Vial condition monitoring during lyophilization process

Abstract

To perform real-time monitoring of conditions in a vial during a lyophilization process occurring in a lyophilization chamber.SOLUTION: The method includes determining, for each time interval of a plurality of time intervals during the lyophilization process, current values of temperature and pressure within the lyophilization chamber, and determining, after each time interval, current values of one or more conditions within the vial. The step of determining the current value of the condition (s) within the vial includes applying these current values as inputs to a heat and mass transfer balance model to determine the current value of the temperature (and possibly the moisture removed or remaining from the product) within the vial. The method includes causing a display to present the current value (s) of the condition (s) in the vial to the user and / or controlling the temperature and / or pressure in the lyophilization chamber based on the current value (s) of the condition (s) in the vial.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This application relates generally to freeze-drying, and more specifically to monitoring and / or controlling conditions within vials (e.g., internal temperature and amount of moisture removed from the product) during freeze-drying processes such as those used in the commercial production of pharmaceuticals. [Background technology]

[0002] A key step in the manufacture of many pharmaceuticals is lyophilization, or "freeze-drying." During the lyophilization process, vials containing the pharmaceutical product are placed in a special freeze-drying chamber. The product is first frozen by lowering the temperature inside the chamber, then a vacuum is created inside the chamber, and finally the product is heated to cause the water (ice) in the product to sublimate (transition directly from solid to gas). Removing the water from the product in this way makes it more stable (i.e., extends its shelf life).

[0003] Because freeze-drying processes typically last for days, even weeks, failure to maintain the proper temperature / pressure conditions over time can damage the product. For example, the dry "cake" formed during the freeze-drying process can collapse if a critical temperature is exceeded, or the product can thaw and / or become excessively moist (and therefore have a shortened shelf life) if the temperature is reduced too quickly. However, developing a suitable freeze-drying process can be extremely challenging, as the success of a given process generally depends on the characteristics of the product, the freeze-drying chamber, and the vial. Furthermore, in medical / commercial manufacturing, this process is complicated by regulatory requirements prohibiting the use of sensors / probes inside vials containing pharmaceutical products. Thus, while the temperature and pressure of the freeze-drying chamber can be set to specific levels (according to a recipe), the internal conditions of the vial itself (e.g., temperature and amount of moisture removed from the product) cannot be directly measured.

[0004] A conventional process 200 for developing a freeze-drying recipe is shown in FIG. 2. First, in stage 202, a technician develops a recipe at a laboratory scale (i.e., on a small scale using laboratory equipment rather than commercial production facilities). Stage 202 may include calculating chamber temperature and pressure setpoints before the freeze-drying process begins using known mathematical equations that model the relationship between the setpoints for product temperature and the amount of moisture removed from the product. For example, the chamber temperature and pressure setpoints may be determined using the mathematical equations described in "Mass and Heat Transfer in Vial Freeze-Drying of Pharmaceuticals: Role of the Vial," Journal of Pharmaceutical Sciences, Vol. 73, No. 9, September 1984, pp. 1224-37 (Pikal et al.)). Furthermore, because the aforementioned regulatory requirements do not apply within laboratories, stage 202 may include obtaining in-vial measurements of temperature and / or moisture content (e.g., the percentage of moisture removed from the product) throughout the freeze-drying process. In this manner, the laboratory-scale relationships between chamber temperature, chamber pressure, and conditions within the vial can be accurately determined.

[0005] In stage 204, the results of the laboratory-scale lyophilization are evaluated. For example, the lyophilized product can be analyzed to determine whether the moisture content is sufficiently low and to ensure that the cake has not collapsed. If performance is insufficient, laboratory-scale development continues in stage 202. However, if performance is adequate, a commercial-scale recipe is developed in stage 206 using the same commercially available lyophilization equipment that will be used in the final stages of drug manufacturing. Development in stage 206 can often use the laboratory-scale recipe as a starting point, with a safety factor added to account for differences between commercial and laboratory-scale equipment. In stage 208, the results of the commercial-scale lyophilization are evaluated (e.g., similar to stage 204). If performance is insufficient, commercial-scale development continues in stage 206. If performance is adequate (e.g., based on a rigorous qualification process), the lyophilization recipe may be used during commercial production of the drug product.

[0006] Overall, process 200 can be quite time-consuming, with stage 206 alone potentially requiring several weeks of work. The lengthy development effort in stage 206 is particularly undesirable because using commercially available lyophilization equipment for recipe development generally precludes the use of such equipment for commercial-scale pharmaceutical manufacturing. Another significant drawback of recipe development process 200 is that it assumes that the temperature and pressure within the lyophilization chamber can be tightly controlled. In reality, deviations in temperature and pressure within the chamber (from control settings) are not uncommon. Thus, even if the recipe developed via process 200 generally provides good results, these deviations can result in a significant number of rejected products that must be discarded, thereby increasing manufacturing costs. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Pikal et al.Mass and Heat Transfer in Vial Freeze-Drying of Pharmaceuticals:Role of the Vial,Journal of Pharmaceutical Sciences,Vol.73,No.9,Sep.1984,pp.1224-37 Summary of the Invention [Means for solving the problem]

[0008] The systems and methods described herein generally employ a scalable soft-sensor deployment framework for real-time monitoring systems to enable more agile decision-making and / or control / optimize the processes being monitored. More specifically, embodiments described herein perform real-time monitoring of conditions within a vial during the freeze-drying process occurring within a freeze-drying chamber. As used herein, the term "vial" refers to any container capable of holding a material and allowing the material to be freeze-dried when the appropriate temperature and pressure conditions are applied. While the technology is described below with respect to pharmaceuticals, it should be understood that it can also be used for other non-pharmaceutical applications (e.g., freeze-drying other types of products to extend their shelf life).

[0009] Real-time monitoring of conditions within a vial (e.g., temperature and amount of moisture removed from the product) can be achieved through "soft sensing" without necessarily incorporating sensor / probe hardware into the vial during product production, thus satisfying regulations prohibiting the introduction of such hardware. Alternatively, conditions within a vial can be soft-sensed based on temperature and pressure measured using sensors / probes within the lyophilization chamber but external to the vial. Chamber temperature and pressure are measured at a specified number of time intervals (e.g., regular time intervals such as every minute), and the measured values ​​at each time interval are applied to a mechanical heat and mass transfer balance model (based on first principles) to infer / calculate the conditions within the vial at that time interval. The heat and mass transfer balance model may also take into account other parameters, such as product / formulation properties (e.g., cake resistance) and / or vial properties (e.g., heat transfer coefficient and / or geometric properties). In some embodiments, the model is also used to predict future values ​​of conditions within the vial over an appropriate time window (e.g., the next hour, the next two hours, etc.). The model may, for example, include (or be derived from) the mathematical equations set forth in "Mass and Heat Transfer in Vial Freeze-Drying of Pharmaceuticals: Role of the Vial," Journal of Pharmaceutical Sciences, Vol. 73, No. 9, September 1984, pp. 1224-37 (Pikal et al.). In other embodiments, different models are used. For example, the model may include (or be derived from) the mathematical equations set forth in "Numerical Solutions of Moving Boundary Transport Problems in Finite Media by Orthogonal Collocation," Computers & Chemical Engineering, Vol. 3, 1979, pp. 615-21 (Liapis et al.). In yet other embodiments, the model may include a 3D finite element analysis (FEA) model of a full vial and / or combine the vial model with a computational fluid dynamics (CFD) model of the freeze-drying chamber.

[0010] These techniques can be used to present current and predicted in-vial conditions to the user and / or generate feedback signals to automatically control / adjust chamber temperature and / or pressure. Whether chamber temperature and pressure are manually or automatically controlled, these techniques can improve upon conventional techniques by accounting for unexpected chamber temperature and pressure excursions. For example, a user observing a spike in measured chamber temperature along with predicted in-vial (product) temperatures near or exceeding a critical temperature may decide to manually lower the chamber temperature setting to avoid a cake collapse event, or a control algorithm may automatically perform such a reduction. This real-time manual or automatic control is not possible with conventional techniques that use mathematical models (if any) only to generate approximate initial estimates of appropriate chamber temperature and chamber pressure settings before the freeze-drying process begins (e.g., as an initial stage in stage 202 of FIG. 2 ). Thus, the systems and methods described herein can reduce waste and costs due to temperature / pressure excursions during the freeze-drying process. Additionally, the agility / adaptability afforded by real-time monitoring through manual or automated feedback / control can reduce the time required for commercial-scale recipe development by reducing the need to identify the optimal "lowest failure rate" recipe for a given product and vial. For example, stage 206 of Figure 2 may be shortened or omitted entirely.

[0011] Those skilled in the art will appreciate that the drawings described herein are included for illustrative purposes, and are not intended to limit the present disclosure. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the present disclosure. It should be understood that in some instances, various aspects of the described implementations may be shown exaggerated or enlarged to facilitate understanding of the described implementations. In the drawings, like reference numbers generally refer to functionally similar and / or structurally similar elements throughout the various views. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 is a simplified block diagram of an exemplary system that can be used to manually monitor and control a freeze-drying process. [Figure 2] FIG. 1 is a block diagram of a conventional process for developing a commercial-scale freeze-drying recipe. [Figure 3] 2 illustrates an exemplary freeze-drying chamber that can be used in the system of FIG. 1. [Figure 4] FIG. 1 is a simplified block diagram of an exemplary system that can be used to provide automated closed-loop control of a freeze-drying process. [Figure 5] 10 illustrates an exemplary user interface that may be presented to a user of the system of FIG. 1 or the system of FIG. 4. [Figure 6] FIG. 1 is a flow diagram of an exemplary method for facilitating real-time monitoring of conditions within a vial during a freeze-drying process occurring within a freeze-drying chamber. DETAILED DESCRIPTION OF THE INVENTION

[0013] The various concepts introduced above and discussed in more detail below may be implemented in any of many ways, and the concepts described are not limited to any particular implementation manner. Example implementations are provided for illustrative purposes.

[0014] FIG. 1 is a simplified block diagram of an exemplary system 100 that can be used for real-time manual monitoring and control of the freeze-drying process. As used herein, "real-time" monitoring refers to monitoring during the freeze-drying process. Thus, real-time monitoring can be near-immediate (e.g., reflecting conditions within a vial within milliseconds) or significantly delayed (e.g., seconds or minutes), depending on the embodiment. While FIG. 1 illustrates a system 100 for freeze-drying pharmaceutical products in vials, it will be understood that the system 100 can be used in other embodiments to freeze-dry other types of products for other applications.

[0015] System 100 includes a lyophilization chamber 102 configured to receive a vial 104 and, when closed, to provide a fluid-tight seal between the interior of chamber 102 and the environment external to chamber 102. Chamber 102 includes or is coupled to a temperature control device (e.g., a heating element, and possibly also a cooling element) that varies the temperature within sealed chamber 102, and a pressure control device (e.g., a vacuum pump) that varies the pressure within sealed chamber 102. Chamber 102, according to one embodiment, is described in more detail below with reference to FIG. 3.

[0016] The exemplary system 100 also includes a computing system 106 and a model server 108 coupled to each other via a network 110. The system 100 further includes a user station 112, which may be coupled to the computing system 106 (and / or to the model server 108) via the network 110 or another suitable network. The network 110 may be a single communications network or may include multiple communications networks of one or more types (e.g., one or more wired and / or wireless local area networks (LANs) and / or one or more wired and / or wireless wide area networks (WANs), such as the Internet or an intranet).

[0017] The computing system 106 is communicatively coupled to both a temperature sensor 116 and a pressure sensor 118. The temperature sensor 116 and the pressure sensor 118 are configured to measure the temperature and pressure, respectively, within the chamber 102 but external to the vial 104, as described in more detail below with reference to FIG. 3. Generally, as described in more detail below, the computing system 106 accesses the model server 108 to process measurements from the sensors 116, 118 to generate real-time data reflecting current conditions (e.g., temperature and amount of moisture removed from the product) and predicted future conditions within the vial 104, while the user station 112 allows an on-site or remote user (e.g., a scientist or engineer) to view the real-time data to make control decisions during processing (e.g., increasing or decreasing the temperature and / or pressure within the chamber 102 via the temperature and / or pressure control devices described above).

[0018] Computing system 106 may be a server, a desktop computer, a laptop computer, a tablet device, or any other suitable type of computing device or group of devices. In the exemplary embodiment shown in FIG. 1, computing system 102 includes a processing unit 120, a network interface 122, a display device 124, a user input device 126, and a memory unit 128. However, in some embodiments, computing system 106 includes two or more computers, either co-located with each other or remote from each other. In these distributed embodiments, operations described herein related to processing unit 120, network interface 122, and / or memory unit 128 may be shared among multiple processing units, network interfaces, and / or memory units, respectively.

[0019] Processing unit 120 includes one or more processors, each of which may be a programmable microprocessor that executes software instructions stored in memory unit 128 to perform some or all of the functionality of computing system 106 described herein. Alternatively, some of the processors in processing unit 120 may be other types of processors (e.g., application specific integrated circuits (ASICs), field programmable gate arrays (FPGAs), etc.), and some of the functionality of computing system 106 described herein may alternatively be implemented in part or in whole in hardware. Memory unit 128 may include one or more physical memory elements or units containing volatile and / or non-volatile memory. Any suitable type or types of memory may be used, such as read-only memory (ROM), solid-state drives (SSDs), hard disk drives (HDDs), etc.

[0020] Network interface 122 may include any suitable hardware (e.g., front-end transmitter and receiver hardware), firmware, and / or software configured to communicate over network 110 using one or more communication protocols. For example, network interface 122 may be or include an Ethernet interface.

[0021] Display device 124 may use any suitable display technology (e.g., LED, OLED, LCD, etc.) to present information to a user, and user input device 126 may be a keyboard or other suitable input device. In some embodiments, display device 124 and user input device 126 are integrated into a single device (e.g., a touchscreen display). Generally, display device 124 and user input device 126 may cooperate to enable a user to interact with a graphical user interface (GUI) provided by computing system 106, such as for manually monitoring the lyophilization process occurring in chamber 102. However, in some embodiments, computing system 106 does not include display device 124 and / or user input device 126 (e.g., in some embodiments where inferred / predicted values, or a GUI generated based on such values, are simply transmitted to a remote device, such as user station 112).

[0022] The memory unit 128 stores instructions for one or more software applications, including a freeze-drying monitoring application 130. The freeze-drying monitoring application 130, when executed by the processing unit 120, is generally configured to communicate with the sensors 116, 118 and the model server 108 to infer and predict conditions (e.g., temperature and amount of moisture removed from the product) within a vial (e.g., vial 104) based on current temperature and pressure values ​​within the chamber 102. To this end, the application 130 includes a measurement unit 140, a prediction unit 142, and a GUI unit 144. It will be understood that the various units of the application 130 may be distributed among different software applications and / or the functionality of any one of such units may be divided among different software applications.

[0023] The measurement unit 140, when executed by the processing unit 120, preferably obtains temperature and pressure measurements from the sensors 116, 118 at regular time intervals (e.g., every minute, every five minutes, etc.). The prediction unit 142 provides the measurements / values ​​for each time interval to the model server 108 in real time by having the computing system 106 transmit the data to the model server 108 via the network interface 122 and the network 110. The model server 108 then applies these measurements / values ​​as inputs to a heat and mass transfer balance model 146 stored in the model server's memory unit (not shown in FIG. 1 ). The heat and mass transfer balance model 146 is a mechanical / first-principles model relating conditions within a vial (e.g., vial 104) to conditions outside the vial (e.g., within the chamber 102 but outside the vial 104). An exemplary set of mathematical equations that may constitute part or all of the heat and mass transfer balance model 146 is described below.

[0024] The model server 108 may execute (or otherwise make available) the heat and mass transfer balance model 146, e.g., as part of a web services model, and exchange data with the computing system 106. However, in other embodiments, the system 100 does not include a server 108, and the computing system 106 stores the heat and mass transfer balance model 128 locally (e.g., in the memory unit 128) and executes the heat and mass transfer balance model 146 locally (e.g., by the processing unit 120 when executing instructions of the prediction unit 142).

[0025] For each time interval, the model server 108 uses the model 146 to calculate values ​​related to the conditions in the vial 104 (e.g., temperature and amount of moisture removed from the product) and returns the calculated values ​​to the prediction unit 142 via the network 110. The application 130 stores these values ​​in the memory unit 128 (or another suitable memory), and the GUI unit 144 organizes the stored values ​​for presentation to the user in an appropriate format. For example, the GUI unit 144 may generate and display on the display device 124 a graph, such as the graph described below with reference to FIG. 5, showing past, current, and predicted / future values ​​for the conditions in the vial 104. Alternatively or additionally, the GUI unit 144 may cause the display device 124 to display the past, current, and future values ​​in a table or some other appropriate format.

[0026] In some embodiments, GUI unit 144 may alternatively, or may also, communicate with user station 112 (and possibly one or more other similar stations) to cause user station 112 (and any other such stations) to display a GUI. User station 112 may be a desktop computer, laptop computer, tablet device, smartphone, or any other suitable type of computing device, and may include or be coupled to a display device (e.g., similar to device 124) and a user input device (e.g., similar to device 126). In this manner, real-time monitoring may be performed by one or more local and / or remote users.

[0027] It will be appreciated that other configurations and / or components may be used in place of those shown in Figure 1. For example, a different computing device or system (not shown in Figure 1) may transmit measurements provided by sensors 116, 118 to model server 108, one or more additional computing devices or systems may act as intermediaries between computing system 106 and model server 108, some of the functionality of computing system 106 described herein may be performed remotely by model server 108 and / or another remote server, etc.

[0028] FIG. 3 illustrates an exemplary embodiment of the freeze-drying chamber 102 used in the system 100 of FIG. 1. As can be seen in FIG. 3, the vial 104, at least at some point during freeze-drying, includes a frozen product layer 300, a cake layer 302, and a gas layer 304. The upward arrows in FIG. 3 indicate the flow of vapor from the frozen product layer 300 through the cake layer 302 as freeze-drying occurs. The exemplary chamber 102 includes a freeze-dryer shelf 306 on which the vial 104 rests, and a freeze-dryer wall (or door) 308 that is generally perpendicular to the shelf 306 and spaced from the vial 104. The shelf 306 includes or is thermally coupled to one or more heating elements (not shown in FIG. 3) to warm the vial 104 by heat transfer (where the vial 104 is in direct contact with the shelf 306) and by thermal convection (where an air gap separates the bottom of the vial 104 from the shelf 306). Wall 308 provides radiant heat to vial 104. Wall 308 may be thermally coupled to (e.g., attached to) shelf 306 and / or may form a cylinder extending around some or all of the circumference of vial 104. For example, shelf 306 and wall 308 may be part of a single cylindrical container (e.g., with a removable lid not shown in FIG. 3). It will be understood that in other embodiments, chamber 102 used in system 100 may differ from that shown in FIG. 3.

[0029] The heat and mass transfer balance model 146 models the thermal energy input to the vial 104 (e.g., via heat transfer, convection, and radiation as shown in FIG. 3 ) and the thermal energy consumed by sublimation within the vial 104. More precisely, the model 146 may set the thermal energy input equal to the thermal energy consumed. To more accurately model the lyophilization process, the model 146 may reflect one or more properties of the chamber 102 and / or the vial 104, and / or one or more properties of the product / formulation within the vial 104.

[0030] An exemplary set of equations that may comprise at least a portion of model 146 is described below, although it should be understood that in other embodiments, model 146 may differ from those described below in one or more respects (e.g., by incorporating appropriate constants / coefficients, by using more or fewer terms to account for more or fewer physical phenomena, etc.). In some alternative embodiments, for example, model 146 may incorporate (or be derived from) the equations set forth in "Numerical Solutions of Moving Boundary Transport Problems in Finite Media by Orthogonal Collocation," Computers & Chemical Engineering, Vol. 3, 1979, pp. 615-21 (Liapis et al.), or may include a 3DFEA model of the complete vial (and / or coupling the vial model to a CFD model of the freeze-drying chamber 102), or the like.

[0031] In this particular embodiment, model 146 reflects the heat transfer rate of vial 104 (as a function of pressure in chamber 102), the geometry (i.e., specific surface area) of vial 104, and the cake resistance (as a function of cake height) of the dried product. Model 146 sets the heat energy input equal to the heat energy dissipated via sublimation. heat in =heat out Formula (1) Model 146 also applies the ordinary differential rate formula to calculate the mass of sublimated water (mass ice ) to find the change.

number

[0032] The model 146 calculates the quantity heat in equations (1) and (2). inis defined as follows:

number

number

number

[0033] Model 146 is the heat of Eq. out is defined as follows:

number

number

number

[0034] The model 146 calculates the sublimation surface pressure of equation (5) as follows:

number

number

number

number

[0035] Using these and other suitable formulas, the server 108 (or computing system 106) can calculate the current chamber temperature (T shelf ), and the current chamber pressure (P chamber ) to solve equations (1) and (2) to determine the temperature of the product in the vial 104 (T product ) and the amount (e.g., fraction) of water removed by sublimation from vial 104 (e.g., mass since the last time interval ice As mentioned above, in some embodiments, the server 108 (or computing system 106) uses the model 146 not only to calculate / infer current values ​​of temperature and amount of moisture removed, but also to predict those values ​​at one or more future time intervals. The model 146 is used to calculate / infer current values ​​of temperature and amount of moisture removed, as well as to predict those values ​​at one or more future time intervals. shelf and P chamber future values ​​can be predicted by assuming that T remains constant over the prediction time window. However, at each time interval, the server 108 or computing system 106 makes a prediction based on a new assumption (i.e., T shel f and P chamber These predictions may be updated (by assuming that σ remains fixed at the newly measured value).

[0036] In some embodiments, server 108 (or computing system 106) executes an "orchestrator" algorithm that stores intermediate data in memory (e.g., memory unit 128 or a similar memory unit of server 108) and executes model 146. The orchestrator algorithm can track (i) the final value of the vial temperature and the fraction of moisture removed in the previous time interval (e.g., the previous 5 minute period), or (ii) the entire time history of shelf and temperature values ​​measured since the start of primary drying.

[0037] In some embodiments, the computing system 106 can use inferred and / or predicted conditions within the vial 104 (e.g., the temperature and amount of moisture removed from the product) to control the temperature and / or pressure within the chamber 102 using feedback in a closed-loop control system. One such system 400 is shown in Figure 4, where like reference numerals are used to indicate elements corresponding to those in Figure 1. As can be seen in Figure 4, in the system 400, the application 130 is used not only for real-time monitoring but also for real-time control, and therefore includes a control unit 402.

[0038] The control unit 402 is configured to generate feedback signals to one or more controllers 404 based on conditions inferred and / or predicted by the heat and mass transfer balance model 146. The controller(s) 404 may include, for example, a temperature controller coupled to one or more heating elements of the shelf 306 and a pressure controller coupled to the vacuum pump of the chamber 102. The controller(s) 404 may include, for example, software instructions executed by one or more processors and / or appropriate firmware and / or hardware. The control unit 402 may implement any suitable algorithm to control the temperature and pressure within the chamber 102 in a manner that reduces the likelihood of failure / rejection (e.g., cake collapse). By way of example only, the control unit 402 may implement a model predictive control (MPC) technique using a predicted temperature within the vial and a predicted amount of moisture removed from the product over a fixed future time window (e.g., the next 30 minutes, the next 2 hours, etc.) as inputs in a closed-loop architecture, and the controller(s) may implement a proportional-integral-derivative (PID) architecture.

[0039] Figure 5 shows an exemplary user interface 500 that may be presented to a user of system 100 of Figure 1 or system 400 of Figure 4. User interface 500 may be arranged and / or generated by GUI unit 144, for example, and may be displayed by display device 124 and / or a similar display device of user station 112.

[0040] The user interface 500 includes a graph of temperature over time, with the data points of trace 502 representing measured temperatures (e.g., T measured every 5 minutes or at other suitable time intervals) within the chamber 102. shelf As can be seen in FIG. 5, the chamber (e.g., shelf) temperature reflected by trace 502 is not constant and can vary over several degrees Celsius even when a fixed temperature setting is applied (e.g., to controller(s) 404). Also as can be seen in FIG. 5, the product temperature (e.g., T product) with a minimum value (corresponding to trace 504a) and a maximum value (corresponding to trace 504b). Model 146 can determine these minimum and maximum values ​​based on the uncertainty or range in any of the parameters used (e.g., in equations (1)-(9)), such as, for example, the accuracy range of the measured temperature in chamber 102. In other embodiments, user interface 500 includes only a single trace of the inferred / predicted temperature, rather than minimum and maximum traces 504a, 504b.

[0041] 5 reflects user interface 500 at a time when the freeze-drying process has been completed (i.e., all data shown is historical data). However, it will be appreciated that the depicted graph may be dynamically generated / updated at each time interval (e.g., every 5 minutes) beginning when the freeze-drying process is initiated and continuing until the freeze-drying process is terminated. Furthermore, while GUI unit 144 generates / updates user interface 500, traces 504a, 504b may extend further along the time axis than trace 502, such that the additional data points in traces 504a, 504b (relative to the data points in trace 502) reflect future predicted values ​​of chamber temperature calculated using model 146.

[0042] In some embodiments, the GUI unit 144 also generates / updates a trace of the inferred and predicted amount (e.g., fraction) of moisture removed from the product in the vial 104 (e.g., using a different scale to the right of the graph in FIG. 5 or on a different graph) and / or updates a trace of the measured pressure in the chamber 102.

[0043] 6 is a flow diagram of an example method 600 that facilitates real-time monitoring of conditions within a vial (e.g., vial 104) undergoing a freeze-drying process within a freeze-drying chamber (e.g., chamber 102). Method 600 can be performed by a system such as system 100 of FIG. 1 or system 400 of FIG. 4 (e.g., by processing unit 120 executing instructions of freeze-drying monitoring application 130). In some embodiments, blocks 602 and 604 are performed by measurement unit 140, block 606 is performed by prediction unit 142, and block 608 and / or block 610 are performed by GUI unit 144 and / or control unit 402, respectively.

[0044] In block 602, the current value of the temperature within the lyophilization chamber but external to the vial is determined using a temperature sensor (e.g., sensor 116). The temperature may be, for example, the measured temperature of the lyophilization shelf (e.g., shelf 306), e.g., T shelf etc. In some embodiments, block 602 includes electronically receiving a current value from a temperature sensor (e.g., by sampling a temperature value or receiving a response to a measurement request, etc.).

[0045] In block 604, the current value of the pressure within the lyophilization chamber but outside the vial is determined using a pressure sensor (e.g., sensor 118). The pressure can be determined, for example, by P chamber In some embodiments, block 604 includes electronically receiving the current value from the pressure sensor (e.g., by sampling the pressure value or receiving a response to a measurement request).

[0046] Blocks 602, 604 may each be repeated once at each of a number of time intervals, which may be once every minute, once every two minutes, once every five minutes, once every ten minutes, or any other suitable regular / periodic time interval.

[0047] For each given time interval, after the current temperature and pressure values ​​are determined in blocks 602 and 604, the current values ​​of one or more conditions within the vial are determined in block 606. The conditions within the vial include the product temperature (e.g., T from equations (3) and (8)), product ), the amount (e.g., fraction) of water removed from (or, alternatively, remaining in) the product (e.g.,

number

[0048] Block 606 applies the current temperature and pressure values ​​determined in blocks 602 and 604 as inputs to a heat and mass transfer balance model (e.g., model 146) and calculates at least the temperature within the vial (e.g., T product ) in the vial. References herein to "determining," "calculating," or "determining" a value using a model, or "applying" inputs to a model, etc., may refer to direct execution of the model (e.g., by model server 108 in a web services embodiment), but also encompass remote use of the model (e.g., by computing system 106 when communicating with model server 108 in a web services embodiment). Thus, for example, computing system 106 may perform block 606 by sending measured temperature / pressure values ​​to model server 108, which may apply those values ​​to model 146 and request return of corresponding model outputs.

[0049] Method 600 also includes, for each given time interval, block 608 and / or block 610, depending on the embodiment. In block 608, a display device (e.g., display device 124 or a similar device in user station 112) is caused to display the current value(s) of the condition(s) in the vial determined in block 606. For example, GUI unit 144 can perform block 608 by providing or generating a user interface (e.g., user interface 500, and possibly also the current and predicted amount (e.g., fraction) of water removed from the product via sublimation, etc.) for presentation to the user. Block 608 may more generally include providing a real-time platform with efficient monitoring and / or troubleshooting tools to assist the user in making critical decisions related to the lyophilization process. In block 610, the temperature and / or pressure in the lyophilization chamber is controlled based on the current value(s) of the condition(s) in the vial determined in block 606. For example, the control unit 402 can perform block 610 by generating one or more feedback signals based on the current value(s) of the condition(s) in the vial and by causing the computing system 106 to transmit the feedback signal(s) to the controller(s) 404.

[0050] In some embodiments, method 600 includes one or more additional blocks not shown in Figure 6. For example, method 600 may include an additional block that predicts one or more future values ​​(corresponding to one or more future time intervals) of the condition(s) in the vial after each time interval of the plurality of time intervals. In such embodiments, block 608 may further include causing a display device to display the future value(s), and / or block 610 may further include controlling the temperature and / or pressure in the chamber using the future value(s).

[0051] Additional considerations regarding the present disclosure are now provided.

[0052] Some of the drawings described herein show example block diagrams having one or more functional elements. It will be understood that such block diagrams are for illustrative purposes only, and that the described devices may have more, fewer, or alternative elements than those shown. Also, in various embodiments, the elements (and the functionality provided by each element) may be associated with or otherwise integrated as part of any suitable element.

[0053] Embodiments of the present disclosure relate to non-transitory computer-readable storage media having computer code thereon that perform various computer-implemented operations. The term "computer-readable storage medium" is used herein to include any medium that can store or encode a set of instructions or computer code that perform the operations, methods, and techniques described herein. The medium and computer code may be specially designed and constructed for embodiments of the present disclosure, or they may be of the kind known and available to those skilled in the computer software arts. Examples of computer-readable storage media include, but are not limited to, magnetic media such as hard disks, floppy disks, and magnetic tape; optical media such as CD-ROMs and holographic devices; magneto-optical media such as optical disks; and hardware devices specially configured to store and execute program code, such as ASICs, programmable logic devices ("PLDs"), and ROM and RAM devices.

[0054] Examples of computer code include machine code produced by a compiler and files containing high-level code executed by a computer using an interpreter or compiler. For example, an embodiment of the present disclosure may be implemented using Java, C++, or other object-oriented programming languages ​​and development tools. Additional examples of computer code include encryption and compression code. Furthermore, an embodiment of the present disclosure may be downloaded as a computer program product and transferred from a remote computer (e.g., a server computer) to a requesting computer (e.g., a client computer or a different server computer) over a transmission channel. Other embodiments of the present disclosure may be implemented in hardwired circuitry in place of, or in combination with, machine-executable software instructions.

[0055] As used herein, the singular terms "a," "an," and "the" may include plural referents unless the context clearly indicates otherwise.

[0056] As used herein, the terms "approximately," "substantially," "substantial," and "about" are used to describe and reflect small variations. When used in connection with events or circumstances, these terms may refer to not only the exact occurrence of the event or circumstance, but also to events or circumstances that are very close. For example, when used in conjunction with a numerical value, these terms may refer to a variation of ±10% or less of the numerical value, such as ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.1%, or ±0.05% or less. For example, two numerical values ​​can be considered "substantially" identical if they differ by ±10% or less of the mean of those values, such as ±5%, ±4%, ±3%, ±2%, ±1%, ±0.5%, ±0.1%, ±0.05%, or less.

[0057] Additionally, amounts, ratios, and other numerical values ​​may be presented herein in a range format. It should be understood that such range format is used for convenience and brevity and should be understood with flexibility to include not only the numerical values ​​expressly stated as the limits of the range, but also all individual numerical values ​​or subranges subsumed within that range, as if each numerical value and subrange were expressly stated.

[0058] While the present disclosure has been described and illustrated with reference to several specific embodiments, these descriptions and illustrations do not limit the disclosure. Those skilled in the art will recognize that various changes can be made and equivalents substituted without departing from the true spirit and scope of the present disclosure, as defined by the appended claims. The drawings are not necessarily drawn to scale. Differences between the artistic depictions in this disclosure and actual devices may occur due to manufacturing processes, tolerances, and / or other reasons. There may be other embodiments of the present disclosure not specifically illustrated. The specification and drawings (other than those in the claims) are to be understood as illustrative rather than restrictive. Changes may be made to adapt particular situations, materials, compositions of matter, techniques, or processes to the objective, concept, and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto. While the technology disclosed herein has been described with reference to specific operations performed in a particular order, it will be understood that these operations may be combined, subdivided, or reordered to form equivalent techniques without departing from the scope of the present disclosure. Accordingly, unless specifically indicated herein, the order and grouping of the operations is not a limitation of the present disclosure.

Claims

1. 1. A method for enabling real-time monitoring of conditions within a vial during a freeze-drying process occurring within a freeze-drying chamber, comprising: determining, for each of a plurality of time intervals during the freeze-drying process, (i) a current temperature within the freeze-drying chamber and external to the vial using a temperature sensor, and (ii) a current pressure within the freeze-drying chamber and external to the vial using a pressure sensor; After each time interval of the plurality of time intervals, determining, by one or more processors, a current value of one or more conditions within the vial by at least (i) applying current values ​​of temperature and pressure within the freeze-drying chamber as inputs to a heat and mass transfer balance model, and (ii) determining a current value of temperature within the vial; The following steps i.e. causing, by the one or more processors, a display device to present to a user the current value of one or more conditions within the vial; The method includes controlling, by the one or more processors, one or both of (i) the temperature within the freeze-drying chamber and / or (ii) the pressure within the freeze-drying chamber based on current values ​​of one or more conditions within the vial.

2. 2. The method of claim 1, wherein determining the current value of one or more conditions in the vial further comprises determining a current amount of moisture removed from or remaining in the product in the vial.

3. 3. The method of claim 1, wherein determining the current temperature within the freeze-drying chamber comprises determining the current temperature of a shelf supporting the vials within the freeze-drying chamber.

4. 4. The method of claim 1, wherein determining the current values ​​of one or more conditions within the vial comprises applying the current values ​​of temperature and pressure within the freeze-drying chamber, and one or more properties of the freeze-drying chamber and / or the vial, as inputs to a heat and mass transfer balance model.

5. 5. The method of claim 4, wherein the one or more properties of the lyophilization chamber and / or the vial include heat and mass transfer coefficients associated with the lyophilization chamber and the vial.

6. 6. The method of claim 1, wherein determining the current values ​​of one or more conditions in the vial comprises applying the current values ​​of temperature and pressure in the freeze-drying chamber and one or more properties of the product in the vial as inputs to the heat and mass transfer balance model.

7. The method of claim 6 , wherein the one or more properties of the product include cake resistance of the product.

8. 8. The method of any one of claims 1 to 7, comprising controlling the temperature and / or pressure in the freeze-drying chamber by using one or more current values ​​in the vial to provide one or more feedback signals to one or more controllers.

9. A method according to any one of claims 1 to 8, comprising causing the display device to present to the user the current value of one or more conditions within the vial.

10. The display device includes:

10. The method of claim 9, further comprising dynamically updating one or more graphs showing (i) the temperature and pressure within the freeze-drying chamber, and / or (ii) the conditions within the vial over time.

11. After each time interval of the plurality of time intervals, predicting, with one or more processors, one or more future values ​​of one or more conditions in the vial corresponding to one or more future time intervals; The method of any one of claims 1 to 10, further comprising the step of causing the one or more processors to cause the display device to present to the user one or more future values ​​of one or more conditions within the vial.

12. 12. The method of claim 11, wherein predicting the one or more future values ​​comprises assuming constant temperature and pressure within the freeze-drying chamber over the one or more future time intervals.

13. 1. A system comprising: a lyophilization chamber configured to hold a vial; a temperature sensor configured to measure the temperature within the lyophilization chamber and outside the vial; a pressure sensor configured to measure the pressure within the freeze-drying chamber and the pressure outside the vial; 1. A computing system comprising: For each of a plurality of time intervals during a freeze-drying process occurring in the freeze-drying chamber, (i) obtain a current value of the temperature within the freeze-drying chamber from the temperature sensor, and (ii) obtain a current value of the pressure within the freeze-drying chamber from the pressure sensor; After each time interval of the plurality of time intervals, determining a current value of one or more conditions within the vial by at least (i) applying the current values ​​of temperature and pressure within the freeze-drying chamber as inputs to a heat and mass transfer balance model, and (ii) determining a current value of temperature within the vial; The following operations: causing a display device to present to a user the current value of one or more conditions within said vial; and A system comprising: a computing system configured to control one or both of (i) the temperature within the freeze-drying chamber and / or (ii) the pressure within the freeze-drying chamber based on current values ​​of one or more conditions within the vial.

14. 14. The system of claim 13, wherein determining a current value of one or more conditions in the vial further comprises determining a current amount of moisture removed from or remaining in the product in the vial.

15. 15. The system of claim 13 or 14, wherein the temperature within the freeze-drying chamber comprises the temperature of a shelf supporting the vials within the freeze-drying chamber.

16. 16. The system of claim 13, wherein the computing system is configured to determine current values ​​of one or more conditions in the vial by applying at least (i) current values ​​of temperature and pressure in the freeze-drying chamber, (ii) one or more properties of the freeze-drying chamber and / or the vial, and (iii) one or more properties of the product in the vial as inputs to a heat and mass transfer balance model.

17. 17. The system of claim 16, wherein the one or more characteristics of the freeze-drying chamber and / or the vial include a heat transfer coefficient associated with the freeze-drying chamber and the vial, and the one or more characteristics of the product include a cake resistance of the product.

18. A system according to any one of claims 13 to 17, further comprising one or more controllers configured to control a temperature within the freeze-drying chamber; The system, wherein the computing system is configured to control the temperature and / or pressure within the freeze-drying chamber by providing one or more feedback signals to the one or more controllers using one or more current state current values ​​within the vial.

19. A system according to any one of claims 13 to 18, comprising: The display device further includes: The computing system is configured to cause the display device to present to the user the current value of one or more conditions within the vial.

20. 20. The system of claim 19, wherein the computing system is configured to cause the display device to dynamically update one or more graphs showing changes over time in (i) the temperature and pressure within the freeze-drying chamber and / or (ii) conditions within the vial.

21. The computing system further comprises, after each time interval of the plurality of time intervals: predicting one or more future values ​​of one or more conditions in the vial corresponding to one or more future time intervals; 21. The system of any one of claims 13 to 20, wherein the display device is configured to present to the user one or more future values ​​of one or more conditions within the vial.

22. When executed by one or more processors, the one or more processors: During each of a plurality of time intervals during the freeze-drying process, (i) determining a current temperature within the freeze-drying chamber and external to the vial using a temperature sensor, and (ii) determining a current pressure within the freeze-drying chamber and external to the vial using a pressure sensor; After each time interval of the plurality of time intervals, determining a current value of one or more conditions within the vial by at least (i) applying current values ​​of temperature and pressure within the freeze-drying chamber as inputs to a heat and mass transfer balance model; and (ii) determining a current value of temperature within the vial; The following operations: presenting to a user on a display device the current value of one or more conditions within said vial; and One or more non-transitory computer-readable media storing instructions for controlling one or both of (i) the temperature within the freeze-drying chamber and / or (ii) the pressure within the freeze-drying chamber based on the current value of one or more conditions within the vial.

23. 23. The one or more non-transitory computer-readable media of claim 22, wherein determining a current value of one or more conditions in the vial further comprises determining a current amount of moisture removed from or remaining in the product in the vial.

24. 24. The one or more non-transitory computer-readable media of claim 22 or 23, wherein determining current values ​​of one or more conditions within the vial comprises applying (i) current values ​​of temperature and pressure within the freeze-drying chamber, (ii) one or more characteristics of the freeze-drying chamber and / or the vial, and (iii) one or more characteristics of the product within the vial as inputs to a heat and mass transfer balance model.

25. 25. The one or more non-transitory computer-readable media of claim 24, wherein the one or more characteristics of the lyophilization chamber and / or the vial include a heat transfer rate associated with the lyophilization chamber and the vial, and the one or more characteristics of the product include a cake resistance of the product.

26. 26. The one or more non-transitory computer-readable media of any one of claims 22-25, wherein the instructions cause the one or more processors to control the temperature and / or pressure in the freeze-drying chamber by providing one or more feedback signals to one or more controllers using one or more current state current values ​​in the vial.

27. The instructions cause the one or more processors to:

27. The one or more non-transitory computer-readable media of any one of claims 22 to 26, causing the display device to present to the user the current value of one or more conditions within the vial.

28. The instruction:

28. The one or more non-transitory computer-readable media of claim 27, wherein the one or more processors cause the display device to dynamically update one or more graphs showing (i) the temperature and pressure within the lyophilization chamber, and / or (ii) changes in conditions within the vial over time.

29. The instructions cause the one or more processors to, after each time interval of the plurality of time intervals: predicting one or more future values ​​of one or more conditions within the vial corresponding to one or more future time intervals; 29. The one or more non-transitory computer-readable media of any one of claims 22-28, causing the display device to present to the user one or more future values ​​of one or more conditions within the vial.

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