DE102019106261A1 - METHOD AND SYSTEM, ESPECIALLY IN MODULAR DESIGN, FOR THE, PREFERABLY CONTINUOUS, MICROWAVE FREEZING DRYING OF PHARMACEUTICAL ACTIVE SUBSTANCES AND, IN PARTICULAR EDIBLE, FOAMING, EXTRACTS AND VIRTUALLY, CONTENTLY - Google Patents

Abstract

Process for, preferably continuous, microwave freeze-drying of active pharmaceutical ingredients and, in particular edible, foams, extracts, concentrates and purees based on fruit in vials and trays.

Description

The present invention relates to a method and a plant, in particular in modular construction, for, preferably continuous, microwave freeze-drying of pharmaceutical active ingredients and, in particular edible, foams, extracts, concentrates and purees based on fruit in vials (ampoules) and trays (bowls), e.g. Trays with Goretex membranes (e.g. Gore Lyoguard freeze drying trays).

Freeze drying (lyophilization) is the usual method to actively dry and stabilize active pharmaceutical ingredients.

More and more active pharmaceutical ingredients are based on biotechnological processes. Their molecular structure is becoming increasingly complex and the drying times in conventional freeze drying are becoming increasingly critical. Usual drying times in conventional multi-day freeze dryers are in the range of 50 to 70 hours.

There is great interest in alternative freeze drying processes to both reduce the drying time and dry the product more gently.

Protein solutions are currently being developed in drug development, the mode of action of which can intervene very selectively in metabolic processes. However, these new generations of active ingredients are also much more sensitive to drying, whereby drying temperatures above approx. 20 to approx. 50 ° C are to be avoided over longer periods. Conventional freeze-drying with drying times in the range of approx. 50 to approx. 70 hours means that the respective active substance remains in the final drying for a long time at temperatures above freezing point, usually at approx. 20 to approx. 50 ° C and above. The survival rates of this new generation of active substances are significantly impaired by the long-lasting thermal stress in the final drying.

Microwave freeze-drying potentially offers the possibility of drastically shortening these long drying times by a factor of approx. 6 to approx. 10. Thus, microwave freeze-drying would not only be more economical, but also more gentle on the product for the new generation of active ingredients.

The usual logistics for active pharmaceutical ingredients is based on vials in various sizes, in which the active ingredients are embedded in sugar-containing foam solutions. However, foams are also conceivable, for example, in trays. In the food sector there is also a need for microwave freeze drying of fruit foams that are processed in trays.

In the dissertation by James P. Dolan on "Use of volumentric heating to improve heat transfer during vial freeze-drying", Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA, September 1998, it is shown that a single vial in a cylindrical microwave single-mode resonator can be dried in three to four hours. This is due to the fact that the microwave energy acts in the entire volume of the active ingredient and thus the sublimation is much more effective and the drying process takes place much faster.

In the paper "Significant drying time reduction using microwave-assisted freeze-drying for a monoclonal antibody", Julian H. Gitter, Raimund Geidobler, Ingo Presser, Gerhard Winter, Journal of Pharmaceutical Sciences 107 (2018) 2538-2543 , significant improvements in drying time compared to conventional freeze dryers with microwave freeze drying in a multimode system on a laboratory scale are also described.

From the U.S. Patent 20170115057 B1 is a microwave multimode chamber with inlet and outlet lock for organic products in trays is known. Several individual microwave waveguide couplings are guided into a large multimode vacuum chamber via round microwave feeds. The microwave field distribution is to a large extent dependent on the load or product and generally not homogeneous.

From the German patent DE 10 2013 009 064 B3 a continuous microwave oven with a so-called single-mode or single-mode microwave system is known.

The European patent EP 1205 724 B1 relates to a device for drying and / or sintering compacts made of composite materials also with a so-called single-mode or monomode microwave system. Tungsten carbide rods are cyclically moved within a vacuum chamber with the microwave system and back and forth during drying.

Up-scaling to an industrial scale is difficult, however, since the microwave chambers used generally have dimensions which are a multiple of the wavelength of the microwaves used. These so-called multi-mode microwave chambers do not have a good distribution of the microwave energy. The spatial temperature differences also lead to considerable scatter in the drying results.

In addition, there is a trend in drug development towards small and specific batch sizes to produce customer-specific drugs.

In order to both avoid the contamination of active substances and to ensure a defined logistics of the active substances, vials in different sizes are usually used. Likewise, in the patent EP 1 750 760 B1 Trays with Goretex membranes are described as replacements for vials that are used on the market under the name "Gore Lyoguard Freeze Drying Trays".

Similar problems also exist with edible foams, extracts, concentrates and purees based on fruit.

The present invention is therefore based on the object of providing a quick, product-friendly and space-saving drying method for drying active pharmaceutical ingredients and, in particular edible, foams, extracts, concentrates and purees based on fruit.

• - Hineinfahren von Vials oder Trays mit zu trocknendem pharmazentrischen Wirkstoff und, insbesondere essbaren, Schäumen, Extrakten, Konzentraten und Pürees auf Fruchtbasis in eine Einlaufvakuumschleuse,
• - Reduzieren von Druck in der Einlaufvakuumschleuse auf einen Druck unterhalb Atmosphärendruck,
• - Überführen der Vials oder Trays aus der Einlaufvakuumschleuse in einen nachgeschalteten Vakuumkanal, in dem derselbe Druck unterhalb Atmosphärendruck wie in der Einlaufvakuumschleuse erzeugt ist, wobei in dem Vakuumkanal mindestens zwei, vorzugsweise vier, sich in Längsrichtung des Vakuumkanals erstreckende Mikrowellen-Monomodekanäle direkt nebeneinander ausgebildet sind,
• - Verfahren der Vials oder Trays in Längsrichtung der Mikrowellen-Monomodekanäle des Vakuumkanals in mehreren Etappen unter gleichzeitiger gezielter Einstrahlung von Mikrowellen mit einer vorgegebenen Mikrowellenfrequenz zur Erzeugung einer Single Mode- bzw. Monomode-Mikrowellen-Feldverteilung, wobei jedes Mal nach Erreichen eines Etappenziels das Verfahren der Vials oder Trays und Einstrahlen der Mikrowellen unterbrochen wird und nur einige in Förderrichtung zuvorderste Vials oder Trays aus dem Vakuumkanal in eine nachgeschaltete Auslaufvakuumschleuse, in der derselbe Druck unterhalb Atmosphärendruck wie im Vakuumkanal erzeugt ist, überführt werden und zwischen dem Erreichen der jeweiligen Etappenziele das Vakuum in der Einlaufvakuumschleuse zur Außenseite gebrochen wird und neue Vials oder Trays mit zu trocknendem Wirkstoff oder, insbesondere essbaren, Schäumen, Extrakten, Konzentraten und Pürees auf Fruchtbasis in die Einlaufvakuumschleuse überführt werden und erneut der Druck in der Einlaufvakuumschleuse auf den Druck unterhalb Atmosphärendruck reduziert wird und zwischen dem Erreichen der jeweiligen Etappenziele das Vakuum in der Auslaufvakuumschleuse gebrochen wird und die Vials oder Trays in der Auslaufvakuumschleuse aus derselben nach außen überführt werden.

According to the invention, this object is achieved by a method for, preferably continuous, microwave freeze-drying of active pharmaceutical ingredients and, in particular edible, foams, extracts, concentrates and purees based on fruit in vials and trays, comprising:

• Driving vials or trays with pharmacentric active ingredient to be dried and, in particular edible, foams, extracts, concentrates and purees based on fruit into an inlet vacuum lock,
• - reducing pressure in the inlet vacuum lock to a pressure below atmospheric pressure,
• - Transfer the vials or trays from the inlet vacuum lock into a downstream vacuum channel, in which the same pressure is generated below atmospheric pressure as in the inlet vacuum lock, with at least two, preferably four, microwave monomode channels extending in the longitudinal direction of the vacuum channel being formed directly next to one another in the vacuum channel ,
• - Method of the vials or trays in the longitudinal direction of the microwave single-mode channels of the vacuum channel in several stages with simultaneous targeted irradiation of microwaves with a predetermined microwave frequency to generate a single-mode or single-mode microwave field distribution, the method each time after reaching a stage target the vials or trays and microwave radiation is interrupted and only a few vials or trays in the conveying direction, which are first in the conveying direction, are transferred from the vacuum channel to a downstream outlet vacuum lock, in which the same pressure is generated below atmospheric pressure as in the vacuum channel, and the vacuum is reached between the respective stages in the inlet vacuum lock is broken to the outside and new vials or trays with active ingredient to be dried or, in particular edible, foams, extracts, concentrates and purees based on fruit are transferred into the inlet vacuum lock and again the Pressure in the inlet vacuum lock is reduced to the pressure below atmospheric pressure and the vacuum in the outlet vacuum lock is broken between reaching the respective milestones and the vials or trays in the outlet vacuum lock are transferred out of the same.

A single-mode cavity has exactly one maximum of a fundamental wave.

• - einen, vorzugsweise viereckigen, insbesondere rechteckigen, Vakuumkanal mit einem Eingangsende und einem Ausgangsende,
• - eine Druckreduzierungseinrichtung zur Reduzierung von Druck innerhalb des Vakuumkanals auf einen Druck unterhalb Athmosphärendruck,
• - mindestens zwei, vorzugsweise vier, in dem Vakuumkanal direkt nebeneinander ausgebildete, sich in Längsrichtung des Vakuumkanals erstreckende Mikrowellen-Monomodekanäle,
• - mindestens einen Mikrowellen-Generator zur Generierung von Mikrowellen mit einer vorgegebenen Mikrowellenfrequenz,
• - mindestens ein Mikrowellen-Einkoppelelement je Mikrowellen-Monomodekanal, das konfiguriert ist, um von dem Mikrowellen-Generator oder einem der Mikrowellen-Generatoren mit Mikrowellen mit der Mikrowellenfrequenz gespeist zu werden,
• - eine Fördereinrichtung zum Verfahren von Vials oder Trays in Längsrichtung der Mikrowellen-Monomodekanäle vom Eingangsende zum Ausgangsende des Vakuumkanals,
• - eine der Vakuumkammer vorgeschaltete Einlaufvakuumschleuse,
• - eine der Vakuumkammer nachgeschaltete Auslaufvakuumschleuse,
• - je eine Fördereinrichtung in der Einlaufvakuumschleuse und der Auslaufvakuumschleuse zum Verfahren der Vials oder Trays in den Vakuumkanal hinein, bzw. aus dem Vakuumkanal hinaus und
• - eine Steuereinrichtung zur Steuerung der Druckreduzierungseinrichtung, des mindestens einen Mikrowellen-Generators und der Fördereinrichtungen zum Verfahren der Vials oder Trays in den Mikrowellen-Monomodekanälen und in der Einlaufvakuumschleuse sowie in der Auslaufvakuumschleuse.

Furthermore, this object is achieved by a system, in particular in modular construction, for, preferably continuously, microwave freeze-drying of active pharmaceutical ingredients and, in particular edible, foams, extracts, concentrates and purees based on fruit in vials and trays, comprising:

• one, preferably square, in particular rectangular, vacuum channel with an input end and an output end,
• a pressure reducing device for reducing pressure within the vacuum channel to a pressure below atmospheric pressure,
• at least two, preferably four, microwave monomode channels formed directly next to one another in the vacuum channel and extending in the longitudinal direction of the vacuum channel,
• at least one microwave generator for generating microwaves with a predetermined microwave frequency,
• at least one microwave coupling element per microwave single-mode channel, which is configured to be supplied with microwaves with the microwave frequency by the microwave generator or one of the microwave generators,
• a conveying device for moving vials or trays in the longitudinal direction of the microwave single-mode channels from the input end to the output end of the vacuum channel,
• - an inlet vacuum lock upstream of the vacuum chamber,
• - an outlet vacuum lock downstream of the vacuum chamber,
• - One conveyor each in the inlet vacuum lock and the outlet vacuum lock for moving the vials or trays into the vacuum channel, or out of the vacuum channel and
• - A control device for controlling the pressure reducing device, the at least one microwave generator and the conveying devices for moving the vials or trays in the microwave single-mode channels and in the inlet vacuum lock and in the outlet vacuum lock.

The method can provide that the microwave frequency is 915 MHz or 2450 MHz and / or the width of the microwave single-mode channels is between approximately 0.05 m and approximately 0.6 m and / or the length of the microwave single-mode channels is between approx. 3 m and approx. 4 m.

The temperature of the pharmaceutical active ingredient or, in particular, edible, foams, extracts, concentrates and purees based on fruit is advantageously measured in the vials or trays at several locations along the conveying direction, preferably also transversely thereto.

The microwaves are expediently irradiated in such a way that the microwave intensity decreases in the spatial direction in the conveying direction.

According to a further particular embodiment of the present invention, an in-situ energy balance is / are based on the thermally introduced microwave energy and the microwave energy absorbed by the active ingredient or foam, extract, concentrate or puree in the vials or trays, preferably also process monitoring for temporally controlling the temperature in the active ingredient or foam, extract, concentrate or puree in the vials or trays.

In particular, it can be provided that between the reaching of the respective milestones before the vacuum is broken in the outlet vacuum lock, the vials are sealed with caps, preferably using a stamp plate.

The vacuum channel, the inlet vacuum lock and the outlet vacuum lock are advantageously arranged in a glove box, preferably with the vacuum channel having at least one inspection flap, preferably on the top, and / or the microwave technology part belonging to the microwave single-mode channels and encapsulated and below the vacuum channel, preferably below the Glovebox is arranged, and / or the glovebox has at least one lateral and / or at least one upper glove insert. The latter serves to separate a sterile area from the technical part.

According to a special embodiment of the system, the at least two microwave single-mode channels have a common side wall which is provided with a continuous longitudinal opening.

Each microwave single-mode channel is advantageously square, in particular rectangular.

According to a particular embodiment, the at least one microwave generator comprises a magnetron or a semiconductor source.

The microwave frequency is advantageously 915 or 2450 MHz and / or the width of the microwave monomode channels is between approximately 0.05 m and approximately 0.6 m and / or the length of the microwave monomode channels is between approximately 3 m and approximately 6 m.

The system expediently has a plurality of temperature measuring devices along the conveying direction, preferably also transversely thereto, for measuring the temperature of the active substance or foam, extract, concentrate or puree in the vials or trays.

According to a further particular embodiment of the present invention, the system has an energy balancing device for in-situ energy balancing based on the thermally introduced microwave energy and the microwave energy absorbed by the active ingredient or foam, extract, concentrate or puree in the vials or trays, preferably also a process monitoring device for time control the temperature in the active ingredient or foam, extract, concentrate or puree in the vials or trays.

The system advantageously has a closure cap press-on device, in particular a stamp plate, for pressing a closure cap onto the vials in the outlet vacuum lock.

The system expediently has a conveyor for moving the vials or trays into the inlet vacuum lock and / or a conveyor for moving the vials or trays out of the outlet vacuum lock.

Finally, it can be provided that the system has a glovebox and the vacuum channel and the inlet vacuum lock in addition to the Outlet vacuum lock are arranged in the glovebox, preferably with the vacuum channel having at least one inspection flap, preferably on the top, and / or the microwave technology part belonging to the microwave monomode channels is coupled and arranged below the vacuum channel, preferably inside the glovebox, and / or Glovebox has at least one side and / or at least one upper glove insert. The latter serves to separate a sterile area from the technical part.

Preferably, the microwave technology part of the system is housed on an independent support frame within the glovebox and can, for. B. on the back of the glove box for service purposes e.g. B. completely removed on rolls.

In a special embodiment, the entire system can be removed on an independent support frame on the back of the glovebox.

The present invention is based on the surprising finding that, by using a microwave monomode, more uniform microwave field distributions and thus also spatially more uniform temperature distributions and associated spatially more uniform drying can be achieved. At the same time, the dimensions of the drying system can be reduced. Since several single-mode microwave channels are arranged next to one another, an adequate throughput is also achieved.

At least in special embodiments, the present invention provides a compact, fast, gentle and efficient drying method with a system that is small enough that it can be integrated into a glove box structure. Since conventional multi-level freeze dryers usually freeze several tens of thousands of vials, the footprint and the equipment environment of these conventional freeze dryers are considerable (approx. 10 m × 10 m × 5 m (WxDXH)) with long drying times of approx. 60 to approx. 90 hours. This means that such conventional freeze dryers cannot be integrated into the continuous preparation and pretreatment of vials in gloveboxes. The loading times for conventional freeze drying are usually approx. 1-8 hours. Thus, the first vials are already approx. 8 hours old, which already affects the quality of the active ingredient.

With the load sizes of conventional multi-day freeze dryers mentioned above, energy and temperature monitoring to control the drying process in a targeted manner is hardly possible. Although there are wireless temperature measurements for reference vials so that the actual temperature profile of individual vials is known, precise temperature and energy monitoring to control the process profile of the entire vials is not possible.

• 1 eine perspektivische Ansicht von einer Anlage zur kontinuierlichen Mikrowellen-Gefriertrocknung von pharmazeutischen Wirkstoffen in Vials und Trays gemäß einer besonderen Ausführungsform der vorliegenden Erfindung schräg von oben;
• 2 eine Seitenansicht der Anlage von 1;
• 3 eine Draufsicht auf den linken Teil der Anlage in 2;
• 4 eine Schnittansicht entlang der Linie IV-IV in 2;
• 5 eine perspektivische Ansicht von einem Werkzeugträger-Tray mit Vials;
• 6 eine perspektivische Ansicht von einem der in der 5 gezeigten Vials mit einer (locker) aufgesetzten Verschlusskappe;
• 7 eine perspektivische Ansicht von einer Anlage zur kontinuierlichen Mikrowellen-Gefriertrocknung von pharmazeutischen Wirkstoffen in Vials und Trays gemäß einer weiteren besonderen Ausführungsform der vorliegenden Erfindung schräg von oben; und
• 8 eine Seitenansicht ähnlich der Seitenansicht der Anlage von 1 nebst Kurven betreffend die räumliche Verteilung der Mikrowellenenergie sowie die zeitlichen Verläufe der Feuchte und Temperatur in den zu trocknenden Produkten.

Further features and advantages of the invention emerge from the appended claims and from the following description, in which several exemplary embodiments are explained in detail on the basis of the schematic drawings. It shows:

• 1 a perspective view of a plant for continuous microwave freeze-drying of active pharmaceutical ingredients in vials and trays according to a particular embodiment of the present invention obliquely from above;
• 2nd a side view of the plant of 1 ;
• 3rd a plan view of the left part of the plant in 2nd ;
• 4th a sectional view along the line IV-IV in 2nd ;
• 5 a perspective view of a tool carrier tray with vials;
• 6 a perspective view of one of the in the 5 shown vials with a (loosely) attached cap;
• 7 a perspective view of a plant for continuous microwave freeze-drying of active pharmaceutical ingredients in vials and trays according to another particular embodiment of the present invention obliquely from above; and
• 8th a side view similar to the side view of the plant of 1 in addition to curves relating to the spatial distribution of microwave energy and the temporal profiles of the humidity and temperature in the products to be dried.

The in the 1 to 4th shown plant 10th has a rectangular vacuum channel 12th with an input end 14 and an exit end 16 , a pressure reducing device for reducing pressure within the vacuum channel 12th to a pressure below atmospheric pressure, in particular vacuum, in the present example exactly two in the vacuum channel 12th trained right next to each other, lengthways L , the vacuum channel 12th the one with the conveying direction F is identical, extending microwave single-mode channels 18th and 20th , at least one microwave generator (not shown) for generating microwaves with a microwave frequency in the present case of 2450 MHz, four microwave coupling elements in the longitudinal direction L spaced apart and configured to be fed by the at least one microwave generator with microwaves with the aforementioned microwave frequency, a conveyor for moving trays 28 or tool carriers in the longitudinal direction of the microwave single-mode channels 18th and 20th from the entrance end 14 to the exit end 16 of the vacuum channel 12th , one the vacuum channel 12th upstream inlet vacuum lock 30th , one the vacuum channel 12th downstream outlet vacuum lock 32 , one conveyor each in the inlet vacuum lock 30th and the outlet vacuum lock 32 for moving the trays 28 into the vacuum channel 12th in or out of the vacuum channel 12th and a control device (not shown) for controlling the pressure reducing device, the at least one microwave generator and the conveying devices for moving the trays 28 in the microwave single-mode channels 18th and 20th (Double monomode microwave channel) and in the inlet vacuum lock 30th as well as in the outlet vacuum lock 32 on. The conveyor in the vacuum channel 12th comprises several conveyor units arranged one behind the other in the longitudinal direction 26 , in the present case three conveyor units 26 which, for example, a drive shaft 27 or a drive gear (see 4th ) include and can be controlled both individually and in combination. For example, the conveyor units 26 are plastic conveyor belts as well as plastic hinge chain belts (microwaves (MW) -transparent). Gears can also be incorporated in the trays, for example, and a drive gear can be used for the trays 28 move.

The conveyor in the inlet vacuum lock 30th has a corresponding conveyor unit 36 on. The conveyor in the discharge vacuum lock 32 also has a corresponding conveyor unit 40 on.

In front of the inlet vacuum lock 30th is also a funding unit 42 and behind the outlet vacuum lock 32 is also a funding unit 44 intended.

At the entrance 46 and at the exit 48 the inlet vacuum lock 30th is a separating slide 50 that the inlet vacuum lock 30th can be independently vacuum-sealed on both sides. Accordingly, is at the entrance 52 and at the exit 54 the outlet vacuum lock 32 one slide valve each 58 arranged which the inlet vacuum lock 30th can independently seal on both sides in a vacuum-tight manner.

Only vacuum connections are from the pressure reducing device 60 shown on the underside of the vacuum channel 12th longitudinal L the same are arranged spaced apart. At the top of the vacuum channel 12th are inspection hatches 62 longitudinal L of the vacuum channel spaced apart.

Furthermore, are in the area of the two upper longitudinal edges 64 and 66 of the vacuum channel 12th longitudinal L of the vacuum channel 12th spaced two infrared temperature measuring probes 68 and 70 , eg infrared cameras, arranged in pairs. The temperature probes 70 are each on the center line L of the vacuum channel 12th aligned.

How to get out of the 4th results, the two microwave single mode channels 18th and 20th a common side wall 73 on, which is provided with a continuous longitudinal opening.

The microwave single-mode channels 18th and 20th are rectangular.

The vacuum channel 12th has a width of 100 mm in the present example. A simple single-mode microwave channel would thus have a width of approximately 50 mm in the present example (microwave frequency = 2450 MHz) and a four-way single-mode microwave channel would have a width of approximately 200 mm. For a microwave frequency of 915 MHz, on the other hand, the width for a single-mode microwave channel is approximately 150 mm, for a double single-mode microwave channel approximately 300 mm and for a quadruple microwave single-mode channel approximately 600 mm. In an embodiment with a width of 600 mm and a microwave channel length of approximately 3 to 4 m, approximately 800 to approximately 1200 10R vials per hour can be freeze-dried with microwaves.

Using an example where vials 76 on trays 28 With inserts for vials, with pharmaceutical active ingredients embedded in a foam matrix (preferably from sugar solutions) and possibly other auxiliary substances (pH adjustment, as a stabilizing or preserving agent, as scaffolding agent, etc.) in the vials continuous microwave freeze drying according to a particular embodiment of the present invention.

1. 1. Es befinden sich im vorliegenden Beispiel vier belegte Trays 28 im Vakuumkanal 12 mit im Prinzip drei unabhängigen Fördereinheiten 26, 34, 35. In jeder der Einlaufvakuumschleuse 30 und der Auslaufvakuumschleuse 32 befindet sich jeweils eine unabhängige Fördereinheit 36 und 40 und vor der Einlaufvakuumschleuse 30 sowie hinter der Auslaufvakuumschleuse 32 befindet sich ebenfalls jeweils eine unabhängige Fördereinheit 42 bzw. 44.
2. 2. Der belegte Tray 28 in der Einlaufvakuumschleuse 30 ist bereit, um aus der Einlaufvakuumschleuse 30 in den Vakuumkanal 12 auf den freien ersten Abschnitt schnell, z.B. mit einer Geshwindigkeit ≥ 0,5-5 m/min., einzufahren. In dem Vakuumkanal 12 sind die davor in Längsrichtung L liegenden vier Abschnitte bereits mit belegten Trays 28 besetzt.
3. 3. Die Einlaufvakuumschleuse 30 ist unter Vakuum (gleiches Systemvakuum wie im Vakuumkanal 12) mit dem Tray 28 und der Trennschieber 50 zum Vakuumkanal 12 wird geöffnet. Ebenso wird die Mikrowelle ausgeschaltet.
4. 4. Die Auslaufvakuumschleuse 32 ist unter Vakuum und leer. Der Trennschieber 58 zur Auslaufvakuumschleuse 32 wird geöffnet.
5. 5. Die Fördereinheit 36 fährt schnell gemeinsam mit dem Tray 28 auf den freien Abschnitt mit der Fördereinheit 34 in dem Vakuumkanal 12.
6. 6. Die vorderste Fördereinheit 35 in dem Vakuumkanal 12 fährt gemeinsam mit dem belegten Tray 28 aus dem Vakuumkanal 12 schnell in die Auslaufvakuumschleuse 32.
7. 7. Der Trennschieber 50 am Eingangsende 14 und der Trennschieber 58 am Ausgangsende 16 schließen wieder.
8. 8. Die Mikrowelle wird wieder eingeschaltet und die Fördereinheiten 34, 26 und 36 versetzen alle Trays mit definierter langsamer Geschwindigkeit, z.B. ca. 0,5 bis 1 Meter pro Stunde um eine Position bzw. um einen Abschnitt.
9. 9. Während dieser Zeit werden die Verschlussklappen 78 der Vials 76 in diesem Beispiel mit einer Stempelplatte 80 im Bereich einer oberen Inspektionsklappe 82 in der Auslaufvakuumschleuse 32 von oben auf die Vials 76 gedrückt bzw. gepresst. Danach wird das Vakuum in der Auslaufvakuumschleuse 32 z.B. mit N₂ (Stickstoff) gebrochen. Das Pressen der Verschlusskappen 78 auf die Vials 76 dient dazu, die Vials zu verschließen, um stark hygroskopische Wirkstoffkuchen in den Vials vor Feuchtigkeit aus der Atmosphäre zu schützen.
10. 10. Ein neuer belegter Tray 28 wird über den Trennschieber 50 in die Einlaufvakuumschleuse 30 bewegt und über das Vakuum nach- bzw. eingefroren (z.B. bei 0,03 mbar). Vorteilhafterweise wird das Vakuum, z.B. über N₂ oder z.B. über Wandkühlung gemäß eines definierten Profils abgesenkt, um die Kristallbildung für den jeweiligen Wirkstoff sinnvoll zu beeinflussen.
11. 11. Der zyklische Prozess beginnt von neuem.

The incoming trays 28 with vials 76 on which caps 78 are loosely applied (see also 5 and 6 ) are in the inlet vacuum lock 30th evacuated until the vacuum level of the microwave freeze dryer is reached. After that, the trays 28 with the vials 76 into the vacuum channel 12th with the two microwave single-mode channels 18th and 20th with the conveyor unit 36 retracted. A tray becomes synchronous 28 with vials 76 by means of the foremost conveyor unit 26 from the vacuum channel 12th into the outlet vacuum lock 50 driven so that the free section in the vacuum channel 12th during the lock times defined travel path allowed. The following procedure according to a special embodiment of the present invention results in an already (partially) loaded vacuum channel 12th :

1. 1. There are four occupied trays in the present example 28 in the vacuum channel 12th with basically three independent conveyor units 26 , 34 , 35 . In each of the inlet vacuum lock 30th and the outlet vacuum lock 32 there is an independent conveyor unit 36 and 40 and in front of the inlet vacuum lock 30th as well as behind the outlet vacuum lock 32 there is also an independent conveyor unit 42 respectively. 44 .
2. 2. The occupied tray 28 in the inlet vacuum lock 30th is ready to get out of the inlet vacuum lock 30th into the vacuum channel 12th Approach the free first section quickly, e.g. at a speed ≥ 0.5-5 m / min. In the vacuum channel 12th are the lengthways in front of it L lying four sections with trays already occupied 28 occupied.
3. 3. The inlet vacuum lock 30th is under vacuum (same system vacuum as in the vacuum channel 12th ) with the tray 28 and the isolating slide 50 to the vacuum channel 12th will be opened. The microwave is also switched off.
4. 4. The outlet vacuum lock 32 is under vacuum and empty. The slide valve 58 to the outlet vacuum lock 32 will be opened.
5. 5. The conveyor unit 36 drives quickly together with the tray 28 to the free section with the conveyor unit 34 in the vacuum channel 12th .
6. 6. The foremost conveyor unit 35 in the vacuum channel 12th runs together with the occupied tray 28 from the vacuum channel 12th quickly into the outlet vacuum lock 32 .
7. 7. The separating slide 50 at the entrance end 14 and the isolating slide 58 at the exit end 16 close again.
8. 8. The microwave is switched on again and the conveyor units 34 , 26 and 36 move all trays at a defined slow speed, e.g. approx. 0.5 to 1 meter per hour by one position or by one section.
9. 9. During this time, the shutters 78 the vials 76 in this example with a stamp plate 80 in the area of an upper inspection hatch 82 in the outlet vacuum lock 32 from the top of the vials 76 pressed or pressed. Then the vacuum is in the outlet vacuum lock 32 eg broken with N ₂ (nitrogen). Pressing the caps 78 on the vials 76 serves to close the vials in order to protect highly hygroscopic active ingredient cakes in the vials from moisture from the atmosphere.
10. 10. A new occupied tray 28 is over the slide valve 50 into the inlet vacuum lock 30th moved and frozen or frozen via the vacuum (eg at 0.03 mbar). The vacuum is advantageously reduced, for example via N ₂ or, for example, via wall cooling in accordance with a defined profile in order to influence the crystal formation for the respective active ingredient in a meaningful manner.
11. 11. The cyclical process starts again.

The trays 28 have dimensions of 0.5 m × 0.09 m with 50 vials each.

Instead of the active pharmaceutical ingredients in vials, e.g. also dry trays with frozen protein granules (e.g. grain sizes from approx. a few millimeters up to um and nm diameter or sugar foam solutions).

7 shows a perspective view of a plant 84 for the continuous microwave freeze-drying of active pharmaceutical ingredients in vials and trays according to a further particular embodiment of the present invention. Said facility 84 differs from the plant 10th essentially in that they're a glovebox 86 and the vacuum channel 12th as well as the inlet vacuum lock 30th in addition to the outlet vacuum lock 32 and also the areas in front of the inlet vacuum lock 30th as well as behind the outlet vacuum lock 32 (see also the description of the system 10th ) in the glove box 86 are arranged. The one for the microwave single-mode channels 18th and 20th associated microwave technology part is coupled below the vacuum channel 12th inside the glovebox 86 arranged. In addition, the glovebox 86 several side glove inserts or openings 88 for inserting glove inserts. Glove inserts enable the operating personnel 90 to intervene manually at individual process stations. The vacuum channel can also be 12th or the microwave single-mode channels 18th and 20th via glove inserts on the inspection flaps 62 in the glovebox 86 to open.

It is also fundamentally conceivable that the systems described above are provided as mobile systems on the underside, for example with rollers. In addition, the systems could have a modular structure.

Preferably, the microwave technology part of the system is housed on an independent support frame within the glovebox and can, for. B. on the back of the glove box for service purposes e.g. B. completely removed on rolls.

In a special embodiment, the entire system can be removed on an independent support frame on the back of the glovebox.

Based on 8th In-situ energy balance and process monitoring according to a particular embodiment of the present invention is to be explained. The facility shown below 92 is essentially similar to the facility 10th in the 1 to 4th designed. For this reason, reference is made to the above description in this regard.

About the microwave coupling elements 22 , which are deliberately arranged at the bottom to facilitate handling in the upper area (sterile area - below microwave technology area) using glove boxes of a glovebox, such as the glovebox 86 , to enable a microwave energy profile E (see 8th above) and the corresponding temperature profile Temp (see 8th above) along with moisture profile moisture for the product along the longitudinal direction L or direction of conveyance F and thus also build up in dependence on the time, which corresponds to the ideal - maximally fast and gentle on the product - drying process for a certain active pharmaceutical ingredient. Using the infrared temperature probes 68 and 70 the temperature of the active ingredient in the vials 76 along the conveying direction F measured at reference points to monitor an optimal temperature profile.

Special quartz glass or sapphire vials or similar infrared-transparent materials have transmission areas that can be used with narrow-band infrared temperature probes in the range of approx. 1.8 to 2.8 µm or in the range of 7-8 µm to directly measure the Active substance temperature through the vial 76 to eat.

The measured temperatures together with the calculated entered microwave power and measured reflected microwave power in the different microwave zones or sections make it possible to determine the absorbed thermal energy in the loaded vacuum / drying channel.

Microwave freeze-drying in a single or multiple single-mode microwave channel thus enables an exact energy balance for the vials along the conveying direction F and the control of the actually measured active substance temperature along the conveying direction F . This in-situ energy balance and process monitoring is a major advantage when validating new drying processes compared to international approval bodies (e.g. FDA). Equally important, if not more important, is the possibility of process control and regulation, which is not possible with conventional freeze dryers.

There is still a special feature related to the description of the facility 92 of 8th Please note: In the system is in the vacuum channel 12th or the microwave single-mode channels 18th and 20th between the microwave coupling elements 22 one filter plate each 94 arranged. By coupling microwave energy at several points in the longitudinal direction of the system via the microwave coupling elements 22 takes place between the to the microwave coupling elements 22 crosstalk belonging to the microwave sections (additive superimposition of the E field) instead. These sections are not supplied independently from a microwave source. If the absorption behavior of the product to be dried over the effective lengths along the conveying direction F not completely up to the filter plates 94 is sufficient, there are reflections and a standing wave ratio (minima and maxima of the field distribution along the conveying direction F ). It is therefore advantageous to adjust the effective length based on the absorption behavior of the product to be dried and the microwave energy density of the microwave source so that reflections do not occur as far as possible. In other words, the preferred goal is to achieve independence of the sections. The individual sections should be between the microwave coupling elements 22 decoupled, especially at the end of the vacuum channel, where the MW energy density has to be lowered in order to precisely regulate the temperature limits in the final drying.

A filter plate 94 is particularly useful in the last section before the outlet vacuum lock, so that microwave energy is prevented from reaching the backward area, that is, towards the inlet vacuum lock.

Alternatively or additionally, by using different sugar solutions (maltodextrin or sucrose with low dielectric properties is sometimes used - loss factor of approx. 0.1), sugar solutions with higher dielectric properties can also be used (e.g. sorbitol - loss factor of approx. 10) higher loss factor causes a greater thermal conversion of the MW power and thus a higher sublimation power. Drying / sublimation runs faster. This means that the throughput can be increased or the overall length of the systems can be shortened because a higher loss factor enables a higher thermal drying capacity.

The systems described above can also be used for drying in particular edible foams, extracts, concentrates and Fruit-based purees can be used. The systems could, for example, be operated accordingly.

The features of the invention disclosed in the above description, in the drawings and in the claims can be essential both individually and in any combination for realizing the invention in its various embodiments.

Reference list

10th

investment

12th

Vacuum channel

14

Input end

16

Exit end

18, 20

Microwave single mode channels

22

Microwave coupling elements

26

Conveyor units

27

drive shaft

28

Trays

30th

Inlet vacuum lock

32

Outlet vacuum lock

34

Conveyor unit

35

Conveyor unit

36

Conveyor unit

40

Conveyor unit

42

Conveyor unit

44

Conveyor unit

46

entrance

48

output

50

Isolating slide

52

entrance

54

output

56

Isolating slide

58

Isolating slide

60

Vacuum connections

62

Inspection hatches

64, 66

Long edges

68, 70

Infrared temperature probes

73

Side wall

74

Longitudinal opening

76

Vials

78

Sealing caps

80

Stamp plate

82

Inspection hatch

84

investment

86

Glovebox

88

openings

90

Operating personnel

92

investment

94

Filter plate

F

Direction of conveyance

L

Longitudinal direction

QUOTES INCLUDE IN THE DESCRIPTION

This list of documents listed by the applicant has been generated automatically and is only included for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Patent literature cited

• US 20170115057 B1 [0010]
• DE 102013009064 B3 [0011]
• EP 1205724 B1 [0012]
• EP 1750760 B1 [0015]

Non-patent literature cited

• Julian H. Gitter, Raimund Geidobler, Ingo Presser, Gerhard Winter, Journal of Pharmaceutical Sciences 107 (2018) 2538-2543 [0009]

Claims (17)

Process for the, preferably continuous, microwave freeze-drying of active pharmaceutical ingredients and, in particular edible, foams, extracts, concentrates and purees based on fruit in vials (76) and trays (28), comprising: Driving vials (76) or trays (28) with pharmaceutical active ingredient to be dried or, in particular edible, foams, extracts, concentrates and purees based on fruit into an inlet vacuum lock (30), Reducing pressure in the inlet vacuum lock (30) to a pressure below atmospheric pressure, - Transfer the vials (76) or trays (28) from the inlet vacuum lock (30) into a downstream vacuum channel (12) in which the same pressure is generated below atmospheric pressure as in the inlet vacuum lock (30), at least in the vacuum channel (12) two, preferably four, microwave monomode channels (18, 20) extending in the longitudinal direction of the vacuum channel (12) are formed directly next to one another, - Method of the vials (76) or trays (78) in the longitudinal direction (L) of the microwave monomode channels (18, 20) of the vacuum channel (12) in several stages with simultaneous targeted irradiation of microwaves with a predetermined microwave frequency to generate a single mode - or single-mode microwave field distribution, the process of the vials (76) or trays (28) and irradiation of the microwaves being interrupted each time after a milestone has been reached, and only some of the first vials (76) or trays (28) in the conveying direction are interrupted the vacuum channel (12) into a downstream outlet vacuum lock (32), in which the same pressure is generated below atmospheric pressure as in the vacuum channel (12), and the vacuum in the inlet vacuum lock (30) is broken to the outside between reaching the respective milestones and new vials (76) or trays (28) with active ingredient to be dried or, in particular edible, foams, extracts, concentrates and purees a uf transferred to the inlet vacuum lock (30) and the pressure in the inlet vacuum lock (30) is again reduced to the pressure below atmospheric pressure and the vacuum in the outlet vacuum lock (32) is broken and the vials (76) or trays (28) in the outlet vacuum lock (32) can be transferred from the same to the outside. Procedure according to Claim 1 , wherein the microwave frequency is 915 MHz or 2450 MHz and / or the width of the microwave single-mode channels (18, 20) is between approximately 0.05 m and approximately 0.6 m and / or the length of the microwave single-mode channels (18 , 20) is between approx. 3 m and approx. 6 m. Procedure according to Claim 1 or 2nd , wherein the temperature of the active substance in the vials (76) or trays (28) is measured at several locations along the conveying direction F, preferably also transversely thereto. Method according to one of the preceding claims, wherein the microwaves are irradiated in such a way that the microwave intensity in the conveying direction F decreases on a spatial average. Method according to one of the preceding claims, wherein an in-situ energy balance based on the thermally introduced microwave energy and the microwave energy absorbed by the active ingredient or foam, extract, concentrate or puree in the vials (76) or trays (28), preferably also a process monitoring for temporal Control of the temperature in the active ingredient or foam, extract, concentrate or puree in the vials (76) or trays (28) is / are carried out. Method according to one of the preceding claims, wherein the vials (76) are closed with closure caps (78), preferably using a stamp plate (80), between reaching the respective milestones before breaking the vacuum in the outlet vacuum lock (32). Method according to one of the preceding claims, wherein the vacuum channel (12), the inlet vacuum lock (30) and the outlet vacuum lock (32) are arranged in a glove box, preferably wherein the vacuum channel (12) has at least one inspection flap (62), preferably on the top and / or the microwave technology part belonging to the microwave single-mode channels (18, 20) is encapsulated and is arranged below the vacuum channel (12), preferably below the glovebox, and / or the glovebox has at least one lateral and / or at least one upper glove insert . Plant (10; 84; 92), in particular in modular construction, for, preferably continuous, microwave freeze-drying of active pharmaceutical ingredients and, in particular edible, foams, extracts, concentrates and purees based on fruit in vials (76) and trays (28) : - a, preferably quadrangular, in particular rectangular, vacuum channel (12) with an inlet end (14) and an outlet end (16), - a pressure reducing device for reducing pressure within the vacuum channel (12) to a pressure below atmospheric pressure, - at least two, preferably four microwave single-mode channels (18, 20) formed directly next to one another in the vacuum channel (12) and extending in the longitudinal direction (L) of the vacuum channel (12), at least one microwave generator for generating microwaves with a predetermined microwave frequency, - at least one microwave coupling element (22) per microwave monomode channel (18, 20), which is configured to transmit from the microwave generator or one of the microwave generators To be fed with microwaves at the microwave frequency, - a conveying device for moving vials (76) or trays (28) in the longitudinal direction (L) of the microwave monomode channels (18, 20) from the input end (14) to the output end (16) of the vacuum channel ( 12), - an inlet vacuum lock (30) upstream of the vacuum channel (12), - an outlet vacuum lock (32) downstream of the vacuum channel (12), - a conveyor in the inlet vacuum lock (30) and the outlet vacuum lock (32) for moving the vials ( 76) or trays (28) into the vacuum channel (12) or out of the vacuum channel (12) and - a control device for controlling the pressure reducing device, the m at least one microwave generator and the conveying devices for moving the vials (76) or trays (28) in the microwave monomode channels (18, 20) and in the inlet vacuum lock (30) and in the outlet vacuum lock (32). Appendix (10; 84; 92) after Claim 8 , wherein the at least two microwave single-mode channels (18, 20) have a common side wall (72) which is provided with a continuous longitudinal opening. Appendix (10; 84; 92) after Claim 8 or 9 , wherein each microwave single-mode channel (18, 20) is square, in particular rectangular. Plant (10; 84; 92) according to one of the Claims 8 to 10th , wherein the at least one microwave generator comprises a magnetron or a semiconductor source. Plant (10) according to one of the Claims 8 to 11 , wherein the microwave frequency is 915 MHz or 2450 MHz and / or the width of the microwave single-mode channels (18, 20) is between approximately 0.05 m and approximately 0.6 m and / or the length of the microwave single-mode channels (18, 20) is between approx. 3 m and approx. 4 m. Plant (10; 84; 92) according to one of the Claims 8 to 12th , wherein it has several temperature measuring devices along the conveying direction F, preferably also transversely thereto, for measuring the temperature of the active substance in the vials (76) or trays (28). Appendix (10; 84; 92) after Claim 13 , with an energy balancing device for in-situ energy balancing based on the thermally introduced microwave energy and the microwave energy absorbed by the active ingredient or foam, extract, concentrate or puree in the vials (76) or trays (28), preferably also a process monitoring device for temporally controlling the temperature in the active ingredient or foam, extract, concentrate or puree in the vials (76) or trays (28). Plant (10; 84; 92) according to one of the Claims 8 to 14 , wherein it has a sealing cap pressing device, in particular a stamp plate (80), for pressing a sealing cap (78) onto the vials (76) in the outlet vacuum lock (32). Plant (10; 84; 92) according to one of the Claims 8 to 15 , It has a conveyor for moving the vials (76) or trays (28) into the inlet vacuum lock (30) and / or a conveyor for moving the vials (76) or trays (28) out of the outlet vacuum lock (32). Plant (84) according to one of the Claims 8 to 16 , wherein it has a glove box (86) and the vacuum channel (12) and the inlet vacuum lock (30) are arranged in the glove box (86) together with the outlet vacuum lock (32), preferably the vacuum channel (12) has at least one inspection flap (62), preferably has on the top and / or the microwave technology part belonging to the microwave single-mode channels (18, 20) is arranged coupled below the vacuum channel (12), preferably below the glovebox (86), and / or the glovebox (86) at least has a side and / or at least one upper glove insert.

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