Best practice for maximum tablet quality
Jörg Gierds, Fette Compacting, says that training of tablet press operators will help manufacturers stay on the right side of the US Food and Drug Administration (FDA)
The number of warning letters sent by the FDA increased from around 500 in 2009 to more than 8,500 in 2014. According to the organisation, the companies’ processes and manufacturing environments were not complying with good manufacturing practices (GMPs).
According to an assessment conducted in 2012 (published in International Pharmaceutical Quality (IPQ) magazine, March 2012; Fred Rowley), there are two reasons why out-of-specification tablets are placed on the market: 1/the machine operator and 2/the tablet press. To understand the causes, manufacturers need to focus on answers to problems that can be avoided by means of good operator guidance and the technologies used in tablet machinery. To offer a couple of examples, even the best machine will fail if the operator does not regularly calibrate his scales in the external test station (one reason indicated in the assessment), and it will also fail if the operator sets the cycle rates higher than the SOP guidelines in order to increase tablet output.
The principles and concept of tablet production
Machine operators and those responsible for the production processes have a good understanding of the manufacturing process and its tablet presses. Nevertheless, there are indicators for some serious misunderstandings on the part of the operator.
Like many other machines deployed in oral solid dosage (OSD) production, tablet presses are complex machines featuring a variety of parameters, some of which are of particular relevance, such as tablet weight. Modern machines feature technologies and constructive elements that prevent heavier or lighter tablets from reaching the good-channel. An operator who understands the machine and the process is generally more confident in how he handles the machine, for example, when selecting the setting parameters. It is however recommendable that manufacturers offer their operators and process managers qualification in the form of certified training by the machine manufacturer.
Operating the tablet press
You need a driver's licence to drive a car. Likewise, verifiable and certified qualification of operators is evidence of the quality of the manufacturing enterprise as well as the quality of the respective production process. GMP defines the personnel qualification very precisely: ‘Each person engaged in the manufacture, processing, packing or storage of a drug product shall have education, training and experience or a combination thereof to enable that person to perform assigned functions.’
Fortunately, machine manufacturers provide integrated protection features. Modern tablet presses are safeguarded against accidental or intentional maloperation. Password-protected parameter entries through to the four-eyes principle ensure protection against unauthorised machinery settings or manipulation. All machine parameters, operating conditions, operator entries, modifications and statistics are saved in databases in line with GMP, are tamper-proof and can be retrieved at any time, as well as being trackable and transparent. Accordingly trained personnel will ensure that these integrated protection features will work properly.
The role of the material to be pressed
The mixing and granulation processes are followed directly by the flowing of the product into the tablet press. Millions of tablets are pressed by high-performance rotary presses during the production stage and at a speed of more than 600,000 tablets per hour or more than 180 tablets per second. Problematic product characteristics and poor flow properties can cause considerable faults.
Experienced tablet press manufacturers have a technical laboratory or pilot plant for testing the tablet material at both laboratory- and production-scale. These tablet specialists possess extensive practical knowledge covering thousands of different materials and product mixtures. They are well versed with regard to interaction between the product and machine. Tests at laboratory- and production-scale are offered through to production batches involving millions of tablets. This bodes well for subsequent major series, even before investments are made in machinery, which in turn ensures that good tablets are produced, even after the validation process and the restrictions associated with it. If the material is problematic in terms of handling — for example, with regards to its flow properties and problems relating to stickiness or compacting — the experts are able to find a solution.
The influence of the tablet press
One critical factor is the machine start-up phase after changeover, cleaning or a machine stop. Older machines only count a defined number of initial tablets before approving the good-channel. More recent machines such as Fette Compacting’s FE55 (Figure 1) now also take other parameters into consideration; the good-channel is not approved until the press punches have returned to their final position and the compression force levels have been re-established in the set range.
The filling system plays a more-or-less critical role when it comes to tablet quality depending on the product (powder) and the filling hole (tablet dimensions and shape). Modern filling systems in line with the best practice principle for correct filling and tablet weight are based on three adjustment and control options. First of all, the turret speed and filling speed (adjusting the filling wheel speed) can be optimised for a good tablet. Second, the compression force monitoring checks the correct filling during the pressing process. Deviations are detected causing the dosage (filling volume) to be adjusted. Depending on the degree of deviation or frequency established, the machine may deem that the tablet is bad and eject it and/or the machine stops. As a third option, the statistic tablet weight monitoring by the tablet test system supplies the tablet weight with a resolution of 1/1000 grams. The tablet weight established also leads to direct or indirect adjustment of the dosage (filling).
Another important factor is compression force, which is applied to the punches via the compression rollers. It correlates with the tablet mass (tablet weight).
State-of-the-art technology enables the monitoring of a single tablet by measuring the force in the compression stations. But only force measured in the mechanical power flow path supplies the requisite high measuring signal quality. Only high measurement resolution of this force curve and detection of the peak force in these signals represents reliable correlation to the tablet weight.
Automatic tablet test systems such as Checkmaster or AutoTest 4 are usually positioned beside the machine and are designed for in-process control of the following test parameters: tablet weight, tablet hardness, tablet diameter, tablet thickness and active substance analysis. At adjustable intervals, tablets are automatically fed into the external test system where they are measured in a fully automatic process. The tablet weight and other tablet parameters measured are reported back to the tablet press via data interfaces.
Of course, a tablet found to be faulty must be rejected. While older machines still use mechanical sorting guides, which are susceptible to faults as well as being slow, rejection by means of compressed air nozzles has asserted itself in newer presses. A clever airflow represented by air curtains in front of and inside the ejection channels ensures that the tablets are guided accordingly.
Additionally, a good software product offering comprehensible diagnoses provides operators with support via the graphic user interface during operation and in the event of a fault (Figure 2).
Summary
Manufacturers and their technologies play an essential role in tablet production. The innovative technologies deployed in machinery today are milestones that continue to evolve in response to demands for improvement in tablet manufacturing.
A reliable machine manufacturer will be able to provide the user with support in each of the areas highlighted above. Such support should integrate operator training together with tests with products in the manufacturer's own technical laboratory and pilot plant where experience gleaned over many decades is focused and employees are the true experts.