Method for determining displacement of stopper of pre-filled medical container during change in heat and / or pressure

Abstract

The present disclosure relates to a method for determining displacement of a stopper of a pre-filled medical container during a heat and / or pressure change, the pre-filled medical container comprising a cartridge containing a pharmaceutical composition, the stopper being slidably arranged at a proximal end of the cartridge, and a bubble extending from a free surface of the pharmaceutical composition, the method comprises:-calculating parameters of a thermomechanical model of the pre-filled medical container from an analysis of the pre-filled medical container; calculating a heat distribution of the component on the basis of a thermomechanical model of the pre-filled medical container; -calculating the air pressure in the bubble and the displacement of the plug over time during said heat and / or pressure change, following the gas law, on the basis of the calculated heat distribution of the component; -based on the calculated displacements, determining a risk of disrupting the container closure integrity due to accumulated proximal stopper displacements.

Description

Technical Field

[0001] The present disclosure relates to a method for determining the displacement of a stopper of a prefilled medical container during thermal and / or pressure changes, and in particular during at least one cycle. In particular, the method can be used to determine the risk of loss of integrity of a prefilled medical container due to plunger movement during storage and / or shipping throughout a supply chain that includes thermal and / or pressure cyclic changes, and in particular during at least one cycle. The present disclosure also relates to a method for maintaining the integrity of a prefilled medical container during such storage and / or shipping periods. Background Art

[0002] Prefilled medical containers are widely used in the pharmaceutical industry to provide a medical user or patient with a ready-to-use product to be injected into the patient.

[0003] During storage and / or shipment throughout the supply chain, prefilled medical containers may be subjected to at least one or more and repeated combinations of the following:

[0004] (i) one or more thermal cycles comprising a substantial temperature decrease (e.g., from about 20°C to about -20°C or -80°C) and a substantial temperature increase (e.g., from about -20°C or -80°C to about 20°C);

[0005] (ii) one or more pressure cycles, including a large pressure drop (e.g., from about 1000 hPa to about 500 hPa) and a large pressure increase (e.g., from about 500 hPa to about 1000 hPa);

[0006] (iii) one or more thermal fluctuations, including small amplitude temperature oscillations (e.g., + / -10°C or + / -1°C around nominal temperature at 1 Hz or 1 MHz);

[0007] (iv) One or more pressure fluctuations, including small amplitude pressure oscillations (eg, + / -100 hPa or + / -1 hPa around nominal pressure at 1 Hz or 1 mHz).

[0008] Such temperature and / or pressure changes may be applied, for example, to pre-filled medical containers whose pharmaceutical compositions need to be frozen to maintain their stability prior to use and / or shipped under reduced pressure transport conditions (eg, air freight, high altitude trucking).

[0009] Such thermal and / or pressure changes may cause a loss of integrity of the medical container due to movement of the plunger in a non-sterile field.Container closure integrity (CCI) is defined as the ability of a medical container to prevent the ingress of microorganisms, ingress of gases and / or debris, and loss of contents.

[0010] likeFigure 1 As shown in , a prefilled medical container typically comprises a cartridge 1 containing a pharmaceutical composition 2 .

[0011] The barrel 1 comprises a distal end comprising a tip 10 intended to expel the pharmaceutical composition from the barrel, in particular to inject it into a patient. The tip 10 may comprise a needle (not shown) or may be configured to be connected to a needle.

[0012] The tip 10 may be sealingly closed by a tip cap 11. The tip cap may include a rigid cap 11A, typically made of plastic, and an elastic cap 11B, typically made of an elastomer.

[0013] The barrel 1 further comprises a proximal end 12 sealingly closed by a plug 13. The plug 13, which may be made of an elastomeric material, is slidable in the barrel 1 from a proximal rest position to a distal operating position for expelling the medicinal composition through the tip 10. The barrel 1 and / or the plug 13 may be at least partially covered with a lubricant coating (not shown) to improve the glide of the plug.

[0014] Herein, the term "distal" refers to the portion of the prefilled medical container that is away from the user's hand (e.g., on the side of a needle that can be used to inject the pharmaceutical composition into a patient), and the term "proximal" refers to the portion of the prefilled medical container that is closer to the user's hand (e.g., on the side of a flange that allows the user to grasp the barrel of the prefilled medical container).

[0015] The described prefilled container is shown in a configuration in which it is stored with its distal end facing downwards, ie oriented according to the direction of gravity.

[0016] At 20°C, the pharmaceutical composition is typically in a liquid state, and in the illustrated orientation, gas bubbles exist between the free (proximal) surface of the pharmaceutical composition and the distal surface of the stopper (this space is generally referred to as the "head space").

[0017] The various types of materials involved in a prefilled medical container, in particular the pharmaceutical composition, the air trapped inside the barrel and the elastomeric material of the stopper, generally behave differently when subjected to temperature changes as mentioned above.

[0018] During temperature changes, all components will shrink or expand according to their respective coefficients of thermal expansion. In addition, pharmaceutical compositions will also change volume during their phase transitions (expanding during freezing and shrinking during thawing).

[0019] Therefore, the behavior of pre-filled medical containers during thermal cycling is difficult to predict.

[0020] The effect of the above thermal phenomena is that the stopper moves in the barrel during thermal cycling. During a decrease in temperature, the contraction of the air in the headspace may cause the stopper to move distally. However, freezing of the pharmaceutical composition (which increases the volume of the pharmaceutical composition) may cause the stopper to move proximally. During an increase in temperature, expansion of the air in the headspace may cause the stopper to move proximally. However, thawing of the pharmaceutical composition (which reduces the volume of the pharmaceutical composition) may cause the stopper to move distally.

[0021] Additionally, pressure changes in the atmosphere surrounding the prefilled medical container may also contribute to movement of the stopper inside the barrel.

[0022] During said back and forth movement of the stopper, the extreme position reached by the stopper may vary.

[0023] In particular, the stopper may move in a non-sterile region of the barrel. When sterilization of the pre-filled medical container has been implemented, this region is located proximal to the proximal surface of the stopper. Movement of the stopper in the non-sterile region may damage the integrity (particularly sterility) of the pharmaceutical composition.

[0024] Therefore, it is desirable to prevent the cumulative proximal displacement of the stopper from its initial sterilization position from reaching a threshold distance, referred to as the sterile barrier height, at which container closure integrity may be compromised.

[0025] Currently, there does not exist any method that allows estimating the risk of reaching the sterile barrier height, nor does it exist any method that allows efficient tracking of stopper movement for a batch of product.

[0026] A method is included in the top of the stopper (in the non-sterile proximal region) after the tube is filled with a pharmaceutical composition, and the initial position of the stopper is marked. When the stopper moves, it can leave carbon black particles along the inner wall of the tube, and form a ring at its most proximal position. Determining the distance between the initial position of the stopper and the ring formed by the carbon black particles can allow the amplitude of the proximal stopper to be estimated. However, this method does not take into account the smaller back and forth displacement below the carbon black ring, which accumulates and increases the risk of damaging the integrity of the container closure.

[0027] Another countermeasure is to monitor stopper movement with a camera. However, this method requires leaving a large volume around the medical container, which is not possible under regular storage or shipping conditions, and does not allow monitoring of multiple medical containers at the same time. Therefore, this method can be used in a laboratory environment, but is not suitable for industrial scale.

[0028] Documents WO 2015 / 138261 and US 2018 / 250474 propose mechanical solutions to prevent the stopper from moving during thermal cycling. However, these solutions require a specific design of the medical container and may therefore increase manufacturing complexity and cost. Summary of the invention

[0029] The goal of the present disclosure is to determine with sufficient accuracy how the stopper is expected to move during pressure and / or temperature changes. Another goal of the present disclosure is to predict whether pressure and / or thermal cycles or more pressure and / or thermal cycles and fluctuations may lead to a breach in container closure integrity.

[0030] To this end, a first object of the present disclosure is a method for determining the displacement of a stopper of a prefilled medical container during thermal and / or pressure changes,

[0031] The prefilled medical container comprises a barrel containing a pharmaceutical composition, a stopper is slidably disposed at a proximal end of the barrel, and a gas bubble extends from a free surface of the pharmaceutical composition, the method comprising:

[0032] - calculating parameters of a thermomechanical model of the prefilled medical container based on the analysis of the prefilled medical container;

[0033] - calculation of the thermal distribution of the component based on a thermomechanical model of the prefilled medical container;

[0034] - based on the calculated thermal profile of the component, calculate the air pressure in the gas bubble and the displacement of the plug over time during said thermal and / or pressure changes following the gas laws;

[0035] - Based on the calculated displacements, determining the risk of breaching the container closure integrity due to cumulative proximal stopper displacements.

[0036] Preferably, the heat and / or pressure changes may include at least one or more of the following and repeated combinations:

[0037] (i) one or more thermal cycles comprising a substantial temperature decrease (e.g., from about 20°C to about -20°C or -80°C) and a substantial temperature increase (e.g., from about -20°C or -80°C to about 20°C);

[0038] (ii) one or more pressure cycles, including a large pressure drop (e.g., from about 1000 hPa to about 500 hPa) and a large pressure increase (e.g., from about 500 hPa to about 1000 hPa);

[0039] (iii) one or more thermal fluctuations, including small amplitude temperature oscillations (e.g., + / -10°C or + / -1°C around nominal temperature at 1 Hz or 1 mHz);

[0040] (iv) One or more pressure fluctuations, including small amplitude pressure oscillations (eg, + / -100 hPa or + / -1 hPa around nominal pressure at 1 Hz or 1 mHz).

[0041] In some embodiments, the thermomechanical model takes into account the average temperature of each component of the plug during at least one thermal variation and convection phenomena at interfaces between said elements during at least one thermal variation to calculate the displacement of the plug over time.

[0042] In some embodiments, the thermomechanical model is a one-dimensional model assuming that the pre-filled medical container has an axisymmetric geometry.

[0043] In some embodiments, the thermomechanical model assumes that the pharmaceutical composition freezes or thaws axisymmetrically during at least one thermal transition.

[0044] Additionally, thermomechanical models may assume that the free surface of the pharmaceutical composition remains flat during thermal and / or pressure changes.

[0045] In some embodiments, the thermomechanical model takes into account the variable slip force of the plug that is dependent on temperature.

[0046] In some embodiments, the resulting displacement is the magnitude of displacement of the plug during at least one thermal change.

[0047] In some embodiments, the resulting displacement of the plug is the cumulative displacement of the plug in the proximal direction.

[0048] In some embodiments, the method further comprises plotting a nomogram representing the maximum number of thermal cycles allowed as a function of the volume of the pharmaceutical composition and the volume of air in the pre-filled medical container.

[0049] Another object of the present disclosure is a method for assessing the risk of loss of integrity of a prefilled medical container during storage and / or shipping involving at least one thermal and / or pressure change, comprising:

[0050] - determining the sterile barrier height, which is defined as the distance between the most distal contact point and the most proximal contact point of the sealing stopper and the barrel in the initial position of the stopper;

[0051] - determining the resulting displacement of the stopper during said storage and / or shipment by the method as described above;

[0052] - comparing said resulting displacement to the sterile barrier height;

[0053] - If the resulting displacement is greater than the sterile barrier height, then it is determined that there is a risk of loss of integrity, or if the resulting displacement is less than the sterile barrier height, then it is determined that there is no risk of loss of integrity.

[0054] In some embodiments, the method further comprises determining a maximum number of thermal and / or pressure changes allowed to maintain the integrity of the prefilled medical container such that for said maximum number of thermal and / or pressure changes the resulting displacement of the stopper is below the sterile barrier height.

[0055] The maximum number of thermal cycles can be calculated from the ratio between the sterile barrier height and the resulting displacement of the stopper during a single thermal cycle.

[0056] The present disclosure also relates to a method for maintaining the integrity of a prefilled medical container during a storage and / or shipping period that includes at least one thermal and / or pressure change, the prefilled medical container including a barrel containing a pharmaceutical composition and a stopper slidably engaged within the barrel, the method comprising:

[0057] - determining the maximum number of thermal and / or pressure changes using the method as described above;

[0058] - subjecting the prefilled medical container to a number of thermal and / or pressure changes which is less than a determined maximum number.

[0059] In some embodiments, during each thermal shift, the temperature is reduced to or below -80°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Further features and advantages of the invention will appear from the following description based on the accompanying drawings, in which:

[0061] - Figure 1 is a cross-sectional view of a pre-filled medical container;

[0062] - Figure 2 yes Figure 1 Representation of a thermomechanical model of a pre-filled medical container;

[0063] - Figure 3A and Figure 3B denote the main interfaces considered in the model when the pharmaceutical composition is in a liquid state and when the pharmaceutical composition is partially frozen during temperature reduction, respectively;

[0064] - Figure 4 is an example of the simulated displacement (in mm) of the plug over time (in s), assuming that the plug slides freely in the tube;

[0065] - Figure 5 is an example of simulated displacement (in mm) of a plug over time (in s) taking into account a variable sliding force that depends on temperature;

[0066] - Figure 6 shows how to determine the plug displacement amplitude and the cumulative positive plug displacement from a curve representing the simulated displacement of the plug over time;

[0067] - Figure 7 is an example of a nomogram representing a mapping of the stopper displacement amplitude and the maximum number of thermal cycles depending on the volume of the pharmaceutical composition and the size of the headspace;

[0068] - Figure 8 is an example of a nomogram representing a mapping of cumulative positive stopper displacement and maximum number of thermal cycles depending on the volume of the pharmaceutical composition and the size of the headspace. DETAILED DESCRIPTION

[0069] The present disclosure is based on the definition of a simplified thermomechanical model of a prefilled medical container that takes into account a number of parameters related to the design of the prefilled medical container and the conditions of thermal / pressure variations to which the prefilled medical container will be subjected.

[0070] In particular, the heat and / or pressure changes may include one or more and repeated combinations of the following:

[0071] One or more thermal cycles, including a large temperature decrease (e.g., from about 20°C to about -20°C or -80°C) and a large temperature increase (e.g., from about -20°C or -80°C to about 20°C);

[0072] One or more pressure cycles, including a large pressure drop (e.g., from about 1000 hPa to about 500 hPa) and a large pressure increase (e.g., from about 500 hPa to about 1000 hPa);

[0073] One or more thermal fluctuations, including small-amplitude temperature oscillations (e.g., + / -10°C or + / -1°C around nominal temperature at 1 Hz or 1 mHz);

[0074] • One or more pressure fluctuations, including small amplitude pressure oscillations (eg, + / -100 hPa or + / -1 hPa around nominal pressure at 1 Hz or 1 mHz).

[0075] Already referenced Figure 1 Prefilled medical containers are described.

[0076] exist Figure 1 In the figure, the prefilled container is shown in a configuration in which it is stored with its distal end facing downwards, ie oriented according to the direction of gravity.

[0077] However, in other embodiments, the prefilled container may be oriented with its distal end facing upward, ie, 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.

[0078] The thermomechanical model is advantageously defined taking into account at least the following parameters of the prefilled medical container and the conditions of the thermal / pressure cycles:

[0079] - the temperature and pressure ranges reached during the thermal cycle; for example, the temperature may reach -80°C or even below -80°C;

[0080] - The geometrical characteristics of the tube, such as the inner and outer diameters of the tube;

[0081] - The design of the stopper, in particular the sterile barrier height;

[0082] - the volume of the pharmaceutical composition in the cartridge;

[0083] - the size of the head space (ie the air bubbles between the pharmaceutical composition and the stopper when the prefilled medical container is positioned with its distal end facing the ground according to the direction of gravity).

[0084] The sterile barrier height is defined as the distance between the most proximal and most distal contact points of the stopper and the barrel. The distance may be less than the height of the stopper, since the stopper may not be in contact with the barrel over its entire height. For example, if the stopper is in contact with the barrel via distal and proximal ribs, the sterile barrier height is the distance between the ribs.

[0085] The thermomechanical model can be simplified based on the assumption of the geometry of the medical container, such as the cylindrical axisymmetric geometry of the barrel and the stopper. Therefore, the model can be a 1D (one-dimensional) model.

[0086] Thermomechanical systems may also be based on the assumption that the temperature is uniform in each component of the medical container; the temperature may be chosen to be the average temperature of the component (which of course varies during thermal cycling).

[0087] In the thermomechanical model, the pharmaceutical composition can be considered as water, which is usually the main component of the pharmaceutical composition, or any other suitable fluid whose thermal and mechanical properties (e.g., freezing temperature, melting enthalpy, conduction, convection, thermal expansion coefficient, specific heat) are known. In the following description, the fluid is considered to be water, just for illustration and not limitation.

[0088] Depending on the stage of the thermal cycle, the water may be in liquid state or at least partially frozen (ice).

[0089] If the medical container is stored or shipped with the distal end facing downward (according to the direction of gravity), such as Figure 1As shown in , the thermomechanical model can be based on the assumption that freezing and thawing of water occurs according to an axisymmetric geometry. In particular, it is assumed that water first freezes at the interface with the barrel (i.e., with the inner and distal surfaces of the barrel) and at the interface with the bubble (i.e., at the free surface of the pharmaceutical composition). It is also assumed that ice first melts at the same interfaces. In addition, it can be assumed that the free (proximal) surface of the pharmaceutical composition remains flat even when the composition is frozen.

[0090] If the medical container is stored or shipped in another orientation relative to the direction of gravity, the technician will be able to adjust the thermomechanical model to take into account the behavior of the components in this orientation. In this adjustment, the following fact will also be taken into account: if the medical container is stored or shipped with the distal end facing upwards (as opposed to Figure 1 In the embodiment of the present invention, the bubble is located between the composition and the distal end of the medical container. More generally, the bubble always extends above the free surface of the medical composition.

[0091] Although the above assumptions are used to simplify the model and reduce computational time, the thermomechanical model can take into account the physical and thermodynamic characteristics of the pre-filled medical container in order to provide a sufficiently accurate simulation of the stopper behavior.

[0092] In particular, the thermomechanical model takes into account the thermal expansion of each component of the medical container and the change of its specific heat.

[0093] Advantageously but optionally, the thermomechanical model can take into account the sliding properties of the stopper, such as the activation force and the sliding force at various temperatures of the thermal cycle. The activation force is the force required to initiate the movement of the stopper when the composition is injected; the sliding force is the force required to move the stopper within the barrel during injection.

[0094] It should be noted that the complete model of the pre-filled medical container can be calculated using the finite element method, which requires meshing of the entire tube. Such calculations require several hours to calculate the temperature of the pharmaceutical composition and the temperature and pressure evolution of the bubble, and the stopper is considered to be fixed relative to the tube. However, this simulation will closely depend on the temperature / pressure distribution during the thermal cycle, the design of the stopper, the volume of air in the pharmaceutical composition and the tube. Therefore, in practice, it will be a huge burden for the technician to implement such a complete model to determine the risk of closure integrity destruction for various medical containers and / or various thermal cycle conditions.

[0095] In comparison, a thermomechanical model according to the present disclosure can be run quickly (within seconds) to estimate the displacement of a plug during one or several thermal and / or pressure cycles.

[0096] Thus, the thermomechanical model allows integrity breach risk to be easily simulated for various designs of pre-filled medical containers and multiple thermal / pressure cycles.

[0097] In particular, as will be explained in more detail below, the thermomechanical model can allow for the determination of a nomogram that allows a skilled person to identify the risk of integrity breach (expressed as the maximum number of cycles that allow the closure integrity to be maintained) for a given design of a prefilled medical container and given conditions of thermal / pressure cycling. For example, for a specific design of a prefilled medical container, the nomogram can express the maximum number of cycles as a function of the volume of the pharmaceutical composition and the volume of the headspace.

[0098] The thermomechanical model can be converted into an algorithm that is configured to calculate the temperature of different components, the pressure in the headspace, and the displacement of the plug based on input data related to the prefilled medical container and the thermal and / or pressure cycles, and provide as output the maximum number of thermal cycles that allow the closure integrity to be maintained. In particular, such an algorithm can be programmed using the Scilab programming language or any other programming language and can be implemented on a general purpose computer such as a laptop computer.

[0099] In practice, a user interface may be provided that allows the user to input specific parameters of the pre-filled medical container, such as:

[0100] - The geometrical characteristics of the tube, such as the inner and outer diameters of the tube;

[0101] - the nominal volume of the pharmaceutical composition;

[0102] - the nominal height of the bubbles in the headspace;

[0103] - initial temperature and pressure;

[0104] - the lowest temperature reached during the thermal cycle (e.g., refrigeration temperature);

[0105] - Duration of refrigeration;

[0106] - thawing duration, i.e. the time required for the pharmaceutical composition to change from a frozen state to a liquid state;

[0107] - size of the plug;

[0108] -Activation and sliding forces of the stopper at initial and refrigerated temperatures.

[0109] Based on the convection model at various interfaces, the computer can calculate the temperature and behavior of the components of the prefilled medical container at multiple times, assuming that the evolution of the parameters of the prefilled medical container is quasi-static. In particular, the displacement of the stopper relative to its initial position can be calculated at each of the multiple times based on the behavior of the solid components, the freezing or thawing of the pharmaceutical composition, and the pressure changes of the gas bubble and the external atmosphere.

[0110] The user interface may be adapted to display as output a curve showing displacement of the stopper over time, a maximum number of cycles allowed to maintain closure integrity and / or a nomogram representing the maximum number of cycles for various parameters of the prefilled medical container.

[0111] Figure 2 The diagram shows Figure 1 A representation of a simplified model of the interaction between components of a prefilled medical container is shown in FIG.

[0112] The model is limited to include the radial direction r (which is Figure 2 The horizontal direction in the middle) and the longitudinal direction Z (which is Figure 2 The origin O of the coordinate system is located at the center of the inner surface of the distal end of the tube 1. The tube is modeled as a cylinder with a circular base, which has a closed distal end and an open proximal end, with a constant thickness. Therefore, the end of the tube and the end cap are not modeled in the illustrated example. The thickness Δr of the tube is calculated as the outer diameter r of the tube o With inner diameter r i The difference between.

[0113] In the illustrated model, the pharmaceutical composition is considered to comprise a liquid portion 2A and a frozen (solid ice) portion 2B. As explained above, the pharmaceutical composition may be equivalent to water or any other suitable fluid whose thermal and mechanical properties are known.

[0114] In the illustrated model, ε1 defines the thickness of the frozen portion of the liquid 2B on the distal end, ε2 defines the thickness of the frozen portion of the liquid 2B on 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 its respective directions are assumed to be constant over the length of its respective directions. However, the thicknesses ε1, ε2, and δ vary with time, which are expressed by ε1(t), ε2(t), and δ(t). The liquid portion 2A and the frozen portion 2B have respective temperatures T that vary with time. w (t) and t i (t).

[0115] When a frozen liquid melts, the same approach is used to model the thawing step.

[0116] In the headspace 3, the air has a time-varying temperature T a (t) and the pressure varies according to gas laws. In a preferred embodiment, the ideal gas law is used.

[0117] The plug 13 has a temperature T which varies with time. s (t).

[0118] The external atmosphere A surrounding the prefilled medical container is also considered. The external atmosphere has a temperature T that varies with time. atm (t) and the time-varying pressure P atm (t).

[0119] Heat exchange with the environment and between components is indicated by arrows.

[0120] The material level of the medicinal composition in the tube is determined by the distance Z from the origin O. w (t). The position of the plug is represented by the distance Z of its distal surface from the origin O a (t) and the distance Z of its near side surface from the origin O s (t) indicates.

[0121] Figure 3A and Figure 3B Represents the primary interface within a prefilled medical container and between the prefilled medical container and the external atmosphere.

[0122] The following table describes the interfaces and the thermal model used at each interface.

[0123] refer to interface Model I1 External atmosphere / glass (tube) convection I2 Air(Headspace) / Rubber(Stop) convection I3 Air (Headspace) / Glass (Tube) convection I4 Air (head space) / Liquid water (pharmaceutical composition) convection I5 Air (headspace) / Ice (pharmaceutical composition) convection I6 Rubber (stopper) / Glass (tube) Continuous temperature I7 Rubber (stopper) / air (external atmosphere convection I8 Liquid water (pharmaceutical composition) / glass (tube) convection I9 Liquid water / ice convection I10 Ice(pharmaceutical composition) / glass(tube) Continuous temperature

[0124] A skilled person can determine the convection model between components based on the properties of the material accessible, for example, in a materials database.

[0125] If appropriate, a person skilled in the art can use several complete simulations of prefilled medical containers to validate or calibrate the thermomechanical model by comparing the results obtained with the thermomechanical model and the complete finite element model in several specific configurations. In addition, a person skilled in the art can use experimental data measured on several specific configurations of prefilled medical containers to validate or calibrate the thermomechanical model by comparing the results obtained with the thermomechanical model and the results measured in said configurations. However, such complete simulations or experimental measurements are not necessary to run the simulations once the thermodynamic model has been validated.

[0126] In the worst case simulation, the plug can be considered to slide freely within the barrel (in other words, there is no friction force opposing the movement of the plug).

[0127] Figure 4is an example of the simulated displacement of a plug over time, assuming that the plug slides freely within the tube.

[0128] However, a more realistic simulation may take into account the activation force and the sliding force of the plug. Advantageously, the activation force and the sliding force depend on the temperature and the speed of the plug. The activation force and the sliding force may be determined based on the material of the plug, the barrel and the lubricant coating (if any) deposited on the barrel and / or the plug. If appropriate, experimental tests may be performed to measure the activation force and the sliding force at different temperatures, and the measurement results may be used to calibrate the activation force and the sliding force in the model.

[0129] For example, the activation force (ie, the force required to move the stopper from a fixed position) can be estimated to be about 0.1 N at 20°C and about 1 N at -80°C.

[0130] Figure 5 For example Figure 4 Example of simulated displacement of the stopper over time for the same design of a prefilled medical container in FIG. 1 , assuming activation and sliding forces equal to 0.1 N at 20 °C and 1 N at −80 °C.

[0131] It can be seen that the activation force and the sliding force have an impact on the shape and amplitude of the displacement curve, and the sliding force significantly reduces the displacement amplitude of the plug.

[0132] based on Figure 4 or Figure 5 From the displacement curve of the plug, the resulting displacement of the plug can be determined, which can be the displacement amplitude of the plug and / or the cumulative positive displacement of the plug.

[0133] For example, based on Figure 4 The curve Figure 6 As shown in , the displacement amplitude Δda of the plug is the difference between the most proximal and most distal positions of the plug.

[0134] Still reference Figure 6 , the cumulative proximal displacement of the plug Δcd is the sum of the displacements of the plug in the proximal direction. Figure 6 In the example shown in Figure 2, the thermal cycle involves three displacements of the plug in the proximal direction, Δ d1 , Δ d2 and Δ d3 Cumulative proximal displacement Δ cd Yes d1 , Δ d2 and Δ d3 The sum of .

[0135] The resulting displacement of the stopper can therefore be compared to the sterile barrier height:

[0136] - If the resulting displacement of the stopper is greater than the sterile barrier height, there is a risk of loss of container closure integrity;

[0137] - If the resulting displacement of the stopper is less than the sterile barrier height, there is no risk of loss of container closure integrity.

[0138] Due to friction, the position of the plug at the end of the cycle is not necessarily the same as the initial position. Therefore, the displacement is not the same in all cycles.

[0139] The maximum number of thermal cycles can be calculated by dividing the cumulative proximal displacement per thermal and / or pressure change by Δ cd The sum is calculated until it becomes greater than the sterile barrier height.

[0140] Taking into account the sliding force of the plug, it can be based on Figure 5 Similar calculations of the resulting displacements (displacement amplitude and / or cumulative positive displacement) are performed for the curves shown in .

[0141] certainly, Figure 4 and Figure 5 The shape and amplitude of the curves are related to the specific design of the pre-filled medical container and are provided only as illustrative examples. For different designs of pre-filled medical containers or different filling conditions (volume of pharmaceutical composition and head space), the shape and amplitude of these curves may vary, and the resulting displacement of the stopper may also vary.

[0142] These simulations can advantageously be used to calculate nomograms that allow a skilled person to easily determine the level of risk of compromising the integrity of a prefilled medical container, or to determine the maximum number of thermal cycles to avoid compromising said integrity.

[0143] Figure 7 The diagram shows the Figure 4 (if slip force is not considered) or Figure 5 A nomogram of multiple curves of the type shown (if slip force is considered).

[0144] Figure 7 The nomogram will shift the amplitude Δ da It is presented as a function of the volume of the pharmaceutical composition in mL (abscissa) and the headspace height in cm (ordinate). The values ​​of the displacement amplitude are associated with a color map ranging from 0 to 2.5 mm.

[0145] Three curves of stopper displacement over time for different values ​​of the volume of the pharmaceutical composition and the height of the headspace used for the plotting of the nomogram have been presented (all other parameters of the prefilled medical container being the same for all simulations). Figure 6As shown in , the displacement amplitude is measured on each of the curves and used to plot points on the nomogram. The values ​​of the displacement amplitude between adjacent points can be estimated by interpolation. In these simulations, the slip force is not considered, but as pointed out above, similar nomograms can be drawn using curves obtained by simulations that consider the slip force.

[0146] In addition to the color map of the displacement amplitude, the nomogram also displays a number of curves, each of which represents the maximum number N of thermal cycles allowed without damaging the integrity of the medical container. max As explained above, the maximum number of thermal cycles is calculated as the sterile barrier height and the displacement amplitude Δ da In the illustrated example, the sterile barrier height is set to 5.5 mm.

[0147] In practice, a skilled person can use such a nomogram to determine a suitable pair of values ​​for the volume of the pharmaceutical composition and the height of the headspace to ensure a given number of permissible thermal cycles. For example, if the goal is to ensure the integrity of the seal for at least five thermal cycles, a skilled person can choose a value corresponding to N. max =5.

[0148] Alternatively, Figure 8 As shown in , the nomogram can represent the cumulative stopper displacement Δcd as a function of the volume of the pharmaceutical composition in mL (abscissa) and the headspace height in cm (ordinate). The values ​​of the cumulative displacement are associated with a color map ranging from 0.5 to 3.5 mm.

[0149] Despite Figure 8 Not shown, but can be Figure 7 A nomogram was plotted in a similar manner to the nomogram in , using multiple curves of stopper displacement over time for different values ​​of the volume of the pharmaceutical composition and the height of the headspace (all other parameters of the prefilled medical container were the same for all simulations). Figure 6 As shown in , the cumulative displacement is measured on each of the curves and used to plot points on the nomogram. The value of the cumulative displacement between adjacent points can be estimated by interpolation. In these simulations, the slip force is not considered, but as pointed out above, similar nomograms can be plotted using curves obtained by simulations that consider the slip force.

[0150] In addition to the color map of the cumulative displacement, the nomogram also displays multiple curves, each of which represents the maximum number N of thermal cycles allowed without damaging the integrity of the medical container. maxIn this particular case, said maximum number of thermal cycles is calculated as a floor function of the ratio between the sterile barrier height and the displacement amplitude Δcd. In the illustrated example, the sterile barrier height is set to 5.5 mm.

[0151] In practice, a skilled person can use such a nomogram to determine a suitable pair of values ​​for the volume of the pharmaceutical composition and the height of the headspace to ensure a given number of permissible thermal cycles. For example, if the goal is to ensure closure integrity for at least five thermal cycles, a skilled person can select a value corresponding to N. max =5.

[0152] Of course, the nomograms are provided only as illustrative examples and may vary depending on the design of the prefilled medical container and the conditions of the thermal / pressure cycling.

[0153] It should be noted that the heat and / or pressure cycles may not be applied continuously. For example, a prefilled medical container may be subjected to two separate heat and / or pressure cycles, each corresponding to shipment from one location to another.

Claims

1. A method for determining the displacement of a stopper of a prefilled medical container during thermal and / or pressure changes, The prefilled medical container comprises a barrel containing a pharmaceutical composition, the stopper is slidably disposed at a proximal end of the barrel, and a gas bubble extends from a free surface of the pharmaceutical composition, the method comprising: - calculating parameters of a thermomechanical model of the prefilled medical container based on the analysis of the prefilled medical container; - calculating the thermal distribution of a component based on said thermomechanical model of said prefilled medical container; - based on the calculated thermal profile of the component, calculate the air pressure in the gas bubble and the displacement of the plug over time during said thermal and / or pressure changes following the gas laws; - Based on the calculated displacements, determining the risk of breaching the container closure integrity due to cumulative proximal stopper displacements.

2. The method according to claim 1, wherein: The thermomechanical model calculates the displacement of the plug over time taking into account the average temperature of each component of the plug during at least one thermal variation and convection phenomena at interfaces between elements during at least one thermal variation.

3. The method according to claim 1 or claim 2, wherein: The thermomechanical model is a one-dimensional model assuming that the pre-filled medical container has an axisymmetric geometry.

4. The method according to any one of claims 1 to 3, wherein the thermomechanical model assumes that the pharmaceutical composition freezes or thaws axisymmetrically during at least one thermal change.

5. The method of claim 4, wherein the thermomechanical model assumes that the free surface of the pharmaceutical composition remains flat during thermal and / or pressure changes.

6. The method according to any one of claims 1 to 5, wherein: The thermomechanical model takes into account the temperature-dependent variable slip force of the plug.

7. The method according to any one of claims 1 to 6, wherein: The resulting displacement is the magnitude of displacement of the plug during at least one thermal change.

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

9. The method according to any one of claims 1 to 8, further comprising drawing a nomogram that allows a maximum number of thermal cycles (N MAX ) is expressed as a function of the volume of the pharmaceutical composition and the volume of air in the pre-filled medical container.

10. A method for assessing the risk of loss of integrity of a prefilled medical container during storage and / or shipping involving at least one thermal and / or pressure change, comprising: - determining the sterile barrier height, which is defined as the distance between the most distal contact point and the most proximal contact point of the sealing stopper and the barrel in the initial position of the stopper; - determining the resulting displacement of the stopper during the storage and / or shipment by the method of claims 1 to 9; - comparing the obtained displacement to the sterile barrier height; - if the resulting displacement is greater than the sterile barrier height, determining that there is a risk of loss of integrity, or if the resulting displacement is less than the sterile barrier height, determining that there is no risk of loss of integrity.

11. The method according to claim 10 further includes determining a maximum number of thermal changes and / or pressure changes that allow maintaining the integrity of the prefilled medical container, so that for the maximum number of thermal changes and / or pressure changes, the resulting displacement of the stopper is below the sterile barrier height.

12. The method of claim 11, wherein the maximum number of thermal changes is calculated based on the ratio between the sterile barrier height and the resulting displacement of the stopper during a single thermal cycle.

13. A method for maintaining the integrity of a prefilled medical container comprising a barrel containing a pharmaceutical composition and a stopper slidably engaged within the barrel during storage and / or shipping involving at least one thermal and / or pressure change, the method comprising: - Determining the maximum number of thermal and / or pressure changes using the method according to any one of claims 11 or 12; - subjecting the prefilled medical container to a number of thermal and / or pressure changes which is less than a determined maximum number.

14. The method of claim 12, wherein during each thermal shift, the temperature is reduced to or below -80°C.

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