Classifications

• • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
  • F26—DRYING
  • F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
  • F26B5/00—Drying solid materials or objects by processes not involving the application of heat
  • F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
  • F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
  • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
  • G01N21/66—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light electrically excited, e.g. electroluminescence
  • G01N21/68—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light electrically excited, e.g. electroluminescence using high frequency electric fields

Definitions

• the present invention relates to the monitoring and control of the dehydration of substrates during a vacuum drying process, and more particularly to the detection of the end of sublimation of water contained in substrates subjected to lyophilization treatment.
• Lyophilization is a low-temperature process that involves the sublimation of most of the water contained in a substrate.
• the food, pharmaceutical (vaccines, serum, drugs) and bio-industries (yeast) industries are the most strongly concerned by this process which allows them to obtain the long-term preservation of an active principle (showing a biological activity and or drug) in a product that will be stored at near ambient temperature.
• Monitoring the dehydration kinetics during lyophilization is essential to control manufacturing costs, but also to obtain a freeze-dried substrate of quality.
• the lyophilization process involves two successive operations: freezing and dehydration.
• the dehydration operation comprises two stages corresponding to two distinct physical phenomena: on the one hand, the fast vacuum sublimation of the ice crystals which have formed during freezing, most often referred to as “primary desiccation”, and of on the other hand, the final desorption of unfrozen water, most often referred to as "secondary desiccation”.
• EP-1,674,812 incorporated herein by reference, provides a device and method for accurately determining the end of the primary drying step under conditions consistent with high aseptic requirements.
• the device described makes it possible to follow the species present in a freeze-drying chamber by analyzing the evolution of their characteristic lines in the optical spectrum of the light emitted by the plasma of the excited species.
• Active species capable of rapidly destroying microorganisms, are created when the plasma source is energized.
• the plasma source is placed in an ionization chamber communicating with the lyophilization chamber.
• the gases contained in the chamber are brought into the ionization chamber which is in contact with the interior of the lyophilization chamber containing the substrates to be dehydrated.
• the present invention aims to provide a device for controlling the dehydration operation during a lyophilization treatment that does not have the disadvantages of the prior art.
• the invention provides a control device for preserving the activity of the substrates after dehydration.
• the invention also aims to propose a method of controlling the dehydration operation during a freeze-drying treatment which, by minimizing the deactivation, leads to the production of substrates having retained most of their activity.
• the object of the present invention is a device for controlling the dehydration operation during a freeze-drying treatment comprising
• a lyophilization chamber connected to a vacuum line
• the gas analyzer comprising
• a gas ionization system comprising a plasma source in contact with the gases, combined with a generator, capable of generating a plasma from said gases, and
• an ionized gas analysis system comprising a radiation sensor, located near the plasma generation zone, connected to an apparatus for analyzing the evolution of the radiative spectrum emitted by the plasma,
• the gas analyzer further comprises means for switching on and off the plasma repeatedly.
• the control device of the dehydration operation, the ignition and extinguishing means repeated is able to turn on or off the generator, - the ignition means and extinguishing is able to modify the flow rate or the pressure of the gases from which the plasma is generated, an optical gate is arranged between the gas ionization system and the lyophilization chamber, the optical gate is a metal piece which is inserted into a quick connector, the plasma source is produced by inductive coupling.
• Moisture molecules (water vapor), released during the freeze-drying process and ionized by the plasma source, generate oxidative free radicals. Some of these oxidizing free radicals are likely to enter the lyophilization chamber and react with the substrates to be dehydrated, leading to an alteration of their structure and a decrease in their activity. Due to the continuous creation of free radicals oxidants for a long time, their concentration is very high in the chamber, which promotes their entry into contact with the pharmaceutical substrate. When the free oxidizing radicals come into contact with the pharmaceutical substrate, they are capable of chemically reacting with the pharmaceutical substrate, leading to its oxidation and deactivation.
• the invention therefore has the advantage of limiting the formation of free radicals by reducing the oxidizing time of the plasma. Moreover, the presence of the optical gate prevents most of the free oxidizing radicals that nevertheless formed from coming into contact with the pharmaceutical substrate to be dehydrated.
• the invention also proposes a method for controlling the dehydration operation during a lyophilization treatment in an enclosure, during which the gases present in the chamber are analyzed by means of a gas ionization system comprising a source of plasma.
• the method comprises an alternation of phases during which the plasma is lit and during which the plasma is off.
• the phases during which the plasma is lit and the phases during which the plasma is extinguished follow one another periodically,
• the duration of a phase during which the plasma is off is between 2 minutes and 40 minutes
• the ignition time of the plasma is between 1 second and 60 seconds, the ignition duration is between 5 seconds and 30 seconds,
• the plasma is turned on and off manually,
• the ignition or extinction of the plasma is controlled by means of a control device of a radiofrequency generator of the plasma source.
• the invention therefore has the advantage of minimizing the concentration of free oxidizing radicals in the freeze-drying chamber, and thus of limiting the deactivation of the substrates to be dehydrated.
• FIG. 1 represents an installation for the treatment of substrates by lyophilization implementing the invention
• FIG. 2 is a perspective view of an exemplary quick coupling connecting a lyophilization chamber with a gas ionization system according to one embodiment of the invention
• FIG. 3 is a perspective view of an optical door according to one embodiment of the invention.
• FIG. 4 is a perspective view of the optical gate of FIG. 3 cooperating with the connection of FIG. 2;
• the installation comprises an enclosure 1 under vacuum (5.10 "3 to 3 mbar), containing the substrates to be dehydrated 2, in which the lyophilization treatment takes place.
• enclosure 1 comprises a heating source 3, for example integrated in superimposed trays, and is connected to a steam recovery trap 4, a primary vacuum pump 5, and a nitrogen feed pipe 6 equipped with a regulating valve 7.
• the installation also comprises a gas analyzer comprising a gas ionization system 8 connected to the upper part of the enclosure 1 by a quartz tube 9, carrying a valve 10, whose open end communicates directly with the inside the enclosure 1 by a quick coupling 11 made of stainless steel (ISO 2852).
• the closed end 12 of the tube 9 is made of quartz, optical glass or sapphire, and preferably in the form of an aspherical lens allowing efficient collection of light. All the parts 8, 9, 10, 11, 12 of the gas analyzer which are in direct contact with the lyophilization chamber 1 are sterilized according to the SIP cycles (for "Sterilization In Place").
• a plasma is generated inside the tube 9 under vacuum ( ⁇ 3 mbar) in an area located at an induction solenoid 14, or exciter antenna, wound at the outside of the tube 9, this zone forming an ionization chamber.
• the ionization chamber and the surrounding solenoid 14 constitute a plasma source 13.
• the induction solenoid 14 is powered by a 440 MHz 4W ICP RF radio frequency generator 15 associated with an ignition and control means. repeated extinguishing 16 to turn off and then turn on the plasma source repeatedly.
• the light emitted by the plasma is detected at the closed end 12 of the tube 9 by a sensor 17, which may in particular be an optical fiber.
• This light is then led, for example by an optical fiber, to an optical emission spectrometer 18 to be analyzed.
• the information can be recorded and processed by means of a computer 19 connected to the optical emission spectrometer 18.
• the light emitted is characteristic of the compounds present within the plasma, and therefore present inside the freeze-drying enclosure 1.
• characteristic lines of hydrogen (656 nm for example) and nitrogen (337 nm for example) are followed during the dehydration operation.
• the information is recorded and processed by the computer 19.
• a condensing zone may be provided in the duct connecting the lyophilization chamber 1 to the vacuum pump 5 in order to provide a surface for solidifying the water vapor and preventing it from reaching the vacuum pump 5, This could degrade the performance of the vacuum pump 5.
• the temperature of the condensation zone is generally below -50 ° C.
• Part of the water molecules are directed to the gas analyzer. They are excited under the effect of the energy provided by the radiofrequency generator 15 and emit a light called "plasma”. By de-energizing, the water molecules produce light and oxidizing free radicals capable of producing a chemical oxidation reaction with the pharmaceutical substrates 2 to be dehydrated which are very sensitive thereto.
• the repeated ignition and extinguishing means 16 has been developed in order to make it possible to generate a plasma in the so-called "discontinuous" mode, which means that phases during which the source of plasma is lit and phases during which the plasma source is extinguished succeed one another.
• the plasma source is on for about 5 to 30 seconds every 2 to 40 minutes.
• the duration of the ignition phases and the quenching phases may be modified depending on the sensitivity of the pharmaceutical substrate 2 to be dehydrated.
• the total ignition time of the plasma source has thus been reduced. As a result, the amount of free oxidizing radicals formed was also reduced, minimizing the effect of the oxidation of the substrate 2 to be dehydrated.
• the plasma source can be turned on and off manually.
• a control device for example a software, has been developed so as to control the ignition and extinguishing means repeated by adjusting the duration of the ignition and extinguishing phases of the source of plasma.
• the repeated ignition and extinguishing means 16 is able to modify the flow rate or the pressure of the gases from which the plasma is generated.
• the repeated ignition and extinguishing means 16 comprises a neutral gas injection means for modifying the gas flow rate. For example, from a lit plasma, the increase in the gas flow rate is controlled until the plasma is extinguished.
• the repeated ignition and extinguishing means 16 comprises an opening control means of the valve 10, upstream of the plasma source 13, for modifying the pressure of the gases.
• the repeated ignition and extinguishing means 16 capable of modifying the flow rate or the pressure of the gases has the advantage of being a simple method to implement and inexpensive.
• Shown in Figure 2 is an example of quick coupling 20 stainless steel two-way, such as the quick connector type ISO-KF 25 or one sold under the trademark "TriClamp ®" by the company "QUALITY CONTROLS” .
• the connector 20 comprises an inlet 21 provided with a seal 22 of fluoroelastomer intended to establish communication with the freeze-drying enclosure and an outlet 23 adapted to be connected to the open end of the tube leading to the system. ionization of gases.
• a fastener 24 secures the connector 20 to the lyophilization chamber.
• an optical gate 25 is mounted on the connection 20, by means of three fixing tabs 26, for example, as shown in FIG. 3.
• the optical gate 25 makes it possible to block the oxidizing free radicals for prevent them from entering the lyophilization chamber 1.
• the optical gate 25 makes it possible to block the luminous radiations of the plasma which are capable of generating oxidizing free radicals inside the freeze-drying chamber 1.
• the optical door 25 is for example a metal part whose shape is adapted to the shape of the inlet 21 of the quick connector 20.
• the optical gate 25 is disposed at the inlet 21 of the connector 20 connected to the lyophilization enclosure 1, as shown in FIG. 4.
• the optical gate 25 is inserted inside the inlet 21 of the connection, so as not to disturb the tight connection created by the seal 22 between the connector 20 and the lyophilization chamber 1.
• the opening of the optical door 25 is represented by the space 27 between the outer edge of the door 25 and the inside diameter of the inlet 21 of the quick connector 20.
• the opening of the optical door 25 varies depending on the accuracy of the moisture measurement and the oxidation reaction. Lyophilization of a substrate begins with a freezing operation of the substrate. The water contained in the substrate is then cooled to a temperature below its triple point, the lowest temperature at which the solid and liquid phases can coexist.
• the freezing temperature is between -50 ° C and -80 ° C.
• the freezing operation is very critical because the substrate can be degraded if this operation is poorly conducted.
• the substrates 2 are subjected to the dehydration operation, which is shown diagrammatically in the FIG. 5.
• the sublimation of the water contained in the substrate is carried out by supply of heat, by conduction or radiation, by means of the heating source 3. It avoids the occurrence of fusion by maintaining the temperature in the enclosure below the triple point.
• the water vapor formed is then recovered by means of trap 4.
• the primary vacuum pump 5 When the dehydration operation starts, the primary vacuum pump 5 is started, and the pressure drops inside the freeze-drying chamber 1.
• the pumping of the gases contained inside the freeze-drying chamber 1 by the primary vacuum pump 5 is first intended to allow the lowering of the total pressure inside the chamber 1. Then the pump aims to maintain the pressure inside the chamber 1 at low values compatible with the conditions necessary for sublimation, and during the entire dehydration operation.
• the pressure is reduced (of the order of a few millibars) and heat is supplied in sufficient quantities to the substrate to sublimate about 95% of the water it contains.
• the amount of heat required can be calculated using the latent heat of sublimation of the water molecules.
• the primary drying step 50 is slow, for example several days in the industry, because if too much heat is provided quickly the structure of the substrate could be modified.
• the pressure in the lyophilization chamber 1 is controlled by the imposition of a partial vacuum.
• the low pressure in the lyophilization chamber 1 is stabilized by means of the regulating valve 7 placed on the nitrogen supply duct 6 connected to the freeze-drying enclosure 1.
• the valve 7 opens to inject more nitrogen into the freeze-drying chamber 1. During the period when the sublimation of the water is important, little nitrogen is injected.
• the dehydration operation is carried out under a vacuum generally between 0.005 mbar and 0.5 mbar.
• a source of inductively coupled Inductive Coupled Plasma (ICP) type plasma is therefore well suited since its operating pressure range is from 0.005 mbar to 10 mbar.
• the primary drying step 50 ends when all the water present as ice has been removed (point 53).
• the secondary drying step 54 is intended to eliminate the unfrozen water molecules, since those present in the form of ice were removed during the primary drying step 51.
• This step of the freeze-drying process is governed by the isotherms of adsorption of the substrate.
• the temperature is higher than in the primary drying step 51, and may even be greater than 0 ° C., in order to break the physicochemical interactions which have formed between the water molecules and the frozen substrate 2.
• pressure is also lowered at this stage to encourage desorption (typically in the range of microbars, or fractions of a Pascal). However, there are some substrates for which increased pressure is more favorable.
• the final residual water content in the substrate is extremely low and represents about 1% to 4% of its weight.
• the vacuum is usually broken with an inert gas such as nitrogen before the substrate is sealed.
• the enzyme activity was measured after a freeze-drying treatment conducted in the presence or absence of the repeated ignition and quenching means 16.
• the plasma is ignited for 30 seconds. every 10 minutes.
• the activity is expressed as a percentage of the initial activity of the enzyme before lyophilization.
• the result is related to the specific activity which is the activity per mg of substrate.
• the result obtained takes into account all the dilutions necessary to perform the measurements of the activity with a spectrophotometer.
• the freeze-dried enzymes were rehydrated, so as to obtain the same volume as before the lyophilization treatment.
• a first series of measurements of the activity of the substrates was carried out before and after a lyophilization treatment of substrates by not using a control device. The measurements were made on substrates placed respectively on trays at the top in the middle and at the bottom of the enclosure 1. This series constitutes the series of measurements A.
• a second series of measurements of the activity of the substrates was carried out before and after a lyophilization treatment of substrates using a control device having neither repeated ignition and extinguishing means 16 nor optical gate 25. This second series constitutes the series of measures B.
• a third series of measurements of the activity of the substrates was carried out before and after a freeze-drying treatment of substrates using a control device comprising a means of ignition and extinguishing of the plasma source 16 allowing a discontinuous operation of the plasma source.
• This third series constitutes the series of measurements C.
• a fourth series of measurements of the activity of the substrates was carried out before and after a lyophilization treatment of substrates using a control device comprising a means of ignition and extinguishing repeated 16 of the plasma source and an optical gate 25
• This fourth series constitutes the series of measurements D.
• a first part of the study concerned the biological activity still present in the pharmaceutical substrate after undergoing the lyophilization treatment. The remaining activity of the substrate, expressed in%, is calculated for each series of measurements according to the formula: Activity after lyophilization
• Table 1 shows that the activity remaining in a substrate after a freeze-drying treatment is significantly lower when the freeze-drying treatment has been carried out in the presence of a control device having no means of ignition and repeated extinguishing, or optical door (B series). It can be interpreted by the fact that the control device generates oxidizing free radicals which affect the properties of the substrates subjected to freeze-drying treatment.
• the loss of biological activity of the treated enzymes is independent of the location of these substrates within the enclosure of lyophilisation.
• the relative position of the control device with respect to the position of the substrates in the enclosure has no influence on the intensity of the oxidation of the pharmaceutical substrates.
• the activity present in the substrates after a lyophilization treatment in the case where the treatment has been carried out using a control device comprising a means of ignition and extinguishing repeated of the plasma source (series C) is very close to the remaining activity after a lyophilization treatment in the case where the treatment has been carried out without using a control device (series A).
• the activity present in the substrates after freeze-drying treatment is only slightly lower than the initial activity in the case where the treatment has been carried out using a control device comprising an ignition and extinguishing means. repeated from the plasma source and an optical gate (D series). It is further observed that the remaining activity in this case is of the same order as the remaining activity in the case where the treatment was performed without using a control device (series A).
• a second part of the study focused on the oxidation rate measured on pharmaceutical substrates after lyophilization treatment.
• Table 4 gives the oxidation rates, expressed in%, for the series of measurements A to D as defined above.
• the oxidation rate is further reduced and of the same order as the rate of oxidation observed in the absence of a control device (measurement series A).

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Chemical & Material Sciences (AREA)
• Pathology (AREA)
• Analytical Chemistry (AREA)
• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• General Physics & Mathematics (AREA)
• Immunology (AREA)
• Physics & Mathematics (AREA)
• Molecular Biology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Mechanical Engineering (AREA)
• General Engineering & Computer Science (AREA)
• Drying Of Solid Materials (AREA)
• Freezing, Cooling And Drying Of Foods (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=42670744

Family Applications (1)

Country Status (5)

Families Citing this family (19)

Family Cites Families (15)

• 2010
  • 2010-02-01 FR FR1050686A patent/FR2955927B1/fr not_active Expired - Fee Related
• 2011
  • 2011-02-01 JP JP2012550475A patent/JP2013518242A/ja not_active Ceased
  • 2011-02-01 WO PCT/EP2011/051392 patent/WO2011092344A1/fr not_active Ceased
  • 2011-02-01 US US13/576,320 patent/US8793896B2/en not_active Expired - Fee Related
  • 2011-02-01 EP EP11701522A patent/EP2531795A1/de not_active Withdrawn

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events