Field of invention

The invention relates to the technical field of melt-solidification in pharmaceutical applications. Furthermore, the invention relates to the technical field of monitoring devices in pharmaceutical applications.

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

Art Background

Melt-solidification is a method involving a melting step prior to a shaping operation, and a solidification step during or after the shaping operation. Injection molding and (hot-melt) extrusion (HME) are only two of many examples of a melt-solidification process. For example, HME is based on the principle that a material to be processed, e.g. a polymer such as a thermoplastic, is fed into an extruder where it is first heated to a temperature above a melting point. The material melted in this way can then be mixed with further substances, and these further substances can (after their addition) be dispersed in the material. Usually, at the end of the process, a strand -the extrudate- is formed or shaped. The material is then cooled and thus hardens again. In particular in pharmaceutical applications, hot melt extrusion offers the advantage that poorly water-soluble active ingredients, to which about half of all newly developed drugs belong, can be incorporated into a matrix without the need for a solvent. It is also possible to incorporate heat-sensitive substances into the material by keeping the processing time short. Moisture-sensitive materials can be processed as well as materials that are not easily compressible since neither water nor high pressure (as in the case of a compaction or pelleting process) are involved in the HME process. After HME, the extrudate can then be further processed as desired. Similar effects may be observed in other melt-solidification processes as will be described further with respect to embodiments of this invention. In general, the use of (amorphous) solid dispersions is an interesting strategy to increase the bioavailability of poorly soluble drugs by improving their rate and extent of dissolution. However, like other processes, a meltsolidification process has to be controlled precisely in order to meet the high demands placed on pharmaceutical products. For example, a distribution of an ingredient usually has to be homogeneous, a particle size distribution has to be in a certain range, and more. In order to control these parameters, the values during the process must be known. This is often problematic due to various effects like interference of a measurement with a polymer matrix. Thus, it often requires post-production analysis (off-line measurements), resulting in increased time and cost for the product development.

Therefore, there may be a need to determine a property of a pharmaceutical product quickly and accurately and to obtain a deeper understanding of a meltsolidification process.

Summary of the Invention

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 monitoring a pharmaceutical product, the method comprising i) manufacturing the pharmaceutical product using a melt-solidification process; and ii) monitoring the pharmaceutical product, in particular during the manufacturing process, using low coherence interferometry, LCI.

According to a further aspect of the invention there is provided an arrangement for manufacturing a pharmaceutical product, in particular for carrying out the method according to embodiments of the invention, the arrangement comprising i) a manufacturing device configured to produce the pharmaceutical product by melt-solidification, and ii) a monitoring device associated with the manufacturing device and configured to monitor the pharmaceutical product, in particular during the 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 a further aspect of the invention there is provided a method for using fixed-wavelength low coherence interferometry, in particular optical coherence tomography, for real-time monitoring of a pharmaceutical product during a melt-solidification process in the manufacturing of the pharmaceutical product.

According to yet another aspect of the invention, there is provided a method for using fixed-wavelength low coherence interferometry, in particular optical coherence tomography, for visualizing and/or evaluating the formation of pharmaceutical particles in melt-solid and liquid solution.

These aspects of the invention are mainly based on the idea that, according to exemplary embodiments, it is possible to see a structure, in particular a three- dimensional structure, of a particle, in particular an active pharmaceutical ingredient (API) particle within a material of a pharmaceutical product being manufactured in a melt-solidification process. The pharmaceutical product may be, for example, an amorphous solid dispersion, but also a dosage form (like a tablet) or a medical device such as an implant. In general, the scope of this invention may extend from simple dosage forms to (polymer) matrix based medical devices, in particular comprising an API. In the prior art, it has not been possible to retrieve in-process images of the afore-mentioned (API) particles within the material of the pharmaceutical product by any available method. For instance, in the prior art, no API crystal can be visualized in a polymer matrix due to a lack of penetration in conventional methods. However, it has been surprisingly found by the inventors that it is possible to see said particles within said material, in particular in a melt state, using LCI, in particular OCT. It has also been found by the inventors that the invention may be used to directly visualize microcrystals, agglomerates, and size distribution thereof, temperature and/or time dependent crystallization processes, etc. It has furthermore been found that it is highly advantageous to place a suitable probe such as an OCT probe close to an aperture of a die used in the manufacturing. At the aperture, the polymer is usually still in the melt state, which is the state of highest interest in the process. In conclusion, the unexpected invention provides a new way of determining a property of a pharmaceutical product in a melt-solidification process quickly and accurately and enables obtaining a deeper understanding of the melt-solidification process itself without the detrimental effects of conventional methods.

In the context of this document, the term "polymer" may particularly denote a molecule which has been formed by polymerization. For example, it can be a plastic. Further, in particular, the term "polymer" may denote a hydrophobic or a hydrophilic plastic. Further in particular, the term "polymer" may refer to a thermoplastic plastic, i.e. a plastic which is composed of few or non-branched, i.e. linear, carbon chains which are connected to one another only by weak physical bonds and can thus be processed when subjected to heat and pressure, e.g. by bringing the polymer into a flowable state by means of heating above a melting temperature (e.g. in the range between 150°C and 350°C). Further in particular, the term "polymer" may refer to a biocompatible and/or biodegradable plastic, in particular, for example, a plastic that complies with the ISO 10993 series of standards. According to an exemplary embodiment of the present invention, the polymer may be any extrudable polymer. In particular, the polymer may comprise at least one of the group consisting of: An acrylic polymer, caprolactone, a cellulose derivative, a (co)polyester, ethylene vinyl acetate, poly(lactic-co-glycolic acid), a polycaprolactone, a polycarbonate, polyethylene, polyethylene glycol, polyethylene oxide, polyglycolic acid, polylactic acid, a polyolefin, polypropylene, polyurethane, polyvinyl chloride, a polyvinyl lactam polymer. Other polymers such as sugars or derivatives thereof, any polymer that may function as a carrier substance for an API, and in particular 3D-printable polymers and any polymer suitable for melt-solidification in the sense of the present document, are also referred to as "polymer" in the sense of this document.

In the context of this document, the term "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 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.

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 amorph 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 melt-solidification process 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. The autocorrelation signal may result from an interference of light reflected from different positions of the pharmaceutical product during the dissolution procedure. Thus, a reference arm of the interferometer may alternatively be omitted.

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 in process monitoring method. 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 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. The aspects defined above, and further aspects of the invention are apparent from the examples of embodiments 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 onto the pharmaceutical product, and guiding secondary electromagnetic radiation, generated by an interaction between the primary electromagnetic radiation and the pharmaceutical product from the pharmaceutical product. 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 a dosage form, in particular an amorphous solid dispersion, ASD, or a medical device, in particular a matrix based medical device, and the pharmaceutical product comprises at least one active pharmaceutical ingredient, API. These pharmaceutical products may preferably be manufactured by means of a melt-solidification process and are increasingly important in the development of new, highly innovative medicinal and pharmaceutical applications.

According to a further exemplary embodiment of the invention, a monitoring resolution is 5 micron or higher. This is particularly advantageous since the particles of interest, e.g. API particles resulting from a melt-solidification process in the sense of this invention, may have a size of 5 micron or more, as will also be apparent from further embodiments described below. In the context of this document, a particle 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 in pharmaceutical applications fall within the scope of this invention. 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., the measuring device generates primary electromagnetic radiation comprising a fixed wavelength. The wavelength is further selected to attain a higher axial resolution. The major drawbacks of conventional spectroscopic techniques are that they do not provide an absolute value directly and have a limited capability for inter- and intrasample analysis. These problems may be overcome using fixed wavelength OCT, which has the further technical effects and advantages that it is easily deployable, non-destructive and has a high data acquisition rate, a good transversal resolution and an extremely high axial resolution.

According to a further exemplary embodiment of the invention, monitoring the pharmaceutical product comprises monitoring the property of a micron or millimeter range particle, in particular a crystal particle, of a compound present in the pharmaceutical product. According to yet another exemplary embodiment of the invention, the compound comprises at least one of an API, an excipient, a protein. In other words, it may be possible to detect the presence and certain properties of an API, of an excipient, and/or even of a protein, in the pharmaceutical product.

According to a further exemplary embodiment of the invention, monitoring the pharmaceutical product comprises at least one of the group consisting of: visualizing, in particular without modeling, the micron range particle; analyzing, in particular without modeling, a size of the micron range particle; analyzing, in particular without modeling, a size distribution of a plurality of micron range particles; detecting, in particular without modeling, the presence of an agglomerate of micron range particles; detecting, in particular without modeling, a separation of an agglomerate of micron range particles; analyzing, in particular without modeling, when the micron range particle is a crystal, a melting point of the crystal; analyzing, in particular without modeling, a temperature and/or time de-pendent crystallization process; analyzing, in particular without modeling, a reduction of a size of the micron range particle, in particular up to a pre-defined particle size level (or range).

In a pharmaceutical product, in particular if it contains an API, it is usually highly desirable to reach homogeneity and to keep the values of parameters in a certain desired range. For example, it is desirable to keep the (particle) size distribution of an API in a formulation (pharmaceutical product) within a certain range. In some formulations it may be desirable that an API is crystalline, in other formulations it may, however, be desirable that the API is in an amorphous state. In particular if the desired quality or quantity of a certain parameter cannot be reached, the process needs to be adapted and process parameters such as a temperature, a mixing speed, a dwell time etc., have to be set onto an appropriate value. In order to do so, it is crucial to have a deep understanding of the process and also to have a good awareness of an offset. E.g. a particle size distribution has to be known in order to determine whether it is within the desired boundaries or not. It is therefore a beneficial technical effect of the afore-mentioned embodiments of the invention that critical parameters (properties) of the pharmaceutical product during the manufacture can be analyzed, and based on this analysis, the manufacturing process may be adjusted appropriately, if necessary, in order to reach a target (i.e. desired) value of a monitored properties.

Monitoring the pharmaceutical product according to at least one of the examples mentioned above without complex modeling or simulation or complex post processing of instrumental data may have the great advantage that monitoring the pharmaceutical product during manufacturing can be carried out in a particular simple and quick way, e.g. using simple excel based spreadsheets or basic models. 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.

It will be apparent to the skilled person that the monitoring may 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.

According to a further exemplary embodiment of the invention, manufacturing the pharmaceutical product comprises one of the group consisting of: additive manufacturing, in particular three-dimensional printing; spray drying; spray congealing; hot melt extrusion, HME.

In the context of this document, the term "additive manufacturing" (AM) may particularly denote a process in which a product, such as a pharmaceutical product (for instance an implant or a tablet) are formed in a layer-by-layer manner and not, as would conventionally be the case, by removing material (e.g. by milling) or, in the case of the tablet, by compression of powder material.

Additive manufacturing can be highly advantageous in the building of prototypes, but increasingly also in series production. Additive manufacturing is usually also referred to as three-dimensional printing (3D printing). In order to perform an AM process, a material such as a plastic, may be melted such that a filament is formed through a die. By moving the die in three dimensions relative to a support or mold, thereby layering the filaments on top of each other, the final shape, i.e. the final (pharmaceutical) product, may be formed.

In the context of this document, the term "spray drying" may particularly denote a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas. This may be a preferred method of drying of thermally sensitive materials or materials which may require extremely consistent, fine, particle size. Spray dryers commonly use some type of atomizer or spray nozzle (i.e. a die) to disperse the liquid or slurry into a controlled drop size spray. Depending on the process requirements, drop sizes from 10 to 500 pm (micrometers or micron) can be achieved with the appropriate choices. The most common applications are in the 100 to 200 pm diameter range.

In the context of this document, the term "spray congealing" (also referred to as "melt congealing", "spray chilling" or "spray cooling") may particularly denote a method to produce microparticles without the use of organic or aqueous solvent. Spray congealing is a process that transforms a melt into well-defined spherical solid particles. The main characteristic of this technology is the absence of solvent, either aqueous or organic, with related advantages such as low cost, possibility to load hygroscopic and water-sensitive substances and no toxicity related to the presence of organic solvents. Other advantages include the ability to obtain spherical free-flowing micro particles suitable for tableting or capsule filling without the need of other downstream processes. Spray congealing technology is based on the atomization of a fluid in a chamber whose temperature is below the melting point of the carrier and a subsequent solidification of the droplets, leading to the formation of solid particles with dimensions in the micron range. Typical diameters range from 50 to 500 pm. Since there is no solvent evaporation, the particles present a dense structure with neither hollow nor wide porous. The process substantially comprises three steps: feed, atomization (which may be regarded as corresponding to the extrusion in other melt-solidification processes) and solidification stages. Spray congealing may lead to solid dispersions comprising crystalline APIs, amorphous APIs, or to solid solutions comprising a molecular dispersion of the API.

In the context of this document, the term "hot melt extrusion" (HME) may particularly denote a process for the production of a solid dispersion. In particular, "hot melt extrusion" can be construed as a continuous, i.e. uninterrupted, process for the production of a solid dispersion. Furthermore, "hot melt extrusion" may also be a discontinuous process, i.e. a process carried out batchwise. HME may be used to manufacture pharmaceutical products such as implants comprising (crystalline) APIs.

All of the above-mentioned techniques have in common that it is extremely difficult to monitor the respective manufacturing processes. It has, however, surprisingly been found that by using LCI, in particular OCT, these difficulties may be overcome, in particular because effects like interactions between the measurement and the (polymer) matrix of the pharmaceutical product do not interfere with the monitoring process anymore. Further advantages of employing a method comprising the use of LCI, in particular OCT, further in particular fixed- wavelength OCT, for monitoring a pharmaceutical product according to embodiments of the invention, may be summarized as follows. : An interference from the polymer matrix may be eliminated due to the molten state of the polymer. An on-line analysis may be performed at the time of the polymer being in melt state. Thus the particles are clearly visible. Monitoring the pharmaceutical product according to embodiments of the invention may thus comprise at least one of the group consisting of: i) evaluating an optimization of particle size reduction of particles (API, protein, peptide, biologies, etc) during the formulation development or synthesis of API/intermediate may be assisted using the present invention; ii) evaluating a formation of particles (API, protein, peptide, biologies, etc) during the formulation development or synthesis of API/intermediate may be monitored, which was not possible in the prior art; iii) evaluating a residence time in a HME required to completely melt an API, which is a critical parameter for heat sensitive materials. Using this information, a reduction in the exposure time to high temperature of an API may be achieved; iv) evaluating a particle formation or to confirm a complete melting (absence of particles) in spray congealing based formulations; v) evaluating supersaturation kinetics, i.e. embodiments of this invention can also be applied in order to evaluate solubility studies and supersaturation kinetics (e.g. spring- parachute mechanism). Such supersaturation kinetics are e.g. critical in optimizing amorphous solid dispersions. The evaluating steps described above may be performed with or without modeling, according to a further embodiment of the invention.

It has furthermore been surprisingly found that a synthesis of (pharmaceutical) particles (e.g. API, protein, peptide, biologies, excipients, intermediates, etc.) may also be visualized and/or evaluated in melt-solid, and liquid solution. Hence, according to another aspect of the invention, fixed-wavelength low coherence interferometry, in particular optical coherence tomography, may be used in a method for visualizing and/or evaluating the formation of pharmaceutical particles in melt-solid and liquid solution.

According to an exemplary embodiment of the invention, the method is a continuous method, in particular wherein the monitoring is carried out on-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 on-line (or, in yet further embodiments, "in-line" or "at-line") has the great advantage that the process is not interrupted, which may be particularly important for industrial applications. 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 may be highly advantageous to carry out the monitoring on-line without interrupting the manufacturing process. A further advantage of carrying out the monitoring online is that the analysis is done in real-time, i.e. the manufacturing process may be understood in real-time, 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 quantity or quality.

However, sometimes it may be desirable to take a sample of the pharmaceutical product (or, in some cases, the whole finished product like a 3D-printed implant) and carry out the monitoring off-line, e.g. in a (separate) laboratory. 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, and the manufacturing device comprises a die for forming the pharmaceutical product, the die having a die frame comprising an aperture. Furthermore, the arrangement may comprise one of the following features: at least a part of the probe is arranged at the aperture and outside of the die frame, such that the primary electromagnetic radiation can be guided to the pharmaceutical product being manufactured; at least a part of the probe is integrally arranged in the aperture within the die frame such that the primary electromagnetic radiation can be guided to the material of the unfinished pharmaceutical product being manufactured; the manufacturing device comprises a melt inlet configured for feeding a material of the unfinished pharmaceutical product to the die, and at least a part of the probe is integrally arranged in the melt inlet such that the primary electro-magnetic radiation can be guided to the material of the unfinished pharmaceutical product. Depending on which stage of the manufacturing process should be monitored, e.g. a feeding step, a melting step, an extrusion step, or a step of forming the final product, it may be advantageous to arrange the probe of the monitoring device at different positions within the arrangement, in particular with regard to the die. In any case, it is important that 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 that the secondary electromagnetic radiation, which is generated by an interaction between the primary electromagnetic radiation and the pharmaceutical product from the pharmaceutical product, can be guided in an unobstructed way back to the probe.

According to yet another exemplary embodiment of the invention, the probe physically contacts the material of the pharmaceutical product, in particular the unfinished pharmaceutical product, or the probe does not physically contact the pharmaceutical product, in particular the unfinished pharmaceutical product.

Arranging the probe such that it does physically contact the pharmaceutical product may have the advantage that certain properties of the pharmaceutical product could be monitored that would otherwise not be possible, as has been explained above with reference to further embodiments.

Arranging the probe such that it does not physically contact the pharmaceutical product may have the advantage that there is no mechanical interaction between the material of the pharmaceutical product and the probe. This may lead to increased longevity of the probe and may also be advantageous for monitoring different effects (properties) than the ones that could be monitored if the probe is in physical contact with the material of the pharmaceutical product. It may also be advantageous for ensuring that the path of the material is not obstructed by the probe.

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 Drawings

Figure 1 shows a method of monitoring a pharmaceutical product using a meltsolidification process and using low coherence interferometry, LCI, according to an embodiment of the invention.

Figure 2 shows an arrangement for manufacturing a pharmaceutical product according to an embodiment of the invention.

Figure 3 shows an arrangement for manufacturing a pharmaceutical product according to an embodiment of the invention.

Figure 4 shows a spray congealing arrangement for manufacturing a pharmaceutical product according to an embodiment of the invention.

Figure 5 shows a 3D printing arrangement for manufacturing a pharmaceutical product according to an embodiment of the invention.

Figure 6 shows an arrangement according to an embodiment of the invention, wherein a probe is arranged at a melt inlet of a die.

Figure 7 shows an arrangement according to an embodiment of the invention, wherein a probe is arranged within a die.

Figure 8 shows an arrangement according to an embodiment of the invention, wherein a probe is arranged in proximity to an aperture of a die.

Figure 9 shows an interaction between electromagnetic radiation and a pharmaceutical product.

Figure 10A shows a top view image of an implant at room temperature obtained using OCT.

Figure 10B shows an area of an implant formulation analyzed in OCT, the image being obtained from microscopy

Figure IOC shows an image of API particles in melt state of the polymer matrix obtained using OCT.

Figure 10D shows a cross-section area of an implant formulation analyzed in OCT, the image being obtained from microscopy.

Detailed Description

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 method of monitoring a pharmaceutical product 101 using a melt-solidification process and using low coherence interferometry, LCI, according to an embodiment of the invention. Substantially, the method of manufacturing the pharmaceutical product 101 comprises using a meltsolidification process, as shown in block A, and monitoring the pharmaceutical product 101, in particular during the manufacturing process, using low coherence interferometry (LCI), as shown in block B. The method step of block A may comprise one of the group consisting of additive manufacturing, in particular three-dimensional printing; spray drying; spray congealing; hot melt extrusion, (HME). Some of these examples will be explained in more detail below with reference to figures depicting further embodiments of this invention. Block A may be segmented into further blocks C, D, and/or E. The steps are as follows: feeding raw material, C; producing an intermediate product (such as an extrudate), D; forming a final product, E. The steps are optional and further steps (not shown) may be added.

The monitoring step represented by block B comprises, for example, visualizing, in particular without modeling, the micron range particle; analyzing, in particular without modeling, a size of the micron range particle; analyzing, in particular without modeling, a size distribution of a plurality of micron range particles; detecting, in particular without modeling, the presence of an agglomerate of micron range particles; detecting, in particular without modeling, a separation of an agglomerate of micron range particles; analyzing, in particular without modeling, when the micron range particle is a crystal, a melting point of the crystal; analyzing, in particular without modeling, a temperature and/or time dependent crystallization process; analyzing, in particular without modeling, a reduction of a size of the micron range particle, in particular up to a pre-defined particle size level. The method as depicted in the block diagram of Figure 1 is either a continuous method, in particular wherein the monitoring is carried out on-line and/or in real time, or is a discontinuous method, in particular wherein the monitoring is carried out off-line. Further in particular, monitoring the pharmaceutical product 101 may comprise monitoring one manufacturing step only, or monitoring a plurality or all of the manufacturing steps comprised by block A. If the monitoring is done offline in accordance with embodiments of the invention, samples of the pharmaceutical product 101 from one step only, or from a plurality or all of the manufacturing steps comprised by block A, may be taken, and analyzed e.g. in a laboratory.

Figure 2 shows an arrangement 100 for manufacturing a pharmaceutical product 101 according to an embodiment of the invention. The arrangement 100 for manufacturing a pharmaceutical product 101 comprises a manufacturing device 110 configured to produce the pharmaceutical product 101 by meltsolidification; and a monitoring device 120 associated with the manufacturing device 110 and configured to monitor the pharmaceutical product 101, in particular during the manufacturing process, using low coherence interferometry, LCI. In this particular embodiment, there is shown a hot melt extrusion (HME) arrangement 100, comprising a manufacturing device 110 for carrying out a HME process. The manufacturing device, which comprises a funnel 116 for feeding a pharmaceutical product 101, which at this stage is still a raw material 102, which may comprise one or more excipients and/or one or more active pharmaceutical ingredients (APIs). The raw material 102 is fed into heating barrels 117, where the raw material is substantially melted, homogenized (mixed) and/or further processed. The thus processed raw material 102 is then fed into a melt inlet 114 (not shown) of a die 111 for forming the pharmaceutical product 101, the die 111 having a die frame 112 comprising an aperture 113; The pharmaceutical product 101 is then extruded through the aperture 113 and an extrudate is produced as an intermediate product 103 in the process of manufacturing the final product 104. In the embodiment that is depicted in Figure 2, the final product is formed by means of a mold 115. As can be taken from Figure 2, the monitoring device 120 is associated with the manufacturing device 110. In particular, at least a part of the probe 121 is integrally arranged in the aperture 113 within the die frame 112 such that the primary electromagnetic radiation can be guided to the material of the unfinished pharmaceutical product 101 being manufactured. Figure 3 also shows an arrangement 100 for manufacturing a pharmaceutical product 101 according to an embodiment of the invention. Substantially, the arrangement 100 is the same as the one shown in Figure 2. However, in accordance with a further embodiment of the invention, at least a part of the probe 121 is arranged at the aperture 113 and outside of the die frame 112, such that the primary electromagnetic radiation can be guided to the pharmaceutical product 101 being manufactured. The embodiments shown in Figure 2 and Figure 3 will be described in more detail below with reference to further Figures and further embodiments.

Figure 4 shows a spray congealing arrangement 100 for manufacturing a pharmaceutical product 101 according to an embodiment of the invention. In brief, there is depicted raw material 102 of the pharmaceutical product 101 which is fed into a die 111, comprising a die frame 112 which comprises a heated jacket. The raw material 102 is then processed by means of spray congealing into an intermediate product 103 or final product 104. Further details regarding the die 111 encompassed by the circle are explained with reference to Figures 7 to 9. Figure 5 shows a 3D printing arrangement 100 for manufacturing a pharmaceutical product 101 according to an embodiment of the invention. In brief, there is depicted raw material 102 of the pharmaceutical product 101 which is fed as a filament into a die 111 comprising a die frame 112 comprising a heated jacket. The filament 102 is processed into a 3D printing filament which is the intermediate product 103. The final product 104, which may be a 3D printed formulation or a 3D printed implant, for example, is formed on a support structure 118. Further details regarding the die 111 encompassed by the circle are explained with reference to Figures 7 to 9.

Figure 6 shows an arrangement 100 according to an embodiment of the invention, wherein a probe 121 is arranged at a melt inlet 114. Figure 7 shows an arrangement 100 according to an embodiment of the invention, wherein a probe 121 is arranged within a die 111. Figure 8 shows an arrangement 100 according to an embodiment of the invention, wherein a probe 121 is arranged in proximity to an aperture 113 of the die 111. The die in Figure 6 to Figure 8 comprises a melt inlet 114 configured for feeding a material of the unfinished pharmaceutical product 101 to the die 111, a die frame 112, which may for example comprise a heated jacket, and an aperture (or outlet, nozzle) 113. The probe 121 in Figure 6 to Figure 8 is arranged such that electromagnetic radiation (e.g., primary, and secondary electromagnetic radiation 122, 123) can be guided to and from the pharmaceutical product 101. According to embodiments, the probe 121 is arranged integrally in the respective melt inlet, die, and/or aperture. In Figure 6, in particular, the probe 121 is arranged at the melt inlet 114. Therefore, it is possible to monitor the raw material 102 that is fed into the die 111 at the melt inlet 114. As has been explained above already, the probe 121 may be integrally arranged with the melt inlet 114, such that the raw material 102 may be monitored at the exact point of entry into the die 111. In Figure 7, the probe 121 is integrally arranged within the die frame 112 in proximity to the aperture 113. Therefore, the probe has insight into the die 111 and the pharmaceutical product 101 can be monitored before or while exiting the die at or through the aperture 113. Lastly, in Figure 8, the probe 121 of the monitoring device 121 is arranged in proximity to an aperture 113 of the die 121, i.e. outside of the die 121 but such that the primary and secondary electromagnetic radiation can be guided in an unobstructed manner to and from the pharmaceutical product 101, in particular the intermediate product 103 which may for example be a 3D-printing filament, an extrudate, or the atomized liquid or slurry in a spray drying process. As has been explained above already, the probe 121 may be integrally arranged with the aperture 113, such that the intermediate product 103 may be monitored at the exact point of exit from the die 111.

In the embodiments depicted in Figure 6 to Figure 8, it is possible that the probe 121 either physically contacts the material of the pharmaceutical product 101 or that the probe 121 does not physically contact the pharmaceutical product 101. It furthermore lies within the scope of the invention that in particular any or all of the embodiments depicted in Figure 6 to Figure 8 are combined, i.e. an arrangement 100 according to a further embodiment of the present invention may comprise any combination of a probe 121 being arranged at a melt inlet 114, and/or a further probe 121 being arranged within a die 111, and/or another probe 121 being arranged in proximity to an aperture of the die.

The arrangements 100 as shown in Figures 2 to 8, or similar arrangements 100 according to other embodiments of this invention, can be comprised in a pharmaceutical plant (not shown).

Figure 9 shows an interaction between electromagnetic radiation and a pharmaceutical product 101. Primary electromagnetic radiation 122 is generated in the monitoring device 120 and then guided onto the pharmaceutical product 101 (which may comprise either a raw material 102, an extrudate or a different intermediate product 103, or the final product 104). In consequence, secondary electromagnetic radiation 123, generated by an interaction between the primary electromagnetic radiation 122 and the pharmaceutical product 101, is guided from the pharmaceutical product 101 back to the probe 121 of the monitoring device 120. The pharmaceutical product 101 is, for example, a dosage form, in particular an amorphous solid dispersion, ASD, or a medical device, in particular a matrix based medical device, and comprises in an embodiment of the invention at least one active pharmaceutical ingredient, API. The monitoring as shown in the Figures, according to preferred embodiments of the invention, uses low coherence interferometry, 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 9 comprises one wavelength of the electromagnetic spectrum only. It can furthermore be taken from Figure 9 that the probe 121 does not physically contact the pharmaceutical product 101. However, as has been described with respect to other Figures and/or embodiments, the probe 121 may physically contact the material of the pharmaceutical product 101, in particular the unfinished pharmaceutical product 101.

Figures 1OA to 1OD show images resulting from monitoring a pharmaceutical product according to embodiments of the present invention. Figure 1OA shows a top view image of an implant at room temperature obtained using OCT. Figure 10 B shows an area of an implant (e.g. a HME based implant) formulation analyzed in OCT (Figure 10A), the image being obtained from microscopy. Figure IOC shows an image of crystalline API particles in melt state of the polymer matrix obtained using OCT. Figure 10D shows a cross-section area of an implant formulation analyzed in OCT (Figure 10C), the image being obtained from microscopy. The monitoring resolution in these images is 5 micron or higher, in accordance with embodiments of the invention. The analyzed particles are micron or millimeter range particles, such as crystal particles, of a compound present in a pharmaceutical product 101. Compounds comprising at least one of an API, an excipient, a protein, a peptide, or (other) biologies may be analyzed as shown in Figures 10A to 10D.

As is apparent from all Figures, using fixed-wavelength low coherence interferometry, in particular optical coherence tomography, for real-time monitoring of a pharmaceutical product 101 during a melt-solidification process in the manufacturing of the pharmaceutical product 101, 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 sions:

A Manufacturing a pharmaceutical product using a melt-solidification process B Monitoring the pharmaceutical product using low coherence interferometry C Feeding raw material

D Producing an intermediate product

E Forming a final product

100 Arrangement

101 Pharmaceutical product

102 Raw material

103 Intermediate product

104 Final product

110 Manufacturing device

111 Die

112 Die frame

113 Aperture

114 Melt inlet

115 Mold

116 Funnel

117 Heating barrels

118 Support structure

120 Monitoring device

121 Probe

122 Primary electromagnetic radiation

123 Secondary electromagnetic radiation