WO2015189655A1

WO2015189655A1 - System for monitoring the quantity of solvent extracted during the step of lyophilizing of substances

Info

Publication number: WO2015189655A1
Application number: PCT/IB2014/062104
Authority: WO
Inventors: Marco ALBERIO; Maurizio BATTISTINI; Davide MAINETTI
Original assignee: Individual
Current assignee: Individual
Priority date: 2014-06-10
Filing date: 2014-06-10
Publication date: 2015-12-17
Anticipated expiration: 2016-12-10

Abstract

The invention consists in introducing a system for detecting the quantity of solvent (or more generally a mixture constituted by more solvents including, but not necessarily, even water), extracted from a product to be subjected to lyophilization, by measuring the quantity of material solidified on the condenser of a lyophilizing system. The amount of liquid extracted by sublimation from the product to be subjected to lyophylization is accumulated on the condenser in solid form, hence, the measurement of the quantity of material formed is detectable through weighing cells or any other alternative measuring system subject of the present description. Detecting the quantity through alternative measuring systems regarding which a few embodiments are indicated in the description is also an integral part of the invention. Thus, the main object of the invention is to determine - at any stage of a lyophilization process - the amount of solvent extracted from the matrix to be subjected to lyophilization, with the aim of monitoring the process to intervene where required, establish the end-point in a definite manner and guarantee constant reproducibility.

Description

SYSTEM FOR MONITORING THE QUANTITY OF SOLVENT EXTRACTED DURING THE STEP OF LYOPHILIZING OF SUBSTANCES

The present invention regards an improved system and method of lyophilization.

Lyophilization or freeze-drying is a technological process which allows eliminating water or other solvents from an organic and non-organic matrix, with the least deterioration possible of the structure and components of the same substance.

Such process is mainly, but not exclusively, used in the pharmaceutical and food industry. The method fundamentally comprises two physical transformations: the freezing of the initial substance and the sublimation of the solvent. The principle of the process provides for administering heat to the material to be subjected to lyophilization frozen and kept under vacuum; the solvent, contained in the product and separated in the form of ice (in case of solvents different from water reference shall be made to solidified material) , is extracted directly in vapour form by sublimation given that the operation occurs under very low pressure values (proximal to the absolute vacuum) . Very low pressures, generally below 6.10 mbars (or 4.58 mmHg) , allows operating in proximity to the triple point of the solvent mixture, i.e. at the conditions that allow the simultaneous presence of the solvent in the three solid-liquid- vapour states. The extracted water vapour (or generally the solvent vapour) is captured by freezing on cold coils called condensers (using an improper term which seems to refer to a passage from vapour to liquid while actually it is from vapour to solid) ; the incondensable gases are suctioned and eliminated by the vacuum pump. The process is carried out under accurately controlled temperature and pressure conditions so as to avoid damaging the chemical structure of the product and preserve it from degradation in solution, so that the initial matrix can be restored when intending to re- hydrate it for use.

The main steps of the lyophilization process are:

a) freezing the solution;

b) the sublimation of the solvent;

c) the end of lyophilization step: constituted by vacuum loss tests in the chamber where the product is placed, isolating it from the condenser.

Knowing the precise quantity of solvent present at the beginning of the process in the products to be subjected to lyophilization, the invention allows accurately verifying the state of progress (quantity of solvent extracted and remaining amount) of the sublimation step in progress. This information is of considerable use in that, according to the progress of the process, monitored through the knowledge of the step in progress, it will be possible to correct the parameters associated to the step (for example managing the ramp associated to the temperature increase) avoiding damaging the product and thus optimizing the obtained result and the quality of the product, as well as accurately establishing whether the end-point (almost complete removal of the solvent) was attained successfully.

Currently, the parameters to be used during the lyophilization cycle are defined a priori starting from the data present in literature, or through the support of the persons skilled in the art or through preliminary destructive tests performed up to attaining the final conditions deemed most suitable. This allows the lyophilization cycle to be a non-monitorable process as regards the most important point, i.e. the progressively removed quantity of solvent. Thus, knowing the main parameter, i.e. the progressive and complete elimination of the solvent from the matrix is the innovative fulcrum of the present invention.

The criticality of the process are particularly related to the management of the temperature of the shelves on which the product is positioned and the duration of the sublimation cycle with related maintenance of the vacuum conditions. As of the state of the art, given the impossibility to directly monitor the state of the lyophilization step and given that the management of the main parameter is solely experimental, it is easy to end up in an imprecise management of said value which may lead to the failure of the process and which may only be discovered at the end of the cycle thus obtaining a product that does not meet the required specifications as regards the element or the most critical aspect, or the value of the residue solvent, which jeopardizes the quality and stability thereof beyond given limits.

WO 2011/067780, DE 10 2006 019641 and WO 01/36888, describe known systems for monitoring quantities of extracted solvent during the step of lyophilizing substances .

However, none of these prior art documents discloses, as observable from the following description, also how to detect the presence of value acquisition means that allow determining the quantities of solvent accumulated in the condensation chamber, for example in the coil or generally in the condenser.

This innovation offers a non-obvious solution, i.e. not disclosed in the prior art, to the problem of improving the accuracy in the process for monitoring the quantities of extracted solvent during the step of lyophilizing substances.

Characteristics and advantages of the present invention shall be more apparent from the following detailed description of an embodiment, provided by way of non- limiting example with reference to the attached drawings, wherein:

figure 1 shows a schematic view of a lyophilization system by identifying the main components and the areas subject of the present invention;

figure 2 shows a sectional view a lyophilization system with the identification of the main components and areas subject of the present invention;

figure 3 shows the sectional view of a first embodiment comprising a system for monitoring the quantity of extracted solvent, by determining the progressive increase of weight of the condenser, through weighing cells according to the present invention;

figure 4 shows a sectional view of a second embodiment of a system for monitoring the quantity of extracted solvent by determining the volume using cameras or thermographic cameras according to the present invention;

figure 5 shows a sectional view of a third embodiment of a system for monitoring the quantity of extracted solvent through position detectors or distance measuring detectors according to the present invention;

figure 6 shows a sectional view of a fourth embodiment of a system for monitoring the quantity of extracted solvent through weighing cells (shelves) for monitoring the progressive loss of weight of the material subjected to lyophilization according to the present invention.

Even should it not be indicated explicitly, the single characteristics described with reference to the specific embodiments they shall be deemed as accessory and/or interchangeable with other characteristics, described with reference to other embodiments.

In addition it should be observed that anything already known or obvious to a person skilled in the art before the date of priority shall not be deemed claimed (and thus specific object of the present document) .

A lyophilization system according to the embodiment of the present invention comprises the main chamber 2 with relative shelves 3, the condenser 4 constituted by a coil (generally formed by a steel pipe) 5 within which there circulates the cooling fluid which allows progressively solidifying the extracted solvent and various components for detecting the accumulated quantity of material which takes different position and configuration, according to the type of embodiment. A further possibility, according to the present invention, regards the installation of weighing cells for monitoring the weight of the material subjected to lyophilization on the shelves 3 of the main chamber (the detailed configuration shall be indicated hereinafter) , with the aim of determining the progressive loss of weight by extracting the solvent. Actually, during the process, the progressive extraction of the solvent corresponds to a reduction of the weight of the product subjected to lyophilization due to the reduction of the quantity of solvent present in solid form (passing from the liquid form to the solid form in the first step of the process) in the initial solution.

Hereinafter there are indicated, by way of non-limiting example, some of the types of instruments that can be used for meeting the object of the present invention with reference to the single embodiments:

Embodiment n°l: Weighing cells (condenser)

Embodiment n°2: Cameras or thermographic cameras (Infrared camera)

Embodiment n°3: Position or distance measuring detectors

Embodiment n°4: Weighing cells (shelves)

In all these embodiments there is present a control system 16 through which the information acquired by the detection devices according to the various embodiments subject of the present invention is processed and the parameters associated to the lyophilization cycles are managed (verified and possibly corrected continuously) . Embodiment n°l: Weighing cells (condenser) 6a/b

The weighing cells 6a are installed in the lower part of the condenser 4 and they support it completely. The condenser 4, mainly constituted by the coil 5 in which the cooling fluid circulates, is anchored to the structure of the machine in that it is necessary to guarantee the continuous passage of the cooling fluid (liquid nitrogen or cooling fluid cooled by the cooling group) from outside to inside the condensation chamber. The weighing cells 6a require, to allow detecting the borne weight, a minimal dimensional excursion (about 0.3 mm), thus the coil 5 shall not be rigidly constrained to the structure to allow the excursion required to detect the weight. For such purpose it is required to provide a system capable of allowing such free movement. A possible embodiment, commonly used for meeting such needs, is represented by providing "damper spiral elements" 7 (which would become an integral part of the coil itself) inside the condensation chamber. Such embodiment would allow considerably lightening the inevitable constraint constituted by the connection between the coil and the interspace of the condensation chamber. It is necessary to maintain a rigid connection between the coil 5 and the interspace of the condensation chamber 8 in that flexible connections may not be suitable for attaining a high degree vacuum required for the lyophilization process.

Due to the high thermal stress and the high humidity (washings and vapour sterilization) to which the weighing cells 6a would be subjected if installed in the condensation chamber 8, it is advisable, even if not compulsory, to provide an installation outside the chamber itself. Such embodiment inevitably requires a rigid connection 9 between the weighing cells 6b and the coil, thus a passage between inside and outside the condensation chamber 8. The rigid connection may be obtained through a cylindrical-section component made of stainless steel (AISI 316L) so as to guarantee the desired rigidity of the connection between the external cells and the coil and the suitability of the material to meet the internal cleaning requirements.

In order to guarantee the transfer of the weight of the coil 5 to the weighing cells 6b through the aforementioned rigid component, the possibility of movement (dimensional excursion of about 0.6 mm - twice with respect to the weighing cells requirements) shall be allowed thereto, thus it shall not be necessarily constrained to the structure of the chamber 8 so that the weight of the coil 5 shall completely lie on the weighing cells 6b. Such mobility may be allowed by membranes or "bellows" 10 which, connected between the rigid component for transferring the weight 9 and the condensation chamber 8, allow perfect sealing during the process (the dimensional excursion for allowing detecting the weight is limited to 0.6 mm) and they resist to stresses generated by the lyophilization conditions (vacuum and temperatures) and to the steps for preparing the cycles (sterilization under pressure etc . ) .

The latter embodiment option, though most complex, allows avoiding the weighing cells high stresses and it also allows a greater measurement accuracy given that the main components are not subjected to uncertainties due to temperature variation in the chamber 8.

The control system 16 allows detecting the weights acquired by the n weighing cells 6a/b, processing an actual and instantaneous value of the weight of the solidified material accumulated on the coil 5 and managing the parameters related to the lyophilization cycle with reference to the actual state of the process .

Embodiment n°2: Cameras 11a or Thermographic cameras lib

The present embodiment consists in the identification of the quantity of solvent extracted from a product during lyophilization through the integration and interpolation of the images acquired by cameras 11a or thermographic cameras lib arranged in proximity of the condensation chamber 8 of a lyophilization system.

The cameras 11a are installed outside the condensation chamber 8, in n points evaluated and defined according to the dimensional and structural characteristics of every single machine. The positions shall be necessarily defined so as to be able to completely detect the areas occupied by the maximum quantity of material accumulated on the coil 5 of the condenser 4. The structure of the machine shall be provided with a observation window 12 to allow the suitable lighting of the condensation chamber 8 and allow, through the acquisition of the images through cameras 11a, detecting the volume of accumulated solvent. The observation windows 12 shall be of the complete sealing type to allow attaining the vacuum level required for the lyophilization process and the preparation steps (sterilization by vapour) .

Another embodiment is constituted by the use of thermographic cameras lib for detecting the quantity of solidified material (generally ice) accumulated on the coil. At structural level, the embodiment is identical to that of the conventional cameras 11a, just like the logic related to the calculation of the area occupied by the accumulated solvent, the only difference lies in the unnecessary lighting of the condensation area in that the operativeness of the thermographic cameras lib not related to the aforementioned condition. The embodiment requires the application of a filter (inside the thermographic cameras) capable of allowing solely focusing the area of interest and avoid the influence on the measurement of the temperature of the interspace, which is generally constituted by the observation windows 12, in proximity of the thermographic cameras lib.

The control system 16 allows acquiring the images detected by the cameras 11a or by the thermographic cameras lib, calculating the actual quantity of the solidified material on the coil 5 of the condenser 4 and managing the parameters related to the lyophilization cycle with reference to the actual state of the process.

Embodiment n°3: Position detector 13a or distance measuring detectors 13b

The use of position detectors 13a or distance measuring detectors 13b constitutes a further possibility of detection of the volume occupied by the solidified material accumulated on the coil 5 of the condenser 4. The number and the position of the detectors shall be defined according to the configuration of the machine and in a number such to be able to cover the entire area of potential accumulation of material.

Depending on the type of sensors, the installation may be performed inside the condensation chamber 8 or outside. The internal installation is clearly to be preferred in that easier to obtain and in that it allows a better accuracy of the measurement due to the absence of interposed elements (observation windows 12) .

The accuracy of the measurement may be optimised through calculation systems conceived within the control system 16 which allow the integration and interpolation of the detected measurements. Besides this it is possible to study the method of accumulation of solidified material on the coil 5 which, in absence of variations not attributable to the process and considering the same characteristics of the solvent, would remain almost unvaried. The validity of such hypothesis can be verified by detecting the measurement related to the amount of material (point distance) accumulated in 2 or more points which, once compared with the historical and/or statistical data, would allow confirming the soundness of such condition. The measurement of the detected distance with the occupied volume and thus with the quantity of the accumulated solidified material, i.e. with the corresponding quantity of extracted solvent can be easily associated to such point.

The distance measuring detectors 13b, installed in the condensation chamber 8, shall be capable of resisting against the thermal stresses associated to the process and the preparation steps (vapour sterilisation, washing, etc) . For measurement accuracy, the distance measuring detectors 13b are clearly to be preferred to position detectors 13a in the that the first are capable of providing a dimensional output while the second only a signal of the binary type.

The control system 16 allows acquiring the detected measurements through distance measuring detectors 13b and calculating the actual volume occupied by the material accumulated on the coil 5 and thus managing the parameters related to the lyophilization cycle with reference to the actual state of the process.

Embodiment n°4: Weighing cells (shelves) 14a/b

The product to be subjected to lyophilization is generally, but not exclusively, received in containers which are arranged on the shelves 3 of the machine. Such shelves 3 are generally made of steel and therein there circulates the diathermic fluid capable of reaching temperatures ranging between -50°C approximately and + 100°C approximately. Such fluid allows the freezing of the described solution through cooling and the sublimation of the solvent through heating. The invention, subject of the present embodiment, consists in the installation of weighing cells 14a on the shelves where there the product to be subjected to lyophilizing is positioned so as to monitor the loss in weight due to the sublimation of the solvent during the process. Such loss in weight of the product corresponds to the quantity of material accumulating on the coil 5 of the condenser 4. Besides use as it is, the utility of detecting subject of the present embodiment consists in being able to perform a double control on the quantity of extracted solvent from the matrix to be subjected to lyophilization at any stage of the process and compare the object of detection with the quantity of material accumulating on the condenser 4 so as to improve the monitoring accuracy .

There are two possible embodiments, different according to the configuration of the machine. In a first configuration, should the machine be made with fixed shelves (in such solution the loading of the product in the machine usually occurs manually) , there is provided for the installation of weighing cells at the base of each shelve 14a. Should the shelves 3 be mobile (according to the configuration generally coinciding with an automated loading system) there is provided for the installation of a single weighing cell 14b on the support cylinder and moving the shelves so as to monitor the overall weight of the shelves 3 and of the products present thereon. The installation of the weighing cells on each shelf 14a is difficult to obtain but it is however indicated in that it is however a possible embodiment.

The control system 16 allows detecting the weights acquired by the n weighing cells 14a/b, processing an actual value of the weight of the product subjected to sublimation which, compared with what is accumulated on the condenser, allows a finer management of the parameters related to the lyophilization cycle with reference to the actual state of the process.

Obviously a person skilled in the art may subject the configurations described above to numerous modifications and variants with the aim of meeting contingent and specific requirements also due to the alternative measuring techniques provided by the state of the art. Such variants and modifications fall within the scope of protection of the invention as defined by the claims that follow.

Claims

1. System for monitoring quantities of extracted solvent during the step of lyophilizing substances comprising :

means for detecting the quantity of extracted solvent during the lyophilization step in the condensation chamber 8 accumulated in the coil 5 or generally in the condenser 4 ;

means for monitoring the amount of extracted solvent from the matrix during the lyophilizing by detecting the residue in the main chamber 2 near the shelves 3 or near the shelf-support structure;

a system 16 for data controlling and processing for calculating the quantity of extracted solvent detected through the measurements carried out and relative correction interventions on the lyophilization cycle.

2. System according to claim 1 wherein said means for detecting the quantity of extracted solvent during the lyophilization step in the condensation chamber 8 comprise weighing cells 6a/b or cameras 11a or thermographic cameras lib or position detectors 13a or distance measuring detectors 13b or any other means for detecting the quantity or the space occupied by the material solidified on the condenser 4.

3. System according to claim 1 wherein said means for monitoring the residue amount in the main chamber 2 during the lyophilizing comprise one or more weighing cells 14a/b for monitoring the weight of the amount of product arranged on the shelves or any type of detection of such amount applicable for the purpose.

4. System according to claim 1 wherein said control system 16 is suitable for acquiring and processing the data for resetting - at any stage of the lyophilization process in progress - the lyophilization parameters according to the amount of solidified material measured directly or indirectly.

5. Method for controlling the quantity of extracted solvent during a lyophilization process carried out by a system according to claim 1, said method comprising the steps of:

(a) interpolation and/or integration through the system 16 for controlling the data acquired by the value detection means that allow determining the quantity of solvent accumulated in the coil 5 or generally in the condenser 4, in the condensation chamber 8 and by the value detection means which allow determining the quantity of solvent extracted from the matrix in the main chamber 2 near the shelves 3 or near the shelf-support structure to obtain only one value of the quantity of extracted solvent;

(b) comparison, through the control system 16 according to the preceding claims, between the actual state of the cycle and the reference cycle;

(c) modifying and correcting parameters of the lyophilization cycle in progress so as to be able to optimize the process.