points according to the PAT measurements and synchronizes all process units to allow their simultaneous operation. Constant manufacturing reports referencing the process times of the source and target lots are generated, meaning that the system fulfills the requirements for real time release.
Glatt also offers Modcos as an upgrade to existing tablet presses to serve as an introduction to continuous direct compression. In the event of such a request, Glatt’s experts will work out case studies with the customer and create the necessary specifications. Glatt also offers sealed systems for applications with highly potent active substances, for which Glatt can draw on long-term in-house experience of designing containment solutions up to OEB 5. Glatt’s new Innovation Center allows the testing of continuous direct compression, continuous wet granulation and batch processes with integrated PAT systems.