Improved method for sterilizing a prefilled syringe (PFS)

Abstract

The invention consists essentially in applying a sterilization cycle to a prefilled syringe (PFS) according to predetermined parameters (volume of air bubble, value of the back pressure to be applied to the seal after the sterilization tray) which make it possible to absolutely guarantee the complete sterilization of the syringe and a return to the initial position of the seal that it has before the application of said sterilization cycle.

Description

[0001] Description

[0002] Title: IMPROVED STERILIZATION PROCESS FOR A PRE-FILLED SYRINGE (PFS)

[0003] Technical field

[0004] The present invention relates to the field of packaging injectable drugs for parenteral administration in liquid form.

[0005] More particularly, the invention relates to pre-filled syringes (PFS) in which drugs are packaged and which require aseptic presentation, i.e. the interface for transferring the drugs to their place of administration (injection site in a patient) must be sterile at the time of use.

[0006] The invention aims to propose a solution for improving the sterilization of an injection device, in particular a PFS syringe, before its packaging / storage, and in any event before its use.

[0007] Prior art

[0008] A pre-filled syringe is a syringe in which a liquid medication has been packaged and sterilized, either before or after filling the syringe, for storage, which may be for a long period. This avoids the need to withdraw the medication from a bottle or ampoule at the time of use, for immediate administration.

[0009] This ready-to-use packaging eliminates the need to prepare the medication before injection and the associated risks of error. It also avoids the risk of microbiological contamination during collection.

[0010] To prevent the drug from leaking out while it is being stored in a syringe, the syringe is sealed at one end of the volume containing the drug by a seal mounted on the syringe plunger, and at the other end by a tip with a removable stopper. The stopper with a breakable stopper may advantageously be like those described respectively in patent applications EP1973592, EP3829681 and that filed on November 26, 2020 under number FR2012159.

[0011] Figure 1 shows a pre-filled hypodermic syringe 1 according to the state of the art with an axisymmetric shape around a longitudinal axis X.

[0012] The syringe 1 comprises a tubular body 2 of generally cylindrical shape with two open longitudinal ends 3, 4.

[0013] A rod forming a pusher 5 passes through the opening of the first end 3 of the tubular body 2. The end of the pusher 5 mounted in the tubular body 2 is surmounted by a seal 6. The pusher 5 and the seal 6 form a piston which is adapted to slide inside the tubular body 2 along the longitudinal axis X.

[0014] The seal 6 forming the piston head is preferably provided with peripheral ribs 60 directly in surface contact with elastic deformation against the interior of the body 2 to guarantee sealing.

[0015] The pusher 5 forming the piston rod allows a user to activate the translational movement of the piston to release the packaged liquid, once the syringe is open.

[0016] The tubular body 2 comprises at the first end 3, a support collar 7 which projects outwards. Thus, the fingers of a user come to rest under the collar 7, while another finger, generally the thumb, comes to move the pusher 5 and therefore the piston with its seal 6 by pressing on the end 50 of the pusher 5 opposite that forming the piston.

[0017] The second end 4 of the tubular body comprises a wall 8 which is substantially transverse and open in its center and which is extended by a connection end piece 9 of the Luer-lock or Luer or NR Fit or EN Fit type (or other specific connector developed for specific applications allowing error correction with other existing connectors).

[0018] The tip 9 comprises a tubular inner part 10 and an outer part 11, coaxial with the inner part, which forms a neck and whose internal surface is threaded to allow the screwing of a tip of complementary shape for connection to a needle or an infusion line or a catheter or a device known by the Anglo-Saxon designation “Luer Activated Device” (LAD) or any other connector on the market, once the syringe 1 is open.

[0019] The tubular inner part 10 is of substantially truncated cone shape and opens, on the side of its largest diameter which coincides with the opening of the transverse wall 8, onto the interior of the tubular body 2.

[0020] A plug 12 is screwed into the threaded part 11 of the tip 9, thereby closing the tubular inner part 10 of the tip 9. The tubular body 2, the piston with its seal 6, the tip 9 and the plug 12 delimit a sealed space serving as a reservoir for a liquid to be administered to a patient. In this sealed space, more precisely in the inner chamber delimited by the body 2, a gas bubble B, generally air, remains.

[0021] To make the syringe 1 operational, the cap 12 is unscrewed which opens the syringe, then a needle or an infusion line or a catheter or a LAD device or any other connector on the market, is connected to the tip 9.

[0022] Once the needle or infusion line or catheter or other connector on the market is implanted in a patient, a user can operate the push button 5 which administers the liquid contained in the reservoir to the patient.

[0023] The primary advantage of a PFS pre-filled syringe is that it eliminates the need for the user to transfer medication from any container into the syringe before use. In other words, a pre-filled syringe reduces preparation, confusion, and the risk of contamination during injection, as all contact areas are sterile. Thus, a PFS syringe allows for quick and safe medication administration. Such a PFS syringe generally has a graduation that allows for the desired dosage.

[0024] Prefilled syringes are often filled and sterilized in a production facility, packaged, and then shipped to a medical facility or healthcare institution.

[0025] The usual industrial process for filling and sterilizing a syringe 1 according to figure 1 is as follows.

[0026] After fitting the stopper 12 and filling the inside of body 2 with the medication in liquid form, the seal 6 is fitted, then the piston 5 is screwed into the seal 6.

[0027] The syringe 1 is then packaged in a packaging, usually known as a "blister", comprising a thermoformed plastic part closed by a peelable paper cover. This paper has the particularity of being permeable to water vapor but of being a substantially impermeable barrier to microorganisms. It can be a specific peelable paper having the good properties of permeability to water vapor and barrier to bacteria / microorganisms. Typically, a Tyvek® film can be used.Steam sterilization, to meet regulatory requirements (sterility guarantee even in the event of high initial contamination), must be carried out with at least one sterilization tray at a temperature of at least 121°C for at least 15 minutes in so-called "humid" heat, i.e. all parts requiring sterilization must be in contact with the steam, whether the latter comes from the enclosure of an autoclave after passing through the packaging seal, or from the vaporized contents of the syringe. Regulatory requirements also specify that the sterilization cycle may be shorter than 15 minutes, if and only if the product does not withstand 15 minutes at 121°C. In this case, the duration is shorter, provided that the initial bio-load is controlled.

[0028] However, since the annular chambers formed between the lips 60 of the piston 6 are sealed, they are not accessible to steam. Sterilization is therefore carried out using so-called "dry" heat in this area.

[0029] Consequently, in order to guarantee the sterility of these annular chambers, it is necessary for the sterilization time to be much longer than in "humid" heat (around 60 minutes, instead of 15 minutes). This extended sterilization cycle has three major drawbacks:

[0030] - significantly higher production cost;

[0031] - greater degradation of the material constituting the syringe body, increasing the risk of release of degradation products (plastic additives or glass components such as aluminum) into the liquid with which the PFS syringe is filled;

[0032] - impossibility of sterilizing certain active ingredients at a 121°C plate for 60 minutes because they would undergo prohibitive degradation.

[0033] To overcome these drawbacks, the Applicant has proposed a new pre-filled syringe PFS, as described and claimed in patent EP1919537B1, with steam passage means, provided at the rear of the tubular body of the syringe. One of the advantageous embodiments of the passage means consists of at least one groove / notch provided substantially axially in the side wall of the syringe body, from the inner face and which preferably opens out of the body, locally interrupting an annular bead provided internally at the proximal end of the chamber delimited internally by the body. During sterilization in an autoclave, the piston seal moves back into the tubular body towards the rear thereof until it is in abutment with a rim in the form of a bead at the rear of the body provided to prevent its ejection.In this stop position, water vapor can penetrate through the passage means provided, into the space between the lips of the seal to sterilize the latter. Then, at the end of the sterilization cycle, the seal returns to its initial position, i.e. its position once filling is complete.

[0034] This solution is generally satisfactory, as it works safely for most PFS syringes. However, the Applicant has noted that for certain types of PFS syringes, sterilization was not or only partially carried out and / or the seal did not necessarily return to its initial position.

[0035] Therefore, there is a need to further improve the sterilization process of a PFS pre-filled syringe, in particular according to patent EP1919537B1, in particular in order to guarantee the desired sterilization and / or the return of the seal to its initial position, once the syringe has been filled.

[0036] The aim of the invention is to meet at least part of this need.

[0037] Statement of the invention

[0038] To this end, the invention relates, in one of its aspects, to a method for sterilizing a syringe of the pre-filled syringe (PFS) type,

[0039] - a syringe barrel internally comprising an inner chamber filled with a liquid pharmaceutical product to be injected, the inner chamber comprising a proximal end in the vicinity of which is present at least one mechanical locking means;

[0040] - a chamber closing cap at its distal end;

[0041] - a seal arranged in the inner chamber of the cylinder forming a piston head; the method comprising a sterilization cycle including a sterilization tray and the following steps: i) before the sterilization cycle, generation within the inner chamber of the cylinder of at least one gas bubble, preferably air or nitrogen, of sufficient volume to allow the seal to move back from its initial position in which it is after filling the inner chamber with the liquid pharmaceutical product to an intermediate sterilization position in which it abuts against the mechanical locking means; and / or ii) after the sterilization tray, application of sufficient counter-pressure to the seal to allow the seal to move forward from its intermediate sterilization position to substantially its initial position.

[0042] According to an advantageous embodiment, the syringe comprises a pusher forming a piston rod at one end and / or to which is fixed, directly or by means of an adapter, the seal, the piston rod being introduced and capable of sliding in the body, the fixing of the rod to the adapter or directly to the seal taking place, before or after the sterilization cycle.

[0043] According to an advantageous embodiment variant, the seal of the syringe comprises at least two annular sealing lips between which at least one annular chamber is defined, the syringe comprising passage means provided in the body of the syringe and arranged to place the annular chamber(s) of the seal in communication with the exterior of the body, when the seal is in abutment against the mechanical locking means.

[0044] Advantageously, the sterilization tray is produced at a temperature between 115 and 130°C, preferably at least 121°C for at least 8 minutes, preferably at least 15 minutes.

[0045] According to an advantageous embodiment of the invention, step i) is carried out with an air bubble volume at least equal to 200 pL.

[0046] According to another advantageous embodiment of the invention, step ii) is carried out with a back pressure on the seal being at least equal to 1 bar, preferably equal to at least 1.2 bar, more preferably equal to at least 1.6 bar.

[0047] According to an advantageous embodiment, the sterilization cycle comprises, before the sterilization tray, a continuous heating phase followed by a phase comprising several heating pulses by injection of water vapor and several vacuum pulses.

[0048] Preferably, step ii) is carried out during cooling after the sterilization tray. The invention therefore essentially consists of applying a sterilization cycle to a PFS pre-filled syringe according to predetermined parameters (air bubble volume, value of the back pressure to be applied to the seal after the sterilization tray) which make it possible to guarantee complete sterilization of the syringe and a return to the initial position of the seal that it has before the application of said sterilization cycle.

[0049] Within the framework of the invention, these parameters can be adapted according to the type (materials, dimensions) of syringe, seal and their possible siliconization.

[0050] In an industrial process, the volume of a gas bubble to be produced in a PFS syringe will be defined by the following parameters:

[0051] - dimensions of the syringe;

[0052] -volume of liquid added to the syringe;

[0053] - position of the seal relative to the rear of the syringe barrel;

[0054] These parameters are easily controllable, which allows standardization of the syringes to be produced according to the invention.

[0055] Other advantages and characteristics of the invention will become more apparent upon reading the detailed description of examples of implementation of the invention given by way of illustration and not limitation with reference to the following figures.

[0056] Brief description of the drawings

[0057] [Fig 1] Figure 1 is a longitudinal sectional view of a pre-filled syringe according to the prior art in the filled configuration before use.

[0058] [Fig 2] Figure 2 illustrates in the form of curves the displacement of the seal during a sterilization cycle with different volumes of air bubbles in a PFS syringe according to patent EP1919537B1.

[0059] [Fig 3] Figure 3 illustrates in the form of curves the displacement of the seal during a sterilization cycle with an air bubble volume fixed at 200pL in a PFS syringe according to patent EP1919537B1.

[0060] [Fig 4] Figure 4 illustrates in the form of curves the displacement of the seal during a sterilization cycle with an air bubble volume set at 1000L in a PFS syringe according to patent EP1919537B1, with cooling after the sterilization tray. [Fig 5] Figure 5 illustrates in the form of curves the displacement of the seal during a sterilization cycle with an air bubble volume set at 1000L in a PFS syringe according to patent EP1919537B1, with different values ​​of back pressures applied to the seal, in addition to that intrinsic to the cooling after the sterilization tray.

[0061] [Fig 6] Figure 6 illustrates in the form of curves the displacement of the seal during a sterilization cycle with an air bubble volume fixed at 800pL in a PFS syringe according to patent EP1919537B1, with different values ​​of back pressures applied to the seal, in addition to that intrinsic to cooling after the sterilization tray.

[0062] [Fig 7] Figure 7 illustrates in the form of curves the displacement of the seal during a sterilization cycle with an air bubble volume fixed at 200pL in a PFS syringe according to patent EP1919537B1, with different values ​​of back pressures applied to the seal, in addition to that intrinsic to cooling after the sterilization tray.

[0063] Detailed description

[0064] The terms “lower”, “upper”, “above”, “below”, are to be understood in relation to a pre-filled syringe in an upright configuration with the cap above the tubular body of the syringe.

[0065] The terms "proximal" and "distal" are to be understood in relation to the gripping of a pre-filled syringe. Thus, the closing cap of the syringe is arranged at the distal end of the syringe.

[0066] It is specified that the ordinate scale for the pressure (bar) and the measured displacement of the seal (mm) is the same.

[0067] Figure 1 relating to a pre-filled syringe according to the state of the art has already been described in the preamble. It will therefore not be commented on below.

[0068] The inventors were able to observe that, on certain types of PFS syringes as according to patent EP1919537B1, the desired sterilization and / or the return of the seal to its initial position once the syringe has been filled, were not guaranteed.

[0069] They then studied the influence of two parameters during sterilization, namely on the one hand the size of the air bubble B for the recoil of the seal during the sterilization tray of the sterilization cycle and the counter pressure applied to the seal after the sterilization tray. The inventors thus carried out several sterilization tests.

[0070] For each test, the 10 mL syringe, fitted with its cap, pre-filled and equipped with its rod, is placed in a “blister” type packaging, then the assembly is introduced into an autoclave for steam sterilization of the syringe.

[0071] When the assembly is introduced into the autoclave, the seal has an initial position defined by the volume of pre-filled liquid (and the size of the air bubble) in the cylinder body.

[0072] It should be noted that the seal and the syringe body were previously siliconed with a medical grade silicone during filling and assembly between the different components.

[0073] It is also specified that for all tests, the displacement of the seal inside the syringe body is measured with a motion sensor, marketed under the name TMI-Orion NanoVACQ serial number NV130803.

[0074] For the tests, the inventor carried out an additional preparation of the syringe to allow the volume of air bubbles to be perfectly known by proceeding according to the following steps:

[0075] - fill the inner chamber of the syringe cylinder with a volume greater than the nominal volume of the syringe, for example with a volume of 1 ImL for a nominal volume equal to 10ml;

[0076] - position the syringe seal with the usual tool in its intended position. An elongated element is introduced from the outside of the cylinder on the side of the seal so that excess liquid can escape and exit the syringe by flowing along this elongated element. This results in a filled syringe without air bubbles and with the seal in contact with the liquid;

[0077] - manually pull the plunger to remove the seal and the rod from the body of the syringe, taking care not to spill any liquid;

[0078] - take the desired volume of liquid with a precision pipette. For example, for a bubble volume of 200pL, 200pL of liquid is taken;

[0079] - replace the seal using the tool to put it back in the same position it was initially in.

[0080] At the end of these steps, we obtain a PF S syringe filled with a liquid at the nominal volume containing a calibrated bubble volume, for example 200pL. The sterilization cycle applied was as follows:

[0081] A / Heating phase of approximately 1000s to increase the temperature in the autoclave.

[0082] B / When the autoclave has reached a temperature of around 90°C, several heating pulses are applied, by injecting water vapor, and vacuum. During this phase, the pressure and temperature increase and decrease simultaneously in the autoclave. This allows the air to be removed from the autoclave and replaced with water vapor. Generally speaking, the more air is removed during this phase, the more effective the sterilization. In this phase B, the aim is to achieve maximum retraction of the seal in the cylinder body, i.e. until it reaches the stop with the annular bead. This also allows the air to be removed from the space between the lips of the seal and replaced with water vapor.

[0083] C / Sterilization tray: once the autoclave temperature has reached 121°C, this temperature is maintained for a plateau of approximately 15 minutes (temperature and pressure stable). During this phase, the seal must be moved back as far as possible to allow sterilization of the space between the seal lips. In Figure 2, the start of the sterilization tray is symbolized by the solid vertical black line.

[0084] D / At the end of the sterilization tray, the autoclave is allowed to cool. During this cooling, gas counterpressure is applied or not to the seal.

[0085] Figure 2 illustrates the influence of the volume of an air bubble during the sterilization cycle.

[0086] We observe in this figure 2 that:

[0087] - the seal begins to move back in phase B, i.e. when the vacuum is applied and moves forward again when steam is injected and there is an increase in pressure;

[0088] - for bubble volumes of 250, 350 and 500 pL respectively, the seal recoil is maximum at the start of the sterilization tray, and it is constant during this tray,

[0089] - for a bubble volume of 125 pL, the seal recoil is partial and increases as the sterilization tray progresses.

[0090] We can therefore conclude that there is a threshold value of the bubble volume between 125 and 250 pL below which the seal recoil only occurs partially and even if it reaches its maximum, this is only reached at the end of the sterilization tray. This therefore means that below this threshold value, sterilization does not occur completely, because the space between the lips of the seal is exposed to the sterilization steam for a shorter time.

[0091] The inventors therefore carried out another series of tests with an air bubble, setting its volume to 200 pL. Figure 3 illustrates the result of this other series of tests. Of the three displacement curves observed, the seal recoil is maximum at the start of the sterilization tray, with a gap of 0.6 mm observed for bubble no. 2.

[0092] Following these tests, the inventors conclude that by generating an air bubble volume B of at least 200 pL for a PFS syringe whose inner chamber has a volume of 10 mL, maximum retraction of the seal is guaranteed, i.e. up to its position in abutment against the annular bead and thereby that sterilization is complete.

[0093] Figure 4 illustrates the performance of a sterilization cycle for a 10 mL syringe with a 1000 pL air bubble. For this test, no additional back pressure is applied to the seal after the sterilization tray, during cooling. In other words, the back pressure exerted on the seal is the usual one linked to the cooling phase. Typically, this intrinsic back pressure during cooling decreases rapidly since it is equal to 1.8 bar at 119°C and decreases to 1.1 bar at 111°C. It is clear from this figure 4 that there is no return of the seal to its initial position before the application of the sterilization cycle, even after an additional 2 hours of cooling during which the temperature drops from 40°C to 13°C (and the pressure is equivalent to atmospheric pressure of 1 bar).

[0094] Figure 5 illustrates the performance of a sterilization cycle for a 10 mL syringe with a 1000 pL air bubble. For this test, no additional back pressure is applied to the seal after the sterilization tray, during cooling. Typically, the back pressure decreases slowly since it is equal to 1.8 bar at 108°C and decreases to 1.1 bar at 81°C (decrease only due to cooling). Then, a back pressure is applied once the temperature is below 40°C with a plateau lasting 20 minutes at 1.5 bar, 2.0 bar, 2.5 bar and 3.0 bar respectively.

[0095] It is noted that when the pressure drops during cooling, it reaches a pressure equal to 1 bar at room temperature, there is a slight sinking of the seal without reaching a plateau. On the other hand, for the plateau of the counter-pressure at 1.5 bar there is a sudden sinking of the seal to its initial position.

[0096] The inventors conclude that with an applied back pressure of at least 1.5 bar and for an air bubble B of 1000L for a PFS syringe whose inner chamber has a volume of 10 mL, a maximum return of the seal is guaranteed, i.e. to its initial position before sterilization, possibly to within a few tens of mm.

[0097] Figure 6 illustrates the performance of a sterilization cycle for a 10 mL syringe with an 800 pL air bubble. For this test, no additional back pressure is applied to the seal after the sterilization tray, during cooling. Typically this applied back pressure decreases rapidly since it is equal to 1 bar at 115°C. There is also an increase in the applied back pressure once the temperature falls below 40°C with a tray lasting 20 min respectively at 1, 1.6 bar, 2.2 bar, 2.8 bar and 3.4 bar.

[0098] Note that with a pressure equal to 1 bar (atmospheric pressure), the seal remains retracted.

[0099] On the other hand, for the back pressure plateau at 1.6 bar there is a sudden sinking of the seal to its almost initial position upon reaching a plateau. There is also an additional sinking, without reaching a plateau, with a return to the initial position of the seal during the plateau of 2.2 bar. The sinking is greater than the initial position after 5 minutes at 2.2 bar.

[0100] The inventors conclude that with an applied back pressure of at least 1.6 bar and for an air bubble B of 800 pL for a PFS syringe whose inner chamber has a volume of 10 mL, a maximum return of the seal is guaranteed, i.e. to its initial position before sterilization, possibly to within a few tens of mm.

[0101] Figure 7 illustrates the performance of a sterilization cycle for a 10 mL syringe with a 200 pL air bubble. For this test, no additional back pressure is applied to the seal after the sterilization tray, during cooling. Typically this pressure decreases rapidly since it is equal to 1 bar at 117°C. There is also an increase in the applied back pressure once the temperature falls below 40°C with a tray lasting 20 min respectively at 1, 1.6 bar, 2.2 bar, 2.8 bar and 3.4 bar. It is noted that with an applied back pressure equal to 1 bar, there is a sinking of the seal with a tray at 7.5 mm.

[0102] On the other hand, for the back pressure plateau at 1.6 bar there is a sudden sinking of the seal to its almost initial position upon reaching a plateau. There is also an additional sinking, without reaching a plateau, with a return to the initial position of the seal during the plateau of 2.2 bar. The sinking is greater than the initial position after 5 minutes at 2.2 bar.

[0103] The inventors conclude that with an applied back pressure of at least 1.6 bar and for an air bubble B of 200 pL for a PFS syringe whose inner chamber has a volume of 10 mL, a maximum return of the seal is guaranteed, i.e. to its initial position before sterilization, possibly to within a few tens of mm.

[0104] Therefore, applying a suitable counter-pressure on the seal, in addition to that intrinsic to the cooling phase, returns the seal to its initial position.

[0105] Other variants and embodiments may be envisaged without departing from the scope of the invention.

[0106] Thus, the sufficient volume of the gas bubble and / or the level of backpressure to be applied to the seal will be determined in particular based on the internal coatings of the syringe cylinder, the seal as well as the shape and material of the latter and the possible siliconization of the surfaces.

Claims

Demands 1. Method for sterilizing a pre-filled syringe (PFS) type syringe (1), - a syringe cylinder (2) comprising internally an inner chamber filled with a liquid pharmaceutical product for injection, the inner chamber comprising a proximal end in the vicinity of which is present at least one mechanical locking means - a closing cap (12) for the chamber at its distal end; - a sealing ring (6) arranged in the inner chamber of the cylinder forming a piston head; the process comprising a sterilization cycle including a sterilization tray and the following steps: i) before the sterilization cycle, generation within the inner chamber of the cylinder of at least one gas bubble, preferably of air or nitrogen, of sufficient volume to allow the seal to move back from its initial position in which it is after filling the inner chamber with the liquid pharmaceutical product to an intermediate sterilization position in which it is against the mechanical blocking means; and / or ii) after the sterilization tray, application of a counter-pressure on the seal sufficient to allow the seal to move forward from its intermediate sterilization position to substantially its initial position.

2. Sterilization method according to claim 1, the syringe comprising a plunger (5) forming a piston rod to one end of which is fixed, directly or via an adapter, the sealing ring, the piston rod (10) being introduced and capable of sliding in the body (2), the fixing of the rod to the adapter or directly to the sealing ring taking place, before or after the sterilization cycle.

3. Sterilization method according to claim 1 or 2, the syringe seal comprising at least two annular sealing lips (60) between which at least one annular chamber is defined, the syringe comprising means for passage formed in the body (2) of the syringe (1) and arranged to connect the annular chamber(s) of the joint with the outside of the body (2), when the joint is against the mechanical locking means.

4. A sterilization method according to any one of claims 1 to 3, the mechanical locking means being an annular bead (9) formed internally within the cylinder.

5. A sterilization method according to any one of the preceding claims, the sterilization tray being prepared at a temperature between 115 and 130°C, preferably at least 121°C, for at least 8 minutes, preferably for at least 15 minutes.

6. Sterilization method according to any one of the preceding claims, step i) being carried out with an air bubble volume of at least 200 pL.

7. Sterilization method according to any one of the preceding claims, step ii) being carried out with a back pressure on the seal of at least 1 bar, preferably at least 1.2 bar, preferably even more at least 1.6 bar.

8. Sterilization method according to any one of the preceding claims, the sterilization cycle comprising, before the sterilization tray, a continuous heating phase followed by a phase comprising several steam injection heating strokes and several vacuum strokes.

9. Sterilization method according to any one of the preceding claims, step ii) being carried out during cooling after the sterilization tray.

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