Method and system for monitoring vial conditions during a commercial scale lyophilization process

Abstract

A method of facilitating real-time monitoring of conditions within a vial during a lyophilization process occurring within a lyophilization chamber includes, for each of a plurality of time intervals during the lyophilization process, determining current values of temperature and pressure within the lyophilization chamber, and, after each time interval, determining current values of one or more conditions within the vial. Determining the current values of the condition(s) within the vial includes applying the current values as inputs to a heat and mass transfer balance model, and solving for a current value of temperature within the vial (and possibly water removed from or retained in the product). The method further includes causing a display device to display, to a user, the current value(s) of the condition(s) within the vial, and / or controlling the temperature and / or pressure within the lyophilization chamber based on the current value(s) of the condition(s) within the vial.

Description

Technical Field

[0001] This application relates generally to lyophilization, and more specifically to monitoring and / or controlling conditions inside vials (e.g., internal temperature and the amount of water removed from the product) during a lyophilization process, such as that used in the commercial manufacture of pharmaceutical products. Background Technology

[0002] In the manufacture of many pharmaceutical products, a crucial step is lyophilization, or freeze-drying. During lyophilization, vials containing the drug product are placed in a special lyophilization chamber. First, the product is frozen by lowering the temperature inside the chamber. Then, the chamber is evacuated, and finally, the product is heated to cause the water (ice) within it to sublimate (i.e., directly transform from a solid to a gaseous state). By removing moisture from the product in this way, it becomes more stable (i.e., has a longer shelf life).

[0003] Lyophilization processes typically last for days or even weeks, and without maintaining a proper temperature / pressure profile over time, the product can be damaged. For example, if the critical temperature is exceeded, the dried "cake" formed during the lyophilization process may collapse, or if the temperature drop causes the process to be too short, the product may thaw and / or retain excessive moisture (and thus a shorter shelf life). However, because the success of a given process often depends on the characteristics of the product, the lyophilization chamber, and the vial, developing the correct lyophilization process is by no means easy. Furthermore, for clinical / commercial manufacturing, regulatory requirements prohibit the use of sensors / probes within vials containing pharmaceutical products, complicating the process. Therefore, while the temperature and pressure of the lyophilization chamber can be set to specific levels (depending on the formulation), the conditions within the vial itself (e.g., temperature and the amount of water removed from the product) are not directly measurable.

[0004] Figure 2 illustrates a typical process 200 for developing freeze-drying formulations. Initially, at stage 202, engineers develop a laboratory-scale formulation (i.e., a smaller-scale development using laboratory equipment rather than commercial production equipment). Stage 202 may require calculating setpoints for chamber temperature and chamber pressure using known equations prior to the start of the freeze-drying process. These equations model the relationship between these setpoints and product temperature and the amount of water removed from the product. For example, Mass and Heat Transfer in Vial Freeze-Drying of Pharmaceuticals: Role of the VialThe equations described in *Journal of Pharmaceutical Sciences, Vol. 73, No. 9, Sep. 1984, pp. 1224-37* [Mass and heat transfer in freeze-drying of pharmaceutical vials: the role of the vial, Journal of Pharmaceutical Sciences, Vol. 73, No. 9, Sep. 1984, pp. 1224-37] (Pikal et al.) can be used to determine the set points for chamber temperature and chamber pressure. Furthermore, since the aforementioned regulatory requirements are not applicable to laboratories, Phase 202 may require measurements of the temperature and / or water content (e.g., the fraction of water removed from the product) within the vial throughout the freeze-drying process. In this way, a laboratory-scale relationship between chamber temperature, chamber pressure, and conditions within the vial can be plotted.

[0005] At stage 204, the results of the laboratory-scale freeze-drying are evaluated. For example, the freeze-dried product can be analyzed to determine if the moisture content is sufficiently low and to confirm the absence of cake collapse, etc. If the performance is insufficient, laboratory-scale development continues at stage 202. However, if the performance is suitable, a commercial-scale formulation is developed at stage 206 using commercial freeze-drying equipment identical to that used in the final stage of drug manufacturing. Development at stage 206 can use the laboratory-scale formulation as a starting point, typically with safety factors added to account for differences between commercial and laboratory-scale equipment. At stage 208, the results of the commercial-scale freeze-drying are evaluated (e.g., similar to stage 204). If the performance is insufficient, commercial-scale development continues at stage 206. If the performance is suitable (e.g., based on a rigorous identification process), the freeze-dried formulation can be implemented during the commercial manufacturing process of the drug product.

[0006] Overall, process 200 can be very time-consuming, with stage 206 alone potentially requiring several weeks of work. Extensive development work at stage 206 is particularly undesirable because using commercial lyophilization equipment for formulation development often hinders its application in commercial-scale drug manufacturing. Another significant drawback of this formulation development process 200 is its assumption that the temperature and pressure within the lyophilization chamber can be strictly controlled. In reality, deviations in temperature and pressure within the chamber (relative to control settings) are not uncommon. Therefore, even if the formulations developed via process 200 generally provide good results, these deviations can lead to a large number of defective products that must be discarded, resulting in higher manufacturing costs. Summary of the Invention

[0007] 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 / optimization of the monitored processes. More specifically, the embodiments described herein provide real-time monitoring of conditions within vials during a freeze-drying process occurring within a freeze-drying chamber. As used herein, the term "via" refers to any container capable of holding material and allowing that material to be freeze-dried when suitable temperature and pressure conditions are applied. While the techniques described below are referenced to pharmaceutical product descriptions, it should be understood that these techniques can be alternatively used in other non-pharmaceutical scenarios (e.g., for freeze-drying other types of products to improve shelf life).

[0008] Real-time monitoring of vial conditions (e.g., temperature and the amount of water removed from the product) is achieved via “soft sensing” without introducing any sensor / probe hardware into the vial during the product manufacturing process. This satisfies regulatory prohibitions against the introduction of such hardware. Instead, vial conditions are soft-sensed based on temperature and pressure measurements taken using sensors / probes located inside the freeze-drying chamber but outside the vial. Chamber temperature and pressure are measured at multiple time intervals (e.g., at fixed time intervals, such as per minute), where the measurements for each time interval are applied to a mechanical (first-principles-based) combined heat and mass transfer balance model to infer / calculate the vial conditions for these time intervals. This heat and mass transfer balance model may also take into account other parameters, such as product / formulation characteristics (e.g., cake resistance) and / or vial characteristics (e.g., heat transfer coefficient and / or geometry). In some embodiments, the model is also used to predict future values ​​of the vial conditions within a suitable time window (e.g., the next hour, the next two hours, etc.). This model may include (or be derived from) the equations presented in 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, the entire contents of which are incorporated herein by reference. In other embodiments, different models are used. For example, the model may include (or be derived from) the equations presented 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.), the entire contents of which are incorporated herein by reference. In yet another embodiment, the model may include a 3D finite element analysis (FEA) model of a full vial, and / or a computational fluid dynamics (CFD) model that couples the vial model to the freeze-drying chamber.

[0009] Current and predicted vial conditions can be displayed to the user and / or used to generate feedback signals for automatic control / adjustment of chamber temperature and / or chamber pressure. Regardless of whether chamber temperature and pressure are manually or automatically controlled, these techniques improve upon conventional techniques by taking into account unexpected deviations in chamber temperature and pressure. For example, a user might decide to manually lower the chamber temperature setting to avoid a cake collapse event when observing a peak in the measured chamber temperature and a predicted vial (product) temperature close to or above a critical temperature, or the control algorithm could automatically implement such an increase. This real-time manual or automatic control is not feasible in conventional techniques, where mathematical models (if available) are used merely to generate approximate initial estimates of appropriate chamber temperature and pressure settings before the freeze-drying process begins (e.g., as an initial step in stage 202 in Figure 2). Therefore, the systems and methods described herein can reduce waste / costs caused by temperature / pressure deviations during the freeze-drying process. Furthermore, the agility / adaptability provided by real-time monitoring, coupled with manual or automated feedback / control, can reduce the need to determine the optimal "lowest failure rate" formulation for a given product and vial, thereby reducing the amount of time required for commercial-scale formulation development. For example, stage 206 of Figure 2 can be shortened or skipped entirely. Attached Figure Description

[0010] Those skilled in the art will understand that the accompanying drawings described herein are included for illustrative purposes and are not intended to limit this disclosure. The drawings are not necessarily drawn to scale, but rather focus on illustrating the principles of this disclosure. It should be understood that in some cases, different aspects of the described embodiments may be shown enlarged or amplified to aid in understanding the described embodiments. Throughout the drawings, similar reference numerals generally refer to components that are functionally similar and / or structurally similar.

[0011] Figure 1 This is a simplified block diagram of an example system that can be used to manually monitor and control the freeze-drying process.

[0012] Figure 2 is a block diagram of a routine process for developing commercial-scale freeze-dried formulations.

[0013] Figure 3 Depicting what can be Figure 1 The example freeze-drying chamber used in the system.

[0014] Figure 4 This is a simplified block diagram of an example system that can be used to provide automated closed-loop control for the freeze-drying process.

[0015] Figure 5 Depicting what can be presented to Figure 1 System users or Figure 4 The system's user interface is an example of a user interface.

[0016] Figure 6 This is a flowchart of an example method for facilitating real-time monitoring of conditions inside vials during the freeze-drying process that occurs inside a freeze-drying chamber. Detailed Implementation

[0017] The various concepts described above and discussed in more detail below can be implemented in any of a variety of ways, and the described concepts are not limited to any particular implementation. Examples of implementations are provided for illustrative purposes.

[0018] Figure 1 This is a simplified block diagram of an example system 100 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. Therefore, depending on the embodiment, real-time monitoring may be nearly instantaneous (e.g., reflecting conditions among those present in the vial within milliseconds) or may have a significant delay (e.g., a delay of several seconds or even minutes). Although Figure 1 System 100 is described for lyophilizing pharmaceutical products in vials, but it should be understood that in other embodiments, system 100 may be used to lyophilize other types of products in other contexts.

[0019] System 100 includes a freeze-drying chamber 102 configured to receive vials 104 and provide a fluid seal between the interior of chamber 102 and the external environment when closed. Chamber 102 includes or is coupled to temperature control devices (e.g., heating elements, and possibly cooling elements) for changing the temperature inside the sealed chamber 102, and pressure control devices (e.g., a vacuum pump) for changing the pressure inside the sealed chamber 102. According to one embodiment, reference is made below. Figure 3 Let's discuss box 102 in more detail.

[0020] Example system 100 also includes computing system 106 and model server 108 coupled to each other via network 110. System 100 further includes user station 112, which can be coupled to computing system 106 (and / or model server 108) via network 110 or another suitable network. Network 110 may be a single communication network, or may include multiple communication 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).

[0021] The computing system 106 is communicatively coupled to 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, inside the chamber 102 but outside the vial 104, as referenced below. Figure 3Further discussion follows. Typically, as discussed in further detail below, computing system 106 accesses model server 108 to process measurements from sensors 116, 118 and generates real-time data reflecting current conditions within vial 104 (e.g., temperature and the amount of water removed from the product) and predicted future conditions. User station 112 enables on-site or remote users (e.g., scientists or engineers) to view this real-time data in order to make control decisions in the process (e.g., increasing or decreasing the temperature and / or pressure within chamber 102 via the temperature and / or pressure control devices discussed above).

[0022] The computing system 106 can be a server, desktop computer, laptop, tablet device, or any other suitable type of computing device. Figure 1 In the example embodiment shown, computing system 102 includes processing unit 120, network interface 122, display device 124, user input device 126, and memory unit 128. However, in some embodiments, computing system 106 includes two or more computers that are co-located or geographically separated. In these distributed embodiments, the operations described herein relating to processing unit 120, network interface 122, and / or memory unit 128 may be divided among the various processing units, network interfaces, and / or memory units.

[0023] 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 functions of computing system 106 as described herein. Alternatively, some 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 functions of computing system 106 as described herein may alternatively be implemented in part or in whole in hardware. Memory unit 128 may include one or more physical memory devices or units containing volatile and / or non-volatile memory. Any suitable type of memory, such as read-only memory (ROM), solid-state drive (SSD), hard disk drive (HDD), etc., may be used.

[0024] Network interface 122 may include any suitable hardware (e.g., front-end transmitter and receiver hardware), firmware, and / or software configured to communicate via network 110 using one or more communication protocols. For example, network interface 122 may be or include an Ethernet interface.

[0025] Display device 124 may use any suitable display technology (e.g., LED, OLED, LCD, etc.) to present information to the 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). Typically, display device 124 and user input device 126 may together enable the user to interact with a graphical user interface (GUI) provided by computing system 106, for example, for purposes such as manually monitoring the freeze-drying process occurring within 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, inferred / predicted values ​​or GUIs generated based on these values ​​are only sent to a remote device such as user station 112).

[0026] Memory unit 128 stores instructions for one or more software applications, including freeze-drying monitoring application 130. When executed by processing unit 120, freeze-drying monitoring application 130 is typically configured to communicate with sensors 116, 118 and model server 108 to infer and predict conditions (e.g., temperature and amount of water removed from the product) within vials (e.g., vial 104) based on current temperature and pressure values ​​within chamber 102. For this purpose, application 130 includes measurement unit 140, prediction unit 142, and GUI unit 144. It should be understood that the various units of application 130 may be distributed across different software applications, and / or the functionality of any such unit may be partitioned across different application software programs.

[0027] When executed by processing unit 120, measurement unit 140 preferably obtains temperature and pressure measurements from sensors 116, 118 at fixed time intervals (e.g., every minute or every five minutes). Prediction unit 142 provides measurement results / values ​​for each time interval to model server 108 in real time by causing computing system 106 to transmit data to model server 108 via network interface 122 and network 110. Model server 108 then applies these measurement results / values ​​as input to memory units stored in the model server. Figure 1 The heat and mass transfer equilibrium model 146 (not shown in the diagram) is a mechanical / first-principles model that relates conditions inside the vial (e.g., vial 104) to conditions outside the vial (e.g., inside box 102 but outside vial 104). A set of example equations that may constitute some or all of the heat and mass transfer equilibrium model 146 are discussed below.

[0028] Model server 108 can execute (or otherwise provide) the heat and mass transfer balance model 146 and (e.g., as part of a network service model) exchange data with computing system 106. However, in other embodiments, system 100 does not include server 108, and computing system 106 locally stores heat and mass transfer balance model 128 (e.g., in memory unit 128) and locally executes heat and mass transfer balance model 146 (e.g., by processing unit 120 when executing instructions of prediction unit 142).

[0029] For each time interval, model server 108 uses model 146 to calculate values ​​for conditions within vial 104 (e.g., temperature and the amount of water removed from the product) and returns the calculated values ​​to prediction unit 142 via network 110. Application 130 stores these values ​​in memory unit 128 (or another suitable memory), and GUI unit 144 arranges to present the stored values ​​to the user in a suitable format. For example, GUI unit 144 may generate graphs displaying past, current, and predicted / future values ​​of conditions within vial 104 (such as those referenced below). Figure 5 The GUI unit 144 can display the graph (discussed) and cause the display device 124 to display the graph. Alternatively or additionally, the GUI unit 144 can cause the display device 124 to display past values, current values, and future values ​​in tabular or other suitable formats.

[0030] In some embodiments, GUI unit 144 alternatively or also communicates with user station 112 (and possibly one or more other similar stations) to enable 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 way, real-time monitoring can be provided to one or more on-site and / or remote users.

[0031] It should be understood that other configurations and / or components can be used instead. Figure 1 The configuration and / or components shown. For example, different computing devices or systems ( Figure 1 (Not shown) Measurement results provided by sensors 116, 118 can be transmitted to model server 108. One or more additional computing devices or systems can act as intermediaries between computing system 106 and training server 108. Some functions of computing system 106 as described herein can be performed remotely by model server 108 and / or another remote server, etc.

[0032] Figure 3 Depicting in Figure 1An example embodiment of the freeze-drying chamber 102 used in system 100. For example... Figure 3 As shown, vial 104 includes, at least at some point during freeze-drying, a frozen product layer 300, a cake layer 302, and a gas layer 304. Figure 3 The upward-pointing arrow indicates that steam flows from the frozen product layer 300 through the cake layer 302 during freeze-drying. Example container 102 includes a freeze dryer shelf 306 and a freeze dryer wall (or door) 308, on which vials 104 are placed. The freeze dryer wall (or door) may be substantially perpendicular to the shelf 306 and spaced apart from the vials 104. The shelf 306 includes or is thermally coupled to one or more heating elements. Figure 3 (Not shown in the diagram), and the vial 104 is heated by thermal conduction (where the vial 104 is in direct contact with the shelf 306) and thermal convection (where an air gap separates the bottom of the vial 104 from the shelf 306). The wall 308 provides radiant heat to the vial 104. The wall 308 may be thermally coupled (e.g., attached) to the shelf 306, and / or may form a cylinder extending around part or all of the circumference of the vial 104. For example, the shelf 306 and the wall 308 may be a single cylindrical container (e.g., having...). Figure 3 The removable top portion (not shown). It should be understood that in other embodiments, the box 102 used in system 100 may differ from... Figure 3 The box shown.

[0033] The heat and mass transfer equilibrium model 146 was established (e.g., via... Figure 3 The model 146 illustrates the heat energy input to vial 104 (including heat conduction, convection, and radiation) and the heat energy consumed by sublimation within vial 104. More precisely, model 146 can be configured to set the input heat energy equal to the consumed heat energy. To more accurately model the freeze-drying process, model 146 can consider one or more characteristics of chamber 102 and / or vial 104, and / or one or more characteristics of the product / formulation within vial 104.

[0034] A set of example equations that can constitute at least a part of Model 146 will now be described. It should be understood that in other embodiments, Model 146 may differ from the following in one or more respects (e.g., by incorporating appropriate constants / coefficients, using more or fewer terms to account for more or fewer physical phenomena, etc.). In some alternative embodiments, for example, Model 146 may include (or be derived from) equations proposed 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 3D FEA model of a full vial (and / or a CFD model of the vial coupled to the freeze-drying chamber 102), etc.

[0035] In this particular embodiment, model 146 considers the heat transfer coefficient of vial 104 (as a function of the pressure inside box 102), the geometry of vial 104 (i.e., specific surface area), and the cake resistance of the dried product (as a function of cake height). Model 146 sets the input thermal energy to be equal to the thermal energy consumed via sublimation:

[0036] hot 输入 =heat 输出 Equation (1)

[0037] Model 146 also applies ordinary differential equations to solve for the mass change of the sublimated water (mass). 冰 ):

[0038]

[0039] In equation (2), ΔH s It is the heat of sublimation or enthalpy. Model 146 can directly calculate the height change of the frozen cake layer 302 from the mass change of the sublimated water determined by the above equation (2).

[0040] Model 146 will incorporate the calorific values ​​in equations (1) and (2). 输入 Defined as:

[0041]

[0042] in, Let K be the surface area of ​​the horizontal outer cross-section of vial 104 (i.e., the area of ​​a circle whose diameter is equal to the outer diameter of vial 104). 小瓶(P 箱 The heat transfer coefficient of vial 104 is P, which is a function of the pressure within box 102, for example, measured by pressure sensor 118. 箱 ), T 搁板 It is the temperature of shelf 306 (e.g., measured by temperature sensor 116), T 产品 It is the product within vial 104 (i.e., one of the conditions for solving model 146), and eps is a constant chosen to ensure solution stability. To solve equation (3), model 146 calculates the heat transfer coefficient of vial 104 as follows:

[0043]

[0044] In equation (4), ht a ht b and ht c These are arbitrary coefficients derived from experimental measurements (e.g., using curve fitting) of a specific combination of vial 104 and freeze-drying chamber 102. These coefficients have constant values ​​and characterize the heat transferred from chamber 102 to vial 104. For example, these heat transfer coefficients can be determined whenever a new vial / freeze-dryer combination is introduced (i.e., new measurements can be used).

[0045] Model 146 will use the calorific value in equation (1) 输出 Defined as:

[0046]

[0047] Among them, area 小瓶 The surface area of ​​the horizontal inner cross-section of the vial 104 (i.e., the area of ​​a circle with a diameter equal to the inner diameter of the vial 104) is where the cake layer 302 meets the gas layer 304. 升华表面 It is the pressure at the sublimation surface, and R (height) 干层 ) is as height 干层 The pie resistance is a function of the height of pie layer 302. Model 146 solves for the pie resistance in equation (5) as follows:

[0048]

[0049] Among them, R R0 R A1 and R A2 These are constants derived from experimental measurements (e.g., using curve fitting) of a specific product within vial 104 and / or a specific procedure involving that product. For example, these constants can be determined whenever a new product / procedure is introduced (i.e., new measurements can be used).

[0050] Model 146 solves for the sublimation surface pressure in equation (5) as follows:

[0051]

[0052] Where C1 and C2 are constants, and T 升华表面 It is the temperature at the sublimation surface. Model 146 will use T 升华表面 Defined as:

[0053]

[0054] Among them, h 冷冻 It is the height of the frozen product at the start of the initial drying (i.e., the fill volume multiplied by the product density, divided by). Among them, rho 冰 (where λ is the density of ice), and λ is the thermal conductivity of the frozen cake layer 302. Model 146 defines the height of the cake layer 302 in equations (6) and (7) as:

[0055]

[0056] Model 146 calculates the mass based on the mass of the previous time interval and the mass change determined using equation (2). 冰 Water content is the mass fraction of water in a pharmaceutical product. Pharmaceutical products are typically made of water, active ingredients / proteins, and excipients, and water content indicates how much water needs to be sublimated from a 10⁴ vial.

[0057] Using these or other suitable equations, server 108 (or computing system 106) can use the current chamber temperature (T) measured by temperature sensor 116. 搁板 ) and the current tank pressure (P) measured by pressure sensor 118. 箱 ), to solve equations (1) and (2) to obtain the temperature (T) of the product in vial 104. 产品 and the amount (e.g., fraction) of water removed from vial 104 via sublimation (e.g., by mass since the last time interval). 冰 The change in temperature determines the amount of water removed from the product. As described above, in some embodiments, server 108 (or computing system 106) uses model 146 not only to calculate / infer the current values ​​of temperature and water removal, but also to predict those values ​​for one or more future time intervals. Model 146 can be based on the assumption that T... 搁板 and P 箱 The future value will be predicted by keeping it constant within the prediction time window. However, at each time interval, the server 108 or computing system 106 can predict based on new assumptions (i.e., by assuming T). 搁板 and P 箱 These predictions will be updated (keeping their new measurements unchanged).

[0058] In some embodiments, server 108 (or computing system 106) implements an "orchestrator" algorithm that stores intermediate data in memory (e.g., memory unit 128 or a similar memory unit of server 108) and runs model 146. The orchestrator algorithm may maintain a complete time history of tracking (i) the final values ​​of the bottle temperature and the fraction of water removed at previous time intervals (e.g., previous five-minute intervals), or (ii) the shelf and temperature values ​​measured since the initial drying began.

[0059] In some embodiments, the computing system 106 can control the temperature and / or pressure within the tank 102 using inferred and / or predicted conditions (e.g., temperature and the amount of water removed from the product) within the vial 104, based on feedback from the closed-loop control system. Figure 4 A system 400 of this kind is described. Figure 4 In the figures, the same reference numerals are used to indicate Figure 1 The corresponding components. For example... Figure 4 As shown, in system 400, application 130 is used not only for real-time monitoring but also for real-time control, and therefore includes control unit 402.

[0060] Control unit 402 is configured to generate feedback signals to one or more controllers 404 based on conditions inferred and / or predicted by heat and mass transfer balance model 146. For example, controller(s) 404 may include a temperature controller coupled to one or more heating elements of shelf 306 and a pressure controller coupled to a vacuum pump of chamber 102. Control unit(s) 404 may include, for example, software instructions executed by one or more processors, and / or appropriate firmware and / or hardware. Control unit 402 may implement any suitable algorithm to control the temperature and pressure within chamber 102, thereby reducing the likelihood of failed / defective products (e.g., pie collapse). As merely an example, control unit 402 may implement model predictive control (MPC) techniques by using a predicted temperature within the vial and a predicted amount of water removed from the product over a fixed future time window (e.g., the next half hour or the next two hours, etc.) as inputs in a closed-loop architecture, and controller(s) may implement a proportional-integral-derivative (PID) architecture.

[0061] Figure 5 Depicting what can be presented to Figure 1 System 100 users or Figure 4 The system 400 provides an example user interface 500 for its users. For example, the user interface 500 may be populated and / or generated by the GUI unit 144 and may be displayed by the display device 124 and / or a similar display device of the user station 112.

[0062] User interface 500 includes a temperature curve over time, wherein the data points of trace 502 represent the measured temperature inside chamber 102 (e.g., T measured every five minutes or at other suitable time intervals). 搁板 (Value). For example Figure 5 As shown, the temperature of the box (e.g., shelf) reflected by trace 502 is not constant; even if a fixed temperature setting is applied (e.g., to (multiple) controllers 404), it can vary by several degrees Celsius. For example... Figure 5 As shown, the product temperature (e.g., T) 产品 The range of inferred / predicted values ​​is indicated by a minimum value (corresponding to trace 504a) and a maximum value (corresponding to trace 504b). For example, model 146 can derive these minimum and maximum values ​​based on the uncertainty or range of any parameter used (e.g., in equations (1) through (9)) such as the accuracy range of the measured temperature within chamber 102. In other embodiments, user interface 500 includes only a single trace of the inferred / predicted temperature, instead of a minimum trace 504a and a maximum trace 504b.

[0063] Figure 5 The user interface 500 reflects the situation as the freeze-drying process is complete (i.e., all data shown is historical data). However, it should be understood that the plotted graphs may be dynamically generated / updated at each time interval (e.g., every five minutes) from the start to the end of the freeze-drying process. Furthermore, when the GUI unit 144 generates / updates the user interface 500, traces 504a and 504b may extend further along the time axis than trace 502, wherein the additional data points of traces 504a and 504b (relative to the data points of trace 502) reflect the predicted future values ​​of the chamber temperature calculated using model 146.

[0064] In some embodiments, GUI unit 144 similarly generates / updates the inferred and predicted traces of the amount (e.g., fraction) of water removed from the product within vial 104 (e.g., in...). Figure 5 Use another scale on the right side of the graph (or in a separate graph), and / or update the trace of pressure measured inside chamber 102.

[0065] Figure 6 This is a flowchart of an example method 600 for facilitating real-time monitoring of conditions within vials (e.g., vial 104) during a freeze-drying process occurring within a freeze-drying chamber (e.g., chamber 102). Method 600 can be derived from, for example... Figure 1 System 100 or Figure 4The system 400 (e.g., by a processing unit 120 that executes instructions for the freeze-drying monitoring application 130) is implemented. In some embodiments, blocks 602 and 604 are executed by the measurement unit 140, block 606 by the prediction unit 142, and blocks 608 and / or block 610 by the GUI unit 144 and / or the control unit 402, respectively.

[0066] At box 602, a temperature sensor (e.g., sensor 116) is used to determine the current value of the temperature inside the freeze-drying chamber but outside the vials. This temperature could be, for example, the measured temperature of the freeze-drying shelf (e.g., shelf 306), such as T in equation (3). 搁板 In some embodiments, block 602 includes electronically receiving a current value from a temperature sensor (e.g., by sampling a temperature value, or by receiving a response to a measurement request, etc.).

[0067] At box 604, a pressure sensor (e.g., sensor 118) is used to determine the current value of the pressure inside the freeze-drying chamber but outside the vial. For example, this pressure could be P from equations (4) and (5). 箱 In some embodiments, block 604 includes electronically receiving current values ​​from a pressure sensor (e.g., by sampling a pressure value, or by receiving a response to a measurement request, etc.).

[0068] For each of the multiple time intervals, boxes 602 and 604 can be repeated once. These time intervals can be fixed / periodic time intervals, such as once every minute, every two minutes, every five minutes, every ten minutes, or some other suitable time period.

[0069] For each given time interval, after determining the current temperature and pressure values ​​at boxes 602 and 604, the current value of one or more conditions within the vial is determined at box 606. Conditions within the vial may include the product temperature (e.g., T in equations (3) and (8)). 产品 (e.g., based on equations (2) and (9)) or quality 冰 The determined amount (e.g., fraction) of water removed from (or retained within) the product, and / or one or more other vial conditions (e.g., sublimation surface pressure, etc.).

[0070] Box 606 includes applying the current temperature and pressure values ​​determined at boxes 602 and 604 as input to a heat and mass transfer equilibrium model (e.g., model 146) and determining the conditions inside the vial(s), which include at least the temperature inside the vial (e.g., T). 产品In this document, references to using a model to “determine,” “calculate,” or “derive” values, or to “apply” input to a model, can refer to the direct execution of the model (e.g., by model server 108 in the web service embodiment) or to remote utilization of the model (e.g., by computing system 106 when communicating with model server 108 in the web service embodiment). Thus, for example, computing system 106 can execute block 606 by sending measured temperature / pressure values ​​to model server 108 and requesting server 108 to apply these values ​​to model 146 and return the corresponding model output.

[0071] According to an embodiment, for each given time interval, method 600 further includes blocks 608 and / or 610. In block 608, a display device (e.g., display device 124 or a similar device to user station 112) displays multiple current values ​​of the conditions within the vials(s) determined at block 606. For example, GUI unit 144 may perform block 608 by populating or generating a user interface (e.g., user interface 500, and possibly including current and predicted water levels (e.g., fractions) removed from the product via sublimation) displayed to the user. More generally, block 608 may include effective monitoring and / or troubleshooting tools for a real-time platform to assist the user in making critical decisions related to the freeze-drying process. In block 610, the temperature and / or pressure within the freeze-drying chamber are controlled based on the multiple current values ​​of the conditions within the vials(s) determined in block 606. For example, control unit 402 may generate one or more feedback signals based on the current values ​​of the conditions in the vial(s), and execute block 610 by having computing system 106 send the feedback signals(s) to controller 404.

[0072] In some embodiments, method 600 includes Figure 6 One or more additional boxes are not shown in the diagram. For example, method 600 may include additional boxes in which, after each of a plurality of time intervals, one or more future values ​​of the conditions inside the vial(s) (corresponding to one or more future time intervals) are predicted. In such embodiments, box 608 may further include causing a display device to display the future values(s), and / or box 610 may further include using the future values(s) to control the temperature and / or pressure inside the chamber.

[0073] Other considerations relating to this disclosure will now be addressed.

[0074] Some of the figures described herein illustrate example block diagrams with one or more functional components. It will be understood that such block diagrams are for illustrative purposes, and the devices described and illustrated may have additional, fewer, or alternative components than those shown. Furthermore, in various embodiments, components (and the functionality provided by the respective components) may be associated with or otherwise integrated into any suitable component.

[0075] Embodiments of this disclosure relate to non-transitory computer-readable storage media having computer code on it for performing various computer-implemented operations. The term "computer-readable storage medium" is used herein to include any medium capable of storing or encoding a series of instructions or computer code for performing the operations, methods, and techniques described herein. The medium and computer code may be specifically designed and constructed for the purposes of embodiments of this disclosure, or the medium and computer code may be of a type known and available to those skilled in the art of computer software. Examples of computer-readable storage media include, but are not limited to: magnetic media such as hard disks, floppy disks, and magnetic tapes; optical media such as CD-ROMs and holographic devices; magneto-optical media such as optical disks; and hardware devices specifically configured to store and execute program code, such as ASICs, programmable logic devices ("PLDs"), and ROM and RAM devices.

[0076] Examples of computer code include machine code generated by a compiler, and files containing higher-level code that a computer executes using an interpreter or compiler. For example, embodiments of this disclosure can be implemented using Java, C++, or other object-oriented programming languages ​​and development tools. Additional examples of computer code include encrypted and compressed code. Furthermore, embodiments of this disclosure can be downloaded as a computer program product that can be transmitted via a transmission channel from a remote computer (e.g., a server computer) to a requesting computer (e.g., a client computer or a different server computer). Another embodiment of this disclosure can be implemented using a hardwired circuit system instead of or in combination with machine-executable software instructions.

[0077] As used herein, unless the context clearly indicates otherwise, the singular terms “a”, “an”, and “the” may include plural references.

[0078] As used herein, the terms “approximately,” “substantially,” “basically,” and “about” are used to describe and explain small variations. When used in conjunction with an event or situation, these terms can refer to a situation where the event or situation occurs exactly as it does or approximately as it does. For example, when used in conjunction with a numerical value, these terms can refer to a range of variation where the value is less than or equal to ±10%, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%. For example, if the difference between values ​​is less than or equal to ±10% of the average of the values, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%, less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%, then the two values ​​can be considered “substantially” the same.

[0079] In addition, quantities, ratios, and other values ​​are sometimes presented in range format in this document. It should be understood that this range format is used for convenience and brevity, and should be interpreted flexibly to include values ​​that are explicitly specified as the limits of the range, but also to include all individual values ​​and subranges covered within the range, as if each value or subrange were explicitly specified.

[0080] While this disclosure has been described and illustrated with reference to specific embodiments thereof, such descriptions and illustrations are not intended to limit this disclosure. Those skilled in the art will understand that various changes and substitutions may be made without departing from the true spirit and scope of this disclosure as defined by the appended claims. These illustrations are not necessarily drawn to scale. Differences may exist between artistic representations in this disclosure and actual devices due to manufacturing processes, tolerances, and / or other reasons. Other embodiments of this disclosure may exist that are not specifically shown. The specification (other than the claims) and drawings should be considered illustrative rather than restrictive. Modifications may be made to adapt particular circumstances, materials, composition, techniques, or processes to the purpose, spirit, and scope of this disclosure. All such modifications are intended to fall within the scope of the appended claims. While the techniques disclosed herein have been described with reference to specific operations performed in a particular order, it should be understood that these operations may be combined, subdivided, or reordered to form equivalent techniques without departing from the teachings of this disclosure. Therefore, unless specifically indicated herein, the order and grouping of operations are not a limitation of this disclosure.

Claims

1. A method for facilitating real-time monitoring of conditions inside vials during a commercial-scale freeze-drying process occurring within a freeze-drying chamber, the method comprising: For each of the multiple time intervals during the freeze-drying process, (i) the current value of the external temperature of the vial inside the freeze-drying chamber is measured using a temperature sensor, and (ii) the current value of the external pressure of the vial inside the freeze-drying chamber is measured using a pressure sensor. as well as After each of these multiple time intervals, One or more processors determine the current values ​​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 input to a heat and mass transfer equilibrium model, and (ii) calculating the current value of the temperature within the vial. One or both of the following operations: The one or more processors cause the display device to display to the user the current values ​​of one or more conditions within the vial, and The temperature and / or pressure within the freeze dryer are controlled by the one or more processors and based on the current values ​​of one or more conditions within the vial.

2. The method as described in claim 1, wherein, Determining the current value of one or more conditions within the vial further includes determining the current amount of water removed from or retained in the product within the vial.

3. The method as described in claim 1, wherein, Determining the current temperature inside the freeze dryer includes determining the current temperature of the shelf supporting the vials inside the freeze dryer.

4. The method of claim 1, wherein, Determining the current values ​​of one or more conditions within the vial involves applying the current values ​​of temperature and pressure within the freeze dryer, as well as one or more characteristics of the freeze dryer and / or the vial, as input to the heat and mass transfer equilibrium model.

5. The method of claim 4, wherein, One or more characteristics of the freeze dryer and / or vials include the heat transfer and mass transfer coefficients associated with the freeze dryer and vials.

6. The method according to any one of claims 1 to 5, wherein, Determining the current values ​​of one or more conditions within the vial involves applying the current values ​​of the temperature and pressure within the freeze-drying chamber, as well as one or more characteristics of the product within the vial, as input to the heat and mass transfer equilibrium model.

7. The method of claim 6, wherein, One or more characteristics of this product include its pancake resistance.

8. The method according to any one of claims 1 to 5, comprising: By using the current value of one or more current conditions within the vial to control the temperature and / or pressure within the freeze-drying chamber, one or more feedback signals are provided to one or more controllers.

9. The method according to any one of claims 1 to 5, comprising: This causes the display device to show the user the current values ​​of one or more conditions within the vial.

10. The method of claim 9, comprising: The display device is made to dynamically update one or more graphs that indicate (i) the temperature and pressure inside the freeze-drying chamber and / or (ii) the changes in conditions inside the vial over time.

11. The method of any one of claims 1 to 5, further comprising, after each of the plurality of time intervals: The one or more processors predict one or more future values ​​of one or more conditions within the vial corresponding to one or more future time intervals; and The one or more processors cause the display device to display to the user one or more future values ​​of one or more conditions within the vial.

12. The method of claim 11, wherein predicting the one or more future values ​​includes assuming that the temperature and pressure inside the freeze-drying chamber are constant during the one or more future time intervals.

13. A system comprising: A freeze-drying chamber configured to hold vials; A temperature sensor configured to measure the temperature outside the vial inside the freeze dryer; A pressure sensor configured to measure the pressure outside the vial inside the freeze-drying chamber; as well as The computing system is configured as follows: For each of several time intervals during a commercial-scale freeze-drying process occurring within the freeze-drying chamber, obtain (i) the current value of the temperature inside the freeze-drying chamber from the temperature sensor, and (ii) the current value of the pressure inside the freeze-drying chamber from the pressure sensor, and After each of these multiple time intervals, At least by (i) applying the current values ​​of the temperature and pressure inside the freeze-drying chamber as input to the heat and mass transfer equilibrium model, and (ii) determining the current value of one or more conditions inside the vial, and One or both of the following operations: To enable the display device to show the user the current values ​​of one or more conditions within the vial, and Based on the current values ​​of one or more conditions within the vial, control (i) the temperature within the freeze dryer and / or (ii) the pressure within the freeze dryer.

14. The system of claim 13, wherein, Determining the current value of one or more conditions within the vial further includes determining the current amount of water removed from or retained in the product within the vial.

15. The system of claim 13, wherein, The temperature inside the freeze dryer includes the temperature of the shelves that support the vials inside the freeze dryer.

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

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

18. The system of any one of claims 13 to 17, further comprising: One or more controllers are configured to control the temperature inside the freeze-drying chamber. The computing system is configured to control the temperature and / or pressure within the freeze-drying chamber by using the current values ​​of one or more current conditions within the vial, in order to provide one or more feedback signals to the one or more controllers.

19. The system of any one of claims 13 to 17, further comprising: The display device, The computing system is configured to enable the display device to show the user the current values ​​of one or more conditions within the vial.

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

21. The system as claimed in any one of claims 13 to 17, wherein, The computing system is further configured to operate after each of the plurality of time intervals: Predict one or more future values ​​of one or more conditions within the vial corresponding to one or more future time intervals; and The display device displays to the user one or more future values ​​of one or more conditions within the vial.

22. A non-transitory computer-readable medium storing instructions that, when executed by one or more processors, cause the one or more processors to perform the following operations: For each of several time intervals during a commercial-scale freeze-drying process, (i) the current value of the external temperature of the vials inside the freeze-drying chamber is measured using a temperature sensor, and (ii) the current value of the external pressure of the vials inside the freeze-drying chamber is measured using a pressure sensor; and After each of these multiple time intervals, At least by (i) applying the current values ​​of the temperature and pressure inside the freeze-drying chamber as input to the heat and mass transfer equilibrium model, and (ii) determining the current value of one or more conditions inside the vial, and One or both of the following operations: To enable the display device to show the user the current values ​​of one or more conditions within the vial, and Based on the current values ​​of one or more conditions within the vial, control (i) the temperature within the freeze dryer and / or (ii) the pressure within the freeze dryer.

23. The non-transitory computer-readable medium according to claim 22, wherein, Determining the current value of one or more conditions within the vial further includes determining the current amount of water removed from or retained in the product within the vial.

24. The non-transitory computer-readable medium according to claim 22, wherein, Determining the current values ​​of one or more conditions within the vial includes (ii) the current values ​​of temperature and pressure within the freeze dryer, (iii) one or more characteristics of the freeze dryer and / or the vial, and (iv) one or more characteristics of the product within the vial, which are applied as inputs to the heat and mass transfer equilibrium model.

25. The non-transitory computer-readable medium according to claim 24, wherein, One or more characteristics of the freeze-drying chamber and / or vial include the heat transfer coefficient associated with the freeze-drying chamber and vial, and wherein one or more characteristics of the product include the cake resistance of the product.

26. The non-transitory computer-readable medium according to any one of claims 22 to 25, wherein, These instructions enable the one or more processors to control the temperature and / or pressure within the freeze-drying chamber by using the current values ​​of one or more current conditions within the vial, in order to provide one or more feedback signals to one or more controllers.

27. The non-transitory computer-readable medium according to any one of claims 22 to 25, wherein, This instruction causes one or more processors to: This causes the display device to show the user the current values ​​of one or more conditions within the vial.

28. The non-transitory computer-readable medium according to claim 27, wherein, These instructions cause one or more processors to: The display device is made to dynamically update one or more graphs that indicate (i) the temperature and pressure inside the freeze-drying chamber and / or (ii) the changes in conditions inside the vial over time.

29. The non-transitory computer-readable medium according to any one of claims 22 to 25, wherein, These instructions further cause the one or more processors to follow each of the plurality of time intervals: Predict one or more future values ​​of one or more conditions within the vial corresponding to one or more future time intervals; and The display device displays to the user one or more future values ​​of one or more conditions within the vial.

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