Method for determining displacement of a stopper of a filled medical container during fluctuations in heat and / or pressure

Abstract

The present disclosure relates to a method for determining the displacement of a stopper of a filled medical container during thermal and / or pressure fluctuations. The filled medical container includes a barrel containing a medical composition, a stopper slidably disposed at the proximal end of the barrel, and a gas bubble extending from the free surface of the medical composition. The method comprises the following. That is, a step of calculating parameters for a thermal processing model of the filled medical container according to the analysis of the filled medical container. A step of calculating the thermal profile of the components based on the thermal processing model of the filled medical container. A step of calculating over time the air pressure in the gas bubble according to the gas law and the displacement of the stopper during the aforementioned thermal and / or pressure fluctuations based on the calculated thermal profile of the components. And a step of determining, based on the calculated displacement, the risk of violating the integrity of the container stopper as a result of the cumulative proximal displacement of the stopper.

Description

Technical Field

[0001] The present disclosure relates to a method for determining displacement of a stopper of a pre-filled medical container during heat and / or pressure, particularly during at least one cycle. In particular, the aforementioned method can be used to determine the risk of loss of integrity of a pre-filled medical container due to movement of a plunger during a storage period and / or a shipping period across an entire supply chain, including cyclic variations in heat and / or pressure, particularly during at least one cycle. The present disclosure also relates to a method for maintaining the integrity of a pre-filled medical container during such storage and / or shipping periods. Further, the present invention relates to a method for maintaining the integrity of a pre-filled medical container during such storage and / or shipping periods.

Background Art

[0002] Pre-filled medical containers are widely used in the pharmaceutical industry to provide a sterilized product to be injected into a patient's body to a medical user or patient.

[0003] During storage and / or transportation across an entire supply chain, pre-filled medical containers may be exposed to at least one or multiple, repeated combinations. (1) One or more thermal cycles including large amplitude temperature drops (e.g., from about 20°C to about -20°C or -80°C, etc.) and large amplitude temperature rises (e.g., from about -20°C or -80°C to about 20°C, etc.). (2) One or more pressure cycles including large amplitude pressure drops (e.g., from about 1000 hPa to about 500 hPa, etc.) and large amplitude pressure rises (e.g., from about 500 hPa to about 1000 hPa, etc.). (3) One or more thermal fluctuations including small-amplitude temperature oscillations (e.g., + / - 10 °C or + / - 1 °C around the nominal temperature at 1 Hz or 1 mHz). (4) One or more pressure fluctuations including small-amplitude pressure oscillations (e.g., + / - 100 hPa or + / - 1 hPa around the nominal pressure at 1 Hz or 1 mHz).

[0004] Such temperature and / or pressure variations may apply, for example, to filled medical containers that need to be frozen to maintain their stability until use and / or are shipped under reduced-pressure transport conditions (e.g., air transport, truck transport at high altitudes, etc.).

[0005] Such thermal and / or pressure variations may cause a loss of integrity of the medical container due to the movement of the plunger in the non-sterile area. Container closure integrity (CCI) is defined as the ability of the medical container to prevent the entry of microorganisms, the ingress of gas and / or debris, and the loss of contents.

[0006] As shown in FIG. 1, a filled medical container typically comprises a barrel 1 containing a medical composition 2.

[0007] The barrel 1 includes a distal end including a tip 10 for discharging the medical composition from the barrel, particularly for injection into a patient's body. The tip 10 may include a needle (not shown) or may be configured to be connected to a needle.

[0008] The tip 10 can be hermetically sealed by a tip cap 11. The tip cap may typically include a rigid cap 11A made of plastic and an elastic cap 11B typically made of elastomer.

[0009] Barrel 1 further includes a proximal end 12 that is hermetically sealed by a stopper 13. The stopper 13, which can be made of an elastomeric material, is slidable within barrel 1 from a proximal rest position to a distal actuation position for discharging the medical composition through tip 10. Barrel 1 and / or stopper 13 can be at least partially coated with a lubricant coating (not shown) to improve the sliding of the stopper.

[0010] As used herein, the term "distal" refers to the portion of the filled medical container that is remote from the user's hand (e.g., on the side of the needle that can inject the medical composition into the patient's body), and the term "proximal" refers to the portion of the filled medical container that is near the user's hand (e.g., on the side of the flange of the barrel that enables the user to grasp the filled medical container).

[0011] The filled container described is represented as being stored in a configuration where its distal end is oriented downward, i.e., in the direction of gravity.

[0012] At 20°C, the medical composition is typically in a liquid state, and in the illustrated orientation, there are air bubbles between the free (proximal) surface of the medical composition and the distal surface of the stopper (this space is generally referred to as the "headspace").

[0013] The various types of materials contained in the filled medical container, particularly the medical composition, the air confined within the barrel, and the elastomeric material of the stopper, generally exhibit different behaviors when exposed to temperature variations, as described above.

[0014] During temperature fluctuations, all components will either contract or expand based on their respective coefficients of thermal expansion. Additionally, the medical composition also changes volume during its phase transitions (expanding upon freezing and contracting upon thawing).

[0015] Therefore, it is difficult to predict the behavior of a filled medical container during a thermal cycle.

[0016] As an influence of the above heat phenomenon, the stopper may move within the barrel during a thermal cycle. During temperature drop, the contraction of the air in the headspace may move the stopper distally. However, the freezing of the medical composition that increases the volume of the medical composition may move the stopper proximally. During temperature rise, the expansion of the air in the headspace may move the stopper proximally. However, the melting of the medical composition that decreases the volume of the medical composition may move the stopper distally.

[0017] Furthermore, fluctuations in the pressure in the atmosphere surrounding the filled medical container may also contribute to the movement of the stopper inside the barrel.

[0018] During the above-described reciprocating movement of the stopper, the extreme positions reached by the stopper may vary.

[0019] In particular, the stopper may move within an unsterilized region in the barrel. This region is located proximally from the proximal surface of the stopper when sterilization of the filled medical container is performed. When the stopper moves within the aforementioned unsterilized region, it may violate the integrity (especially sterility, etc.) of the medical composition.

[0020] Therefore, it is desirable to avoid the cumulative proximal displacement of the stopper from its initial sterilization position reaching a threshold distance called the sterilization barrier height, which may violate the integrity of the container stopper.

[0021] Currently, there is no method that enables the estimation of the risk of reaching the sterilization barrier height. Also, there is no method that enables the efficient tracking of the movement of the stopper for a product batch.

[0022] One method involves filling the barrel with a medical composition and then placing carbon black particles or a similar marker above the stopper (in the non-sterile proximal region), and marking the initial position of the stopper. As the stopper moves, carbon black particles may remain along the inner wall of the barrel, and a ring may be formed at the most proximal position. Determining the distance between the initial position of the stopper and the ring formed by the carbon black particles may make it possible to estimate the magnitude of the movement of the proximal stopper. However, this method does not take into account smaller back-and-forth displacements below the carbon black ring that accumulate and increase the risk of breaching the integrity of the container closure.

[0023] Another approach is to monitor the movement of the stopper using a camera. However, this method requires leaving a large amount of space around the medical container, which is not possible under conventional storage or shipping conditions and does not allow for monitoring multiple medical containers simultaneously. Therefore, this method can be used in a laboratory environment but is not suitable for industrial-scale applications.

[0024] In International Publication No. WO 2015 / 138261 and US Application No. 2018 / 250474, mechanical solutions for preventing the movement of the stopper during thermal cycling have been proposed. However, such solutions require a specific design of the medical container and may increase manufacturing complexity and cost. SUMMARY OF THE INVENTION

[0025] An object of the present disclosure is to determine with sufficient accuracy how the stopper is expected to move during pressure and / or temperature fluctuations. Another object of the present disclosure is to predict whether a pressure cycle and / or a thermal cycle, or a plurality of pressure and / or thermal cycles and fluctuations, may cause a breach of the container closure integrity.

[0026] For this purpose, a first object of the present disclosure is a method for determining the displacement of a stopper of a filled medical container during fluctuations in heat and / or pressure.

[0027] The filled medical container comprises a barrel containing a medical composition, a stopper slidably disposed at the proximal end of the barrel, and a bubble extending from the free surface of the medical composition, and the method comprises the following. That is, - Calculating parameters for a thermomechanical model of the filled medical container according to the analysis of the filled medical container. - Calculating the thermal profile of the components based on the thermomechanical model of the filled medical container. - Based on the calculated thermal profile of the aforementioned components, calculating over time the air pressure in the bubble according to the gas law and the displacement of the stopper during the aforementioned heat and / or pressure fluctuations. - Based on the calculated displacement mentioned above, determining the risk of violating the integrity of the container stopper as a result of the cumulative proximal displacement of the stopper.

[0028] Preferably, the aforementioned heat and / or pressure fluctuations may include at least one or a number of repeated combinations of the following. (1) One or more thermal cycles including a large-amplitude temperature decrease (e.g., from about 20°C to about -20°C or -80°C, etc.) and a large-amplitude temperature increase (e.g., from about -20°C or -80°C to about 20°C, etc.). (2) One or more pressure cycles including a large-amplitude pressure decrease (e.g., from about 1000 hPa to about 500 hPa, etc.) and a large-amplitude pressure increase (e.g., from about 500 hPa to about 1000 hPa, etc.). (3) One or more thermal fluctuations including small-amplitude temperature oscillations (e.g., + / -10°C or + / -1°C centered around the nominal temperature at 1 Hz or 1 mHz, etc.). (4) One or more pressure fluctuations, including small-amplitude pressure oscillations (e.g., + / - 100 hPa or + / - 1 hPa centered around the nominal pressure at 1 Hz or 1 mHz).

[0029] In some embodiments, the thermal processing model calculates the displacement of the stopper over time, taking into account the average temperature of each component of the stopper during at least one thermal fluctuation and the convection phenomenon at the interface between the aforementioned elements during at least one thermal fluctuation.

[0030] In some embodiments, the thermal processing model is a one-dimensional model assuming that the filled medical container has an axisymmetric shape.

[0031] In some embodiments, the thermal processing model assumes that the medical composition freezes or melts axially symmetrically during at least one thermal fluctuation.

[0032] Furthermore, the thermal processing model can be assumed that the free surface of the medical composition remains flat during thermal and / or pressure fluctuations.

[0033] In some embodiments, the thermal processing model takes into account the sliding force of the stopper that varies with temperature.

[0034] In some embodiments, the resulting displacement is the displacement amplitude of the stopper during at least one thermal fluctuation.

[0035] In some embodiments, the resulting displacement of the stopper is the cumulative displacement of the stopper in the proximal direction.

[0036] In some embodiments, the method further comprises the step of drawing an abacus representing the maximum number of allowable thermal cycles as a function of the volume of the medical composition and the volume of air in the filled medical container.

[0037] Another object of the present disclosure is a method for assessing the risk of loss of integrity of a filled medical container during a storage period and / or a shipping period that includes at least one heat and / or pressure variation, comprising: That is, - Determining a sterilization barrier height defined as the distance in the barrel between the most distal contact point of the sealing stopper with respect to the barrel and the most proximal contact point at the initial position of the stopper. - Determining the resulting displacement of the stopper during said storage period and / or transport period by the method described above. - Comparing the resulting displacement with the sterilization barrier height. - If the resulting displacement is greater than the sterilization barrier height, determining that there is a risk of loss of integrity, or if the resulting displacement is less than the sterilization barrier height, determining that there is no risk of loss of integrity.

[0038] In some embodiments, the method determines the maximum number of heat and / or pressure variations that allow maintaining the integrity of the filled medical container, whereby the resulting displacement of the stopper with respect to the maximum number of heat and / or pressure variations is lower than the sterilization barrier height, and further comprises the step of.

[0039] The maximum number of the aforementioned heat cycles can be calculated from the ratio of the sterilization barrier height to the resulting displacement of the stopper during a single heat cycle.

[0040] The present invention relates to a method for maintaining the integrity of a filled medical container during a storage period and / or a shipping period that includes at least one heat and / or pressure variation. The filled medical container includes a barrel containing a medical composition and a stopper that engages slidably within the barrel. The method comprises: That is, - Determining the maximum number of heat and / or pressure variations using the method described above. - exposing the filled medical container to thermal and / or pressure variations a number of times that is less than the determined maximum number of times described above.

[0041] In some embodiments, during each thermal variation, the temperature drops to -80 °C or below -80 °C.

Brief Description of the Drawings

[0042] Further features and advantages of the present invention will become apparent from the following description based on the accompanying drawings.

[0043]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

DETAILED DESCRIPTION OF THE INVENTION

[0044] The present disclosure is based on the definition of a simplified thermal processing model for a filled medical container, taking into account a plurality of parameters related to the design of the filled medical container and the conditions of thermal / pressure fluctuations to which the filled medical container will be exposed.

[0045] In particular, the aforementioned thermal and / or pressure fluctuations may include one or multiple repetitions of the following combinations. That is, · One or more thermal cycles including a large amplitude temperature decrease (e.g., from about 20°C to about -20°C or -80°C, etc.) and a large amplitude temperature increase (e.g., from about -20°C or -80°C to about 20°C, etc.). · One or more pressure cycles including a large amplitude pressure decrease (e.g., from about 1000 hPa to about 500 hPa, etc.) and a large amplitude pressure increase (e.g., from about 500 hPa to about 1000 hPa, etc.). · One or more thermal fluctuations including a small amplitude temperature oscillation (e.g., + / - 10°C or + / - 1°C centered around the nominal temperature at 1 Hz or 1 mHz, etc.). · One or more pressure fluctuations including a small amplitude pressure oscillation (e.g., + / - 100 hPa or + / - 1 hPa centered around the nominal pressure at 1 Hz or 1 mHz, etc.).

[0046] The filled medical container has already been described with reference to FIG. 1.

[0047] In FIG. 1, the filled container is shown in a configuration where it is stored with its distal end facing downwards, i.e., in accordance with the direction of gravity.

[0048] However, in other embodiments, the filled container can be oriented with its distal end facing upwards, i.e., in a direction opposite to the direction of gravity, or perpendicular to the direction of gravity, or at any other angle relative to the direction of gravity.

[0049] The heat processing model is advantageously defined to take into account at least the following parameters of the filled medical container and the conditions of the heat / pressure cycle. That is, - The range of temperatures and pressures reached over the heat cycle. For example, the aforementioned temperature can reach -80°C or less than -80°C. - Geometric characteristics of the barrel, such as the inner diameter and outer diameter of the barrel, etc. - Stopper design, particularly the sterilization barrier height. - Volume of the medical composition within the barrel. - Size of the headspace (i.e., the air bubble between the medical composition and the stopper when the filled medical container is placed with its distal end facing the ground in accordance with the direction of gravity).

[0050] The sterilization barrier height is defined as the distance between the most proximal contact point and the most distal contact point of the stopper with respect to the barrel. Since the stopper does not necessarily contact the barrel over its entire height, the aforementioned distance can be smaller than the height of the stopper. For example, when the stopper contacts the barrel via a distal rib and a proximal rib, the sterilization barrier height is the distance between the aforementioned ribs.

[0051] The heat processing model can be simplified based on the assumption of the geometric shape of the medical container, such as the cylindrical axisymmetric shape of the barrel and the stopper. Therefore, the model can be a 1D (one-dimensional) model.

[0052] The heat processing system can be based on the assumption that the temperature is uniform in each component of the medical container. The aforementioned temperature can be selected as the average temperature of the component (of course, this temperature varies over the thermal cycle).

[0053] In the heat processing model, the medical composition can usually be regarded as water, which is the main component of the medical composition, or another suitable fluid whose thermal and mechanical properties (e.g., freezing temperature, melting enthalpy, conduction, convection, coefficient of thermal expansion, specific heat, etc.) are known. In the following description, the fluid is regarded as water for the purpose of explanation, but this is for illustrative purposes only and is not limiting.

[0054] Depending on the stage of the thermal cycle, the aforementioned water can be in a liquid state or at least partially frozen (ice).

[0055] As illustrated in FIG. 1, when the medical container is stored or shipped with its distal end facing down (in the direction of gravity), the heat processing model can be based on the assumption that the freezing and thawing of water occur according to an axisymmetric shape. In particular, the water is assumed to freeze first at the interface with the barrel (i.e., with the inner side surface and the distal surface of the barrel) and at the interface with the air bubbles (i.e., at the free surface of the medical composition). Also, the ice is assumed to melt first at the same interface. Furthermore, the free (proximal) surface of the medical composition can be assumed to remain flat even when the composition freezes.

[0056] When the medical container is stored or shipped with a direction relative to the direction of gravity, a person skilled in the art can adjust the heat processing model to take into account the behavior of the components in this direction. In this adjustment, when the medical container is stored or shipped with its distal end facing up (a position opposite to the position illustrated in FIG. 1), the fact that the air bubbles are located between the composition of the medical container and its distal end is also taken into account. More generally, the air bubbles always extend above the free surface of the medical composition.

[0057] Regardless of the above assumptions, which are used to simplify the model and reduce the calculation time, the thermal processing model can take into account the physical and thermal processing characteristics of the filled medical container in order to provide a sufficiently accurate simulation regarding the behavior of the stopper.

[0058] In particular, the thermal processing model takes into account the thermal expansion of each component of the medical container and the changes in specific heat.

[0059] Although advantageous, optionally, the thermal processing model can take into account the sliding performance of the stopper, for example, the activation force and the gliding force at various temperatures of the thermal cycle. The activation force is the force required to initiate the movement of the stopper at the start of the injection of the composition, and the gliding force is the force required to move the stopper within the barrel during injection.

[0060] It should be noted that a complete model of the filled medical container can be calculated using the finite element method, which requires meshing the entire barrel. In such calculations, several hours are required to calculate the changes in the temperature of the medical composition, the temperature and pressure of the air bubbles, assuming that the stopper is considered relatively fixed with respect to the barrel. However, such simulations will be closely dependent on the temperature / pressure profile during the thermal cycle, the design of the stopper, and the volume of the medical composition and air within the barrel. Therefore, in practice, implementing such a complete model to determine the risk of compromising the integrity of the stopper for various medical containers and / or various thermal cycle conditions would be a significant burden for those skilled in the art.

[0061] In comparison, the thermal processing model according to the present disclosure can be executed quickly (in seconds) to estimate the displacement of the stopper during one or more thermal and / or pressure cycles.

[0062] Therefore, the aforementioned thermal processing model enables easy simulation of the risk of violating the integrity with respect to multiple designs of filled medical containers and multiple thermal / pressure cycles.

[0063] In particular, as will be described in more detail below, the thermal processing model enables a person skilled in the art to determine an abacus that can identify the risk of integrity violation (expressed as the maximum number of cycles that enable maintaining the integrity of the stopper) for a given design of a filled medical container and given conditions of a thermal / pressure cycle. For example, the abacus may represent the maximum number of cycles as a function of the volume of the medical composition and the volume of the headspace for a particular design of the filled medical container.

[0064] Based on the filled medical container and input data regarding thermal cycles and / or pressure cycles, the thermal processing model can calculate the temperatures of various components, the pressure in the headspace, and the displacement of the stopper, and convert it into an algorithm configured to provide, as output, the maximum number of thermal cycles that enable maintaining the integrity of the stopper. Such an algorithm can be programmed, in particular, using the Scilab programming language or any other arbitrary programming language, and can be implemented on a general-purpose computer such as a laptop.

[0065] In practice, a user interface can be provided that enables a user to input specific parameters of a filled medical container as follows. That is, - Geometric characteristics of the barrel, such as the inner diameter and outer diameter of the barrel, etc. - Nominal volume of the medical composition. - Nominal height of the air bubble in the headspace. - Initial temperature and pressure. - The lowest temperature reached during the thermal cycle (e.g., refrigerated storage temperature, etc.). - Refrigerated storage period. - Thawing period, i.e., the time required to change the medical composition from a frozen state to a liquid state. - Size of the stopper. - Operating force and sliding force of the stopper at the initial temperature and refrigerated storage temperature.

[0066] Based on the convection model at various interfaces, the computer can calculate the temperature and behavior of the components of the filled medical container at multiple time points, assuming that the variation of the parameters of the filled medical container is quasi-static. In particular, the displacement of the stopper relative to its initial position can be calculated at each of the aforementioned multiple time points based on the behavior of the solid components, the freezing or melting of the medical composition, and the variation of the pressure of the bubbles and the external atmosphere.

[0067] The user interface can be adapted to display, as output, a curve showing the displacement of the stopper over time, the maximum number of allowable cycles to maintain the integrity of the stopper, and / or an abacus representing the maximum number of cycles for various parameters of the filled medical container.

[0068] Figure 2 illustrates a representation of a simplified model having an interaction between the components of the filled medical container illustrated in Figure 1.

[0069] This model is defined in a coordinate system that includes a radial direction r (which is horizontal in Figure 2) and a longitudinal direction Z (which is vertical in Figure 2). The origin O of the coordinate system is located at the center of the inner surface of the distal end of the barrel 1. The barrel has a circular bottom surface with a closed distal end and an open proximal end and is modeled as a cylinder having a constant thickness. Therefore, the tip and tip cap of the barrel are not modeled in the illustrated example. The thickness Δr of the barrel is calculated as the difference between the outer diameter r0 and the inner diameter r i of the barrel.

[0070] In the illustrated model, the medical composition is considered to be composed of a liquid portion 2A and a frozen (solid ice) portion 2B. As described above, the medical composition can be assimilated to water or any other suitable fluid whose thermal and mechanical properties are known.

[0071] In the illustrated model, ε1 defines the thickness of the frozen portion of the liquid 2B at the distal end, ε2 defines the thickness of the frozen portion of the liquid 2B at the proximal end (ε1 and ε2 may be equal), and δ defines the thickness of the frozen portion of the liquid 2B in the radial direction. These thicknesses of the frozen portion 2B in their respective directions are assumed to be constant over their respective lengths. However, the thicknesses ε1, ε2, and δ vary over time, which is represented by ε1(t), ε2(t), δ(t) respectively. The liquid portion 2A and the frozen portion 2B have respective temperatures T w (t) and T i (t).

[0072] The same methodology is also used for modeling the melting step when the frozen liquid melts.

[0073] In the headspace 3, the air has a temperature T a (t) that varies over time and a pressure that varies according to the gas law. In a preferred embodiment, the ideal gas law is used.

[0074] The stopper 13 has a temperature T s (t) that varies over time.

[0075] The outside air A surrounding the filled medical container is also considered. The outside air has a temperature T atm (t) that varies over time and a pressure P atm (t).

[0076] Heat exchange with the environment and heat exchange between components are represented by arrows.

[0077] The level of the medical composition within the barrel is represented by the distance Z from the origin O. w (t). The position of the stopper is represented by its distal face distance Z from the origin O a (t), and its proximal face distance Z from the origin O. s (t).

[0078] Figures 3A and 3B depict the main interfaces within the filled medical container, as well as between the filled medical container and the external atmosphere.

[0079] The following table describes the interfaces and the heat models used at each interface.

[0080]

Table 1

[0081] A person skilled in the art can determine the convection model between components, for example, based on the properties of the materials available in a materials database.

[0082] If appropriate, a person skilled in the art can use several complete simulations of the filled medical container to verify or calibrate the heat processing model by comparing the results obtained by the heat processing model for several specific configurations with those obtained by a complete finite element model. Additionally, a person skilled in the art can use experimental data measured for several specific configurations in the filled medical container to verify or calibrate the heat processing model by comparing the results obtained by the heat processing model with the measured results in the aforementioned configurations. However, once the heat processing model has been verified, such complete simulations or experimental measurements are no longer necessary to perform the simulation.

[0083] In the worst-case simulation, the stopper can be considered to slide freely within the barrel (in other words, there is no frictional force opposing the movement of the stopper).

[0084] Figure 4 is an example of a simulation of the displacement of the stopper over time, assuming that the stopper slides freely within the barrel.

[0085] However, a more realistic simulation can take into account the operating force and the sliding force of the stopper. Advantageously, the aforementioned operating force and sliding force depend on the temperature and the speed of the stopper. The operating force and the sliding force can be determined based on the stopper, the barrel, and, if any, a lubricant coating adhering to the barrel and / or the stopper. If appropriate, experimental tests can be carried out to measure the operating force and the sliding force at different temperatures, and the measured values can be used to calibrate the operating force and the sliding force in the model.

[0086] For example, the operating force, which is the force required to start moving the stopper from a fixed position, can be estimated to be approximately 0.1 N at 20°C and approximately 1 N at -80°C.

[0087] Figure 5 is an example of a simulation of the displacement of the stopper over time for a filled medical container with the same design as in Figure 4, assuming that the operating force and the sliding force are equal to 0.1 N at 20°C and 1 N at -80°C.

[0088] As can be seen, the operating force and the sliding force affect the shape and amplitude of the displacement curve, and the sliding force significantly reduces the displacement amplitude of the stopper.

[0089] Based on the displacement curve in Figure 4 or Figure 5, it is possible to determine the resulting displacement of the stopper, which can be the displacement amplitude of the stopper and / or the cumulative positive displacement of the stopper.

[0090] For example, as shown in Figure 6 based on the curve in Figure 4, the displacement amplitude Δ da of the stopper is the difference between the nearest position and the farthest position of the stopper.

[0091] Continuing to refer to FIG. 6, the cumulated proximal displacement Δ cd of the stopper is the sum of the displacements of the stopper in the proximal direction. In the example of FIG. 6, the thermal cycle involves three displacements of the stopper in the proximal direction, namely Δ d1 Δ d2 and Δ d3 . The cumulated proximal displacement Δ cd is the sum of Δ d1 Δ d2 and Δ d3 .

[0092] Therefore, the resulting displacement of the stopper can be compared with the sterilization barrier height. That is, - If the resulting displacement of the stopper is greater than the sterilization barrier height, there is a risk of loss of integrity of the container closure. - If the resulting displacement of the stopper is less than the sterilization barrier height, there is no risk of loss of integrity of the container closure.

[0093] Due to friction, the position of the stopper at the end of the cycle is not necessarily the same as the initial position. Therefore, the displacements are not the same in all cycles.

[0094] The maximum number of thermal cycles can be calculated by summing the cumulated proximal displacements Δ cd of each thermal and / or pressure fluctuation until their sum is greater than the sterilization barrier height.

[0095] A similar calculation of the resulting displacement (displacement amplitude and / or cumulative positive displacement) can be performed based on the curve as shown in FIG. 5, taking into account the sliding force of the stopper.

[0096] Of course, the shapes and amplitudes of the curves in FIGS. 4 and 5 are related to the specific design of the filled medical container and are provided only as examples for illustration. For various designs of the filled medical container, or various filling conditions (volume of the medical composition and volume of the headspace), the shapes and amplitudes of these curves may change, and the resulting displacement of the stopper may also change.

[0097] These simulations can be advantageously used to cause the abacus to calculate, enabling a person skilled in the art to easily determine the level of risk of infringing the integrity of the filled medical container or to determine the maximum number of thermal cycles to avoid the aforementioned infringement of integrity.

[0098] FIG. 7 illustrates the abacus drawn for a plurality of filling conditions from a plurality of curves of the type shown in FIG. 4 (when the sliding force is not considered) or FIG. 5 (when the sliding force is considered).

[0099] The abacus in FIG. 7 represents the displacement amplitude Δ as a function of the volume of the medical composition in mL (on the horizontal axis) and the height of the headspace in cm (on the vertical axis). The values of the displacement amplitude are associated with a color map in the range of 0 to 2.5 mm. da Three curves regarding the displacement of the stopper over time for various values of the volume of the medical composition and the height of the headspace, which were used to draw the abacus (all other parameters of the filled medical container are the same for all simulations), are shown. The displacement amplitude is measured on each of the aforementioned curves as shown in FIG. 6 and is used to plot points on the abacus. The values of the displacement amplitude between adjacent points can be estimated by interpolation. In these simulations, the sliding force is not considered, but as described above, it was also possible to draw a similar abacus using the curves obtained by simulations taking the sliding force into account.

[0100]

[0101] ​ In addition to the color map of the displacement amplitude, the avax also displays a plurality of curves, and each curve represents the maximum number N of thermal cycles that enables the integrity of the medical container not to be violated. max As described above, the maximum number of the aforementioned thermal cycles is calculated as the floor function of the ratio between the sterilization barrier height and the displacement amplitude Δ. da In the illustrated example, the sterilization barrier height is set to 5.5 mm.

[0102] In practice, those skilled in the art can use such an avax to determine an appropriate set of values for the volume of the medical composition and the height of the headspace in order to ensure a given allowable number of thermal cycles. For example, if the goal is to guarantee the integrity of the stopper over at least 5 thermal cycles, those skilled in the art can select the volume of the medical composition and the height of the headspace in the region of the avax located below the curve corresponding to N = 5. max Alternatively, as shown in FIG. 8, the avax can represent the cumulative displacement Δ of the stopper as a function of the volume of the medical composition in mL (on the horizontal axis) and the height of the headspace in cm (on the vertical axis).

[0103] The value of the cumulative displacement is associated with a color map in the range of 0.5 to 3.5 cmm. cd

[0104] Although not shown in Fig. 8, the avax can be drawn in a manner similar to the avax of Fig. 7 using a plurality of curves (all other parameters of the filled medical container are the same for all simulations) regarding the displacement of the stopper over time for various values of the volume of the medical composition and the height of the headspace. The cumulative displacement is measured on each of the aforementioned curves, as illustrated in Fig. 6, and is used to plot points on the avax. The value of the cumulative displacement between adjacent points can be estimated by interpolation. In these simulations, the sliding force is not considered, but as described above, it was also possible to draw a similar avax using the curves obtained by simulations taking into account the sliding force.

[0105] In addition to the color map of the cumulative displacement, the avax also displays a plurality of curves, each curve representing the maximum number N max of thermal cycles that allows the integrity of the medical container not to be violated. In this particular case, the maximum number of the aforementioned thermal cycles is calculated as a floor function of the ratio between the sterilization barrier height and the displacement amplitude Δ cd . In the illustrated example, the sterilization barrier height is set at 5.5 mm.

[0106] In practice, a person skilled in the art can use such an avax to determine appropriate values for the volume of the medical composition and the height of the headspace in order to ensure a given number of allowable thermal cycles. For example, if the goal is to guarantee the integrity of the stopper over at least 5 thermal cycles, the person skilled in the art can select the volume of the medical composition and the height of the headspace in the region of the avax located below the curve corresponding to N max = 5.

[0107] Of course, the avax is provided only as an example for illustration and may vary depending on the design of the filled medical container and the conditions of the thermal / pressure cycles.

[0108] It should be noted that the thermal cycle and / or the pressure cycle may not be applied continuously. For example, filled medical containers may be subjected to two separate thermal cycles and / or pressure cycles, each corresponding to the shipment from one location to another.

Claims

1. A method for determining the displacement of a stopper of a filled medical container during thermal and / or pressure fluctuations, wherein the filled medical container includes a barrel containing a medical composition, the stopper slidably disposed at the proximal end of the barrel, and air bubbles extending from the free surface of the medical composition, and the method comprises calculating parameters of a thermal processing model of the filled medical container according to an analysis of the filled medical container; calculating a thermal profile of components thereof based on the thermal processing model of the filled medical container; calculating over time the air pressure within the air bubbles according to the gas law and the displacement of the stopper during the thermal and / or pressure fluctuations based on the calculated thermal profile of the components; determining a risk of violating the integrity of the container stopper as a result of the cumulative proximal displacement of the stopper based on the calculated displacement A method comprising the above steps.

2. The method according to claim 1, wherein the thermal processing model calculates the displacement of the stopper over time taking into account the average temperature of each component of the stopper during the at least one thermal fluctuation and the convection phenomenon at the interface between the components during the at least one thermal fluctuation.

3. The method according to claim 1 or 2, wherein the thermal processing model is a one-dimensional model assuming that the filled medical container has an axially symmetric geometric shape.

4. The method according to any one of claims 1 to 3, wherein the thermal processing model assumes that the medical composition freezes or melts axially symmetrically during at least one thermal fluctuation.

5. The method according to claim 4, wherein the thermal processing model assumes that the free surface of the medical composition remains flat during thermal and / or pressure fluctuations.

6. The method according to any one of claims 1 to 5, wherein the thermal processing model takes into account the sliding force of the stopper that varies with temperature.

7. The method according to any one of claims 1 to 6, wherein the resulting displacement is the displacement amplitude of the stopper in at least one thermal fluctuation.

8. The method according to any one of claims 1 to 6, wherein the resulting displacement of the stopper is the cumulative displacement of the stopper in the proximal direction.

9. As a function of the volume of the medical composition and the volume of air in the filled medical container, the maximum number of allowable thermal cycles (N ｍａｘ ) to represent, and further comprising the step of drawing an abacus, the method according to any one of claims 1 to 8.

10. A method for evaluating the risk of loss of integrity of a filled medical container during a storage period and / or a shipping period that includes at least one heat and / or pressure variation, Determining a sterilization barrier height, defined as the distance between the most distal point and the most proximal point among the contact points of the stopper sealed to the barrel at the initial position of the stopper, Determining the resulting displacement of the stopper during the storage period and / or the shipping period by the method according to claims 1 to 9, Comparing the resulting displacement with the sterilization barrier height, Determining that there is a risk of loss of integrity if the resulting displacement is greater than the sterilization barrier height, or determining that there is no risk of loss of integrity if the resulting displacement is less than the sterilization barrier height A method comprising.

11. Further comprising determining the maximum number of heat and / or pressure variations that enables maintaining the integrity of the filled medical container, whereby the resulting displacement of the stopper with respect to the maximum number of heat and / or pressure variations is lower than the sterilization barrier height, the method according to claim 10.

12. The method according to claim 11, wherein the maximum number of heat variations is calculated from the ratio between the sterilization barrier height and the resulting displacement of the stopper during one heat cycle.

13. A method for maintaining the integrity of a filled medical container during a storage period and / or a shipping period that includes at least one heat and / or pressure variation, the filled medical container including a barrel containing a medical composition and a stopper that slidably engages within the barrel, Determining the maximum number of heat and / or pressure variations using the method according to claim 11 or 12, Exposing the filled medical container to a number of heat and / or pressure variations less than the determined maximum number A method comprising.

14. The method according to claim 12, wherein during each heat variation, the temperature drops to -80°C or less.

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