Method relating to freeze-drying

Abstract

A METHOD relating to the freeze-drying of basic substances (Sb) in basic vials (Fb) comprises the following operations: preparing one or more open basic vials (Fb); preparing at least one first open vial (F1); preparing at least one second vial (F2); placing said basic vials (Fb) inside a freeze-drying chamber (400); placing at least one first vial (F1) inside said freeze-drying chamber (400); placing at least one second vial (F2) inside said freeze-drying chamber (400); starting the freeze-drying process; detecting the values relating to a first electrical characteristic in relation to said first vial (F1) in order to obtain first electrical values; detecting the values relating to said first electrical characteristic in relation to said second vial (F2) in order to obtain second electrical values; carrying out, during said freeze-drying process, comparisons between said first electrical values and said second electrical values.

Description

[0001] TITLE METHOD Relating to Freeze-drying

[0002] DESCRIPTION

[0003] Field of Invention

[0004] _The present invention concerns methods relating to freeze-drying.

[0005] _More particularly, the present invention concerns a method for monitoring the freeze-drying process in relation to the freeze-drying of substances contained in one or more freeze-drying vials.

[0006] Background to the Invention

[0007] _Freeze-drying is a process by which substances can be preserved in a dehydrated form.

[0008] _This process involves freezing the water contained in the substance being freeze-dried, and then removing the ice by sublimation under partial vacuum, using gentle heating (primary drying).

[0009] _The non-freezable water remaining from primary drying is then removed by heating at high temperatures (secondary drying).

[0010] _The end point (so-called set-point) of the freeze-drying process is defined by the achievement of a desired optimal degree of humidity in the substance being freeze- dried.

[0011] In relation to said optimal humidity level, if the substance to be freeze-dried, at the end of the freeze-drying process, has a higher humidity level or a lower humidity level than said optimal humidity level, said substance must be discarded.

[0012] In fact, in summary: if the substance, at the end of the freeze-drying process, has a higher humidity level than the said optimal humidity level, this excessive humidity may cause rapid deterioration of the product and, therefore, not fulfil the requirements relating to the shelf life that the freeze-dried product must have; if the substance, at the end of freeze-drying, has a lower humidity level than the said optimal humidity level, this excessive drying may cause, for example, changes in the molecular structure of the substance, or may cause problems for its future use, such as, for example, not having certain characteristics relating to solubility and, therefore, creating problems when the freeze-dried product must be dissolved in a liquid substance for the so-called "reconstruction" before use; if the substance, during the freeze-drying process, undergoes a too rapid drying process, this too rapid drying may cause problems, such as, for example, changes in the molecular structure of the substance and / or the formation of lumps and / or other undesirable effects and, therefore, the resulting freeze-dried product must be discarded; if the substance, during the freeze-drying process, undergoes a drying process that is too slow, this too slow drying may cause problems, such as, for example, changes in the molecular structure of the substance and / or unwanted chemical reactions and / or other undesirable effects due, mainly, to the presence of water in the substance for too long a period of time.

[0013] _A first known method relating to the freeze-drying of a substance contained in a plurality of vials, consists in inserting, in each vial, a probe in contact with the substance, in order to detect the degree of humidity in the same substance, wherein said probe is equipped with wireless or other types of transmitting means, in order to be able to insert said complex comprising vial with substance with probe with transmission means, into a freeze-drying chamber and, therefore, once the freeze- drying process has been activated, monitor the degree of humidity of the substance which will gradually decrease, in order to then determine the end of the freeze-drying when a certain degree of humidity is detected for said substance during freeze- drying.

[0014] _This method has a number of drawbacks.

[0015] _A first drawback is due to the fact that the probe is in contact with the substance being freeze-dried and this contact can cause unwanted contamination.

[0016] _A second drawback is due to the fact that this method is very expensive, since, mainly, it involves the use of a plurality of probes that must be associated with each vial, as well as a huge amount of work for the preparation of the vials that must be equipped with the probe and the transmission means.

[0017] _A second known method relating to freeze-drying, consists in theoretically pre- determining, "at the table", what the optimal freeze-drying procedure would be, such as, for example, the process methods with relative temperatures and times, in order to obtain, at the end of the freeze-drying process, a substance presumably free from defects and having a desired specific degree of humidity, without inserting probes inside the substance.

[0018] _The second method has a series of drawbacks.

[0019] _A first drawback is due to the fact that the theoretical, “at the table" estimates regarding the freeze-drying procedure to be adopted and the relative freeze-drying times are not reliable and / or optimal and, therefore, sometimes, non-optimal freeze- drying procedures are carried out in which, for example, in order to avoid the extraction of the vials from the freeze-drying chamber with a substance that is still too wet, it is preferable to extend the freeze-drying time beyond that estimated “at the table”, with the risk of drying the substance too much and with a reduction in the production capacity for the relative freeze-drying machine , since the working times for each freeze-drying session are unnecessarily extended.

[0020] _ln fact, for example, these estimates, "at the table", are very difficult and / or impossible to formulate with precision: _since they must be formulated in correlation with the initial humidity level of the substance, in which it is sometimes not available, where said initial humidity level is not always the same for each freeze- drying session; _since they must be formulated in correlation with the type of vial containing the substance to be freeze-dried, more particularly, for example, in correlation with the shape and / or thickness and / or material of the vial body of the individual vials containing the substance, where said type of vial is not always the same for each freeze-drying session; _since they must be formulated in correlation with the molecular composition of the substance to be freeze-dried, where said molecular composition is not always the same for each freeze-drying session; and, consequently, sometimes incorrect and / or non-optimal freeze-drying procedures are adopted, which generate a defective freeze-dried product that must be discarded, or the need to extend the freeze-drying times beyond what is necessary, with the related consequences already mentioned above.

[0021] _These “at the table" estimates are impossible to formulate when it is necessary to operate with a substance that has never been used before in terms of composition or water content, or when it is necessary to work with vials that have never been used before. Exposition of the Invention

[0022] _The purpose of the present invention is therefore to solve the above-mentioned drawbacks as specified in the description, illustrations and claims.

[0023] _The invention, which is characterized by the claims, solves the problem of creating a method relating to the freeze-drying of basic substances contained within basic vials, wherein said method is characterized by the fact that it comprises the following operations: 1.1)_preparing one or more open basic vials, wherein each basic vial has a basic vial body, wherein each basic vial contains a basic substance, wherein said basic substance is a substance to be freeze-dried;

[0024] 1.2)_preparing at least one first open vial, wherein said first vial comprises a respective first vial body equal to said basic vial body, wherein said first vial contains a first substance, wherein said first substance is equal to said basic substance;

[0025] 1.3)_preparing at least one second vial, wherein said second vial comprises a respective second vial body equal to said basic vial body and equal to said first vial body, wherein said second vial contains a second substance; 1.4)_place a plurality of said basic vials as set up in point 1.1) above inside a freeze-drying chamber; 1.5)_place at least one first vial as set up in above point 1.2) inside said freeze- drying chamber; 1.6)_place at least one second vial as set up in above point 1.3) inside said freeze-drying chamber; 1.7)_start the freeze-drying process in said freeze-drying chamber, 1.8)_detect during said freeze-drying process the values pertaining to a first electrical characteristic in relation to said first vial in order to obtain first electrical values; 1.9)_detect during the freeze-drying process the values pertaining to said first electrical characteristic in relation to said second vial in order to obtain second electrical values; 1.10)_carry out, during said freeze- drying process, comparisons between said first electrical values and said second electrical values.

[0026] _The invention, which is characterized by the claims, always solves the problem of creating a method relating to the freeze-drying of basic substances contained within basic vials, wherein said method is characterized by the fact that it comprises the following operations: 10.1)_ preparing one or more open basic vials, wherein each basic vial has a basic vial body, wherein each basic vial contains a basic substance , wherein said basic substance is a substance to be freeze-dried; 10.2)_preparing at least one first open vial, wherein said first vial comprises a respective first vial body equal to said basic vial body, wherein said first vial contains a first substance, wherein said first substance is equal to said basic substance;

[0027] 10.3)_preparing at least one second vial, wherein said second vial comprises a respective second vial body equal to said basic vial body and equal to said first vial body, wherein said second vial is an EMPTY vial; 10.4)_place a plurality of said base vials as set up in above point 10.1) inside a freeze-drying chamber; 10.5)_place at least one first vial as set up in above point 10.2) inside said freeze- drying chamber; 10.6)_place at least one second vial as set up in above point 10.3) inside said freeze-drying chamber; 10.7)_start the freeze-drying process in said freeze-drying chamber; 10.8)_detect during said freeze-drying process the values pertaining to a first electrical characteristic in relation to said first vial in order to obtain first electrical values; 10.9)_detect during the freeze-drying process the values pertaining to said first electrical characteristic in relation to said second vial in order to obtain second electrical values; 10.10)_carry out, during said freeze- drying process, comparisons between said first electrical values and said second electrical values.

[0028] Brief Description of the attached illustrations

[0029] Further features and advantages of the present invention will be made more evident from the following description of some of its preferred practical embodiments, given here purely by way of example and not of limitation, made with reference to the figures of the attached drawings in which:

[0030] >_Figures 1 , 1 A, 1 B are illustrations of a basic vial;

[0031] >_Figures 2, 2A and 2B are illustrations of a first vial; >_Figures 3, 3A and 3B are illustrations pertaining to a third vial;

[0032] >_Figure 4 is a schematic illustration of a first embodiment of a freeze-drying system;

[0033] Preferred Example Forms of Implementation of the Method

[0034] With reference to the attached figures, the present invention concerns a METHOD relating to freeze-drying in a freeze-drying process, wherein said freeze- drying process is capable of freeze-drying a basic substance Sb contained in one or more basic vials Fb, wherein this freeze-drying takes place inside a freeze-drying chamber of a freeze-drying machine.

[0035] _More particularly, the present invention concerns a method of the aforementioned type capable of estimating, in real time, when the basic substance Sb to be freeze-dried, contained within one or more basic vials Fb has reached a certain degree of humidity, such as, for example, a desired degree of humidity that the basic substance Sb must have as a final freeze-drying.

[0036] _With reference to figures 1_1 A_1 B, 2 2A 2B, 3_3A_3B, the method which is the object of the present invention, as will be better understood below, provides for the use of three types of vials and, more particularly, a multi-vial base vials Fb, one or more first vials F1 and one or more second vials F2, in which each vial extends along a respective vertical axis, Fb.y , F1.y, F2.y and along a respective transverse axis, Fb.x , F1.x, F2.x.

[0037] With reference to figures 1_1 A_1 B, the basic vial Fb can be a vial without a cap, therefore open, see fig. 1 , or a vial Fb equipped with a cap T.Fb, see fig. 1 A and 1 B, in which said cap T.Fb includes transfer ports for the escape of gases and / or vapours and / or other substances, in which said cap can assume a raised position, see fig. 1A, in order to configure an open basic vial Fb, or a lowered position, see fig. 1B, in order to configure a closed basic vial.

[0038] _With reference to figures 2_2A_2B, the first vial F1 can be a vial without a cap, therefore open, see fig. 2, or a vial F1 equipped with a cap T.F1 , see fig. 2A and 2B, in which said capT.F1 includes transfer ports for the escape of gases and / or vapours and / or other substances, in which said cap T.F1 can assume a raised position, see fig. 2A, in order to configure a first open vial F1, or a lowered position, see fig. 2B, in order to configure a first closed vial F1.

[0039] _With reference to figures 3_3A_3B, the second vial F2 can be a vial without a cap, therefore open, see fig. 3, or a second vial F2 equipped with a cap T.F2, see fig. 3A and 3B, in which said cap T.F2 includes transfer ports for the escape of gases and / or vapours and / or other substances, in which said cap T.F2 can assume a raised position, see fig. 3A, in order to configure a second open vial F2, or a lowered position, see fig. 3B, in order to configure a second closed vial F2. _ Preferably, said three vial bodies C.Fb C.F1 C.F2, or said basic vial body C.Fb and said first vial body C.F1, are vial bodies which are equal to each other as regards technical characteristics relating to heat transmission, i.e. equal in relation to the transmission of calories and refrigeration with respect to a substance contained in them, when said vial bodies are subjected to the same environmental conditions and / or to the same changes in said environmental conditions.

[0040] _Again preferably, said three vial bodies C.Fb C.F1 C.F2, or said basic vial body C.Fb and said first vial body C.F1, are vial bodies that are identical to each other as regards the functional characteristic relating to the release of water from said vials in the various shapes during the freeze-drying process, such as, for example, the same characteristics in relation to the size and / or the conformation and / or the position of the openings for the release of water in the various shapes.

[0041] _Still preferably but without any restrictive intent, said three vial bodies C.Fb C.F1 C.F2, or said basic vial body C.Fb and said first vial body C.F1 , may be vial bodies identical to each other and having, optionally, identical closing caps.

[0042] _More particularly, still preferably, said three vial bodies C.Fb C.F1 C.F2, or said basic vial body C.Fb and said first vial body C.F1 , are vial bodies which are equal to each other, where said equality is such as to obtain, in relation to the respective substances contained therein, the same treatment during a freeze-drying process, when said vial bodies are subjected to the same environmental conditions and / or to the same changes in said environmental conditions.

[0043] _With reference to the following description, the METHOD of the present invention, in the various embodiments specified below, for example, can be used to estimate, in real time, when the substance contained in the base vials has reached the final freeze-drying humidity level, or, to perform monitoring as an estimate in relation to the status of the same substance contained in the base vials during the freeze-drying process, as better understood below. _According to a FIRST embodiment, the METHOD which is the object of the present invention, relating to the freeze-drying of basic substances Sb contained within basic vials Fb, comprises the following operations: 1.1)_preparing one or more open basic vials Fb, wherein each basic vial Fb has a basic vial body C.Fb , wherein each basic vial Fb contains a basic substance Sb, wherein said basic substance Sb is a substance to be freeze-dried; 1.2)_preparing at least one first open vial F1, wherein said first vial F1 comprises a respective first vial body C.F1 equal to said basic vial body C.Fb , wherein said first vial F1 contains a first substance S1, wherein said first substance S1 is equal to said basic substance Sb; 1.3)_prepare at least one second vial F2, wherein said second vial F2 comprises a respective second vial body C.F2 equal to said base vial body C.Fb and equal to said first vial body C.F1, wherein said second vial F2 contains a second substance S2; 1.4)_place a plurality of said base vials Fb as prepared in above point 1.1) within a freeze-drying chamber 400; 1.5)_place at least one first vial F1 as prepared in above point 1.2) within said freeze-drying chamber 400; 1.6)_place at least one second vial F2 as prepared in above point 1.3) within said freeze-drying chamber 400; 1.7)_start the freeze-drying process in said freeze-drying chamber 400; 1.8)_detect during said freeze-drying process the values pertaining to a first electrical characteristic in relation to said first vial F1 in order to obtain first electrical values; 1.9)_detect during the freeze-drying process the values pertaining to said first electrical characteristic in relation to said second vial F2 in order to obtain second electrical values; 1.10)_carry out, during said freeze-drying process, comparisons between said first electrical values and said second electrical values. _According to a SECOND embodiment, the METHOD which is the subject of the present invention, relating to the freeze-drying of basic substances Sb contained within basic vials Fb, comprises the following operations: 2.1)_preparing one or more open basic vials Fb, wherein each basic vial Fb has a basic vial body C.Fb, wherein each basic vial Fb contains a basic substance Sb, wherein said basic substance Sb is a substance to be freeze-dried; 2.2)_preparing a plurality of first open vials F1_F1_F1, wherein each first vial F1 comprises a respective first vial body C.F1 equal to said basic vial body C.Fb, wherein each first vial F1 contains a first substance S1, wherein said first substance S1 is equal to said basic substance (Sb); 2.3)_prepare a plurality of second vials F2_F2_F2, wherein each second vial F2 comprises a respective second vial body C.F2 equal to said basic vial body C.Fb and equal to said first vial body C.F1, wherein each second vial F2 contains a second substance S2; 2.4)_place a plurality of said basic vials Fb as prepared by above point 2.1) within a freeze-drying chamber 400; 2.5)_place said plurality of first vials F1_F1_F1 as prepared by above point 2.2) within said freeze-drying chamber 400; 2.6)_place said plurality of second vials F2_F2_F2 as prepared by above point 2.3) within said freeze-drying chamber 400; 2.7)_starting the freeze- drying process in said freeze-drying chamber (400); 2.8)_detecting during said freeze-drying process the values pertaining to a first electrical characteristic in relation to said plurality of first vials F1_F1_F1 in order to obtain first electrical values; 2.9)_detecting during the freeze-drying process the values pertaining to said first electrical characteristic in relation to said plurality of second vials F2_F2_F2 in order to obtain second electrical values; 2.10)_carrying out, during said freeze-drying process, comparisons between said first electrical values and said second electrical values.

[0044] _By means of said second embodiment, compared to the first embodiment, the measurements aimed at obtaining said first values and said second electrical values will be more effective and precise, since they are based on a plurality of first vials and on a plurality of second vials._ Furthermore, preferably, without any limiting intent, the number n1 of rows forming the plurality of first vials F1 is equal to the number n2 of vials forming the plurality of second vials F2 but, in this context, it is understandable that the aforementioned method can operate even if the number n1 of first rows is different from the number n2 of second vials, knowing, for example, the ratio between said two pluralities.

[0045] _With reference to said FIRST and SECOND embodiment , said second vial F2, or each second vial F2 of said plurality of second vials F2_F2_F2, may be a second open vial, such as, for example, a second vial F2 with the relative cap T.F2 raised as illustrated in fig. 3A, or a second vial F2 without the relative cap T.F2, therefore comprising only the relative vial body C.F2, as illustrated in fig.3.

[0046] _Again with reference to said FIRST and SECOND embodiment, said second vial F2, or each second vial F2 of said plurality of second vials F2_F2_F2, may be a second closed vial, such as, for example, a second vial F2 with the relative cap T.F2 lowered as illustrated in fig. 3B, or a second vial F2 without the relative cap T.F2 but closed in another way.

[0047] _With reference to the feature of providing said second vial C.F2 closed, this feature inhibits the second substance S2 contained in the second vial S2 from changing its degree of humidity during the freeze-drying process aimed at freeze- drying the substances Sb and S1, since the water contained in said second substance S2 will not be able to exit from said second vial F2 during said freeze- drying process.

[0048] _With reference to said FIRST and SECOND embodiment, said second substance S2 may be a substance of various nature and / or typology, having certain characteristics, selected and prepared in relation to the type of monitoring that must be implemented.

[0049] In this context, by way of example,

[0050] A)_said second substance S2 may be a freeze-dried form (previously freeze- dried) of the basic substance Sb contained in each vial of basic Fb;

[0051] B)_said second substance S2 may be a freeze-dried form (previously freeze- dried) of the basic substance Sb contained in each vial of basic substance Fb and having a degree of humidity equal to the degree of humidity desired to be obtained at the end of freeze-drying in relation to the basic substance Sb to be freeze-dried;

[0052] C)_said second substance S2 may be a freeze-dried form (previously freeze- dried) of the basic substance Sb contained in each vial of basic Fb and having a precise value as humidity degree, where said humidity value is selected in relation to the function and / or control and / or monitoring that one wishes to perform; as well as

[0053] D)_said second substance S2 may be a substance having an electrical value in relation to said first electrical characteristic equal to the electrical value that said basic substance Sb has when said basic substance Sb has a certain degree of humidity;

[0054] E)_said second substance S2 may be a substance having a value in relation to said first electrical characteristic equal to the value always pertaining to said first electrical characteristic that said basic substance Sb must have at the end of freeze-drying;

[0055] F)_said second substance S2 may be a substance having in relation to said first electrical characteristic properties known as electrical characteristics and / or as relative values, G)_said second substance S2 may be a substance having in relation to said first electrical characteristic properties known as electrical characteristics in which the variations of said characteristics and / or the variations of said values as the environmental conditions (temperature, etc.) vary are also known; in order to be able to set up a specific second vial F2 as a sample vial, or in order to be able to set up a plurality of second vials F2_F2_F2 as a plurality of sample vials, for the execution of comparisons between first electrical values (afferent to vial F1 or plurality of first vials F1_F1_F1 and second electrical values (regarding to vial F2 or plurality of vials F2JF2JF2) as specified above and for the reasons that will emerge later.

[0056] _With reference to the above, for example, if the second substance S2 corresponds to a freeze-dried form of the basic substance Sb contained in each basic vial Fb, preferably with a degree of humidity equal to the degree of humidity that is desired to be obtained at the end of the freeze-drying in relation to the basic substance Sb, the end of the freeze-drying process can be estimated, in relation to the basic substance Sb contained in each basic vial Fb, when said first electrical values, relating to the first vial F1, or relating to the plurality of first vials F1_F1_F1, are equal with respect to said second electrical values, relating to the second vial F2, or relating to the plurality of second vials F2JF2JF2, since, substantially, said basic substance Sb and said first substance S1 were identical in terms of degree of humidity at the beginning of the freeze-drying process and, furthermore, since said two substances Sb and S1 have undergone, during the freeze-drying process, of freeze-drying, the same treatment, that is, the freeze-drying process is interrupted when the first electrical values and the second electrical values have the same value.

[0057] _As a similar example, said second substance S2 may be a different substance with respect to the basic substance Sb and having an electrical value in relation to said first electrical characteristic equal to the electrical value that the basic substance Sb must have when said basic substance Sb has reached the desired degree of humidity as the end of the process, and also in this case, when said first electrical values, pertaining to the first vial F1 , or the plurality of first vials F1_F1_F1 , are equal with respect to the electrical values of said second electrical values, pertaining to the second vial F2, or the plurality of second vials F2_F2_F2, the end of the freeze-drying process can be estimated, in relation to the basic substance Sb contained in each basic vial Fb, for the reasons set out above.

[0058] _Always with reference to said FIRST and SECOND embodiment of the method which is the object of the present invention, as a further example, if in relation to a particular basic substance Sb to be freeze-dried, during the freeze-drying, the secondary drying must be started when the basic substance Sb has reached a certain degree of humidity, here defined as the FIRST intermediate degree of humidity,

[0059] >_the second vial F2 (or each vial of the plurality of second vials F2_F2_F2) is prepared with a second substance S2, where said second substance S2 is a freeze-dried form (previously freeze-dried) of the basic substance Sb but with a humidity level equal to said FIRST intermediate humidity level; or

[0060] >_the second vial F2 (or each vial of the plurality of second vials F2_F2_F2) is prepared with a substance S2, in which said second substance S2 is different from the substance Sb but has an electrical value pertaining to said first electrical characteristic equal to the electrical value that said basic substance Sb must have when the latter has reached said FIRST intermediate degree of humidity; in order to then carry out the aforementioned comparisons between the said first electrical values and the said second electrical values and, therefore, when the said first values are equal to the said second values, begin the secondary drying, since said equality having occurred, it can be estimated that the basic substance Sb has also reached this FIRST intermediate degree of humidity, for the reasons specified above.

[0061] _ln this context, therefore, by means of the method which is the object of the present invention it is also possible to monitor and / or optimise and / or manage the freeze-drying process in relation to the basic substance Sb contained in the basic vials Fb, during the freeze-drying process, such as, for example, determining when to start the secondary drying and / or when to end the primary drying, as well as when to carry out or interrupt other operations or other variations relating to the freeze- drying process. _According to a THIRD embodiment, the METHOD which is the object of the present invention, relating to the freeze-drying of basic substances Sb contained within basic vials Fb, comprises the following operations: 10.1)_preparing one or more open basic vials Fb, wherein each basic vial Fb has a basic vial body C.Fb, wherein each basic vial Fb contains a basic substance Sb, wherein said basic substance Sb is a substance to be freeze-dried; 10.2)_preparing at least one first open vial F1, wherein said first vial F1 comprises a respective first vial body C.F1 equal to said basic vial body C.Fb, wherein said first vial F1 contains a first substance S1, wherein said first substance S1 is equal to said basic substance Sb; 10.3)_prepare at least one second vial F2, wherein said second vial F2 comprises a respective second vial body C.F2 equal to said base vial body C.Fb and equal to said first vial body C.F1 , wherein said second vial F2 is an EMPTY vial; 10.4)_place a plurality of said base vials Fb as prepared in point 10.1) above within a freeze- drying chamber 400; 10.5)_place at least one first vial F1 as prepared in point 10.2) above within said freeze-drying chamber 400; 10.6)_place at least one second vial F2 as prepared in point 10.3) above within said freeze-drying chamber 400;

[0062] 10.7)_start the freeze-drying process in said freeze-drying chamber 400;

[0063] 10.8)_detect during said freeze-drying process the values relating to a first electrical characteristic in relation to said first vial F1 in order to obtain first electrical values;

[0064] 10.9)_detect during the freeze-drying process the values relating to said first electrical characteristic in relation to said second vial F2 in order to obtain second electrical values; 10.10)_carry out, during said freeze-drying process, comparisons between said first electrical values and said second electrical values. _According to a FOURTH form of realization, the METHOD object of the present invention, relating to the freeze-drying of basic substances Sb contained inside basic vials Fb, comprises the following operations: 11.1)_preparing one or more open basic vials Fb, wherein each basic vial Fb has a basic vial body C.Fb, wherein each basic vial Fb contains a basic substance Sb, wherein said basic substance Sb is a substance to be freeze-dried; 11.2)_preparing a plurality of open first vials F1_F1_F1, wherein each first vial F1 comprises a respective first vial body C.F1 equal to said basic vial body C.Fb, wherein each first vial F1 contains a first substance S1 , wherein said first substance S1 is equal to said basic substance Sb; 11.3)_prepare a plurality of second vials F2_F2_F2, wherein each single second vial F2 comprises a respective second vial body C.F2 equal to said basic vial body C.Fb and equal to said first vial body C.F1, wherein each second vial F2 is an EMPTY vial; 11.4)_place a plurality of said basic vials Fb as prepared in point 11.1) above within a freeze-drying chamber 400; 11.5)_place said plurality of first vials

[0065] F1_F1_F1 as prepared in point 11.2) above within said freeze-drying chamber 400; 11.6)_place said plurality of second vials F2_F2_F2 as prepared in point 11.3) above within said freeze-drying chamber 400; 11.7)_starting the freeze-drying process in said freeze-drying chamber 400; 11.8)_detecting during said freeze-drying process the values pertaining to a first electrical characteristic in relation to said plurality of first vials F1_F1_F1 in order to obtain first electrical values; 11.9)_detecting during the freeze-drying process the values pertaining to said first electrical characteristic in relation to said plurality of second vials F2_F2_F2 in order to obtain second electrical values; 11.10)_carrying out, during said freeze-drying process, comparisons between said first electrical values and said second electrical values.

[0066] _By means of said fourth embodiment, compared to the third embodiment, the measurements aimed at obtaining said first electrical values and said second electrical values will be more effective and precise, since they are based on a plurality of first vials and on a plurality of second vials. _ Furthermore, preferably, without any limiting intent, the number n1 of rows forming the plurality of first vials F1 is equal to the number n2 of vials forming the plurality of second vials F2 but, in this context, it is understandable that the aforementioned method can operate even if the number n1 of first rows is different from the number n2 of second vials knowing, for example, the ratio between said two pluralities of vials.

[0067] _With reference to said THIRD and FOURTH embodiment, said second vial F2, or each second vial F2 of said plurality of second vials F2_F2_F2, may be a second open vial, such as, for example, a second vial F2 with the relative cap T.F2 raised as illustrated in fig. 3A, or a second vial F2 without the relative cap T.F2, therefore comprising only the relative vial body C.F2, as illustrated in Fig. 3. _Always with reference to said THIRD and FOURTH embodiment , said second vial F2, or each second vial F2 of said plurality of second vials F2_F2_F2, can be a second closed vial, such as, for example, a second vial F2 with the relative cap T.F2 lowered as illustrated in fig. 3B, or a second vial F2 without the relative cap T.F2 but closed in another way.

[0068] _With reference to the feature of providing said second vial C.F2 empty and closed, this feature prevents the air and / or gas and / or vapour and / or similar compound contained / contained in said second vial F2, before closing the same, from changing in terms of humidity during the freeze-drying process, since the humidity contained in said second vial S2 cannot escape from the same second vial F2 during said freeze-drying process.

[0069] _With reference to the above, in relation to the THIRD and FOURTH embodiments of the method, for example, in relation to some particular basic substances Sb to be freeze-dried, in which the value of the electrical permittivity, when said basic substance Sb has reached the end-of-process humidity level is equal to the value of the air, the end of the freeze-dried process can be estimated, always in relation to said basic substance Sb contained in each basic vial Fb, when said first electrical values, relating to the first vial F1, or relating to the plurality of first vials F1_F1_F1, are equal to the second electrical values, relating to the second vial F2, or relating to the plurality of second vials F2_F2_F2, that is, the freeze-dried process is interrupted when said first electrical values and said second electrical values have the same value.

[0070] First Characteristic Pertaining to the First Electrical Values and the Second Electrical Values

[0071] _With reference to the method defined above, it can be implemented using as the first electrical characteristic for obtaining said first electrical values and said second electrical values the electrical permittivity (also called dielectric constant) and / or the electrical capacity and / or another electrical characteristic, without departing from the inventive contents protected by the present invention.

[0072] _With reference to the method which is the object of the present invention, said FIRST vial F1 comprises a first vial body C.F1 and said SECOND vial F2 comprises a second vial body C.F2 and, preferably, said first vial body C.F1 has a first electrical characteristic equal to that of the second vial body C.F2 when said two vial bodies C.F1 and C.F2 are subjected to the same environmental conditions (e.g. to the same temperature), such as, for example, the same electrical permittivity value if these two vial bodies C.F1 and C.F2 are subjected to the same environmental conditions (i.e. they have the same temperature) and, furthermore, always preferably, said first electrical characteristic, therefore for example said quantity relating to the electrical permittivity, changes in the same manner when the same temperature values vary and / or when the same environmental conditions vary for these two vial bodies C.F1 and C.F2, i.e. at temperatures at which said two bodies will have an identical electrical permittivity value .

[0073] _ Still with reference to the method described above, preferably, the three vial bodies, C.Fb C.F1 C.F2, are equal and / or identical vial bodies to each other.

[0074] In light of the above, by carrying out during the freeze-drying process, at certain temporally spaced moments, a comparison between said first electrical values relating to one or more first F1 vials and said second electrical values relating to one or more second F2 vials, it will be possible, for example:

[0075] >_determine the difference between said two values with reference to specific instants of time or with respect to specific period of time

[0076] >_determine the value of this difference;

[0077] >_determine when this difference is zero;

[0078] >_determine the ratio between said two values at specific instants of time or time spans;

[0079] ▻.determine the value of said ratio

[0080] ▻.determine when this ratio is equal to one. _ Therefore, by means of this method, the freeze-drying process can be interrupted as soon as a desired degree of humidity has been reached in relation to the basic substance Sb, as well as, if desirable, closing the basic vials Fb by lowering the relative cap T.Fb as soon as a desired degree of humidity has been reached, thus mainly avoiding, in both cases:

[0081] >_an erroneous interruption of the freeze-drying process with the basic substance Sb still too moist;

[0082] ▻Incorrect closing of the Fb base vials with the Sb base substance still too moist; >_an incorrect excessive drying of the basic substance Sb;

[0083] >_an erroneous, useless and expensive continuation of the freeze-drying process._ Furthermore, always using the aforementioned method, it is possible to determine when to carry out the phases relating to freeze-drying, such as, for example,

[0084] >_determine when to stop the so-called “primary drying";

[0085] >_determine when to start the so-called “secondary drying”;

[0086] >_determine when to perform and / or how to perform other operational steps related to the freeze-drying process.

[0087] _With reference to Figure 4, the first and / or third embodiment of the method as specified above may find particular but not exclusive application in a first freeze- drying system comprising:

[0088] >_a freeze-drying chamber 400;

[0089] >_at least one tray 410 suitable for containing the Fb base vials;

[0090] >_first detection means 400.M1, such as for example two electrodes 400.M1.a_400.M 1 ,b spaced apart from each other, positioned within said freeze-drying chamber 400, such as for example within or above said tray 410, suitable for detecting one or more electrical characteristics pertaining to at least a first vial F1 ;

[0091] >_second detection means 400.M2, such as for example two electrodes 400.M1.a_400.M 2.b spaced apart from each other, positioned within said freeze-drying chamber 400, for example within or above said tray 410, suitable for detecting one or more electrical characteristics pertaining to at least a second vial F2;

[0092] >_an electrical power supply device 420 suitable for powering said first 400.M1 and said second 400.M2 detection means;

[0093] >_Switching means 430 for selecting said first 400. M 1 or said second sensing means 400. M2;

[0094] >_a sensor device 440 capable of detecting and / or processing and / or conditioning the signals received by said first 400.M1 and second 400.M2 detection means;

[0095] >_control means 450, such as a microprocessor, for controlling said power supply means 420 and / or said switching means 430 and / or said receiving means 440.

[0096] In this context, with reference to said first system , the at least one first vial F1 is positioned within the first detection means 400.M1, in order to obtain the values of the relative electrical permittivity and / or the relative electrical capacity, i.e. said first electrical values, and the at least one second vial F2 is positioned within the second detection means 400.M2, in order to obtain the values of the relative electrical permittivity and / or the relative electrical capacity, i.e. said second electrical values and, therefore, the operations are carried out as specified above, such as, for example, a comparison between said two electrical values.

[0097] _The second and fourth embodiments of the method as specified above may find particular but not exclusive application in a second freeze-drying system comprising:

[0098] >_a freeze-drying chamber;

[0099] >_at least one tray suitable for containing the Fb base vials;

[0100] >_first sensing means, such as for example a plurality of spaced electrodes positioned within said freeze-drying chamber, such as, for example within or above said tray, suitable for sensing one or more first electrical characteristics pertaining to a plurality of first vials F1_F1_F1;

[0101] ▻ second sensing means, such as, for example, a plurality of spaced electrodes positioned within said freeze-drying chamber, for example within or above said tray, capable of sensing one or more second electrical characteristics of at least a plurality of second vials F2_F2_F2;

[0102] >_an electrical power supply device for powering said first and second detection means;

[0103] >_Switching means for selecting said first or said second sensing means;

[0104] >_a sensor device capable of detecting and / or processing and / or conditioning the signals received from said first and second detection means;

[0105] >_control means, such as a microprocessor, for controlling said power supply means and / or said switching means and / or said receiving means.

[0106] In this context, with reference to said second system, a plurality of first vials F1_F1_F1 are positioned within the first detection means, in order to obtain the values of the relative electrical permittivity and / or the relative electrical capacity, i.e. said first electrical values, and a plurality of second vials F2_F2_F2 are positioned within the second detection means, in order to obtain the values of the relative electrical permittivity and / or the relative electrical capacity, i.e. said second electrical values and, therefore, the operations are carried out as specified above, such as, for example, a comparison between said two electrical values.

[0107] _With reference to the above description, preferably, the base vials Fb are positioned in a vertical position above the tray, 410, with the bottom of each vial Fb in contact with the bottom panel of said tray 410 and, furthermore, also the first vial F1, or, the plurality of first vials F1_F1_F1, has or have, the respective bottom of each vial F1 in contact with the bottom panel of said tray 410, in such a way as to obtain the same heat transmission by thermal conduction between the tray and said vials Fb and F1 and, therefore, obtain the same thermal effects for the two vials Fb and F1 and / or for the two vial bodies C.Fb and C.F1, as well as the same thermal effects in relation to the relative substances Sb and S1 contained in the same vials Fb and F1 during the freeze-drying process.

[0108] _With reference to this configuration, preferably, also the second vial F2, or the plurality of second vials F2, has or have, the bottom of each second vial F2 in contact with the bottom panel of the same tray 410, in order to obtain the same thermal effects for the two vials F2 and F1 and / or for the two vial bodies C.F2 and C.F1 during the freeze-drying process.

[0109] Technical Troubleshooting

[0110] _The method which is the object of the present invention solves the problems reported above and more particularly:

[0111] >_probes must not be inserted into contact with the substance to be freeze-dried;

[0112] >_it is not necessary to theoretically estimate, “on the table", freeze-drying procedures to presume that a freeze-dried product with a certain degree of humidity will be obtained;

[0113] >_it is possible to estimate the developments of the freeze-drying process in relation to the substance to be freeze-dried; it is possible to estimate the developments of the freeze-drying process in relation to a substance to be freeze-dried without having to know the characteristics of the vial body and / or the characteristics of the substance to be freeze-dried;

[0114] >_It is possible to estimate the developments of the freeze-drying process of the basic substance to be freeze-dried contained in the basic vials; >__avoid performing non-optimal procedures during the freeze-drying process that could damage the basic substance to be freeze-dried;

Claims

CLAIMS1)_METHOD relating to the freeze-drying of basic substances (Sb) contained within basic vials (Fb), characterized by the fact that to comprises the following operations:1 -1)_set up one or more open basic vials (Fb), in which each basic vial (Fb) has a basic vial body (C.Fb), in which each basic vial (Fb) contains a basic substance (Sb), in which said basic substance (Sb) is a substance to be freeze-dried;1.2)_set up at least a first open vial (F1), in which said first vial (F1) includes a respective first vial body (C.F1) equal to said basic vial body (C.Fb), in which said first vial (F1) contains a first substance (S1), in which said first substance (SI ) is the same as said basic substance (Sb);1.3)_set up at least a second vial (F2), in which said second vial (F2) includes a respective second vial body (C.F2) equal to said basic vial body (C.Fb) and equal to said first vial body (C.F1), in which said second vial (F2) contains a second substance (S2);1.4) _place within a freeze-drying chamber (400 / 500) a plurality of said base vials (Fb) as set up in point 1.1) above;1.5)_place within said freeze-drying chamber (400 / 500) at least one first vial (F1) as set up in point 1.2) above;1.6)_place within said freeze-drying chamber (400 / 500) at least a second vial (F2) as set up in point 1.3) above;1.7)_start the freeze-drying process in said freeze-drying chamber (400 / 500);1.8)_detect during said freeze-drying process the values relating to a first electrical characteristic in relation to said first vial (F1) in order to obtain first electrical values;1.9)_detect during the freeze-drying process the values relating to said first electrical characteristic in relation to said second vial (F2) in order to obtain second electrical values;1.10)_carry out, during said freeze-drying process, comparisons between said first electrical values and said second electrical values.2)_METHOD relating to the freeze-drying of basic substances (Sb) contained within basic vials (Fb), characterized by the fact that it comprises the following operations:2.1)_set up one or more open basic vials (Fb), in which each basic vial (Fb) has a basic vial body (C.Fb), in which each basic vial (Fb) contains a basic substance (Sb), in which said basic substance (Sb) is a substance to be freeze-dried;2.2)_set up a plurality of first open vials (F1_F1_F1), in which each first vial (F1) includes a respective first vial body (C.F1) equal to said basic vial body (C.Fb), in which each first vial (F1) contains a first substance (S1), wherein said first substance (S1) is the same as said base substance (Sb);2.3)_set up a plurality of second vials (F2_F2_F2), in which each single second vial (F2) includes a respective second vial body (C.F2) equal to said basic vial body (C.Fb) and equal to said first vial body (C.F1), in which each second vial (F2) contains a second substance (S2);2.4) _place within a freeze-drying chamber (400 / 500) a plurality of said base vials (Fb) as set up in point 2.1) above;2.5)_place within said freeze-drying chamber (400 / 500) said plurality of first vials (F1_F1_F1) as set up in point 2.2) above;2.6)_place within said freeze-drying chamber (400 / 500) said plurality of second vials (F2_F2_F2) as set up in point 2.3) above;2.7)_start the freeze-drying process in said freeze-drying chamber (400 / 500);2.8)_detect during said freeze-drying process the values relating to a first electrical characteristic in relation to said plurality of first vials (F1_F1_F1) in order to obtain first electrical values;2.9)_detect during the freeze-drying process the values relating to said first electrical characteristic in relation to said plurality of second vials (F2_F2_F2) in order to obtain second electrical values;2.10)_carry out, during said freeze-drying process, comparisons between said first electrical values and said second electrical values.3)_METHOD according to claim 1 or 2, characterized by the fact that said second vial (F2) is an OPEN vial.4)_METHOD according to claim 1 or 2, characterized by the fact that said second vial (F2) is a CLOSED vial.5)_METHOD according to one of the claims from 1 to 4, characterized by die fact that said second substance (S2) corresponds to a freeze-dried form of the basic substance (Sb) contained in each basic vial (Fb).6)_METH0D according to claim 5, characterized by the fact that said second substance (S2) has a degree of humidity equal to the degree of humidity that is desired to be obtained at the end of freeze-drying in relation to the basic substance (Sb) to be freeze-dried.7)_METH0D according to one of the previous claims, characterized by the fact that said second substance (S2) is a substance having an electrical value in relation to said first electrical characteristic equal to the electrical value that said base substance (Sb) has when said base substance has a certain degree of humidity.8)_METODO according to one of the previous claims, characterized by the fact that said second substance (S2) has a known degree of humidity.9)_METH0D according to one of the previous claims, characterized by the fact that the freeze-drying process is interrupted when said first electrical values and said second electrical values have the same value.10)_METHOD relating to the freeze-drying of basic substances (Sb) contained within basic vials (Fb), characterized by the fact that it comprises the following operations:10.1)_set up one or more open basic vials (Fb), in which each basic vial (Fb) has a basic vial body (C.Fb), in which each basic vial (Fb) contains a basic substance (Sb), in which said basic substance (Sb) is a substance to be freeze-dried;10.2)_set up at least one first open vial (F1), in which said first vial (F1) includes a respective first vial body (C.F1) equal to said basic vial body (C.Fb), in which said first vial (F1) contains a first substance (S1), wherein said first substance (S1) is the same as said base substance (Sb);10.3)_set up at least a second vial (F2), in which said second vial (F2) includes a respective second vial body (C.F2) equal to said basic vial body (C.Fb) and equal to said first body vial (C.F1), wherein said second vial (F2) is an EMPTY vial;10.4)_place within a freeze-drying chamber (400 / 500) a plurality of said base vials (Fb) as set up in the previous point 10.1);10.5)_place within said freeze-drying chamber (400 / 500) at least one first vial (F1) as set up in point 10.2) above;10.6)_place within said freeze-drying chamber (400 / 500) at least a second vial (F2) as set up in point 10.3) above;10.7)_start the freeze-drying process in said freeze-drying chamber (400 / 500);10.8)_detect during said freeze-drying process the values relating to a first electrical characteristic in relation to said first vial (F1) in order to obtain first electrical values;10.9)_detect during the freeze-drying process the values relating to said first electrical characteristic in relation to said second vial (F2) in order to obtain second electrical values;10.10)_carry out, during said freeze-drying process, comparisons between said first electrical values and said second electrical values.11)_METHOD relating to the freeze-drying of basic substances (Sb) contained within basic vials (Fb), characterized by the fact that it includes the following operations:11.1)_set up one or more open basic vials (Fb), in which each basic vial (Fb) has a basic vial body (C.Fb), in which each basic vial (Fb) contains a basic substance (Sb), in which said basic substance (Sb) is a substance to be freeze-dried;11.2)_set up a plurality of first open vials (F1_F1_F1), in which each first vial (F1) includes a respective first vial body (C.F1 ) equal to said basic vial body (C.Fb), in which each first vial (F1) contains a first substance (81), wherein said first substance (81) is the same as said base substance (Sb);11.3)_set up a second plurality of second vials (F2_F2_F2), in which each single second vial (F2) includes a respective second vial body (C.F2) equal to said basic vial body (C.Fb) and equal to said first vial body (C.F1), in which each second vial (F2) is an EMPTY vial;11 4)_place within said freeze-drying chamber (400 / 500) a plurality of said basic vials (Fb) as set up in the point 11.1) above;11.5)_place within said freeze-drying chamber (400 / 500) said plurality of first vials (F1_F1_F1) as set up in point 11.2) above;11 6)_place within said freeze-drying chamber (400 / 500) said plurality of second vials (F2_F2_F2) as set up in point 11.3) above;11.7)_start the freeze-drying process in said freeze-drying chamber (400 / 500);11.8)_detect during said freeze-drying process the values relating to a first electrical characteristic in relation to said plurality of first vials (F1_F1_F1) in order to obtain first electrical values;11.9)_detect during the freeze-drying process the values relating to said first electrical characteristic in relation to said plurality of second vials (F2_F2_F2) in order to obtain second electrical values;11.10)_carry out, during said freeze-drying process, comparisons between said first electrical values and said second electrical values.12)_METH0D according to claim 10 o 11, characterized by the fact that said second vial (F2) is an OPEN vial.13)_METHOD according to claim 10 o 11, characterized by the fact that said second vial (F2) is a CLOSED vial.14)_METHOD according one of the claims from 10 to 13, characterized by the fact the freeze-drying process is interrupted when said first electrical values and said second electrical values have the same value.

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