DE102019106261B4 - PROCESS AND PLANT, IN PARTICULAR IN A MODULAR DESIGN, FOR, PREFERABLY CONTINUOUS, MICROWAVE FREEZE-DRYING OF PHARMACEUTICAL INGREDIENTS AND, IN PARTICULAR EDIBLES, FOAMS, EXTRAKES, CONCENTRIES - Google Patents

Abstract

Method for, preferably continuous, microwave freeze-drying of pharmaceutical active ingredients, foams, extracts, concentrates and purees based on fruit in vials (76) and trays (28), comprising: - Inserting vials (76) or trays (28) with to-be-dried active pharmaceutical ingredient, foam, extract, concentrate or puree based on fruit in an inlet vacuum lock (30), - cooling of the active ingredient to be dried, foam, extract, concentrate or puree and reducing the pressure in the inlet vacuum lock (30) to a vacuum level in order to to freeze or post-freeze the active ingredient (s) to be dried, foam, extract, concentrate or puree via the vacuum, - transferring the vials (76) or trays (28) from the inlet vacuum lock (30) into a downstream vacuum channel (12), in the same pressure as in the inlet vacuum lock (30) is generated, wherein in the vacuum channel (12) at least two, preferably four, extending in the longitudinal direction of the vacuum channel (12) micr owave single mode channels (18, 20) are formed directly next to each other, - moving the vials (76) or trays (78) in the longitudinal direction (L) of the microwave single mode channels (18, 20) of the vacuum channel (12) in several stages with simultaneous targeted Radiation of microwaves with a predetermined microwave frequency to generate a single-mode or single-mode microwave field distribution, each time after reaching a stage goal the process of the vials (76) or trays (28) and radiation of the microwaves is interrupted and only some Vials (76) or trays (28) at the front in the conveying direction are transferred from the vacuum channel (12) into a downstream outlet vacuum lock (32), in which the same pressure is generated as in the vacuum channel (12), and the vacuum between reaching the respective stage goals in the inlet vacuum lock (30) is broken to the outside and new vials (76) or trays (28) with pharmaceutical active ingredient to be dried, foam, extract, concentrate entered or fruit-based puree are transferred into the inlet vacuum lock (30) and the active ingredient to be dried, foam, extract, concentrate or puree is cooled and the pressure in the inlet vacuum lock (30) is again reduced to a vacuum level in order to drying agent (s), foam, extract, concentrate or puree via the vacuum to freeze or post-freeze, and between the achievement of the respective stage goals, the vacuum in the outlet vacuum lock (32) is broken and the vials (76) or trays (28) in the outlet vacuum lock (32) are transferred from the same to the outside.

Description

The present invention relates to a method and a system, in particular in a modular design, 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 (ampoules) and trays (bowls), e.g. Trays with Goretex membranes (e.g. Gore Lyoguard freeze drying trays).

Freeze-drying (lyophilization) is the usual method for actively drying and stabilizing active pharmaceutical ingredients.

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

There is great interest in alternative freeze-drying processes in order to reduce the drying time as well as to dry the product more gently.

In drug development, protein solutions are currently being developed whose mode of action can intervene in metabolic processes in a highly selective manner. However, these new generations of active ingredients are also much more sensitive to drying, with drying temperatures above approx. 20 to approx. 50 ° C being avoided over longer periods of time. Conventional freeze drying with drying times in the order of magnitude of approx. 50 to approx. 70 hours mean that the respective active ingredient remains in the final drying process for a long time at temperatures above freezing point, usually at approx. 20 to approx. 50 ° C. and above. The long-term thermal stress in the final drying process significantly affects the survival rates of this new generation of active ingredients.

Using microwave freeze drying there is the potential to drastically shorten these long drying times, namely by a factor of approx. 6 to approx. 10. Microwave freeze drying would not only be more economical, but also gentler on the product for the new generation of active ingredients.

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

In the dissertation of 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 single-mode microwave resonator can be dried in as little as 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 is much faster.

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

From the US 2017/0115057 A1 a microwave multimode chamber with inlet and outlet sluice for organic products in trays is known. Several individual microwave waveguide couplings are fed into a large multimode vacuum chamber via round microwave feeds. The microwave field distribution is to a large extent load-dependent or product-dependent and generally not homogeneous.

From the German patent DE 10 2013 009 064 B3 a microwave oven with a so-called single-mode or monomode 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, likewise with a so-called single-mode or monomode microwave system. Tungsten carbide rods are cyclically moved back and forth within a vacuum chamber with the microwave system and during the drying process.

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

In addition, there is also a trend in active ingredient development towards small and specific batch sizes in order to produce customer-specific active ingredients.

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

Similar problems also exist in particular with edible foams, extracts, concentrates and fruit-based purees.

DE 198 04 386 A1 relates to a method and a device for drying or heat treatment of products, in particular with the aid of microwave radiation, and banana chips and banana powder produced therewith. In particular, it concerns a method and a device for drying or heat treatment of substances or products under a pressure different from atmospheric pressure. For drying or heat treatment, the products to be treated are placed in transport containers, which are then introduced into a treatment chamber via entry lock chambers or are brought out again via discharge lock chambers. At least one microwave source is located in the treatment chamber for drying or heat treatment. An infrared heat source can also be provided. A rest period can be provided after the heat treatment or drying. For this purpose, a vertically running conveyor system is provided in the treatment chamber, in particular for a longer period of rest. The transport container is shell-shaped and can have nets onto which the products are applied. The method is preferably used for drying or heat treatment of basic foodstuffs, for example foodstuffs or pharmaceutical substances.

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

• - Hineinfahren von Vials oder Trays mit zu trocknendem pharmazentrischen Wirkstoff, Schaum, Extrakt, Konzentrat oder Püree auf Fruchtbasis in eine Einlaufvakuumschleuse,
• - Kühlen des zu trocknenden Wirkstoffs, Schaumes, Extrakts, Konzentrats oder Pürees und Reduzieren von Druck in der Einlaufvakuumschleuse auf ein Vakuumniveau, um den/das zu trocknende(n) Wirkstoff, Schaum, Extrakt, Konzentrat oder Püree über das Vakuum ein- oder nachzufrieren,
• - Überführen der Vials oder Trays aus der Einlaufvakuumschleuse in einen nachgeschalteten Vakuumkanal, in dem derselbe Druck 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 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 pharmazeutischen Wirkstoff , Schaum, Extrakt, Konzentrat oder Püree auf Fruchtbasis in die Einlaufvakuumschleuse überführt werden und der/das zu trocknende Wirkstoff, Schaum, Extrakt, Konzentrat oder Püree gekühlt und der Druck in der Einlaufvakuumschleuse erneut auf ein Vakuumniveau reduziert wird, um den/das zu trocknende(n) Wirkstoff, Schaum, Extrakt, Konzentrat oder Püree über das Vakuum ein- oder nachzufrieren, 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 pharmaceutical active ingredients and, in particular edible, foams, extracts, concentrates and purees based on fruit in vials and trays, comprising:

• - Inserting vials or trays with pharmaceutical-centric active ingredients, foam, extract, concentrate or fruit-based puree to be dried into an inlet vacuum lock,
• - Cooling of the active ingredient, foam, extract, concentrate or puree to be dried and reducing the pressure in the inlet vacuum lock to a vacuum level in order to freeze or post-freeze the active ingredient (s) to be dried, foam, extract, concentrate or puree via the vacuum ,
• - Transferring the vials or trays from the inlet vacuum lock into a downstream vacuum channel in which the same pressure is generated as in the inlet vacuum lock, whereby in the vacuum channel at least two, preferably four, microwave single-mode channels extending in the longitudinal direction of the vacuum channel are formed directly next to one another,
• - Moving 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 goal the vials or trays and the irradiation of the microwaves are interrupted and only some of the vials or trays that are at the front in the conveying direction are transferred from the vacuum channel into a downstream outlet vacuum lock, in which the same pressure is generated as in the vacuum channel, and the vacuum in the between reaching the respective stage goals Inlet vacuum lock is broken to the outside and new vials or trays with pharmaceutical active ingredient to be dried, foam, extract, concentrate or fruit-based puree are transferred into the inlet vacuum lock and the active ingredient to be dried, foam, extract, concentrate or The puree is cooled and the pressure in the inlet vacuum lock is reduced again to a vacuum level in order to freeze or post-freeze the active ingredient (s) to be dried, foam, extract, concentrate or puree via the vacuum, and the vacuum between the achievement of the respective stage goals is broken in the outlet vacuum lock and the vials or trays are transferred to the outside in the outlet vacuum lock.

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

• - einen Vakuumkanal mit einem Eingangsende und einem Ausgangsende,
• - eine Kühleinrichtung zum Kühlen eines zu trocknenden pharmazeutischen Wirkstoffes oder eines zu trocknenden Schaumes, Extrakts, Konzentrats oder Pürees,
• - eine Druckreduzierungseinrichtung zur Reduzierung von Druck innerhalb des Vakuumkanals auf einen Vakuumniveau um den zu trocknenden Wirkstoff oder den/das zu trocknenden Schaum, Extrakt, Konzentrat oder Püree über das Vakuum ein- oder nachzufrieren,,
• - 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 Kühleinrichtung Druckreduzierungseinrichtung, des mindestens einen Mikrowellen-Generators und der Fördereinrichtungen zum Verfahren der Vials oder Trays in den

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

• - a vacuum channel with an inlet end and an outlet end,
• - a cooling device for cooling a pharmaceutical active substance to be dried or a foam, extract, concentrate or puree to be dried,
• - a pressure reducing device for reducing the pressure inside the vacuum channel to a vacuum level in order to freeze or post-freeze the active ingredient to be dried or the foam, extract, concentrate or puree to be dried,
• - at least two, preferably four, in the vacuum channel formed directly next to each other, extending in the longitudinal direction of the vacuum channel microwave single mode channels,
• - 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 fed by the microwave generator or one of the microwave generators with microwaves at the microwave frequency,
• - 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 device each in the inlet vacuum lock and the outlet vacuum lock for moving the vials or trays into and out of the vacuum channel
• a control device for controlling the cooling device, the pressure reduction 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.

In the method it can be provided 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 in the vials or trays is advantageously measured at several locations along the conveying direction, preferably also across it.

The microwaves are expediently irradiated in such a way that the spatial average of the microwave intensity decreases 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 the temporal control of the temperature in Active ingredient or foam, extract, concentrate or puree in the vials or trays.

In particular, provision can be made for the vials to be sealed with sealing caps, preferably using a stamp plate, to protect the contents of the vials from moisture from the atmosphere between the achievement of the respective stage goals before the vacuum is broken in the outlet vacuum lock.

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 being 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 particular embodiment of the system, the at least two single-mode microwave 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 single-mode channels is between approx. 0.05 m and approx. 0.6 m and / or the length of the microwave single-mode channels is between approx. 3 m and approx. 6 m.

The system expediently has several temperature measuring devices along the conveying direction, preferably also transversely thereto, for measuring the temperature of the active ingredient, 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, foam, extract, concentrate or puree in the vials or trays, preferably also a process monitoring device for timing the Temperature in the active ingredient, 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 is expediently a conveying device for moving the vials or trays into the inlet vacuum lock and / or a conveying device for moving the vials or trays out of the outlet vacuum lock to protect the contents of the vials from moisture from the atmosphere.

Finally, it can be provided that the system has a glove box and the vacuum channel and the inlet vacuum lock are arranged in the glove box together with the outlet vacuum lock, preferably with the vacuum channel having at least one inspection flap, preferably on the top, and / or the microwaves belonging to the single-mode microwave channels -Technical part coupled and is arranged below the vacuum channel, preferably within the glovebox, 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.

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 glovebox for service purposes z. B. can be completely removed on rollers.

In a special embodiment, the entire system can be removed from a separate support frame on the back of the glove box.

The present invention is based on the surprising finding that by using a single microwave mode, more uniform microwave field distributions and thus also spatially more uniform temperature distributions and consequently 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 particular embodiments, the present invention provides a compact, fast, product-friendly and efficient drying method with a system that is small enough that it can be integrated into a glovebox structure. Since conventional multi-level freeze dryers usually freeze-dry several tens of thousands of vials, the storage space and the equipment surrounding 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. As a result, conventional freeze dryers of this kind cannot be integrated into the continuous preparation and pretreatment of vials in glove boxes. The loading times for conventional freeze-drying are usually around 1-8 hours. The first vials are therefore no longer than approx. 8 hours old, which already affects the quality of the active ingredient.

With the aforementioned load sizes of conventional multi-deck freeze dryers, energy and temperature monitoring in order to control the drying process in a targeted manner is hardly possible. There are wireless temperature measurements for reference vials so that the actual temperature profile of individual vials is known, but 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 attached claims and from the following description, in which several exemplary embodiments are explained in detail with reference to the schematic drawings. It shows:

• 1 a perspective view of a system for continuous microwave freeze-drying of active pharmaceutical ingredients in vials and trays according to a particular embodiment of the present invention at an angle from above;
• 2 a side view of the plant of 1 ;
• 3 a plan view of the left part of the plant in 2 ;
• 4th a sectional view along the line IV-IV in 2 ;
• 5 a perspective view of a tool carrier tray with vials;
• 6th FIG. 3 is a perspective view of one of the FIGS 5 Vials shown with a (loosely) attached closure cap;
• 7th a perspective view of a system for continuous microwave freeze-drying of active pharmaceutical ingredients in vials and trays according to a further particular embodiment of the present invention at an angle 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 the microwave energy as well as the temporal progression of the humidity and temperature in the products to be dried.

The ones in the 1 to 4th shown system 10 has a rectangular vacuum channel 12th with an entry end 14th 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 a vacuum, in the present example exactly two in the vacuum channel 12th formed directly next to each other, extending in the longitudinal direction L. , the vacuum channel 12th the one with the conveying direction F. is identical, extending single mode microwave 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. are arranged at a distance from one another and configured to be fed by the at least one microwave generator with microwaves at the aforementioned microwave frequency, a conveying device for moving trays 28 or tool carriers in the longitudinal direction of the microwave single-mode channels 18th and 20th from the entrance end 14th to the exit end 16 of the vacuum channel 12th , one to the vacuum channel 12th upstream inlet vacuum lock 30th , one to the vacuum channel 12th downstream outlet vacuum lock 32 , one conveyor device 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 In addition, and a control device (not shown) for controlling the pressure reduction device, the at least one microwave generator and the conveyor devices for moving the trays 28 in the microwave single mode channels 18th and 20th (Double single mode 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 26th , in the present case three funding units 26th for example a drive shaft 27 or a drive gear (see 4th ) and can be controlled both individually and in combination. For example, it can be with the conveyor units 26th be plastic conveyor belts as well as plastic chain chain belts (microwaves (MW) -transparent). Likewise, for example, toothing can be incorporated into the trays and a drive gear can move the trays 28 move.

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

Before the inlet vacuum lock 30th is also a conveyor unit 42 and behind the outlet vacuum lock 32 is also a conveyor unit 44 intended.

At the entrance 46 and at the exit 48 the inlet vacuum lock 30th is a slide gate each 50 who have favourited the inlet vacuum lock 30th can independently close vacuum-tight on both sides, arranged. Corresponding is at the entrance 52 and at the exit 54 the outlet vacuum lock 32 a slide gate each 58 arranged that the inlet vacuum lock 30th can be independently vacuum-tight on both sides.

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

Furthermore, 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 , e.g. infrared cameras, arranged in pairs. The temperature measuring probes 70 are each on the center line L. of the vacuum channel 12th aligned.

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

Using an example in which Vials 76 on trays 28 with inserts for vials, where the vials contain active pharmaceutical ingredients embedded in a foam matrix (preferably made from sugar solutions) and possibly other auxiliaries (pH value adjustment, as stabilizers or preservatives, as scaffolding agents, etc.), a method for 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 sealing caps 78 are loosely applied (see also 5 and 6th ) 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 single-mode microwave 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 26th from the vacuum channel 12th into the outlet vacuum lock 50 driven so that the free section in the vacuum channel 12th allows a defined travel path during the lock times. The following process sequence in accordance with a particular embodiment of the present invention results from an already (partially) loaded vacuum channel 12th :

1. 1. In the present example there are four occupied trays 28 in the vacuum channel 12th with basically three independent funding units 26th , 34 , 35 . In each of the inlet vacuum locks 30th and the outlet vacuum lock 32 there is an independent conveyor unit in each case 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 or. 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 to enter the free first section quickly, e.g. at a speed of ≥ 0.5-5 m / min. In the vacuum channel 12th are those in front of it in the longitudinal direction L. four sections already with occupied trays 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 slide gate 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 gate valve 58 to the outlet vacuum lock 32 will be opened.
5. 5. The conveyor unit 36 moves quickly together with the tray 28 on 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 drives together with the occupied tray 28 from the vacuum channel 12th quickly into the outlet vacuum lock 32 .
7. 7. The separating valve 50 at the entrance end 14th and the slide gate 58 at the exit end 16 close again.
8. 8. The microwave is turned back on and the conveyor units 34 , 26th and 36 move all trays at a defined slow speed, eg approx. 0.5 to 1 meter per hour by one position or by one section.
9. 9. During this time, the shutter flaps 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 above onto the vials 76 pressed or pressed. Then the vacuum in the outlet vacuum lock 32 eg broken with N ₂ (nitrogen). Pressing the caps 78 on the vials 76 is used to seal 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 gate 50 into the inlet vacuum lock 30th moved and post-frozen or frozen (eg at 0.03 mbar) via the vacuum. The vacuum is advantageously lowered, for example via N ₂ or, for example, via wall cooling according to a defined profile in order to sensibly influence the crystal formation for the respective active substance.
11. 11. The cyclical process starts again.

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

Instead of the active pharmaceutical ingredients in vials, trays with frozen protein granules (e.g. grain sizes of approx Millimeters down to µm and nm in diameter or sugar foam solutions).

7th shows a perspective view of a plant 84 for continuous microwave freeze-drying of active pharmaceutical ingredients in vials and trays according to a further particular embodiment of the present invention. Said plant 84 differs from the plant 10 essentially in that it is a glovebox 86 and the vacuum channel 12th as well as the inlet vacuum lock 30th together with 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 attachment 10 ) in the glovebox 86 are arranged. The one for the microwave single-mode channels 18th and 20th The 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. In addition, the vacuum channel 12th or can be the microwave single mode channels 18th and 20th via glove inserts on the inspection hatches 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 with, for example, 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 glovebox for service purposes z. B. can be completely removed on rollers.

In a special embodiment, the entire system can be removed from a separate support frame on the back of the glove box.

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

Via the microwave coupling elements 22nd that are deliberately arranged at the bottom to facilitate handling in the upper area (sterile area - below microwave technology area) using glove box inserts, such as the glovebox 86 To enable a microwave energy profile E (s. 8th above) and the corresponding temperature profile Temp (s 8th above) together with the moisture profile, moisture for the product along the longitudinal direction L. or conveying direction F. and thus also build up depending on the time, which corresponds to the ideal - as fast as possible and gentle on the product - drying process for a specific pharmaceutical active ingredient. Using the infrared temperature measuring probes 68 and 70 is 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 ranges that can be used with narrow-band infrared temperature measuring probes in the range from approx. 1.8 to 2.8 µm or in the range 7-8 µm to directly measure the Active ingredient temperature through the vial 76 to eat.

The measured temperatures together with the calculated entered microwave power and measured reflected microwave power in the various 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 enables precise energy balancing for the vials along the conveying direction F. and the control of the active substance temperature actually measured along the conveying direction F. . This in-situ energy balance and process monitoring is a major advantage when validating new drying processes against international approval bodies (e.g. FDA). Just as important, if not even more important, is the possibility of process management and control, which is not possible with conventional freeze dryers.

There is one more peculiarity in connection with the description of the plant 92 from 8th point out: The system is in the vacuum channel 12th or the microwave single mode channels 18th and 20th between the microwave coupling elements 22nd one filter plate each 94 arranged. By coupling in microwave energy at several points in the longitudinal direction of the system via the microwave coupling elements 22nd takes place between the to the microwave coupling elements 22nd crosstalk (additive superposition of the E-field) takes place in the microwave sections. These sections are not supplied independently of a microwave source. When the absorption behavior of the product to be dried over the effective length along the conveying direction F. not all the way 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 set 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 aim is to achieve independence of the sections. The individual sections should be between the microwave coupling elements 22nd be decoupled, especially at the end of the vacuum channel, where the MW energy density has to be reduced in a targeted manner in order to precisely regulate the temperature limits in the final drying.

A filter plate 94 is particularly useful in the last section in front of the outlet vacuum lock so that microwave energy is prevented from reaching the rearward area, i.e. in the direction of the inlet vacuum lock.

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

The systems described above can also be used for drying, in particular, edible foams, extracts, concentrates and fruit-based purees. 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 the implementation of the invention in its various embodiments.

List of reference symbols

10

investment

12

Vacuum channel

14th

Input end

16

Exit end

18, 20

Microwave single mode channels

22nd

Microwave coupling elements

26th

Conveyor units

27

drive shaft

28

Trays

30th

Inlet vacuum lock

32

Outlet vacuum lock

34

Delivery unit

35

Delivery unit

36

Delivery unit

40

Delivery unit

42

Delivery unit

44

Delivery unit

46

entrance

48

output

50

Slide gate valve

52

entrance

54

output

56

Slide gate valve

58

Slide gate valve

60

Vacuum connections

62

Inspection hatches

64, 66

Longitudinal edges

68, 70

Infrared temperature measuring 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.

Conveying direction

L.

Longitudinal direction

Claims (17)

Process for, preferably continuous, microwave freeze-drying of Pharmaceutical active ingredients, foams, extracts, concentrates and purees based on fruit in vials (76) and trays (28), comprising: - Inserting vials (76) or trays (28) with pharmaceutical active ingredient to be dried, foam, extract, concentrate or puree on a fruit basis in an inlet vacuum lock (30), - cooling the active ingredient to be dried, foam, extract, concentrate or puree and reducing the pressure in the inlet vacuum lock (30) to a vacuum level in order to remove the active ingredient (s) to be dried, foam, Freezing the extract, concentrate or puree in or afterwards using the vacuum, - Transferring the vials (76) or trays (28) from the inlet vacuum lock (30) into a downstream vacuum channel (12), in which the same pressure as in the inlet vacuum lock (30) is generated, wherein in the vacuum channel (12) at least two, preferably four, in the longitudinal direction of the vacuum channel (12) extending microwave single mode channels (18, 20) are formed directly next to one another, - Ver move the vials (76) or trays (78) in the longitudinal direction (L) of the microwave single-mode 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 monomode microwave field distribution, each time after reaching a stage goal the process of the vials (76) or trays (28) and irradiation of the microwaves is interrupted and only a few in the conveying direction foremost vials (76) or trays (28) from the Vacuum channel (12) in a downstream outlet vacuum lock (32), in which the same pressure is generated as in vacuum channel (12), and between reaching the respective stage goals, the vacuum in the inlet vacuum lock (30) is broken to the outside and new vials ( 76) or trays (28) with pharmaceutical active ingredient to be dried, foam, extract, concentrate or fruit-based puree are transferred into the inlet vacuum lock (30) and the active ingredient to be dried, foam, extract, concentrate or puree is cooled and the pressure in the inlet vacuum lock (30) is again reduced to a vacuum level in order to remove the active ingredient (s) to be dried, foam, extract, concentrate or To freeze the puree in or out using the vacuum, and between reaching the respective stage goals, the vacuum in the outlet vacuum lock (32) is broken and the vials (76) or trays (28) in the outlet vacuum lock (32) are transferred to the outside. Procedure according to Claim 1 , the microwave frequency being 915 MHz or 2450 MHz and / or the width of the microwave single-mode channels (18, 20) being between approx. 0.05 m and approx. 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 2 , the temperature of the active ingredient in the vials (76) or trays (28) being 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 radiated in such a way that the microwave intensity in the conveying direction F decreases in spatial mean. 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, foam, extract, concentrate or puree in the vials (76) or trays (28), preferably also process monitoring for time control the temperature in the active ingredient, 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 between reaching the respective stage goals before breaking the vacuum in the outlet vacuum lock (32) the vials (76) with closure caps (78), preferably using a stamp plate (80), to protect the contents of the Vials are sealed from moisture from the atmosphere. 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. Plant (10; 84; 92), in particular of modular construction, for, preferably continuous, microwave freeze-drying of pharmaceutical active ingredients, foams, extracts, concentrates or purees based on fruit in vials (76) and trays (28), comprising: Vacuum channel (12) with an inlet end (14) and an outlet end (16), - a cooling device for cooling a pharmaceutical active substance, foam, extract, concentrate or puree to be dried, - a pressure reduction device for reducing pressure within the vacuum channel (12) a vacuum level to freeze or post-freeze the active ingredient (s) to be dried, foam, extract, concentrate or puree via the vacuum, - at least two in the vacuum channel (12) formed directly next to each other, in the longitudinal direction (L) of the vacuum channel (12) extending microwave single mode channels (18, 20), - at least one microwave generator for generating microwaves with a predetermined microwave frequency, - at least one microwave coupling element (22) per microwave single mode channel (18, 20), which is configured to be fed with microwaves at the microwave frequency from the microwave generator or one of the microwave generators, a conveyor device for moving vials (76) or trays (28) in the longitudinal direction (L) of the microwave single mode 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) connected downstream of the vacuum channel (12), - a conveyor device in each of the inlet vacuum lock (30) and the outlet vacuum lock (32) for moving the vials (76) or trays (28) into or into the vacuum channel (12) . out of the vacuum channel (12) and - a control device for controlling the cooling device, pressure reducing device, the at least one microwave generator and the conveying devices for moving the vials (76) or tra ys (28) in the microwave single mode 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 , each single-mode microwave channel (18, 20) being square, in particular rectangular. Plant (10; 84; 92) after one of the Claims 8 to 10 , wherein the at least one microwave generator comprises a magnetron or a semiconductor source. Appendix (10) according to one of the Claims 8 to 11 , the microwave frequency being 915 MHz or 2450 MHz and / or the width of the microwave single-mode channels (18, 20) being between approx. 0.05 m and approx. 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) after 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 , whereby they have 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, foam, extract, concentrate or puree in the vials (76) or trays (28), preferably also a process monitoring device for time control of the temperature in Active ingredient, foam, extract, concentrate or puree in the vials (76) or trays (28). Plant (10; 84; 92) after one of the Claims 8 to 14th wherein it has a closing cap press-on device, in particular a stamp plate (80), for pressing a closing cap (78) onto the vials (76) in the outlet vacuum lock (32) to protect the contents of the vials from moisture from the atmosphere. Plant (10; 84; 92) after one of the Claims 8 to 15th , wherein it has a conveyor device for moving the vials (76) or trays (28) into the inlet vacuum lock (30) and / or a conveyor device 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) together with the outlet vacuum lock (32) are arranged in the glove box (86).

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