Field of the invention

The present invention relates to a method of providing inline sterile freeze drying of a product containing solid matter and a solvent, such as water, in a plurality of trays accommodated in at least one trolley, comprising the steps of i. filling the product into the plurality of trays in a filling station, ii. reducing the temperature of the product, iii. bringing the product to a pressure and a temperature below the triple point of the solvent in a freeze dryer unit, iv. maintaining the under pressure and thereby provide a freeze dried product by removing the solvent as vapour in the freeze dryer unit, v. bringing the freeze dried product to a temperature and pressure above the triple point, and vi. emptying the product from the plurality of trays. The invention furthermore relates to a system for carrying out the method, and to use of the method for freeze drying a product chosen from the selection: probiotic bacteria, lactic bacteria, whey derivatives, yeast bacteria, bacterial cultures.

Background of the invention

Freeze drying is the drying of an already deep-frozen product in a vacuum, below the triple point of the solvent, i.e. basically water, present with the solid matter of the product. The vacuum allows the ice to turn directly into vapor without first passing through the liquid stage, in a sublimation process. This ensures that the product retains most of its original shape, color, taste, and nutrients.

Basically there are four important steps in a freeze drying process: freezing the product, loading the frozen product into suitable trays (or vice versa), freeze drying the product in vacuum, and unloading the dry product afterwards. It is possible to add steps in the process for further optimization of the product or it characteristics.

There are two basic ways of drying the product in the production line. One way is in the form of batch operation, one example of an apparatus for carrying out batch freeze drying is the GEA Niro RAY™, and the other in the form of continuous operation, one example being the GEA Niro CONRAD™.

Throughout the freeze drying process, there is a need for handling the product. In the above examples of known apparatus, the product is loaded into trays which are brought into and out of the individual operational units.

Within the bioindustry there is an increasing interest in providing products of a high quality under controlled conditions, and a number of guidelines and regulations have been formulated during recent years to establish proper quality measurement, analysis and control.

Presently, non-continuous systems are relatively slow processes, requiring substantial time for loading and unloading the product into and out of the individual operational units. The handling of trays and trolleys takes place with partly manual operation. Furthermore, there is a risk of defrosting product during the transportation steps.

When handling products such as bacterial cultures etc., particular requirements are necessary to meet the demands of such biograde systems.

Summary of the invention

On this background, it is an object of the present invention to pro- vide improved operational conditions and to make it possible to handle a wide variety of products.

In a first aspect, this and further objects are met by a method of the kind mentioned in the introduction which comprises the additional steps of vii. sterilizing the at least one trolley with the plurality of trays, and viii. bringing the at least one trolley with the plurality of trays to the filling station.

By placing the trays in trolleys, and having the trolley or trolleys with the trays sterilized in a step before bringing the trays to the filling station, a semi-continuous transportation and handling of the product in the freeze drying line is made possible under sterile conditions. Thus, the method may be described as a continuous operation in batches processed in the individual processing units. The drying time can typically be reduced by a factor of two compared to a typical pharmaceutical freeze drying process being the existing alternative. The cycle time is further reduced by storing the loaded frozen product on trays in trolleys for fast transfer of the entire trolley including the trays into the freeze dryer unit.

The method is based on drying in a batch freeze dryer unit. As the loading and unloading of the trays in trolleys may be carried out automatically or semi-automatically, it is possible to eliminate manual handling of the product, or at least reduce it to a great extent. Once the trays in trolleys are loaded with product they are automatically transported to a freeze storage, and further to the freeze dryer unit, the emptying station, and the cleaning and steril- izing unit by suitable transportation, such as an overhead rail system. The only manual transport of single trays and trolleys is in the emptying station, but it is conceivable to make this operation automatic or semi-automatic as well.

In the present context, the term "sterilization" will be referred to as encompassing any cleaning process that eliminates (removes) or kills various forms of microbial life (such as bacteria, viruses, spore forms, etc.) present on a surface or contained in remains of the product, on a sterilizing level as required according to rules and regulations. Means of sterilization can be under dry (ex. heat, flaming, incineration, electron beams, X-rays, gamma rays, or subatomic particles, ultraviolet light irradiation, reactive gases (ex. alkylating agents such as ethylene oxide, and oxidizing agents such as hydrogen peroxide and ozone), hydrogen peroxide, silver ions and silver compounds) or wet (ex. steam, heat, heat and pressure, filtration, ethanol, chemical, chlorine bleach, glutaraldehyde and formaldehyde, ortho-phthalaldehyde, hydrogen peroxide) conditions.

In another aspect, a system for carrying out the method is devised, the method comprising: a filling station having an inlet end and an outlet end, or a docking station, a freeze storage, a freeze dryer unit, an emptying station having an inlet end and an outlet end, or a docking station, a plurality of trays adapted to be accommodated in at least one trolley, said system being characterized in that a cleaning and sterilizing unit is provided between the outlet end of the emptying station and the inlet end of the filling station.

By inserting a cleaning and sterilizing unit in the process line, the trolleys with empty trays may be introduced through a first gate to be cleaned and sterilized, and let out of a second gate to be filled with product in a clean environment. The cleaning and sterilizing unit thus acts as a sluice or lock, and the room in which the filling station is placed thus has virtually no physical contact to the room in which the emptying station is placed.

The advantage of the invention is a unique design which integrates all the process steps in a single system or plant. In this plant large quantities, compared to pharmaceutical grade plants, of product can be freeze dried un- der sterile conditions.

In a third aspect of the invention, use of the method for freeze drying a product chosen from the selection: probiotic bacteria, lactic bacteria, whey derivatives, yeast bacteria, bacterial cultures is provided.

The products can e.g. be bacterial cultures, yeasts, enzymes, probi- otics and other living cell cultures. Among products particularly suitable are those for use where hygienic production and prevention of cross- contamination between batches is demanded. The high level of hygiene is requested for products such as probiotics and lactic bacteria and various whey derivatives being produced and used by major dairy ingredients pro- ducers.

A further advantage with the system according to the invention is that it is possible to Clean-ln-Place (CIP). This is a requirement in many applications, and for example in the baby food business, fully CIP-able plants are required.

Further details and advantages appear from the dependent claims, and from the detailed description of preferred embodiments and examples for carrying out the method set forth below. Brief description of the drawings

Fig. 1 shows a schematic overview of an embodiment of a system according to the invention;

Fig. 2 shows a schematic overview of another embodiment of a system according to the invention;

Fig. 3 shows a schematic overview of a third embodiment of a system according to the invention;

Fig. 4 shows a schematic overview of a fourth embodiment of a sys- tern according to the invention;

Fig. 5 shows a perspective view of a tray forming part of a system in an embodiment of the invention;

Figs 6a and 6b show a side view and a front view, respectively, of a trolley forming part of a system in an embodiment of the invention;

Fig. 7 shows a perspective view of a filling station forming part of a system in an embodiment of the invention;

Fig. 8 shows a cross-sectional principle view of a freeze dryer unit forming part of a system in an embodiment of the invention;

Fig. 9 shows a perspective view of a freeze storage forming part of a system in an embodiment of the invention; and

Fig. 10 shows a perspective view of cleaning and sterilizing unit forming part of a system in an embodiment of the invention.

Detailed description of the invention and of preferred embodiments

Referring first to Fig. 1 , in which an embodiment of a system for carrying out inline sterile freeze drying of a product is schematically shown, and to Figs 5 to 10 showing embodiments of the five main processing units of the system, the system comprises a filling station 1 , a freeze storage 2, a freeze dryer unit 3, an emptying station 4 and a cleaning and sterilizing unit 5.

The emptying station 4 has an inlet end 41 and an outlet end 42, and the filling station 1 likewise an inlet end 1 1 and an outlet end 12. The emptying station 4 may also be formed to comprise a docking station, and this also applies to the filling station. Suitable specific designs of such structures may readily be conceived by the person skilled in the art. The cleaning and sterilizing unit 5 is provided in line between the outlet end 42 of the emptying station 4 and the inlet end 1 1 of the filling station 1.

Reference numerals denoting the inlet end and outlet end, respectively, of individual units are only shown in Fig. 1 . It is clear that units of other drawing figures have respective inlet ends and outlet ends as well.

Not all elements are indicated in detail in the schematic flow charts of Figs 3 and 4, these Figures thus illustrating the principle underlying the inven- tion.

In the embodiment shown in Fig. 1 , the freeze dryer unit 3 has an inlet end 31 and an outlet end 32, the inlet end 31 being in connection with an outlet end 22 of the freeze storage 2, and the outlet end 32 being in connection with the inlet end 41 of the emptying station 4. The freeze dryer unit 3 is, in the embodiment shown, formed as the commercially available RAY™60.

Furthermore, the outlet end 22 of the freeze storage 2 is selectively connectable to the inlet end of the filling station 1 , such that trays 8 in trolleys present in the freeze storage 2 may be guided back to the filling station, rather than to the freeze dryer unit 3.

Alternatively, or additionally, a supplemental freeze storage 6 may be provided between the cleaning and sterilizing unit 5 and the filling station 1 , as shown in the embodiments in Figs 3 and 4.

Furthermore, a trolley storage 7 may be provided between the outlet end 42 of the emptying station 4 and the cleaning and sterilizing unit 5, as indicated in Fig. 4.

In the embodiments shown in Figs 1 to 4, the cleaning and sterilizing unit 5 has an inlet end 51 and an outlet end 52. The inlet end 51 of the cleaning and sterilizing unit 5 is in connection with the outlet end 42 of the emptying station 4. In the alternative embodiment of Fig. 4, the inlet end of the cleaning and sterilizing unit 5 is in connection with outlet end of the trolley storage 7. The outlet end 52 of the cleaning and sterilizing unit 5 is in connection with the inlet end 1 1 of the filling station 1 . Alternatively, the outlet end 52 of the cleaning and sterilizing unit 5 is in connection with the inlet end of the supplemental freeze storage 6 as in the embodiments of Figs 3 and 4.

In all of the embodiments of Figs 1 to 4, a pass-through section is de- fined between a first line a and a second line b extending on either side of the freeze dryer unit 3 and the cleaning and sterilizing unit 5, a filling section is defined between the second line b and a third line c, and an emptying section is defined between the first line a and a fourth line d. The lines a-d are intended for defining the sections and should thus not be regarded as for in- stance physical demarcation lines.

The pass-through section acts as a sluice or lock, with lock gates at either end, and may thus be provided as a sterile section, as one lock gate at the time only is open. In the embodiment shown, this applies both to the freeze dryer unit 3 and to the cleaning and sterilizing unit 5. In order to in- crease the degree of sterility even further and achieve further protection, it is conceivable to provide an embodiment as shown in Fig. 2, in which the pass- through section, the filling section and the emptying section are located in a clean-room 10. This can for example be an ISO class 7 room.

According to the invention a method of providing inline sterile freeze drying of a product containing solid matter and a solvent, such as water, in a plurality of trays accommodated in at least one trolley, is devised and comprises the steps of:

i. filling the product into the plurality of trays in a filling station, ii. reducing the temperature of the product,

iii. bringing the product to a pressure and a temperature below the triple point of the solvent in a freeze dryer unit,

iv. maintaining the under pressure and thereby provide a freeze dried product by removing the solvent as vapour in the freeze dryer unit,

v. bringing the freeze dried product to a temperature and pressure above the triple point,

vi. emptying the product from the plurality of trays,

vii. sterilizing the at least one trolley with the plurality of trays, and viii. bringing the at least one trolley with the plurality of trays to the filling station.

In the system of the embodiments shown and described in the above, steps iii. and iv. are carried out in the freeze dryer unit 3. Step vii. is carried out in a cleaning and sterilizing unit 5 in the embodiment shown.

The at least one trolley with the plurality of trays may be cooled before step i. as represented in Fig. 3 and in the selective route of Figs 1 and 2. This may take place either in the freeze storage 2, if the trolleys with trays have passed the filling station 1 via route 91 without filling product into the trays, following which the trolleys with trays are selectively passed to the inlet end 1 1 of the filling station 1 via route 92, rather than to the inlet end 31 of the freeze dryer unit 3, or in the supplemental freeze storage 6.

In any event, following step i., the trolley or trolleys with trays is/are brought to a freeze storage after step i. In the embodiment of the system shown and described, the freeze storage is the freeze storage 2.

It is advantageous for sanitary reasons that the filling station is sterilized before step i. at suitable intervals. This needs not necessarily take place after every run-through, but will typically follow a pre-defined cleaning and sterilizing regimen, or when changing from processing one product to an- other.

In a corresponding manner, it may be desirable to sterilize the freeze dryer unit 3 before step iii. or iv., and likewise, the freeze storage 2 and/or the supplemental freeze storage 6 may be sterilized before step i.

In the embodiment of the system shown in Fig. 2, the additional step of providing steps i. to viii. in a clean-room is present.

The freeze drying may take place at any suitable pressure, and will typically lie in the interval 0.1 - 0.25 mbar, preferably 0.1 - 0.2 mbar.

The speed of the process depends on the product and other conditions. Typically, the freeze drying takes place at a mean sublimation rate equal to or above 0.5 kg/m ² /h.

A more detailed description of the method of processing the product in the individual operational units will follow below: Prior to the start of the process, a plurality of freeze drying trays 8 are positioned in a respective trolley 9. The system typically comprises a number of such trolleys which during operation and transport are running on an overhead rail system (not shown), in a manner known per se. Each tray 8 has a main portion 83 which may be flat or finned, in the latter case to promote drying, and a track portion 84 at two opposing sides of the tray 8. Some typical examples of tray dimensions are 800 x 1 100 mm or 550 x 720 mm, both of height 40-50 mm. The trays 8 are accommodated in the trolley 9 on longitudinally extending rods or fingers 94 fastened to a frame 93, which is further- more provided with roller means 95 for rolling engagement with the overhead rail system.

In the embodiments shown in Figs 1 and 2, the trays 8 in the trolley or trolleys 9 are stored inside the freeze storage 2 to be cooled to less than -40°C to avoid product melting during the subsequent loading of the product into the trays 8.

Once the trays 8 are cold, the trays 8 are pulled out of the trolleys 9, possibly rotated to have the open side up and filled with product in the filling station 1 moved one at the time into a trolley 9 in the filling station 1 shown in Fig. 7. This process may take place fully automatically.

Once a tray 8 is full to the desired degree, the tray 8 is pushed back into the trolley 9 and the tray 8 is lifted a step up, hereby allowing the next tray 8 to be filled. When all the trays 8 are full, the trays 8 accommodated in the trolley 9 is pushed back into the freeze storage 2 and stored at below at a suitable temperature, typically -40°C.

While the trays 8 in the trolley or trolleys 9 are in the freeze storage

2, the freeze dryer unit 3 is being prepared for the next batch. This involves a CIP and sterilization procedure and finally a drying and cooling of the cabinet of the freeze dryer unit 3 to about room temperature.

Once the freeze dryer unit 3 is sterile and cool, the door of the freeze storage 2 at the outlet end 22 is opened and the trays 8 on the trolley or trolleys 9 are quickly moved from the freeze storage 2 to the freeze dryer unit 3 through the inlet gate or door at the inlet end 31 thereof. Product temperature probes are connected and the freeze drying chamber of the freeze dryer unit 3 is evacuated to the freeze drying pressure, typically around 0.3 mbar but may be as low as 0.1 mbar. This whole operation takes less than 15 minutes.

The freeze drying of the product is then conducted according to the receipt selected in the control system for temperatures and pressures during the drying, and the data is logged. The vapors from the freeze drying are collected on the vapor traps inside the chamber and the vapor traps are automatically de-iced during the freeze drying as part of the process to maintain low vacuum and reduce the energy consumption.

Once the drying cycle is completed, the program will automatically go to standby mode, where the vacuum is maintained and the heating plates are cooled, until the process stop is selected and the vacuum is broken (e.g. with nitrogen or sterile air) through a sterile filter.

Once vacuum is broken, the lock or door at the outlet end 32 of the freeze dryer unit 3 is opened and the trays 8 in the trolley or trolleys 9 are quickly removed through the door. The door is closed again, so that the sterilizing cycle can start immediately.

The trays 8 in the trolley or trolleys 9 with dry product are moved one at the time into the tray emptying station 4.

The trays 8 are pulled out of the trolleys 9, emptied by sucking the product from the trays through a cyclone to a storage container.

Once emptied the trays 8 are rotated to have the bottom up for cleaning.

When all trays 8 in a trolley 9 are empty, the trays 8 in the trolley or trolleys 9 are pushed into the cleaning and sterilizing unit 5 for automated sterilization.

While the trays 8 are being emptied, the cabinet door at the outlet end 32 of the freeze dryer unit 3 is closed and the CIP/sterilization of the cabinet, heating plates, condensers and de-icing vessel can be started. The vari- ous steps of the CIP are then controlled automatically and followed by Sterili- zation-ln-Place (SIP) with steam at 121 °C. Once the CIP/SIP is concluded, the cabinet of the freeze dryer unit 3 is evacuated to 50 mbar for drying and cooling of the cabinet before the next batch is loaded.

The trays 8 and trolleys 9 in the cleaning and sterilizing unit 5 undergo the same CIP and SIP process where each tray 8 is cleaned by a number of movable spray nozzles ensuring that all parts of the tray and the also the sliding surfaces are cleaned thoroughly before the cabinet is pressurized and heated to 121 °C for sterilizing. The drying process is again conducted under vacuum and after a short tempering time at room temperature the trays and trolleys are ready to be loaded into the freeze storage for cooling of the trays and trolleys.

The freeze storage 2, and the optional supplemental freeze storage

6, are kept cold by circulating refrigerant in the tubular shell and the special fully welded smooth design makes is possible to clean and/or sterilize the storage between the batches without degradation of the insulation as there are no cracks where cleaning fluid may remain and create damage by expansion when frozen again. The cleaning can be executed, e.g. via retractable nozzles. However, as the product is not in direct contact with the storage interior, such cleaning and sterilization may be performed only after a number of batches have passed.

Another benefit of the system is that there is no manual lifting of the trays 8 since they are always supported either in the trolleys 9 or in the emptying station 4 or the filling station 1 . This minimal and semi-automatic handling lives up to the European standards on manual worker safety and recommendations.

Through the process the freeze drying trays 8 and trolleys 9 move through each of these steps and once they have completed a full cycle there will be full integrity and traceability between the batches. The equipment is guaranteed to fulfil the required cleaning and sterilization specifications.

The capacity of the system depends on the number of modules in each of the main processing units, and of the number of trolleys that may be processed at the same time.

In presently preferred embodiments, the cleaning and sterilizing unit 5 is adapted to accommodate one to six trolleys 9, preferably two to four trol- leys. In the embodiments of Figs 1 and 2, it is indicated that two trolleys are accommodated.

The freeze dryer unit 3 is adapted to accommodate one to six trolleys 9, preferably two to four trolleys.

The freeze storage 2 is adapted to accommodate one to six trolleys

9, preferably two to four trolleys. Here four trolleys.

Use of the method may in principle be applied to any suitable product, but in particular for freeze drying a product chosen from the selection: probiotic bacteria, lactic bacteria, whey derivatives, yeast bacteria, bacterial cultures.

Example

In one example, a product containing Lactobacillus acidophilus was freeze dried at 0.2 mbar in a batch size of 1000 kg with a dry-matter content of 20% by use of the method, in a system as shown in Fig. 1. The tray area used in the inventive process example was 55 m ² meaning that the average sublimation rate was 0.77 kg/m ² /h. The results in comparison with prior art processes are shown in Table 1 below.

Table 1

; Prior art process

Prior art process without external Invention process

; freezing

Duration Duration Duration

Preparation

Tray cooling before loading ; 120 minutes Part of drying 120 minutes

Tray filling ; 180 minutes Part of drying 90 minutes

Drying

Coding of the heating plates to -50°C ; 60 minutes 60 minutes Not needed

Loading of product into the freeze dryer :60-120 minutes 120-180 minutes 15 minutes

Freezing of procUct Net needed 300 minutes Not needed

Evacuation of chamber : 10 minutes 10 minutes 10 minutes

Ramping cf heating s xrce to sublimation temperature : 240 minutes 240 minutes 30 minutes

Freeze crying 2200 - 3600 minutes 4000-5000 minutes 960 -1200 minutes

Vacuum breaking : 15 minutes 15 minutes 15 minutes

Uhoadng of cabinet :60-120 minutes 60-120 minutes 15 minutes

De-icing : 60 minutes 60 minutes Continuous

Cleaning in Race of cabinet and condenser 90 minutes 90 minutes 90 minutes

Sterilizing in place of cabinet and condenser 120 minutes 120 minutes 120 minutes

Post processing

Emptying 90 minutes 90 minutes 90 minutes

Vest ng of trays 180 minutes 180 minutes 60 minutes

Sterilising of trays : 180-300 minutes 180-300 minutes 60 minutes

Coding of trays to room temperature 120 minutes 120 minutes Included in sterilizing

Average turnover time 72 hours; 96 hours 24 hours

Calculated average sublimation [kg h] 17,0 kg/h 11,1 kg/h 42,1 kg/h

The invention should not be regarded as being limited to the embodiments shown and described in the above. Several modifications and combinations are conceivable within the scope of the appended claims. The invention may advantageously be used in the dairy, food, chemical, agro- chemical, biotechnology, pharmaceutical and healthcare industries whenever fast and/or sterile production is needed.