Field of invention

The invention relates to the technical field of pharmaceutical products, in particular uncoated pharmaceutical products. Furthermore, the invention relates to the technical field of manufacturing pharmaceutical products, in particular monitoring devices in pharmaceutical applications.

In particular, there are provided a method of monitoring an uncoated pharmaceutical product, an arrangement for manufacturing an uncoated pharmaceutical product, a pharmaceutical plant comprising the arrangement, and the use of low coherence interferometry, in particular optical coherence tomography, for real-time monitoring of an uncoated pharmaceutical product during a manufacturing process.

Art Background

The pharmaceutical industry has some of the highest standards of all industries and the requirements for pharmaceutical products are accordingly high. Consequently, the quality of pharmaceutical products has to be constantly controlled, even during the manufacturing. For example, for pharmaceutical products (in some instances also referred to as dosage forms) such as tablets, the respective pharmacopoeiae such as the European Pharmacopoeia or the United States Pharmacopoeia (USP) demand various tests such as uniformity of weight and content, disintegration, and dissolution. (Material) properties of the respective dosage form, such as porosity, may be indicative of the afore- mentioned characteristics. It is therefore important not only for quality reasons to have a deep understanding of these properties, but also in order to run a successful and economical manufacturing process, because ultimately, both are mutually dependent. I. e., a well-controlled process yields high quality products, and deviations in the quality of the products are often caused by a poorly adjusted process. Hence, properties of the uncoated pharmaceutical product (such as porosity) may be indicative of the quality of both the product and the process. Usually, all of the afore-mentioned characteristics like uniformity of content are tested in separate off-line test setups, which may be very time and cost intensive. Therefore, only a limited number of samples can be analyzed. The result of the analysis is typically only available after an entire batch has been produced. If a criterion is not satisfied, typically the entire batch of an (uncoated) pharmaceutical product needs to be discarded. It may therefore be desirable to accurately predict the characteristics and to reduce the amount of necessary tests and to thus increase the efficiency and the accuracy of a manufacturing process. US 2014/0322429 Al discloses a method and a device for monitoring a property of a coating of a solid dosage form during a coating process for forming the coating of the solid dosage form. Solid dosage forms such as tablets, pellets, capsules, and the like are covered by a coating if required. It is proposed to determine a quality and/or property of a coating during the coating process, using low coherence interferometry. However, properties of a coating of a coated pharmaceutical product do not yield any insight into the interior (e.g. core) of a pharmaceutical product. Hence, no knowledge about the properties of the uncoated pharmaceutical product can be gained from this. Also, the problem of predicting a characteristic of an uncoated pharmaceutical product remains unaddressed.

Summary of the Invention

There may be a need to efficiently manufacture a pharmaceutical product (in particular to determine a property and predict a characteristic of an uncoated pharmaceutical product) quickly and accurately and to obtain a deeper understanding of its manufacturing process.

This need may be met by the subject matter according to the independent claims. Advantageous embodiments of the present invention are described by the dependent claims.

According to a first aspect of the invention there is provided a method of predicting a characteristic of an uncoated pharmaceutical product during a manufacturing process, the method comprising (i) performing the manufacturing process of the uncoated pharmaceutical product; and (ii) monitoring the uncoated pharmaceutical product, in particular simultaneously, during the manufacturing process; wherein the property of the uncoated pharmaceutical product is monitored using low coherence interferometry, LCI.

According to a further aspect of the invention there is provided an arrangement for manufacturing an uncoated pharmaceutical product, comprising a manufacturing device configured for manufacturing the uncoated pharmaceutical product in a manufacturing process, wherein the manufacture device is configured to perform at least a part of the manufacturing process in an interior region of the manufacturing device; and a monitoring device configured for monitoring the property of the uncoated pharmaceutical product during the manufacturing process; wherein at least a part of the monitoring device is arranged such as to have insight into the interior region of the manufacturing device, and wherein the monitoring device is configured for monitoring the property of the uncoated pharmaceutical product simultaneously during a manufacturing process using low coherence interferometry, LCI.

According to a further aspect of the invention there is provided a pharmaceutical plant comprising the arrangement.

According to another aspect of the invention there is provided using low coherence interferometry, in particular optical coherence tomography, for realtime monitoring of an uncoated pharmaceutical product during a manufacturing process of the pharmaceutical product to predict a characteristic of the uncoated pharmaceutical product.

These aspects of the invention are based on the idea that it is possible to predict critical quality attributes (i.e. characteristics) of an uncoated pharmaceutical product through the evaluation of in-line obtained OCT data, and to control manufacturing process settings based on evaluated OCT data. Uncoated pharmaceutical products include, for example, solid dosage forms, tablets, granules, and pellets. In the prior art, it has not been possible to retrieve in-line data indicative of the properties (such as surface and morphological properties including roughness and porosity) of an uncoated pharmaceutical product by any available method. For instance, in the prior art, no porosity of a tablet during manufacture could be visualized using conventional methods. However, it has been surprisingly found by the inventors that it is possible to visualize said properties within said uncoated pharmaceutical product, using LCI, in particular OCT. It has also been found by the inventors that the invention may be used to directly visualize microcrystals, agglomerates, temperature and/or time dependent crystallization processes, etc. Properties like particle size distribution may be derivable from these measurements. It has furthermore been found that it is highly advantageous to drive product and process development and optimization.

In conclusion, these unexpected findings provide a new way of determining and predicting a property of an uncoated pharmaceutical product during its manufacture quickly and accurately and enables obtaining a deeper understanding of the manufacturing process itself without the detrimental effects of conventional methods, one of which being that in conventional methods, the dosage form usually has to be destroyed.

In the context of this document, the term "uncoated pharmaceutical product may particularly denote a product intended for medicinal use in a human or an animal, presented in its finished dosage form or any precursor form thereof (i.e. raw material comprising one or more excipients and/or one or more APIs, and any intermediate product). The term thus also refers to the material (matter) of the uncoated pharmaceutical product. Such a pharmaceutical product is usually well defined by pharmacopoeiae such as the European Pharmacopoeia or the United States Pharmacopoeia (USP), and/or by current research in the field. Uncoated pharmaceutical products include, but are not limited to, solid dosage forms, tablets, granules, capsules, and pellets.

The term "predict" may include (computer implemented) methods such as calculating or correlating measured data with known characteristics.

The term "property" as used herein is intrinsic to the (material of the) respective pharmaceutical product. For example, a density or a porosity of a tablet may be considered a "property" of the tablet. In contrast, the term "characteristic" as used herein denotes a behavior or quality of the (material of the) respective pharmaceutical product, which it has or expresses as a result of the sum of all its properties. For example, a very dense tablet may express the characteristic of a slowly dissolving tablet.

The term "low coherence interferometry" (LCI) may particularly denote an interferometry method which exploits the special properties of light having a low coherence. Examples for low coherence interferometry may be white light interferometry (WLI) and optical coherence tomography (OCT). Typically, a light source with high spatial and low temporal coherence may be employed. Particular examples for suitable light sources may include, among others, super luminescence diodes, femtosecond lasers, and supercontinuum lasers. In special applications also tunable laser sources may be applied.

In particular, low coherence interferometry may allow monitoring a property of a pharmaceutical product without influencing (e.g. disrupting) the manufacturing process. More particularly, low coherence interferometry may be advantageously used as a non-invasive technique for determining or monitoring one of a parameter or property of the product during manufacture, such as a particle size distribution or the presence of an API and a crystalline or amorphous structure thereof.

Low coherence interferometry uses the wave superposition principle to combine light waves, particularly light waves that are modified by the pharmaceutical product to be analyzed, in a way that will cause the result of their combination to extract information from those instantaneous wave fronts.

The basic working principle is as follows: when two waves are combined, the resulting wave pattern may be determined by the phase difference between the two waves. In particular, waves that are in phase will undergo constructive interference while waves that are out of phase will undergo destructive interference. Applying this principle to a manufacturing process of an uncoated pharmaceutical product allows to monitor the pharmaceutical product so as to obtain meaningful information.

In particular, optical coherence tomography (OCT) may refer to a two- or three- dimensional imaging technique, while low coherence light interferometry and white light interferometry may refer to a one-dimensional imaging technique.

The optical setup for low coherence interferometry such as white light interferometry or OCT may comprise an interferometer, for example a Michelson type interferometer. However, also other types of interferometers, such as a Mach-Zehnder interferometer or a Sagnac interferometer, may be employed.

More particularly, the light of the light source may be split into a reference and a sample arm and recombined after the light beam in the sample arm has been modified by the sample. The light of the reference arm and the sample arm may interfere with one another when the light beams are recombined. The recombined light may be used to analyze a property of a pharmaceutical product during the manufacturing procedure. Alternatively, an autocorrelation signal may be used to analyze the pharmaceutical product during the manufacturing procedure.

As mentioned above, optical coherence tomography may refer to a two- or three- dimensional imaging technique, while low coherence light interferometry and white light interferometry may refer to a one-dimensional imaging technique. Therefore, the property of the pharmaceutical product may be monitored in one, two or three spatial dimensions. In particular, monitoring the property of the pharmaceutical product in one spatial dimension may allow for a particularly fast and efficient determining of the property. However, in case a higher accuracy of the monitoring is necessary or in case that multi-dimensional properties shall be monitored, the property of the pharmaceutical product may also be monitored in two or three spatial dimensions. Depending on the property to be monitored, it may be particularly necessary to monitor the property in more than one spatial dimension.

In particular, a depth-resolved OCT signal may be acquired by any suitable variant of OCT such as frequency-domain OCT, e.g. spectral-domain OCT and swept-source OCT, or time-domain OCT.

In time-domain OCT, a reference arm in the interferometer may be varied, particularly by moving a mirror in the reference arm. A signal may only be detected when the photons reflected from both interferometer arms, i.e. the reference arm and a signal or measurement arm, have travelled the same optical distance to a detector. Particularly, mechanical instabilities of an interferometer setup and noise may be induced by the mechanical movement of the mirror in the reference.

The OCT signal acquisition in Fourier-domain OCT may offer advantages in terms of imaging speed and sensitivity and may thus enable the application of OCT as an in-line monitoring method or a method for in-process control (IPC). In Fourier-domain OCT, the reference arm of the interferometer may be fixed and the interference signal of back- reflected and back-scattered light from the reference mirror and the sample may be detected in a spectrally resolved way. This may either be performed in parallel (spectral-domain OCT) by using a dispersing element and a CCD or CMOS camera or sequentially (swept-source OCT) by scanning a narrow laser line over a broad spectral region. In both embodiments the depth information may be accessed by applying an inverse Fourier transform on the acquired interference spectrum.

The employed light source may be chosen in dependence with the employed imaging technique and in dependence of the analyzed pharmaceutical product. For example, time-domain OCT and spectral-domain OCT may employ a light source having a broad bandwidth while swept-source OCT may employ a light source having a smaller or narrower bandwidth, which can be swept in wavelength over a rather large range. In the latter case, the object to be scanned moves past a stationary probe.

In particular, analyzing an obtained interference pattern or obtained signal may depend on the employed variant of LCI. The interference may cause a modulation in the detected or obtained signal. In case of time-domain OCT, an intensity of the signal may be modulated in time. Correspondingly, an intensity of the obtained signal may be modulated in frequency in case of Fourier-domain OCT. A frequency of the modulation may be a function of a difference of a path length between the two interferometer arms. Thus, the frequency of the modulation may describe the depth from which the light may be scattered.

Optical coherence tomography (OCT) is a light-based imaging technology. In OCT systems, the light is reflected and scattered when it passes through an interface between two materials with a different refractive index. The reflected light spectrum is measured and then mathematically transformed into an image of, for example, size 1024x1024 pixels. This may be done in such a way that the surrounding air appears white. Materials which scatter the light significantly due to their structure will appear darker, or scattered, in the image. The images are only snapshots of parts of the object moving past the probe, where some images may only depict small fragments of the edge. Each pixel represents a certain vertical distance, e.g. 1.8 pm. The horizontal distance will however vary with the passing speed of the object and an absolute value cannot be given. As a lightbased technology, OCT can penetrate into an uncoated pharmaceutical product's (such as a tablet's) core (i. e. not only monitoring of the surface of the respective uncoated pharmaceutical product is possible). Novel metrics from image analysis may be used to quantify a part of an OCT image depicting an area within, e. g., the first 100-200 pm from the surface of an uncoated pharmaceutical product. These metrics may quantify the morphology of the product in this region, and it is possible to correlate these metrics with parameters describing characteristics like a dissolution (or disintegration) profile. The extent of the area which will be evaluated is for example determined by a clustering algorithm or any other suitable image analysis. Clustering algorithms agglomerate datapoints, or pixels in this case, which are located near each other into groups (clusters). With this method, the darker pixels on the top layer of the tablet will be grouped into a cluster. Pixels of an intensity above a certain threshold are clustered via a parallelized density-based clustering algorithm, applied for example with the parameters e=20, m = 10. A pixel belongs to the area to be evaluated if it is contained in the main cluster obtained from this. The height of this cluster may be a rough indicator of the penetration depth of the light beam and as such, it may be an indicator for structural properties.

The aspects defined above, and further aspects of the invention are apparent from the examples of embodiment to be described hereinafter and are explained with reference to these examples of embodiments.

According to an exemplary embodiment of the invention, monitoring the pharmaceutical product comprises guiding primary electromagnetic radiation from a probe of the monitoring device to the uncoated pharmaceutical product, and guiding secondary electromagnetic radiation, generated by an interaction between the primary electromagnetic radiation and the uncoated pharmaceutical product, from the pharmaceutical product back to the probe. This may be regarded as the basic requirement for an LCI measurement and therefore it is important that unobstructed electromagnetic radiation paths are ensured.

According to a further exemplary embodiment of the invention, the pharmaceutical product is an uncoated solid dosage form, in particular one of an uncoated tablet, an uncoated granule, an uncoated pellet, a capsule (and its filling), and an uncoated extrudate. Said uncoated pharmaceutical products may preferably be manufactured by suitable means known in the art and are increasingly important in the development of new, highly innovative medicinal and pharmaceutical applications. The uncoated pharmaceutical products (dosage forms) may for example comprise a rough or uneven surface (i. e. not smooth). The pharmaceutical products may be precursors to a coated dosage form. When coating a dosage form, it may be desirable to know properties such as a surface roughness, which has a direct effect on e. g. the required amount of coating material etc., in order to predict characteristics such as coatability (i. e. the characteristic being indicative of how easily and/or efficiently a dosage form may be coated). Hence, it is also an advantage of the present invention that relevant characteristics pertaining to the coating (process) of a pharmaceutical product may be predicted based on (surface) properties of an uncoated pharmaceutical product.

According to a further exemplary embodiment, a monitoring resolution is in the micron-range or sub-micron range. However, with ever-increasing technical progress, resolution of probes (or sensors, respectively) as well as resolution of graphical user interfaces improves rapidly, as will be apparent to the skilled person.

According to a further exemplary embodiment of the invention, using LCI comprises using low coherence optical coherence tomography, LC-OCT, and/or a used wavelength is a fixed wavelength. It has been found that LC-OCT may be preferred when monitoring the manufacturing the pharmaceutical product and its properties according to embodiments of the invention. It has furthermore been found that it may be advantageous to use a fixed wavelength (electromagnetic radiation) only, in contrast to conventional methods. I. e., in some embodiments, the measuring device generates primary electromagnetic radiation comprising a fixed wavelength.

According to a further embodiment, the property is a presence of a particle. Although it may not be possible to distinguish whether the particle is an API or, e. g. an excipient, it may already be a valuable information to know whether a particle is present, e. g. in a certain region of the pharmaceutical product. In one embodiment, the property is at least one of the group consisting of a size of particle; a presence of pores (including voids and entrapped air); a size and/or size distribution of pores; a size distribution of a plurality of particles; a presence of an agglomerate of particles; a crystalline or amorphous state of a particle; a penetration depth; a homogeneity of a region of the uncoated pharmaceutical product, in particular with regard to its constituents; and a surface roughness.

In the context of this document, a particle size (or pore size) may be defined such that a diameter of a coextensive (i.e. equal area) circle can be calculated in images of the particles, e.g. microscopic images of thin sections of the product. Other conventional methods used for determining a particle size (or pore size) in pharmaceutical applications fall within the scope of this invention.

In a further embodiment, monitoring the property of the uncoated pharmaceutical product comprises predicting a characteristic of the uncoated pharmaceutical product based on a, in particular graph-based or, even more preferably, a tree-based machine learning model. Any other suitable computer implemented model (or algorithm) falls within the scope of the invention. Combining the method according to embodiments of the invention with a machine learning model (i. e. "artificial intelligence") is highly advantageous for reliably and efficiently predicting the characteristics of an uncoated pharmaceutical product based on its properties, which are measured using OCT as described herein. For example, a characteristic may be predicted in a very quick manner, the measured property may then be correlated with a manufacturing process setting and/or device setting and said setting(s) may be adjusted such that the property changes in order to obtain a pharmaceutical product with desired characteristics, e. g. as required by the Ph. Eur. and/or the USP. In an embodiment, this method of using data acquired by implementing the method according to embodiments of the invention may be fully automated. This may save significant amounts of resources and time and ensure the efficient manufacture of safe, high-quality pharmaceutical products. It will be apparent to the skilled person that the monitoring may in general comprise the use of appropriate computing means, visualization means, etc. Hence, those parts of the methods, even if not explained in detail hereinafter, are naturally within the scope of this invention.

In an embodiment, the (predicted) characteristic (of the uncoated pharmaceutical product) is at least one of the group consisting of a dissolution or disintegration time, in particular as defined by the European Pharmacopoeia or the United States Pharmacopoeia; a uniformity or, in particular structural, homogeneity, in particular as defined by the European Pharmacopoeia or the United States Pharmacopoeia; a mechanical stability, in particular a breaking force; a coatability as defined herein; and a post processing characteristic. Knowing these characteristics (by prediction based on determined properties), is valuable for adjusting the manufacturing process and allows for an efficient and economical process.

In an embodiment, the method is a continuous method, in particular wherein the monitoring is carried out in-line and/or in real time; or wherein the method is a discontinuous method, in particular wherein the monitoring is carried out off-line.

Carrying out the monitoring in-line (or, in yet further embodiments, "on-line") has the great advantage that the process is not interrupted, which may be particularly important for industrial applications. "On-line" „in-line" and „in realtime" (measurement) as used herein particularly mean „during the manufacture" and „in place", whereas an „at-line" or „off-line" measurement could be performed at any time during or after the manufacture of the pharmaceutical product. It is usually the case that upon restarting a process after an interruption, the process parameters are not exactly the same as they were before the interruption and often an interruption also brings with it the loss of valuable product. Therefore, it is generally preferred and advantageous to carry out the monitoring inline without interrupting the manufacturing process. A further advantage of carrying out the monitoring in-line is that the analysis is done in real-time, i.e. the manufacturing process may be understood in realtime, which allows for a very short reaction time. This is beneficial in the case that adjustments need to be made due to a deviation from a desired property or characteristic. However, sometimes it may be desirable to take a sample of the pharmaceutical product (or, in some cases, the whole finished product like a finished tablet) and carry out the monitoring off-line, e.g. in a (separate) laboratory, or at-line, meaning nearby. This may be done for routine quality control measures and particularly in a research or experimental environment.

According to a further exemplary embodiment of the invention, the monitoring device of the arrangement comprises a probe. The probe is arranged such that the primary electromagnetic radiation can be guided in an unobstructed way to the material of the pharmaceutical product and such that the secondary electromagnetic radiation, which is generated by an interaction between the primary electromagnetic radiation and the pharmaceutical product, can be guided in an unobstructed way from the pharmaceutical product back to the probe.

Monitoring the uncoated pharmaceutical product according to at least one of the examples mentioned above may have the great advantage that it can be carried out in a particular efficient and economical way. Consequently, it is one of many advantageous technical effects when implying the present invention according to the afore-mentioned embodiments that a manufacturing process does not have to be interrupted and/or slowed down when monitoring the pharmaceutical product and that the monitoring may be performed without destroying the respective dosage form.

In another embodiment, the manufacturing device is selected from the group consisting of a pelletizer, a tablet press, in particular of the rotary type, a granulator, a dryer, in particular a fluid bed dryer, a capsule filling device, a roller compacter, an extruder, and a blender. These examples are, although not limiting to the scope, important manufacturing devices in the manufacturing of uncoated pharmaceutical products and it has been surprisingly found that the invention may be carried out in a particular advantageous way when employing any of these manufacturing devices, or a combination thereof.

It has to be noted that embodiments of the invention have been described with reference to different subject matters. In particular, some embodiments have been described with reference to method type claims whereas other embodiments have been described with reference to apparatus type claims. However, a person skilled in the art will gather from the above and the following description that, unless otherwise notified, in addition to any combination of features belonging to one type of subject matter also any combination between features relating to different subject matters, in particular between features of the method type claims and features of the apparatus type claims is considered disclosed with this document.

The aspects defined above, and further aspects of the present invention are apparent from the examples of embodiment to be described hereinafter and are explained with reference to the examples of embodiment. The invention will be described in more detail hereinafter with reference to examples of embodiment but to which the invention is not limited. Brief Description of the Drawing

Figure 1 shows a continuous tablet manufacturing and OCT measurement method, according to an embodiment of the invention.

Figure 2 shows a fluid bed dryer and OCT measurement, according to an embodiment of the invention.

Figure 3 shows a method of monitoring an uncoated pharmaceutical product using OCT, according to an embodiment of the invention.

Figure 4 shows an arrangement for monitoring an uncoated pharmaceutical product using low coherence interferometry, LCI, according to an embodiment of the invention.

Figure 5 shows an arrangement for monitoring an uncoated pharmaceutical product using low coherence interferometry, LCI, according to an embodiment of the invention.

Figure 6 shows an exemplary OCT image evaluation process and process settings according to an exemplary embodiment.

Figure 7 shows an example of an OCT image of an uncoated pharmaceutical product.

Figure 8 shows an example of an evaluated pharmaceutical product internal morphology in OCT image.

Figure 9 shows an example of an evaluated pharmaceutical product OCT image.

Figure 10 shows an example of an evaluated OCT image of an uncoated tablet exhibiting an irregular surface.

Figure 11 shows two examples of OCT images of the same tablet with different parts of the tablet being evaluated.

Figure 12 shows an interaction between electromagnetic radiation and a pharmaceutical product.

Figure 13 shows an arrangement according to an embodiment, comprising a fluid bed dryer and an OCT probe.

Figure 14 shows an example of an evaluated OCT image of granules inside a fluid bed dryer. Detailed Description of the Drawings

The illustrations in the drawings are schematic. It is noted that in different figures, similar or identical elements or features are provided with the same reference signs or with reference signs, which are different from the corresponding reference signs only within the first digit. In order to avoid unnecessary repetitions elements or features, which have already been elucidated with respect to a previously described embodiment, are not elucidated again at a later position of the description.

Furthermore, spatially relative terms, such as „front" and „back", „above ,„ and „below", „left" and „right", et cetera are used to describe an element's relationship to another element(s) as illustrated in the figures. Thus, the spatially relative terms may apply to orientations in use which differ from the orientation depicted in the figures. Obviously, all such spatially relative terms refer to the orientation shown in the figures only for ease of description and are not necessarily limiting as an apparatus according to an embodiment of the invention can assume orientations different than those illustrated in the figures when in use.

Figure 1 shows a continuous tablet manufacturing and LCI measurement method, according to an embodiment of the invention. A represents the manufacturing of an uncoated pharmaceutical product 101 and B represents monitoring the uncoated pharmaceutical product 101 using LCI. According to embodiments of the invention, OCT, LCI, or LC-OCT may be used, as described herein. The manufacturing process is subdivided in several blocks in this example. Block Al is a feeding step (involving a feeder), A2 is an (optional) granulating / pelletizing step (involving an optional granulator), and A3 is an optional drying step (involving an optional dryer). A4 is an optional milling step (involving an optional mill). A5 is another feeding step involving a (further) feeder and A6 is a blending step involving a blender. In block A7, in this example, tablets are pressed in a tablet press, which comprises a tablet outlet 112 for the step of ejecting (i . e. letting out) the manufactured tablets 101. In this example, LCI measurement is carried out simultaneously during the manufacturing of the pharmaceutical product 101, more specifically during steps A7 and A8.

Figure 2 shows a fluid bed dryer and LCI measurement, according to an embodiment of the invention. Accordingly, a fluid drying step A is performed and simultaneously, LCI measurement B is performed. This embodiment will be explained in more detail with reference to Figure 13.

Figure 3 shows a method of monitoring an uncoated pharmaceutical product using LCI, according to an embodiment of the invention. In more detail, step A comprises the continuous manufacturing of a pharmaceutical product 101, e. g. in a fluid bed dryer (FB dryer). The monitoring step B comprises an LCI measurement Bl, an LCI image evaluation B2, and also a classification step B3. Step E represents controlling the LCI measurement, such as (controlling the) position of a probe 121, sensor settings (e. g. settings of a (electromagnetic radiation) sensor comprised by the probe 121, which may also, in embodiments, comprise an electromagnetic radiation generation device), etc. Step F comprises controlling the LCI image evaluation strategy based on classification results. The classification results of step B3 are used for step C for making a discharge decision of „out of specification material". E. g., if a classification result is that a pharmaceutical product 101 in manufacture would not comprise the required characteristics (i. e. specification), which were predicted (evaluated) based on the LCI image evaluation (i. e. based on properties of the pharmaceutical product 101 represented / visible in the LCI image), then the respective uncoated will be discarded. There is also provided a feedback loop D to control process settings. For example, if based on the LCI image evaluation it can be predicted that certain characteristics are out of specification, then the corresponding process settings may be controlled / adjusted in a very quick and efficient manner through the feedback loop D.

Figure 4 shows an arrangement 100 for monitoring an uncoated pharmaceutical product 101 using low coherence interferometry, LCI, according to an embodiment of the invention. In this example, the arrangement 100 for manufacturing an uncoated pharmaceutical product 101 comprises a manufacturing device 110 which is a rotary tablet press, configured for manufacturing the uncoated pharmaceutical product 101 (i. e. a tablet) in an interior region, and the arrangement 100 further comprises a monitoring device 120, configured for monitoring the property of the uncoated pharmaceutical product 101 during the manufacturing process. At least a part of the monitoring device 120, i. e. the probe 121, is arranged such as to have insight into the interior region of the manufacturing device 110, e. g. into the tablet outlet 112, The monitoring device 120 is thus configured for monitoring the property of the uncoated pharmaceutical product 101 simultaneously during the manufacturing process (in this case the tableting process) using low coherence interferometry. Figure 5 shows an arrangement for monitoring an uncoated pharmaceutical product using low coherence interferometry, LCI, according to an embodiment of the invention. In substance, Figure 5 shows an embodiment similar to the one displayed in Figure 4 as described above. However, the probe 121 is arranged such that it has insight into the tablet press 110 (or the manufacturing device 110 in general) and may thus provide for monitoring the uncoated pharmaceutical product 101 simultaneously during its manufacture in the tablet press 110.

Figure 6 shows an exemplary LCI image evaluation process. Exemplary process settings are shown in the first step. An exemplary pressed tablet 101 is shown in the second step. Tablets 101 were manufactured in accordance with the respective exemplary process settings of the table shown for the first step, i. e. tablets were produced under different combinations of process settings. An LCI (or OCT) measurement is performed (not shown), such that an LCI (or OCT) image is obtained. The image of the uncoated pharmaceutical product 101 is evaluated, i. e. material attributes (properties) are evaluated with the LCI system. The data (values) are then plotted in a diagram, e. g. a second value („LCI value 2") is plotted over a first LCI value („LCI value 2"). Each plotted data point corresponds with a process setting. For example, each one of the group of data points in the upper left corner of the diagram result from a measurement of a manufacturing step using the exemplary process settings denominated „Setting 1" in the table comprising the exemplary process settings. This shows that tablets 101 produced under different process conditions can be distinguished by measured LCI values. Further evaluation and/or prediction of characteristics may be performed based on these results, e. g. as explained above with reference to Figure 3.

Figure 7 shows an example of an LCI image of an uncoated pharmaceutical product 101. Such an image may be obtained and used in a method as described herein.

Figure 8 shows an example of an evaluated uncoated pharmaceutical product 101 internal morphology in LCI image. Such an image may be obtained and used in a method as described herein.

Figure 9 shows an example of an evaluated uncoated pharmaceutical product 101 LCI image. Such an image may be obtained and used in a method as described herein.

Figure 10 shows an example of an evaluated LCI image of an uncoated tablet 101 exhibiting an irregular surface (i. e. a very rough or uneven surface). This represents valuable information for a subsequent process, e. g. a subsequent coating process. In other words, the property „surface roughness" may for example be indicative of the characteristic „coatability" but may also be used to predict other characteristics. The property „high surface roughness" could in some cases for example mean that the characteristic „coatability" will be out of specification, because too much coating material would be required.

Figure 11 shows two examples of LCI images of the same tablet 101 with different parts of the uncoated tablet being evaluated. Such images may be obtained and used in a method as described herein. In the image on the left, a region underneath the surface is evaluated, while in the image on the right, a surface of the same uncoated tablet is evaluated.

Figure 12 shows an interaction between electromagnetic radiation and an uncoated pharmaceutical product 101. Primary electromagnetic radiation 122 is generated in the monitoring device 120 and then guided onto the uncoated pharmaceutical product 101 (e. g. a tablet). In consequence, secondary electromagnetic radiation 123, generated by an interaction between the primary electromagnetic radiation 122 and the uncoated pharmaceutical product 101, is guided from the uncoated pharmaceutical product 101 back to the probe 121 of the monitoring device 120. The monitoring as shown in the Figures, according to preferred embodiments of the invention, uses low coherence interferometry (LCI), and more preferably low coherence optical coherence tomography, LC- OCT. In other preferred embodiments, a used wavelength is a fixed wavelength. Hence, at least the electromagnetic radiation 122 as for example shown in Figure 12 comprises one wavelength of the electromagnetic spectrum only.

Figure 13 shows an arrangement 100 according to an embodiment, comprising a fluid bed dryer 110 and an OCT probe 121 of the monitoring device 120. The OCT probe is arranged at a (glass) window 111 in the fluid bed dryer housing 111, such that it has insight into the interior of the fluid bed dryer housing 111. Figure 14 shows an example of an evaluated OCT image of granules inside a fluid bed dryer 110. In consequence of the glass window 111 being arranged between the probe 121 and the uncoated pharmaceutical product 101 (e. g. granules) inside the fluid bed dryer 110, on the example of the evaluated OCT image there appears a line which stems from the glass window 111. This shows that, although it is generally desired that unobstructed electromagnetic radiation paths are ensured, materials which allow the respective primary and secondary electromagnetic radiation to pass in a sufficient and unaltered manner, may be interposed between the probe 121 and the uncoated pharmaceutical product 101, e. g. to protect the probe 121 and/or the product 101, and/or as part of a device housing.

The arrangements 100 as shown in Figures 4, 5 or 13, or similar arrangements 100 according to other embodiments of this invention, may be comprised in a pharmaceutical plant (not shown).

As is apparent from all Figures, using low coherence interferometry, in particular optical coherence tomography, for real-time monitoring of an uncoated pharmaceutical product 101 during a manufacturing process is highly advantageous. It should be noted that the term comprising" does not exclude other elements or method steps and the use of indefinite articles („a" or „an") does not exclude a plurality. Also elements described in association with different embodiments may be combined. It should also be noted that reference signs in the claims should not be construed as limiting the scope of the claims.

List of reference sicins:

A Manufacturing an uncoated pharmaceutical product

Al Feeding step

A2 Optional granulating step

A3 Optional drying step

A4 Optional milling step

A5 Feeding step

A6 Blending step

A7 Tableting step

A8 Tablet outlet

B Monitoring an uncoated pharmaceutical product using low coherence interferometry

Bl LCI measurement

B2 LCI image evaluation

B3 Classification

C Use of classification result

D Feedback loop to control process settings

E Controlling measurement

F Controlling image evaluation

100 Arrangement

101 Pharmaceutical product

110 Manufacturing device

111 Window

112 Tablet outlet

120 Monitoring device

121 Probe

122 Primary electromagnetic radiation

123 Secondary electromagnetic radiation