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NIR shortens release times radically

Determining the actual content of active ingredient after compressing with Near Infrared Spectroscopy
NIR shortens release times radically

The FDA is currently attempting, through the PAT initiative, to detect process faults as early as possible. NIR (Near Infrared Spectroscopy) is one of the early-stage measuring techniques. It can radically shorten release times, i.e. the time between production and shipment, and significantly reduce the volume of wasted resources resulting from inaccurate production.

Ines Andersen

The maximum productive performance of tablet presses often coincides with extremely expensive product formulations. At the same time, the requirements specified for the tablet quality and precisely controlled quantities of active ingredient, which are only allowed to vary by a few percent, are very high. Before the tablets are irreversibly compressed, the preceding processes need to be considered. The mixture of the carrier and auxiliary substances with the active ingredient plays a very important role in preparing the materials for tablet compression. The materials are often granulated after mixing to encourage adequate flow; at the same time, this granulation also fixes the degree of mixing that has been achieved to a certain extent. Nevertheless, powders and even granulates can separate in the course of the production process, such as during transport to the press or die filling. This causes the tablets to contain different quantities of active ingredient.
The parameters weight, thickness, diameter and hardness have traditionally been measured after the pressing step in the production process. Press manufacturer Fette has successfully offered the Checkmaster for these measurements for some time. It is used widely today around the world in many pharmaceutical companies as a tablet tester that provides high quality and very effective integration into the press control system. The NIR Checkmaster now incorporates an NIR function. This is the outcome of cooperation between the three manufacturers Fette (tablet presses), Kraemer Elektronik (Checkmaster) and Büchi Labortechnik (Fourier transform (FT) NIR spectrometer). The proven general concept of the Checkmaster has been preserved. The device continues to offer optimum handling, easy cleaning, user-friendly servicing and simple adjustment and calibration. The function for “examining the active ingredient content by NIR“ has been ideally integrated and placed in the centre of the device. This new development retains the historically small footprint of former Checkmaster generations; the existing parameter testers have been positioned around the NIR equipment in the most efficient and space-saving fashion imaginable. The new device conforms fully to IP 65 and can also be implemented in the Fette isolator.
The NIR Checkmaster, including its sampling process and the frequency with which samples are taken, is controlled by the software in the Fette press. The parameters to be tested, such as weight, thickness, diameter, hardness or NIR, and the number of tablets used for this purpose are defined in advance. The physical and NIR data for the samples is automatically integrated into the batch record created by the press. In addition, the low height of the device allows it to fit under any tablet outlet. Any parts that have to be cleaned can be dismantled without using tools. The lamps and the laser unit in the NIR spectrometer can be easily exchanged by the user. A double-lamp module ensures that operation is not interrupted if one laser fails. Data can be transferred to and from NIR laboratory devices, and integration into the Fette tablet press software is ensured.
High expectations
Having already accumulated some experience of its own with NIR technology, Salutas Pharma GmbH’s attention was drawn to the project at an international customer workshop held by Fette and the company was immediately interested in a joint development venture. Today, Lydia Lehwald and Nadja Doll, respectively a graduate in pharmaceutical technology and a qualified pharmacist, are responsible for the new NIR project at Salutas Pharma. Expectations are high, as is the complexity of the topic. The possibility of integrating this technology into existing systems played an important role in the decision: “Fast, immediate control of the active ingredient content in order to increase understanding of the process is the background idea”, says Lehwald. The decision to take the measurements outside the press (NIR Checkmaster) using a transmission process instead of inside it by means of reflection (VisioNIR) was intended to permit flexible application to other presses. “The training in NIR and press operation, and the support offered by the manufacturers involved, were designed in such a way that even a novice would stand a good chance of becoming familiar with the field of NIR technology,“ Doll explains. The main purpose of this project, which is embedded in the overall PAT initiative, is to understand the process with a view to detecting potential variations in content and compensating for them promptly. Two products from Salutas‘ portfolio that are used as ACE inhibitors were selected for tests. These products were chosen on the basis of a wide range of considerations, namely:
  • Difference in the amount of active ingredient in the products (Captopril 15 %, Ramipril 3 %)
  • Difference in production methods (direct tableting/granulation prior to tableting)
  • Differences in tablet form (clover leaf/oblong)
It was also an explicit objective to test the limits of the system, which is why it was interesting to see how the Checkmaster would react to tablets with salient or unusual features.
A calibration model (75–125 % of the required values) therefore had to be made using laboratory-prepared samples with a known active ingredient content and compressed under production conditions. The calibration curve was generated on an NIR laboratory device made available by Büchi for the duration of the project. Due to the NIR measuring unit’s independence of the tablet press and the higher capacity of the laboratory unit (sample tray for 30 samples), fast and virtually automatic measurements were possible. This is a very important point, as it is necessary to measure the spectra of a large number of samples involved in preparing the calibration curve. After the data had been reviewed, it was transferred to the NIR Checkmaster without difficulty, as both the software and the installed NIR unit are identical. “This is a huge help“, Lydia Lehwald explains. For the sake of comparison, the tablets employed for the calibration model are re-analysed after the NIR measurement using high-performance liquid chromatography, thereby validating the model.
Calibration is a must
Since a great deal of time is required to prepare a calibration curve for each product, the plan is to prepare the curves for additional products step by step. This means, however, that the groundwork costs for the method must be offset very carefully against the potential risk and frequency of variations as well as the production volume of a particular product. A cost/benefit analysis is therefore essential.
When the calibration series is planned, it is necessary to bear in mind that changes in hardness also modify the translucency of the tablets. The calibration initially involves determining the quantity of active ingredient by means of a transmission measurement. Chemometric analysis is then used to ascertain the amount of active ingredient in each individual tablet. This calibration model subsequently serves to identify the actual active ingredient content with the NIR Checkmaster. If the value is outside the preset tolerances, an appropriate diagnostic message is displayed and the press is stopped. The NIR equipment incorporates automatic white balancing as a check and the system can be programmed to run regular self-tests. The procedure is additionally suitable for thermolabile materials, as the NIR measurement does not cause any rise in the tablet temperature. The active ingredient content that has been determined is transferred direct to the press production log together with its position in the collector, so that the active ingredient content can later be precisely assigned to the individual measured tablet. It is not possible to modify the measured data. The measurement begins with the acquisition of the data and spectra and ends with the entry of the results in the batch record of the tablet press.
The following checking steps are per- formed: a separation channel (combined oscillating/vibrating conveyor) transfers one tablet at a time to a station of the NIR Checkmaster’s transport system. The transport star is optimised for improved positioning of very different tablet formats. The classic checks are carried out first: the weight is measured to an accuracy of 0.001 g using a Sartorius WZ64 S measuring cell, whose separate encapsulation incorporates pressure compensation. A digital measurement of the thickness is then taken with the DM-IP II meter, which is precise to 0.02 mm. The diameter and hardness are measured next with a precision of ±1 N. Only the hardness of tablets destined for NIR testing is not measured. The final stage is to determine the active ingredient content using NIR. The tablet is positioned to an accuracy of 0.1 mm using two clamps in a pair of format-specific semi-cavities consisting of special, non-reflective plastic. Exact, reproducible measurements require this extremely accurate positioning, since the NIR measurement must always be taken at equally thick locations on the tablet.
Complex form
The relatively complex profile of the Captopril clover leaf and the oblong format of Ramipril presented particular challenges for the NIR Checkmaster’s positioning equipment. “Krämer’s solution for tablet positioning is very elegant and so far we have been extremely pleased with it“, says Lehwald. Her fear that an inability to position the tablets reproducibly would make it impossible to create a valid method turned out to be unfounded. The obstacle was overcome with the aid of special, product-specific inserts, which can be exchanged very quickly without using tools.
The approach for obtaining the system’s approval is of great importance. “After completing a validation process equivalent to the laboratory method, it is planned to observe the results very closely over a long period of time, so that it will then be pos-sible to assume with high confidence that this novel method is suitable for delivering valid results continuously. It is then neces-sary to consider whether an application should be submitted to the supervising authorities to allow the method to be used as a substitute for the usual quality control methods,“ Lehwald continues. Salutas is more than happy with the prototype of the NIR Checkmaster. Lehwald: “This is because of its compact design, highly reproducible and precise tablet feed to the NIR unit, ease of transfer from the laboratory device to the NIR Checkmaster and user-friendly software.“
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