Multi-medicine manufacturing facility with forecasting function

Abstract

A method of managing a multi-medicine manufacturing facility (100) configured for manufacturing a selected medicine (236) of a set of supported medicines on demand, wherein the method comprises stocking a set of different active pharmaceutical ingredients (102) each in a different one of a set of storage containers (104) separately from excipients (108) under long-term storage conditions, provisioning a set of pre-approved recipes (106) for manufacturing each of the said set of supported medicines by executing a predefined manufacturing process using at least one of said active pharmaceutical ingredients (102) in a predefined formulation at the multi-medicine manufacturing facility (100), forecasting a development of at least one medicine-related parameter, and managing said stocking and / or said provisioning and / or manufacturing of a selected medicine (236) on demand based on said forecasting.

Description

[0001] Multi-medicine manufacturing facility with forecasting function

[0002] The invention relates to a multi-medicine manufacturing facility, and a method of managing a multi-medicine manufacturing facility.

[0003] Medicines such as tablets, pellets, capsules, injections, patches, implants, inhalers and the like are required worldwide. However, shortage of medicines may be a severe problem.

[0004] It is an object of the invention to provide a possibility of avoiding shortage of medicine and / or to accelerate medicine supply.

[0005] In order to achieve the object defined above, a multi-medicine manufacturing facility, and a method of managing a multi-medicine manufacturing facility according to the independent claims are provided.

[0006] According to an exemplary embodiment of the invention, a method of managing a multi-medicine manufacturing facility configured for manufacturing a selected medicine of a set of supported medicines on demand is provided, wherein the method comprises stock-piling (or stocking) a set of different active pharmaceutical ingredients each in a different set of storage containers separately from excipients under long-term storage conditions, provisioning a set of pre-approved recipes for manufacturing each of the said set of supported medicines by executing a predefined manufacturing process using at least one of said active pharmaceutical ingredients in a predefined formulation at the multi-medicine manufacturing facility, forecasting a development of at least one medicine-related parameter, and managing said stocking and / or said provisioning and / or manufacturing of a selected medicine on demand based on said forecasting.

[0007] According to another exemplary embodiment of the invention, a multimedicine manufacturing facility configured for manufacturing a selected medicine of a set of supported medicines on demand is provided, wherein the multi-medicine manufacturing facility comprises a stocking device stock-piling (or stocking) a set of different active pharmaceutical ingredients each in a different one of a set of storage containers separately from excipients under long-term storage conditions, a recipe provisioning unit provisioning a set of pre-approved recipes for manufacturing each of the said set of supported medicines by executing a predefined manufacturing process using at least one of said active pharmaceutical ingredients in a predefined formulation at the multi-medicine manufacturing facility, a forecasting unit for forecasting a development of at least one medicine-related parameter, and a managing unit for managing said stocking and / or said provisioning and / or manufacturing of a selected medicine on demand based on said forecasting.

[0008] In the context of the present application, the term "multi-medicine manufacturing facility" may particularly denote a production facility, such as a factory or manufacturing plant, which is configured as a multi-purpose medicine manufacturing facility. This may encompass different routes of manufacturing, such as tableting via direct compression or roller compaction or wet granulation or hot-melt extrusion routes. Tablets can encompass immediate release or modified release tablets. Alternatively, capsule filling, multi-layer tableting, sachet filling, film extrusion, production of suppositories can be considered. In addition, vial filling for powder for reconstitution can be considered or filling of capsules for dry powder inhalation, or filling of metered-dose and soft mist inhalers. Thus, the multi-medicine manufacturing facility may not be specifically configured for manufacturing only a specific type of medicine, but may in contrast to this be capable of and configured for supporting the manufacture of a plurality (for instance at least 10 or even at least 100) of different types of pre-defined medicines. This configuration may be on a hardware level by providing various machines for manufacturing the different pre-defined types of medicine, what concerns an official authorization or approval to manufacture the different pre-defined types of medicine, and what concerns active pharmaceutical ingredients required to manufacture the different pre-defined types of medicine. The multi-medicine manufacturing facility may be designed to be flexibly configurable and re-configurable for manufacturing one or more selected types of medicine of a larger set of supported types of medicine. Moreover, on-demand manufacturing is possible with said facility.

[0009] In the context of the present application, the term "medicine" may particularly denote a composition which may be adapted to be administered to a human or an animal, and which comprises at least one physiologically active agent. For example, the medicine may be a tablet having a solid outer shell and a liquid core. Further, the medicine may be partially or entirely solid. In particular, a dosage form of the medicine may be a tablet, a pellet, a bead, a pill, a soft- and hard-shell capsule, a suppository, a strand, a patch, a film such as an ODF (oral dispersible film), a film foil, a ring, a filled vial, a filled inhaler and all other pharmaceutical compositions. Further, the medicine may comprise one or more active drug components (such as an active pharmaceutical ingredient) and / or one or more non-drug components. The one or more non-drug components may for example comprise one or more excipients. For example, the medicine may be a pharmaceutical drug and / or a dietary supplement.

[0010] In the context of the present application, the term "a set of supported medicines" may particularly denote a plurality (for example at least 10 or even at least 100) of types of medicines, each of which being manufacturable by the multi-medicine manufacturing facility. However, also any smaller number may be possible in certain embodiments.

[0011] In the context of the present application, the term "active pharmaceutical ingredient" (API) may particularly denote one or more active components in a medicine or pharmaceutical drug that produce(s) a required effect on the body to treat a condition such as a disease. APIs may be produced by processing chemical compounds.

[0012] In the context of the present application, the term "excipients" may particularly denote everything other in a medicine than the one or more active pharmaceutical ingredients. For example, excipients may comprise adjuvants, anti-adherence, binders, coatings, colors, disintegrants, flavors, glidants, lubricants, preservatives, sorbents, sweeteners and / or vehicles for targeted delivery and enhancement of bioavailability. In particular, excipients may be inert constituents of a medicine. Examples for excipients may be polymers, corn, wheat, sugar, minerals, cyclodextrins, dextran, and polyethylene glycol and derivatives thereof. Exemplary functions of excipients are aiding in the processing of the medicine during its manufacture, protection, support and / or enhancement of stability, bioavailability and / or patient acceptability, assistance in product identification, enhancement of one or more attributes of the overall safety, assistance in the effectiveness and / or delivery of the medicine in use, and / or assistance in maintaining the integrity of the medicine during post-manufacture storage.

[0013] In the context of the present application, the term "stock- pi ling (or stocking) under long-term storage conditions" may particularly denote configuring the storage conditions of the active pharmaceutical ingredients in their storage containers so that their storage without decomposition, degradation, change of properties, change of processability and / or loss or reduction of pharmaceutical effectiveness can be ensured for a longer time than under standard conditions (such as frigerated or at room temperature and air atmosphere at normal pressure). In particular, the long-term storage conditions of a respective active pharmaceutical ingredient may be configured so that an inacceptable change of properties rendering the respective active pharmaceutical ingredient inappropriate for medicine manufacture does not occur prior to 10 years of storage, preferably not prior to 20 years of storage.

[0014] In the context of the present application, the term "a set of preapproved recipes" may particularly denote a set of data sets, each data set defining the conditions of manufacturing a specific medicine by the multimedicine manufacturing facility based on at least one active pharmaceutical ingredient and one or more excipients. Said recipe may already be approved by an official authority, such as the EMA (European Medicines Agency) in the European Community, the FDA (Federal Drug Administration) in the United States of America or others. Such an authorization or pre-approval may be obtained before, for example at least 6 months before, receiving a demand for producing the corresponding medicine in the multi-medicine manufacturing facility. Said set of pre-approved recipes may be stored in a database, for instance of a mass storage device such as a hard disk. Upon triggering the manufacture of a specific medicine on demand, access to the assigned preapproved recipe in such a database may be obtained, and the manufacturing process may be executed accordingly.

[0015] In the context of the present application, the term "manufacturing a supported medicine by executing a predefined manufacturing process in a predefined formulation" may particularly denote that a selected medicine may be physically produced by the multi-medicine manufacturing facility by carrying out a manufacturing process corresponding to a pre-approved recipe to form a medicine with a pre-defined composition of one or more stored active pharmaceutical ingredients and one or more excipients.

[0016] In the context of the present application, the term "medicine-related parameter" may particularly denote at least one parameter being correlated with at least one of the medicines or types of medicine being manufacturable by the multi-medicine manufacturing facility. For instance, such a medicine- related parameter may be indicative of or may be correlated with the availability of an active pharmaceutical ingredient and / or an excipient used for manufacturing said medicine by said multi-medicine manufacturing facility. Additionally or alternatively, a medicine-related parameter may be considered being indicative of or correlated with a demand for a medicine being manufacturable by said multi-medicine manufacturing facility, in particular using one or more of the stored active pharmaceutical ingredients. Such one or more medicine-related parameters may provide meaningful information indicating a future development which may have an impact on the managing of the multi-medicine manufacturing facility.

[0017] In the context of the present application, the term "forecasting a development of a medicine-related parameter" may particularly denote making a prediction how the at least one medicine-related parameter or a trend correlated therewith may change in the future. For this purpose, facility internal and / or facility external information, such as historic, present and / or future-oriented information may be processed, for instance using machine learning, data-driven models and / or expert rules. More specifically, forecasting may be made with the goal to identify shortage or volatility of medicine demands and / or to identify information characterizing availability of APIs and / or excipients.

[0018] In the context of the present application, the term "managing stockpiling (or stocking) and / or provisioning and / or selected medication manufacture" may particularly denote adding at least one active pharmaceutical ingredient to the stock and / or removing at least one stocked active pharmaceutical ingredient from the stock and / or adding at least one pre-approved recipe and / or removing at least one provisioned pre-approved recipe and / or selection and / or triggering manufacture of a specific medication for production by the manufacturing facility in accordance with the forecast of the development of the at least one medicine-related parameter. For instance, if the forecast indicates that market availability of a respective active pharmaceutical ingredient or excipient is presently or in the near future advantageous from a buyer's perspective, said active pharmaceutical ingredient or excipient may be added to a corresponding storage container of the multi-medicine manufacturing facility. For example, if the forecast indicates that market demand of a specific medicine is presently or in the near future high, the multi-medicine manufacturing facility may be triggered to manufacture said medicine. If the forecasting information indicates that a certain medicine might have a high market demand in view of a shortage or a volatility, said medicine may be selected for production by the manufacturing facility.

[0019] According to an exemplary embodiment, a multi-medicine manufacturing facility may be operated for manufacturing a selected medicine of a set of supported medicines with a concrete demand as a trigger for the selection and the manufacture of said medicine. Thus, the multi-medicine manufacturing facility is not constructed to be optimized for the manufacture of one medicine only, but functions as a multi-purpose facility which can be flexibly configured or re-configured for manufacturing one of a plurality of supported medicines. Thereby, a quick response to a rapidly evolving or changing demand for a certain medicine, for instance in the event of a shortage, may be possible with the multi-medicine manufacturing facility. Just as an example, in the event of an epidemic or a pandemic, a demand for a specific medicine may rise very quickly so that existing manufacturing capacities may not be able to cope with such sudden changes of demand. As another example, a fire in a big manufacturing plant manufacturing a significant percentage of a national or worldwide number of required doses of a medicine may also lead to a quick need of additional medicine manufacturing capacity to avoid drug shortage with dramatic consequences. In order to be quickly able to provide a considerable amount of manufacturing capacity for a specific medicine, the multi-medicine manufacturing facility may pre-stock a set of different active pharmaceutical ingredients each in a different one of a set of storage containers and separately from excipients. The APIs may be stored under long-term storage conditions. By stocking the active pharmaceutical ingredients (which may for instance contribute only about 1% or a few percents of the entire weight of a medicine) separately from usually less sensitive excipients, the long-term storage conditions (such as cooling, a protection atmosphere, sensor monitoring, mixing and / or vibration to prevent clustering, etc.) need only be provided for a relatively small amount or volume. Moreover, it may be advantageous to provide already long in advance of an actual manufacturing process a set of pre-approved recipes for manufacturing each of the said set of supported medicines by executing a predefined manufacturing process using at least one of said active pharmaceutical ingredients in a predefined formulation at the multi-medicine manufacturing facility. Hence, the usually quite long time needed for obtaining official authorization for manufacturing a specific medicine in a specific plant may be shifted to a time prior to an actual demand for producing a specific medicine, thereby rendering the on-demand manufacture of a specific medicine by the multi-medicine manufacturing facility fast and flexible. Further advantageously, a development of at least one medicine-related parameter (such as market availability of active pharmaceutical ingredients and / or of excipients, as well as a market demand for a specific medicine produced based on one or more active pharmaceutical ingredients and one or more excipients) may be forecasted or predicted by monitoring information, preferably using elements of artificial intelligence. Furthermore, the above described stocking and / or provisioning tasks may be executed under consideration of results obtained by said forecasting. Also manufacturing of a selected medicine on demand may be triggered and / or selected and / or controlled based on said forecasting. Advantageously, the described multi-medicine manufacturing facility architecture may allow to provide a possibility of reliably avoiding shortage of medicines and thereby preventing dramatic health consequences.

[0020] In the following, further exemplary embodiments of the multi-medicine manufacturing facility, and the method will be explained.

[0021] In an embodiment, the method comprises manufacturing a selected medicine of said set of supported medicines in the multi-medicine manufacturing facility triggered by a demand request. Activation of the manufacture of a medicine may then require a dedicated demand request. For instance, said demand request may be generated by the managing unit, by the forecasting unit, manually by an operator or by an external entity.

[0022] In an embodiment, the method comprises manufacturing a selected medicine of said set of supported medicines in the multi-medicine manufacturing facility triggered by a result of said forecasting. In particular, the selection of a medicine to be manufactured from the supported set of medicines may be made in accordance with the result of the forecasting. When for instance the medicine-related parameter indicates that a shortcoming of a specific medicine can be expected or is likely (for instance due to an epidemic or an event- caused reduction of the worldwide medicine manufacturing capacity), specifically the manufacture of this medicine may be triggered.

[0023] In an embodiment, the method comprises manufacturing a selected medicine of said set of supported medicines in the multi-medicine manufacturing facility including milling, sieving, blending, granulating, drying, tableting, capsule filling, vial filling, inhaler filling, hot-melt extrusion and / or coating. Additionally or alternatively, the manufacturing facility may also support other manufacturing stages.

[0024] In an embodiment, the method comprises defining said long-term storage conditions (for instance cooling temperature, relative humidity, presence or absence of an inert gas atmosphere, vibrations to reduce or minimize caking, etc.) individually for each storage container. The long-term storage conditions may thus to be selected in an API-specific way. The more critical a specific API is in terms of instability over time, the higher may be the invested effort for long-term storage, and vice versa. The individual API-specific definition of long-term storage conditions may allow to reliably ensure long-term stability of all APIs while keeping the storage effort moderate.

[0025] In an embodiment, the method comprises obtaining approval of each of the set of pre-approved recipes from an official authority prior to receipt of a demand request for manufacturing a selected medicine of said set of supported medicines in said manufacturing facility. To put it shortly, official approval for manufacturing a specific medicine in the manufacturing facility may be obtained far in advance before receiving an actual go to start the medicine manufacturing process. What concerns official approval, this task may be completed for each supported medicine before a decision is taken which of said medicines will be actually manufactured in the manufacturing facility. This may allow to shorten the response time before actually starting manufacture of a medicine in the event of a sudden demand and may therefore increase the flexibility of the manufacturing facility.

[0026] In an embodiment, the method comprises obtaining said approval in time periods in which no medicine is manufactured in said manufacturing facility. Hence, inactive time intervals in which the multi-purpose manufacturing facility is actually not manufacturing medicines (for instance in the absence of medicine shortage) may be used for completing the process for obtaining official approval to manufacture the medicines.

[0027] In an embodiment, the method comprises forecasting a development of market availability of a respective active pharmaceutical ingredient as one of the at least one medicine-related parameter. Elements of information relating to market availability of a certain API may be delivery time, price, worldwide production capacity, market demands, etc., for said API. When the forecasting unit determines that market availability of a certain API is high, the forecasting unit or the managing unit may trigger acquisition of said API for addition to the facility's API stock.

[0028] In an embodiment, the method comprises forecasting a development of market demand of a medicine comprising a respective active pharmaceutical ingredient as one of the at least one medicine-related parameter. Elements of information relating to market demand of a certain medicine may be a reported shortage of said medicine, a reported volatility of said medicine, an increasing market demand (for instance event-based) of said medicine, or an expected price increase, etc. When a sufficiently high market demand is determined for a certain medicine by the forecasting unit, manufacture of said medicine in the manufacturing facility may be triggered. A sufficiently high market demand may be assumed if the forecast market demand exceeds a predefined threshold value, or when indications of shortage or volatility are present.

[0029] In an embodiment, the method comprises accounting for the management of the stocked active pharmaceutical ingredients in case the end of its storability comes close. For example, if an active pharmaceutical ingredient can be only stored for only 2 (or so) more years, a manufacturing of the respective medicine may be triggered (for instance based on market parameters). Simultaneously the procurement of the same API for restocking may be triggered. Combined with shelf life prediction this may be a very efficient stock management scheme and may involve low effort.

[0030] In an embodiment, the method comprises forecasting a development of market availability of excipients used in combination with said active pharmaceutical ingredients for manufacturing medicines as one of the at least one medicine-related parameter. Elements of information relating to market availability of a certain excipient may be delivery time, price, worldwide production capacity, market demands, etc., for said excipient. When the forecasting unit determines that market availability of a certain excipient is high, the forecasting unit or the managing unit may trigger acquisition of said excipient.

[0031] In an embodiment, the method comprises forecasting said development of said at least one medicine-related parameter using machine learning. The term "machine learning" may particularly denote the implementation of algorithms and / or statistical models that a processor (such as a computer system) may use to perform a specific task without using explicit instructions, relying on patterns and inference instead. Machine learning may be considered as a subset of artificial intelligence. In particular, machine learning algorithms may build a mathematical model based on sample data (which may also be denoted as training data) in order to make predictions or decisions without being explicitly programmed to perform the task. Machine learning algorithms may be particularly appropriately applied in the evaluation of availability of an API and / or demand for a medicine including a certain API, since a large amount of publicly available information (for instance obtainable via the public Internet) can be used for training a machine learning algorithm.

[0032] In an embodiment, the method comprises forecasting based on input data relating to actual health data of a population, demographic data, epidemic and / or pandemic events, existing and / or planned manufacturing plants, medical economics data, demand volatility of a medicine, a demand peak of a medicine, a forecast of population dynamics and / or a delivery shortage of a medicine. However, other input data may be used additionally or alternatively. In an embodiment, the method comprises ordering excipients for manufacturing said selected medicine triggered by a demand request for manufacturing said selected medicine. For instance, such a trigger may be generated by the managing unit or the forecasting unit when a high market availability of a certain excipient is determined or forecast.

[0033] In an embodiment, the method comprises stocking a set of different active pharmaceutical ingredients which comprises active pharmaceutical ingredient required for manufacturing essential medicines according to the WHO Model Lists of Essential Medicines as listed by the World Health Organization. The WHO Model Lists of Essential Medicines are updated every two years by the Expert Committee on Selection and Use of Essential Medicines. By considering APIs for storage according to said lists may ensure that meaningful medicines can be manufactured flexibly by the manufacturing entity, in particular quickly in the event of shortage or volatility.

[0034] In an embodiment, the method comprises stocking a set of different active pharmaceutical ingredients which comprises anti-infective active pharmaceutical ingredients, an anti-cancer active pharmaceutical ingredient, anti-inflammatory, immune-modulators, molecules for neurological diseases, an antipain active pharmaceutical ingredient, an anti-depressant active pharmaceutical ingredient and / or a metabolic agent. However, one or more other APIs may be stocked additionally or alternatively.

[0035] In an embodiment, the method comprises updating the stocked set of different active pharmaceutical ingredients based on said forecasting. For instance, if the forecasting indicates that a demand for a medicine using a stocked API is presently reduced or is probably reduced permanently, such an API may be removed from the stock of APIs. For example, if the forecasting indicates that a demand for a medicine using a non-stocked API is presently increased or is probably increased permanently, such an API may be added to the stock of APIs.

[0036] In an embodiment, said stocking device comprises a cooling device configured for cooling said active pharmaceutical ingredients in said storage containers. Cooling the APIs during storage may increase the storage time before deterioration of API stability. In an embodiment, the cooling device is configured for cooling different active pharmaceutical ingredients in different storage containers in different temperature ranges. Providing different cooling temperature ranges may allow to precisely adjust the cooling characteristics to the specific needs of a respective API.

[0037] In an embodiment, said stocking device is configured for stocking said active pharmaceutical ingredients in an inert gas atmosphere. Such an inert gas atmosphere may reduce the chemical interaction of the API with the environment. Consequently, an inert gas atmosphere may promote long-term storage without loss or reduction of stability of the API. For instance, an inert gas atmosphere may be a nitrogen atmosphere or any other noble gas atmosphere.

[0038] In an embodiment, said stocking device comprises a motion promoting device configured for promoting motion between particles of a respective active pharmaceutical ingredient to suppress clustering (in particular caking) of said particles. Descriptively speaking, active pharmaceutical ingredients may tend over time to cluster by forming grain boundaries or by sintering. Such cluster formation events may be detected by a sensor unit. When cluster formation events are detected, the motion promoting device may promote motion between the particles to avoid clustering and may thereby maintain stability of the active pharmaceutical ingredient. Additionally or alternatively, it is also possible that the motion promoting device is activated to promote motion between particles of a respective API without trigger by a sensor event, for instance from time to time or permanently.

[0039] In an embodiment, said motion promoting device is configured for generating vibration for moving said particles. Promoting vibration of said particles has turned out as highly efficient for avoiding undesired cluster formation events. Thus, vibrating the active pharmaceutical ingredients may promote their long-term stability.

[0040] In an embodiment, said stocking device comprises a sensor unit configured for sensing sensor data indicative of a change of a condition of said active pharmaceutical ingredient in a respective storage container. Preferably, such a sensor unit may sense in real-time changes concerning the stability of active pharmaceutical ingredients. Alternatively, a sensor may detect conditions leading to instability, for example when water vapor (or humidity) or oxygen enters the storage container.

[0041] In an embodiment, the motion promoting device is configured for being activated for promoting motion of particles of a respective active pharmaceutical ingredient when the sensor data indicate a critical change of a condition of said active pharmaceutical ingredient in the respective storage container. Thus, the motion promoting device may be activated when the sensor unit provides sensor data being indicative of an actual risk of clustering of particles of the API.

[0042] In an embodiment, said sensor unit comprises a spectrometer for spectroscopically sensing said sensor data. For instance, said spectrometer may comprise a Raman spectrometer, a near infrared spectrometer, a Fourier Transform infrared spectrometer, an ultraviolet light spectrometer and / or a visual light spectrometer. Other sensor units may be used as well, such as a liquid or gas chromatography device, for instance an HPLC or a GC (gas chromatography device).

[0043] In an embodiment, said sensor unit comprises a sensor head in and / or on the respective storage container for sensing electromagnetic sensor data, an optical fiber optically connected with said sensor head, and an evaluation unit optically connected with the optical fiber and configured for evaluating said sensor data. Preferably, said sensor head may extend into the storage container so as to be highly sensitive to actual properties of the API contained in said storage container. At the same time, the optical fiber or light guide may couple electromagnetic radiation (such as visible light) into and / or out of the sensor head. The evaluation unit may evaluate detected electromagnetic radiation outside of the storage container and thus without reducing the storage capacity thereof.

[0044] In an embodiment, said sensor unit is configured for determining stability information concerning said active pharmaceutical ingredient based on said sensor data evaluated by machine learning. Hence, elements of artificial intelligence or other data-driven methods may be used for processing the sensor data for obtaining meaningful information about the present stability of the API. These methods can also be used to predict stability. In an embodiment, the storage capacity of each of said storage containers is in a range from 10 kg to 2000 kg. Thus, a relatively large amount of API material may be stored, nevertheless allowing to manufacture on demand a significant amount of dosage units of medicine. At the same time, the stored amount of API may be significantly smaller than the amount of material needed for the entire medicine, which may also comprise a major portion of excipient. Hence, the storage volume may still be moderate while allowing at same time to manufacture a large amount of medicine.

[0045] In an embodiment, the manufacturing facility comprises a mirror stocking device stocking a set of said different active pharmaceutical ingredients each in a different one of a set of mirror storage containers, wherein a storage capacity of each of said mirror storage containers is smaller than a storage capacity of an assigned one of said storage containers, and a stress test unit configured for carrying out a stress test for said active pharmaceutical ingredients in said mirror storage containers by applying conditions being less favourable in terms of stability than said long-term storage conditions and configured for monitoring stability of said active pharmaceutical ingredients in said mirror storage containers for deriving stability information concerning said different active pharmaceutical ingredients in said storage containers and / or for predicting stability concerning said different active pharmaceutical ingredients in said storage containers. With the concept of mirror stocking the same API in a significantly smaller amount (for instance less than 10 weight percent or even less than 1 weight percent of the API in the actual storage container), meaningful information about APIs storage stability may be obtained which may also allow to fine-tune the long-term storing conditions of the API in the actual storage container. The less favourable storage conditions in the respective mirror storage container may include a higher temperature, the absence of an inert gas atmosphere, the absence of particle motion for suppressing clustering, etc. Thus, the stability reduction of the API may be studied or analyzed in the mirror storage container in fast motion compared to the API stored in the corresponding storage container under more favorable conditions. Hence, counteractions against reduction or loss of stability of an API in a storage container may be taken in due time based on information received from the same API in the mirror storage container. For instance, such counteractions may include a decrease of the storage temperature, the provision of an inert gas atmosphere and / or the promotion or more frequent promotion of particle motion for suppressing clustering). Advantageously, sensor data of stressed active pharmaceutical ingredients in said mirror storage containers may indicate a critical change of a condition of said active pharmaceutical ingredient in the respective storage container, and may be used to enhance storage conditions in the respective storage containers to promote long-term stability of said active pharmaceutical ingredients in said storage containers.

[0046] 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 embodiment.

[0047] Figure 1 illustrates a schematic view of a multi-medicine manufacturing facility according to an exemplary embodiment.

[0048] Figure 2 illustrates a schematic view of a storage container of a multimedicine manufacturing facility according to an exemplary embodiment.

[0049] Figure 3 illustrates a schematic view of a multi-medicine manufacturing facility according to an exemplary embodiment.

[0050] Figure 4 illustrates a cooled storage room of a multi-medicine manufacturing facility according to an exemplary embodiment.

[0051] Figure 5 illustrates a multi-medicine manufacturing facility according to an exemplary embodiment.

[0052] Figure 6 illustrates elements of a multi-medicine manufacturing facility according to an exemplary embodiment.

[0053] Figure 7 illustrates elements of a multi-medicine manufacturing facility according to an exemplary embodiment.

[0054] Figure 8 illustrates a schematic view of an artificial intelligence-based forecasting unit of a multi-medicine manufacturing facility according to an exemplary embodiment.

[0055] The illustrations in the drawings are schematic. In different drawings, similar or identical elements are provided with the same reference signs. Before, referring to the drawings, exemplary embodiments will be described in further detail, some basic considerations will be summarized based on which exemplary embodiments of the invention have been developed.

[0056] Conventionally, it takes many months and sometime even up to a year to receive large quantities of a medicine, especially during supply chain crises. This may create huge strains on healthcare systems around the globe.

[0057] Stocking (i.e., stockpiling) of essential medicines can counteract shortterm supply chain problems. However, stockpiling of readily manufactured drug products has significant disadvantages: Drug products are expensive and may require significant storage space (typically only less than 1 weight percent of a medicine package is drug). Furthermore, drug products have limited shelf life (typically three years) and must then be destroyed and replaced. This leads to high effort, large facilities, a significant environmental impact and a high carbon footprint.

[0058] According to an exemplary embodiment, a multi-medicine manufacturing facility is provided which may allow to manufacture each selected medicine of a supported set. Advantageously and contrary to conventional approaches, such a multi-medicine manufacturing facility may execute a specific medicine manufacture only upon a trigger being indicative of an actual demand. Hence, the multi-medicine manufacturing facility may be configured as a multi-purpose facility flexibly adaptable for manufacturing specifically what is actually needed, since being presently scarce. Thereby, it may be possible to react quickly on a sudden and urgent demand for a certain medicine. This may allow to avoid or counteract drug shortage, thereby avoiding severe health issues in a population. For a quick response time, the multi-medicine manufacturing facility may pre-stock different active pharmaceutical ingredients in different storage containers separate from excipients. API stocking may be made to allow long-term storage without undesired or even dangerous changes in API properties. By stocking only the active pharmaceutical ingredients in the storage containers apart from excipients, a moderate effort may be sufficient, in view of the limited volume, for maintaining long-term storage conditions. Beyond this, a set of pre-approved recipes for manufacturing each of the said set of supported medicines may be obtained before an actual manufacture of a medicine is envisaged. Thus, the usually quite long time needed for obtaining official authorization for manufacturing a specific medicine may be shifted to a time sufficiently long before an on-demand manufacture of a specific medicine by the multi-medicine manufacturing facility. This may further reduce the response time to a sudden demand for a certain medicine and may render the multi-medicine manufacturing facility even more flexible. In addition, recent changes of one or more medicine-related parameters (like API market availability and / or a demand for or a shortage of a certain medicine) may be predicted early in advance. Stocking and / or provisioning may be done in conformity with said forecasting. Also the selection of a medicine to be produced and / or a start of a corresponding manufacturing process may be made on the basis of the one or more medicine-related parameters. Thus, a multi-medicine manufacturing facility according to an exemplary embodiment may allow to provide a possibility of reliably avoiding shortage of medicines and may thereby contribute to public health.

[0059] Exemplary embodiments of the invention may allow to provide medicines at a million-doses scale within a month of order whenever and wherever on the globe. Advantageously, such an exemplary embodiment may stockpile APIs (active pharmaceutical ingredients) rather than entire medicines. According to exemplary embodiments, APIs may be stored in special containers under safe conditions for many years, for instance up to 20 years or more. Such storage takes little room and is highly efficient. If required, APIs can be rapidly converted to drug products via a multi-medicine manufacturing facility according to exemplary embodiments functioning as a high-speed manufacturing plant (for instance within two weeks after receipt of a demand).

[0060] Exemplary embodiments of the invention have advantages: APIs only need to be replaced after a very long time of for example 20 years or more. The required storage space is small. The effort for manufacturing medicines may be strongly reduced. A multi-medicine manufacturing facility according to an exemplary embodiment of the invention may be lean, may involve only a small economic footprint and may be operable with low to moderate effort. Furthermore, a multi-medicine manufacturing facility according to an exemplary embodiment of the invention may produce medicines using an advanced manufacturing process that cannot be made in pharmacies. Moreover, such a multi-medicine manufacturing facility may give a buffer of many years in case of long-term supply chain problems.

[0061] For example, the following feature combination may be implemented advantageously in a multi-medicine manufacturing facility according to an exemplary embodiment:

[0062] I. Long-term storage of APIs (for instance to achieve a stability of the APIs for 20 years or more)

[0063] II. Get formulations and manufacturing process pre-approved ahead of production

[0064] III. Obtain APIs when there is low or no market demand and distribute manufactured medicine at a high demand

[0065] IV. Perform intelligent forecasting as a decision tool what / when to obtain and what / when to distribute

[0066] What concerns the storage of the APIs at the multi-medicine manufacturing facility, their storage conditions may be configured for enabling storage of the APIs without loss of usability for medicine manufacture for 20 years or more. On demand high-speed production of the medicine may be made in the multi-medicine manufacturing facility, for instance within not more than two weeks.

[0067] Now referring to intelligent forecasting (in particular concerning availability of APIs to be obtained and / or demand for medicine to be produced), this may rely on tools which may be supported by machine learning, in particular artificial intelligence and other data-driven techniques. Said forecasting may be based on one, some or all of the following data: current and past prices per API, annual need per API, current and planned manufacturing plants, analysis of past supply and demand variabilities, demographic shifts at global scale, ability to directly sell to health systems, occurrence of side effects, pipelines of companies.

[0068] Exemplary embodiments of the invention may have the advantage that operational readiness may be maintained at all times. Furthermore, an instant reaction to emerging and acute changes may be possible.

[0069] The APIs stored as a basis for the subsequent manufacture of supported medicines may be selected based on the forecast by applying the criterion which medicines have shown or show demand variability and / or supply chain shortages in the past and / or at present and / or predicted for the future. Moreover, it may be possible to include in the stored set of APIs those APIs which are needed for manufacturing some or all of the essential medicines on the WHO (World Health Organization) Lists. Suitable APIs for storage are anti-in- fectives APIs, anti-cancer APIs, pain medicine APIs, anti-depressant APIs, metabolic agent APIs, etc. Advantageously, the list of stored APIs may be updated in real time, in particular based on one or more medicine-based parameters. Biologies can be stored similarly in frozen form.

[0070] Between subsequent manufacturing events, the multi-medicine manufacturing facility may be used for the development of (for example new) formulations. Furthermore, such periods may be used for obtaining pre-approval of formulations and drug products with relevant authorities (for instance on a global scale, for a plurality of nations or regions, or for one nation or region). Furthermore, such periods may be used for negotiation with health systems, whole-sale suppliers, etc., for example at global scale.

[0071] Next, details concerning the stocking device of the multi-medicine manufacturing facility will be explained.

[0072] In an embodiment, each API may be stored in one or more special containers depending on expected demands and stability. For example, highly potent APIs may require less volume (for example 100 kg), whereas others (for example antibiotics) may require more volume (for example 2000 kg, being equivalent to about 200.000 courses of treatment). Different storage conditions may be adjusted depending on API stability: For example, a first storage zone may be kept at a temperature of 4°C and air atmosphere. A second storage zone may be kept at a temperature of 4°C under an inert atmosphere, such as nitrogen or argon. A third storage zone may be kept at a temperature of -20°C under an inert atmosphere, such as nitrogen or argon. A fourth storage zone may be kept at a temperature of -80°C. Mutually incompatible APIs may be stored in different areas or storage zones. Stability of the APIs may be monitored online via sensors at and / or in each container (for example, spectroscopically, via off-gas, visually, etc.).

[0073] In the following, details concerning the forecasting unit or a process of forecasting or predicting future developments will be explained. One goal of said forecasting or prediction may be to detect early whether stored APIs lose stability. A corresponding forecasting or predicting process or unit may use a combination of stress tests and machine learning (in particular involving artificial intelligence, Al). In the context of such a stress test, a storage of small API amounts under less favorable (i.e. stressed) conditions may be made to see if stability issues can be expected (for example, storage at 10°C instead of 4°C). Thus, every stored API may have a small mirror storage container (for instance having a volume of 100 g) under stressed conditions that is monitored.

[0074] Another goal of said forecasting or prediction may be to monitor the international supply chain market for the availability of excipients (such as diluents, binders, fillers, disintegrants, colors, coatings, taste masks, etc.). In general, excipients may be significantly less critical than API supply, but shortages can occur as well. For each drug product, a recipe may exist (which may be developed), and correspondingly needed excipients may be available. Monitoring tools (which may be Al-based) may detect early supply chain problems and may counteract by obtaining needed excipients.

[0075] Next, details concerning high-speed manufacturing in a multi-medicine manufacturing facility according to an exemplary embodiment will be explained.

[0076] For every drug product, a recipe may exist that has been developed and validated. Formulation and process may be pre-approved by authorities (such as the Austrian Agency for Health and Food Safety (AGES) in Austria, EMA, FDA or others). Preferably, the multi-medicine manufacturing facility of an exemplary embodiment will be GMP (Good Manufacturing Practice)-certified. Furthermore, manufacturing steps may include one, some or all of milling, sieving, blending, granulation, drying, tableting, coating. For example, a secondary manufacturing line may be provided with a production capacity of about 10.000.000 tablets per week on 100m2floor space.

[0077] In the following, details concerning release and quality control in a multi-medicine manufacturing facility of an exemplary embodiment of the invention will be explained.

[0078] Formulation and process may be developed during storage (i.e., in the first years of operation), and medicines to be manufactured may be pre- approved. The corresponding manufacturing technology may be qualified at regular intervals. Release may be based on real-time release testing via process in-line data (for example requiring less than 1 day). Identity may be assessed inline. Assay may be assessed inline. Uniformity may be assessed inline. Dissolution may be assessed inline or offline. Purity or impurities may be assessed by an HPLC (high performance liquid chromatography).

[0079] Figure 1 illustrates a schematic view of a multi-medicine manufacturing facility 100 according to an exemplary embodiment. Figure 2 illustrates a schematic view of one storage container 104 of such a multi-medicine manufacturing facility 100 according to Figure 1.

[0080] The illustrated multi-medicine manufacturing facility 100 may be configured for manufacturing a selected medicine 236 (for instance a specific antibiotic) of a set of supported different types of medicines (which may for example include different antibiotics, different pain relievers, different antidepressants, etc.) on demand. For instance, the number of supported medicines manufacturable by the multi-medicine manufacturing facility 100 may be in a range from 10 to 100, for example in a range from 20 to 50. The construction and design of the multi-medicine manufacturing facility 100, as described in the following, is thus not optimized for manufacture of one single specific medicine, but may be flexibly re-configured in short time for manufacturing one of different medicines on demand.

[0081] As shown, the multi-medicine manufacturing facility 100 comprises a stocking device 110 stocking or storing a set of different active pharmaceutical ingredients 102 (APIs) each in a different one of a set of storage containers 104. For instance, the storage capacity of each of said storage containers 104 may be in a range from 100 kg to 2000 kg. The storage capacity of a respective storage container 104 may be correlated with properties of the stored active pharmaceutical ingredients 102.

[0082] More specifically, the active pharmaceutical ingredients 102 in the storage containers 104 are stored in the stocking device 110 separately from each other and separately from excipients 108 under long-term storage conditions. Preferably, said long-term storage conditions may be pre-defined individually for each storage container 104 and consequently individually for each active pharmaceutical ingredient 102 under consideration of particularities of the respective active pharmaceutical ingredient 102. Under said long-term storage conditions, the active pharmaceutical ingredients 102 may be stored for example at least 20 years, for instance up to 30 years. Thus, they may remain intact even if a corresponding medicine is not requested to be produced over a long time. Since the active ingredients 102 are stored separately from the excipients 108, the long-term storage conditions need to be provided only for a limited volume being much smaller than that of the readily manufactured medicines. For instance, the weight percentage of the active pharmaceutical ingredients 102 in readily manufactured medicines may be less than 5 weight percent, whereas the weight percentage of the excipients 108 in said readily manufactured medicines may be at least 95 weight percent.

[0083] Now referring to Figure 2 showing a detail of the stocking device 110 of Figure 1, said stocking device 110 may comprise a cooling device 118 configured for cooling said active pharmaceutical ingredients 102 in said storage containers 104. For instance, a compressor cooler or a Peltier cooler may be used for that purpose. In one embodiment, a respective cooling device 118 may be provided for each individual storage container 104, so that different storage containers 104 may be operated with different cooling devices 118 and may be kept at different cooling temperatures. In another embodiment, some or all storage containers 104 may share a common cooling device 118 (see for instance Figure 4). Preferably, the cooling device 118 may be configured for cooling different active pharmaceutical ingredients 102 in different storage containers 104 in different temperature ranges which may all be below 20°C. For instance, one or more storage containers 104 cooperating with a corresponding cooling device 118 may operate between 5°C and 15°C, one or more other storage containers 104 cooperating with a corresponding cooling device 118 may operate between -5°C and 5°C, one or more further storage containers 104 cooperating with a corresponding cooling device 118 may operate between -30°C and -10°C, and one or more additional storage containers 104 cooperating with a corresponding cooling device 118 may operate below -50°C. The temperature range assigned to a respective active pharmaceutical ingredient 102 by a corresponding cooling device 118 may correspond to its intrinsic stability properties. Moreover, said stocking device 110 may be configured for stocking said active pharmaceutical ingredients 102 in an inert gas atmosphere. For instance, said inert gas atmosphere may comprise or consist of nitrogen or a noble gas such as argon. In such a protection gas atmosphere (excluding mainly oxygen and water), long-term stability of the respective active pharmaceutical ingredient 102 may be further improved. For storing a respective active pharmaceutical ingredient 102 in a corresponding storage container 104 under inert gas conditions, the storage container 104 comprising the active pharmaceutical ingredient 102 may first be evacuated (for instance by a vacuum pump), before an inert gas is inserted into the hermetically closed storage container 104.

[0084] Further advantageously, said stocking device 110 may comprise a motion promoting device 120 configured for promoting motion between particles of a respective (for instance granular) active pharmaceutical ingredient 102 to suppress clustering of said particles. For instance, the active pharmaceutical ingredient 102 may be present as a granulate of particles. Preferably, said motion promoting device 120 may be configured for promoting motion of said particles by generating vibration. Advantageously, promoting vibration of said particles occasionally, from time to time or even permanently, may avoid clustering among the particles which may be detrimental to long-term stability of the active pharmaceutical ingredients 102.

[0085] A further advantageous feature of said stocking device 110 is a sensor unit 122 which may be configured for sensing sensor data being indicative of a change of a condition (for instance a clustering event) of said active pharmaceutical ingredient 102 in a respective storage container 104. Preferably, the motion promoting device 120 may cooperate with the sensor unit 122 to avoid undesired phenomena in a respective storage container 104 for further extending the long-term stability of the active pharmaceutical ingredients 102 therein. For this purpose, the motion promoting device 120 may be configured for being activated for promoting motion of particles of a respective active pharmaceutical ingredient 102 when the sensor data indicate a critical change of a condition of said active pharmaceutical ingredient 102 in the respective storage container 104. For instance, the sensor data may indicate already started clustering or the risk of clustering of particles or a granulate forming the respective active pharmaceutical ingredients 102 in an assigned storage container 104. For this purpose, said sensor unit 122 may comprise a spectrometer 124 for spectroscopically sensing said sensor data, for instance for identifying clustering of particles of the active pharmaceutical ingredients 102 in the assigned storage container 104. For instance, said spectrometer 124 may comprise a Raman spectrometer, a near infrared (NIR) spectrometer, a Fourier Transform infrared (FTIR) spectrometer, an ultraviolet light (UV VIS) spectrometer and / or a visual light spectrometer. Also an HPLC may be implemented for the purpose of changes in the properties of the active pharmaceutical ingredients 102 being detrimental to long-term stability.

[0086] Referring to Figure 2, said sensor unit 122 may comprise a sensor head 126 in and / or on the respective storage container 104 for sensing electromagnetic sensor data. Furthermore, an optical fiber 128 may be provided which may be optically connected with said sensor head 126. Apart from this, an evaluation unit 130 may be optically connected with the optical fiber 128 and configured for evaluating said sensor data. Further advantageously, said sensor unit 122 may be configured for determining stability information concerning said active pharmaceutical ingredient 102 based on said sensor data evaluated by machine learning, preferably by artificial intelligence (Al). For instance, a corresponding artificial intelligence module may identify patterns in the sensor data which indicate the risk of a reduction or loss of stability of the active pharmaceutical ingredients 102 in a respective storage container 104. In such an event, vibration of the particles in a respective storage container 104 caused by the motion promoting device 120 may be triggered by the artificial intelligence modules.

[0087] Still referring to Figure 2, the mentioned tasks of the stocking unit 110 may be controlled by managing unit 116 described below in further detail.

[0088] Again referring to Figure 1, a mirror stocking device 132 may be provided for stocking a set of said different active pharmaceutical ingredients 102 (i.e., the APIs stored in the storage containers 104) each in a different one of a set of mirror storage containers 104'. A storage capacity of each of said mirror storage containers 104' may be much smaller than a storage capacity of an assigned one of said storage containers 104. To put it shortly, each active pharmaceutical ingredient 102 in an assigned storage container 104 may have a miniature counterpart in form of a mirror storage container 104' storing a significantly smaller amount (for instance less than 10 weight percent or even less than 1 weight percent thereof) of the same active pharmaceutical ingredient 102. Using the respective mirror storage container 104', a stress test with the assigned active pharmaceutical ingredient 102 may be carried out for obtaining information about stability of said active pharmaceutical ingredient 102 in the corresponding larger storage container 104. Correspondingly, a stress test unit 134 may be provided for this purpose and may be configured for carrying out a stress test for said active pharmaceutical ingredients 102 in said mirror storage containers 104'. This can be accomplished by applying conditions to the respective mirror storage container 104' being less favourable in terms of API stability than said long-term storage conditions applied to the corresponding storage container 104 accommodating the same active pharmaceutical ingredient 102. In particular, said less favourable conditions may comprise a higher storage temperature, an air atmosphere rather than an inert gas atmosphere, and / or the lack of a motion promoting device 120. The stress test unit 134 may be configured for monitoring stability of said active pharmaceutical ingredients 102 in said mirror storage containers 104' for deriving API stability information concerning said different active pharmaceutical ingredients 102 in said storage containers 104. Based on said derived stability information obtained from monitoring said mirror storage containers 104', the storage conditions of the active pharmaceutical ingredient 102 in the corresponding or assigned storage container 104 may be adapted if needed, in particular to comply with a pre-defined long-term storage target (such as a stable storage of the API for at least a pre-defined target period of for instance 20 years).

[0089] As shown in Figure 1, the manufacturing facility 100 further comprises a recipe provisioning unit 112 storing or provisioning a set of pre-approved recipes 106. Each of said recipes 106 may include all necessary information for manufacturing an assigned one of the said set of supported medicines by executing a predefined manufacturing process using one or more of said stored active pharmaceutical ingredients 102 and using one or more of said excipients 108 in a predefined formulation at the multi-medicine manufacturing fa- cility 100. As shown, the recipe provisioning unit 112 may comprise a database storing a plurality of data sets, each corresponding to a pre-approved recipe 106. The database may comprise a mass storage device, such as a hard disk providing data storage capacity. When a trigger for manufacturing a certain medicine is obtained, the corresponding recipe 106 may be provided by the recipe provisioning unit 112 for enabling the manufacturing facility 100 to manufacture the assigned medicine. Approval of a corresponding recipe 106 by a competent official authority, for instance EMA or FDA, may be obtained well in advance of receipt of a demand or instruction to manufacture a corresponding medicine. Hence, the manufacturing facility 100 may be configured for obtaining approval for each of the set of pre-approved recipes 106 from an official authority prior to receipt of a demand request for manufacturing a selected medicine 236 of said set of supported medicines in said manufacturing facility 100. In particular, it may be advantageous to obtain said approval in time periods in which no medicine is manufactured in said manufacturing facility 100. Thus, no further delay may occur when a medicine has to be manufactured urgently, for instance to satisfy a market demand or shortage.

[0090] Still referring to Figure 1, the manufacturing facility 100 may comprise a forecasting unit 114 for forecasting a development of at least one medicine- related parameter. For instance, the forecasting unit 114 may comprise a processor for executing forecasting operations. As shown, the forecasting unit 114 may be communicatively coupled via a communication network 150 (as for instance the public Internet and / or an intranet) with a plurality of communication partner devices 152, 154, 156, etc. Thus, the forecasting unit 114 may obtain information from various sources (see reference sign 152, 154, 156) concerning medicine-related parameters. Also a manual input of information concerning at least one medicine-related parameter to the forecasting unit 114 may be possible. The forecasting unit 114, which may comprise an artificial intelligence module (or another module configured for machine learning, such as a neural network), may process received input information for forecasting a development of market availability of active pharmaceutical ingredients 102 as one of the at least one medicine-related parameter. Additionally or alternatively, the forecasting unit 114 may forecast a development of market demand of a medicine comprising a respective active pharmaceutical ingredient 102 as another one of the at least one medicine-related parameter. Further additionally or alternatively, the forecasting unit 114 may forecast a development of market availability of excipients 108 used in combination with said active pharmaceutical ingredients 102 for manufacturing medicines as one of the at least one medicine-related parameter. For example, the forecasting unit 114 may execute forecasting based on input data relating to actual health data of a population, demographic data, epidemic and / or pandemic events, existing and / or planned manufacturing plants, medical economics data, demand volatility of a medicine, a demand peak of a medicine and / or a delivery shortage of a medicine.

[0091] Preferably, active pharmaceutical ingredients 102 to be stocked in stocking device 110 may comprise active pharmaceutical ingredients 102 required for manufacturing essential medicines according to the WHO Model Lists of Essential Medicines as listed by the World Health Organization. Additionally or alternatively, active pharmaceutical ingredients 102 may be stocked in stocking device 110 for which a high market availability is indicated by forecasting unit 114. Further additionally or alternatively, active pharmaceutical ingredients 102 may be stocked for which the forecasting unit 114 indicates that a corresponding medicine shows a high market demand, volatility and / or shortage. Also updating the stocked set of different active pharmaceutical ingredients 102, by reducing and / or increasing the API portfolio in stocking device 110, may be done based on said forecasting by forecasting unit 114. Among the set of stocked different active pharmaceutical ingredients 102, there may be anti-infective active pharmaceutical ingredients, anti-cancer active pharmaceutical ingredients, anti-pain active pharmaceutical ingredients, anti-depressant active pharmaceutical ingredients and / or metabolic agents.

[0092] Furthermore, the manufacturing facility 100 comprises a managing unit 116 for managing operation of the manufacturing facility 100. For instance, managing unit 116 may comprise a processor controlling overall operation of the manufacturing facility 100. More specifically, managing unit 116, which may also be denoted as a control unit, may be communicatively coupled with and may control elements according to reference signs 110, 114, 118, 120, 130, 132, 134. Moreover, managing unit 116 may be coupled with an excipient storage device 158 storing a plurality of excipients 108 in corresponding excipient storage containers 160. Thus, managing unit 116 may also manage the excipient portfolio of manufacturing facility 100.

[0093] Furthermore, managing unit 116 may be communicatively coupled with a manufacturing engine 162 executing an actual medicine manufacturing process which may for instance include manufacturing stages illustrated in Figure 5 and Figure 6. For example, this may comprise the execution of manufacturing stages by the manufacturing engine 162 for manufacturing a selected medicine 236 of said set of supported medicines in the multi-medicine manufacturing facility 100 including milling, sieving, blending, granulating, drying, tableting, capsule filling and / or coating, vial filling, inhaler filling or hot-melt extrusion.

[0094] In particular, managing unit 116 may be configured for controlling said stocking and said provisioning based on said forecasting by forecasting unit 114.

[0095] In the manufacturing facility 100, manufacturing a selected medicine 236 of said set of supported medicines in the multi-medicine manufacturing facility 100 may be triggered by a demand request. For instance, such a demand request may be generated by the managing unit 116. Alternatively, the forecasting unit 114 may generate such a demand request. Thus, it is also possible that manufacturing a selected medicine 236 of said set of supported medicines in the multi-medicine manufacturing facility 100 is triggered based on said forecasting. Further alternatively, such a demand request may be transmitted from a remote entity and may be received by a communication unit 164 (such as a receiver antenna) coupled with the managing unit 116. Also ordering excipients 108, which may be used as well as a basis for manufacturing said selected medicine, may be triggered by a demand request for manufacturing said selected medicine.

[0096] Figure 3 illustrates a schematic view of a multi-medicine manufacturing facility 100 according to an exemplary embodiment.

[0097] One section or floor of such a medicine factory may focus on prediction and control and may thus encompass forecasting unit 114 and managing unit 116. Another section or floor may focus on storage and may thus include API storage device 110 and excipient storage device 158.

[0098] Still another section or floor may focus on medicine manufacture including secondary manufacturing, packaging and quality control, see manufacturing engine 162.

[0099] Thus, an exemplary embodiment may involve the tasks of prediction, storage, medicine manufacture including secondary manufacture, packaging, and quality control. For example, the multi-medicine manufacturing facility may work with 300m2for manufacturing 100.000.000 to 200.000.000 tablets per year (for instance for 100.000 to 500.000 patients) and may be operated with a staff of 20 to 30 people.

[0100] Figure 4 illustrates a cooled storage room of a multi-medicine manufacturing facility 100 according to an exemplary embodiment. Thus, Figure 4 shows an embodiment of a cooling unit 118 for cooling a plurality of storage containers 104 (not illustrated in Figure 4).

[0101] Figure 5 illustrates a multi-medicine manufacturing facility 100 according to an exemplary embodiment. More precisely, Figure 5 illustrates a possible construction of a manufacturing engine 162 thereof.

[0102] The manufacturing engine 162 of Figure 5 comprises a mounting location 180, a blend feeder 182, a pneumatic refill unit 184, a segmented fluidized bed dryer 186, a blender 188, a blend feeder 190, a granule mill and scaling unit 192, a tablet press 194, and a tablet quality monitoring unit 196.

[0103] Figure 6 illustrates elements of a multi-medicine manufacturing facility 100 according to an exemplary embodiment. Figure 6 shows possible elements of a manufacturing engine 162 thereof.

[0104] Material for manufacturing a medicine may be obtained from a receiving unit 200. The material may be supplied to a continuous blending device 202. A subsequent process is a continuous granulation executed in a continuous granulation unit 204. This is followed by a further continuous blending process carried out in a further continuous blending unit 206. The output from the further continuous blending unit 206 can be supplied to a compression unit 208. The output from the compression unit 208 can be supplied to a continuous film coating unit 210. A predefined dissolution model 212 may be applied. Thereafter, a real-time-released testing can be executed in a corresponding unit 214.

[0105] Figure 7 illustrates elements of a multi-medicine manufacturing facility 100 according to an exemplary embodiment. Also Figure 7 shows possible elements of a manufacturing engine 162 with a focus on secondary manufacturing.

[0106] More specifically, the secondary manufacturing processes executed according to Figure 7 may include feeding 220, blending 222, granulation 224, drying 226, milling 228, blending 230, tableting or capsule filling 232, and coating 234. As a result, a medicine 236 embodied as solid dosage form can be obtained.

[0107] Figure 8 illustrates a schematic view of an Al-based forecasting unit 114 of a multi-medicine manufacturing facility 100 according to an exemplary embodiment. Various input data may be supplied to forecasting unit 114 as a basis for a forecast of a development of at least one medicine-related parameter. The output of the forecasting unit 114 is forwarded to a managing unit 116 for managing tasks such as stocking a set of different active pharmaceutical ingredients 102, provisioning a set of pre-approved recipes 106, and / or manufacture of a specific medicine 236 based on said forecasting.

[0108] It should be noted that the term "comprising" does not exclude other elements or steps and the "a" or "an" does not exclude a plurality. Also elements described in association with different embodiments may be combined.

[0109] It should also be noted that reference signs in the claims shall not be construed as limiting the scope of the claims.

[0110] Implementation of the invention is not limited to the preferred embodiments shown in the figures and described above. Instead, a multiplicity of variants are possible which use the solutions shown and the principle according to the invention even in the case of fundamentally different embodiments.

Claims

Claims:

1. A method of managing a multi-medicine manufacturing facility (100) configured for manufacturing a selected medicine (236) of a set of supported medicines on demand, wherein the method comprises: stocking a set of different active pharmaceutical ingredients (102) each in a different one of a set of storage containers (104) separately from excipients (108) under long-term storage conditions; provisioning a set of pre-approved recipes (106) for manufacturing each of the said set of supported medicines by executing a predefined manufacturing process using at least one of said active pharmaceutical ingredients (102) in a predefined formulation at the multi-medicine manufacturing facility (100); forecasting a development of at least one medicine-related parameter; and managing said stocking and / or said provisioning and / or manufacturing of a selected medicine (236) on demand based on said forecasting.

2. The method according to claim 1, wherein the method comprises manufacturing a selected medicine (236) of said set of supported medicines in the multi-medicine manufacturing facility (100) triggered by a demand request.

3. The method according to claim 1 or 2, wherein the method comprises manufacturing a selected medicine (236) of said set of supported medicines in the multi-medicine manufacturing facility (100) triggered by a result of said forecasting.

4. The method according to any of claims 1 to 3, wherein the method comprises manufacturing a selected medicine (236) of said set of supported medicines in the multi-medicine manufacturing facility (100) including milling, sieving, blending, granulating, drying, tableting, capsule filling, vial filling, inhaler filling, hot-melt extrusion and / or coating.

5. The method according to any of claims 1 to 4, wherein the method comprises defining said long-term storage conditions individually for each storage container (104).

6. The method according to any of claims 1 to 5, wherein the method comprises obtaining approval of each of the set of pre-approved recipes (106) from an official authority prior to receipt of a demand request for manufacturing a selected medicine (236) of said set of supported medicines in said manufacturing facility (100).

7. The method according to claim 6, wherein the method comprises obtaining said approval in time periods in which no medicine is manufactured in said manufacturing facility (100).

8. The method according to any of claims 1 to 7, wherein the method comprises forecasting a development of market availability of a respective active pharmaceutical ingredient (102) as one of the at least one medicine-related parameter.

9. The method according to any of claims 1 to 8, wherein the method comprises forecasting a development of market demand of a medicine comprising a respective active pharmaceutical ingredient (102) as one of the at least one medicine-related parameter.

10. The method according to any of claims 1 to 9, wherein the method comprises forecasting a development of market availability of excipients (108) used in combination with said active pharmaceutical ingredients (102) for manufacturing medicines as one of the at least one medicine-related parameter.

11. The method according to any of claims 1 to 10, wherein the method comprises forecasting said development of said at least one medicine-related parameter using machine learning.

12. The method according to any of claims 1 to 11, wherein the method comprises forecasting based on input data relating to actual health data of a population, demographic data, epidemic and / or pandemic events, existing and / or planned manufacturing plants, medical economics data, demand volatility of a medicine, a demand peak of a medicine and / or a delivery shortage of a medicine.

13. The method according to any of claims 1 to 12, wherein the method comprises ordering excipients (108) for manufacturing said selected medicine (236) triggered by a demand request for manufacturing said selected medicine (236).

14. The method according to any of claims 1 to 13, wherein the method comprises stocking a set of different active pharmaceutical ingredients (102) which comprises active pharmaceutical ingredients (102) required for manufacturing essential medicines according to the WHO Model Lists of Essential Medicines as listed by the World Health Organization.

15. The method according to any of claims 1 to 14, wherein the method comprises stocking a set of different active pharmaceutical ingredients (102) which comprises anti-infective, in particular bacterial, viral, fungal, active pharmaceutical ingredients, active ingredients for neurological disorders or disorders of lungs, liver, kidneys, eyes, ears, glands or the vascular system, anti-cancer active pharmaceutical ingredients, anti-pain active pharmaceutical ingredients, anti-depressant active pharmaceutical ingredients and / or active ingredients for metabolic diseases or skin diseases.

16. The method according to any of claims 1 to 15, wherein the method comprises updating the stocked set of different active pharmaceutical ingredients (102) based on said forecasting.

17. A multi-medicine manufacturing facility (100) configured for manufacturing a selected medicine (236) of a set of supported medicines on demand, wherein the multi-medicine manufacturing facility (100) comprises:a stocking device (110) stocking a set of different active pharmaceutical ingredients (102) each in a different one of a set of storage containers (104) separately from excipients (108) under long-term storage conditions; a recipe provisioning unit (112) provisioning a set of pre-approved recipes (106) for manufacturing each of the said set of supported medicines by executing a predefined manufacturing process using at least one of said active pharmaceutical ingredients (102) in a predefined formulation at the multimedicine manufacturing facility (100); a forecasting unit (114) for forecasting a development of at least one medicine-related parameter; and a managing unit (116) for managing said stocking and / or said provisioning and / or manufacturing of a selected medicine (236) on demand based on said forecasting.

18. The manufacturing facility (100) according to claim 17, wherein said stocking device (110) comprises a cooling device (118) configured for cooling said active pharmaceutical ingredients (102) in said storage containers (104).

19. The manufacturing facility (100) according to claim 18, wherein the cooling device (118) is configured for cooling different active pharmaceutical ingredients (102) in different storage containers (104) in different temperature ranges.

20. The manufacturing facility (100) according to any of claims 17 to 19, wherein said stocking device (110) is configured for stocking said active pharmaceutical ingredients (102) in an inert gas atmosphere.

21. The manufacturing facility (100) according to any of claims 17 to 20, wherein said stocking device (110) comprises a motion promoting device (120) configured for promoting motion between particles of a respective active pharmaceutical ingredient (102) to suppress clustering of said particles.

22. The manufacturing facility (100) according to claim 21, wherein said motion promoting device (120) is configured for generating vibration.

23. The manufacturing facility (100) according to any of claims 17 to 22, wherein said stocking device (110) comprises a sensor unit (122) configured for sensing sensor data indicative of a change of a condition of said active pharmaceutical ingredient (102) in a respective storage container (104).

24. The manufacturing facility (100) according to claims 21 and 23, wherein the motion promoting device (120) is configured for being activated for promoting motion of particles of a respective active pharmaceutical ingredient (102) when the sensor data indicate a critical change of a condition of said active pharmaceutical ingredient (102) in the respective storage container (104).

25. The manufacturing facility (100) according to claim 23 or 24, wherein said sensor unit (122) comprises a spectrometer (124) for spectroscopically sensing said sensor data.

26. The manufacturing facility (100) according to claim 25, wherein said spectrometer (124) comprises a Raman spectrometer, a near infrared spectrometer, a Fourier Transform infrared spectrometer, an ultraviolet light spectrometer and / or a visual light spectrometer.

27. The manufacturing facility (100) according to any of claims 23 to 26, wherein said sensor unit (122) comprises a sensor head (126) in and / or on the respective storage container (104) for sensing electromagnetic sensor data, an optical fiber (128) optically connected with said sensor head (126), and an evaluation unit (130) optically connected with the optical fiber (128) and configured for evaluating said sensor data.

28. The manufacturing facility (100) according to any of claims 23 to 27, wherein said sensor unit (122) is configured for determining stability information concerning said active pharmaceutical ingredient (102) based on said sensor data evaluated by machine learning.

29. The manufacturing facility (100) according to any of claims 17 to 28, wherein the storage capacity of each of said storage containers (104) is in a range from 100 kg to 2000 kg.

30. The manufacturing facility (100) according to any of claims 17 to 29, comprising: a mirror stocking device (132) stocking a set of said different active pharmaceutical ingredients (102) each in a different one of a set of mirror storage containers (104'), wherein a storage capacity of each of said mirror storage containers (104') is smaller than a storage capacity of an assigned one of said storage containers (104); and a stress test unit (134) configured for carrying out a stress test for said active pharmaceutical ingredients (102) in said mirror storage containers (104') by applying conditions being less favourable in terms of stability than said long-term storage conditions and configured for monitoring stability of said active pharmaceutical ingredients (102) in said mirror storage containers (104') for deriving stability information concerning said different active pharmaceutical ingredients (102) in said storage containers (104) and / or for predicting stability concerning said different active pharmaceutical ingredients (102) in said storage containers (104).

31. The manufacturing facility (100) according to claim 30, wherein sensor data of stressed active pharmaceutical ingredients (102) in said mirror storage containers (104') indicate a critical change of a condition of said active pharmaceutical ingredient (102) in the respective storage container (104), and are used to enhance storage conditions in the respective storage containers (104) to promote long-term stability of said active pharmaceutical ingredients (102) in said storage containers (104).

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