EP3429546A1

EP3429546A1 - Method for the synthesis of a medical preparation

Info

Publication number: EP3429546A1
Application number: EP17710921.2A
Authority: EP
Inventors: Martin Biehl; Michael Hock; Henrik SCHAAKE; Ulla Schöbel; Martin Bohm
Original assignee: Fresenius Kabi Deutschland GmbH
Current assignee: Fresenius Kabi Deutschland GmbH
Priority date: 2016-03-15
Filing date: 2017-03-15
Publication date: 2019-01-23
Anticipated expiration: 2037-03-15
Also published as: WO2017158032A1; US10966906B2; CN108778228A; EP4218709A1; US20190070074A1; PL3429546T3; ES2945413T3; EP3429546B1; CN108778228B

Abstract

The invention relates to a method and a system for synthesizing a medical preparation, a peristaltic pump being used for pumping liquid from a plurality of source containers. According to the invention, the individual metering steps are verified by a weighing process, even the metering of micro-amounts being verifiable.

Description

Process for the preparation of a medicinal preparation

Description Field of the invention

The invention relates to a method and a plant for producing a medical preparation. In particular, the invention relates to a method by which infusion bags and / or syringes are filled for parenteral nutrition, as well as an associated facility.

Background of the invention

Preparations for parenteral nutrition are produced for example in pharmacies or clinics patient-specific. These are mixtures of different Basic foods, trace elements and vitamins, possibly also together with a medicine, which are individually transferred into an infusion bag.

For this purpose, so-called TPN compounders (TPN = Total Parenteral Nutrition) are used. Practically known and marketed systems, such as the MultiComp® system from Fresenius, comprise a computer-controlled pump unit, by means of which the components of the composition from different source containers are transferred to a destination container located on a scale.

The safety requirements for producing such medical preparations are high. In particular, a high accuracy of the dosage of all components should be ensured. To check the dosage of the target container can be weighed.

The problem is that the medicinal preparations to be prepared comprise components with main constituents such as water, fat, sugar and amino acids, which are added in quite a large amount. In addition, there are components which include, for example, certain vitamins, minerals or a drug which must be supplied in a significantly smaller amount, in particular in the ml range. Such components are also referred to as micro quantities.

Object of the invention

The invention is the object of the invention to provide a method for producing a medicinal preparation, in which by means of a peristaltic pump accurate dosing of the individual components of a medical preparation is possible and in which a precise check of the dosage is possible.

Summary of the invention The object of the invention is achieved by a method for producing a medicinal preparation according to one of the independent claims.

Preferred embodiments and further developments of the invention can be found in the subject matter of the dependent claims, the description and the drawings.

The invention relates to a method for producing a medicinal preparation, in particular the invention relates to a method for producing a preparation for parenteral nutrition.

In this case, liquids are taken from a plurality of source containers and transferred with a peristaltic pump into a target container. The peristaltic pump is a positive displacement pump in which the medium to be delivered is forced through the hose by external mechanical deformation of a hose. For this purpose, the peristaltic pump preferably has a pump wheel with rollers, with which the hose is compressed.

The preparation of the medical preparation is automated, wherein the user of the system used for the process can enter the desired composition in the target container or this can select from a database with a plurality of recipes.

In each case, a defined amount of liquid is withdrawn from the individual source containers, hereinafter also referred to as "metering step." After completion of all metering steps provided for a target container, by definition a "filling process" is completed.

There may be ingredients that are not allowed to come in direct contact or in any particular order.

Typically, as stated at the outset, such a medicinal preparation consists of main components which are supplied in greater quantity, and so-called "micro amounts", which may in particular contain vitamins, minerals or pharmaceutical components. For transfer, a transfer set designed as a disposable component is preferably used, which comprises the tube which is inserted into the peristaltic pump. The transfer set also includes connection tubes for the source containers as well as a connection for the destination container. Furthermore, the transfer set preferably comprises a valve unit, by means of which the connections to the individual source containers can be opened and closed.

Preferably, only a single valve, which leads to a source container, is opened during each individual metering step. So it is always removed only one source container liquid.

In addition to the main components of the medicinal preparation and the micro quantities, each preparation contains a so-called universal liquid, also called "Universal Ingredient" (Ul) .This fluid may come into direct contact with any other ingredient without undesirable side effects and is used in every preparation Preferably, the universal fluid is mostly isotonic water According to the invention, the target container is weighed at preferably every single dosing step and thus the amount of transferred into the target container Checked liquid at every single dosing step.

Preferably, all dosing steps are checked by weighing the target container, ie also the dosing steps of micro quantities of less than 10 ml, preferably of less than 5 ml, more preferably of less than or equal to 3 ml.

The preferred embodiments of the invention described below relate to measures to increase the dosing accuracy and / or the accuracy in the review of the individual dosing steps.

The peristaltic pump used for the method has a region with a linear characteristic and a region with a non-linear characteristic of the pump power. An area with a linear characteristic is understood to mean the angular range of a pump wheel, in which the pump power, that is, the volume relative to the pump Angle of rotation of a pump wheel of the peristaltic pump, is constant. The volume delivered is proportional to the angle of rotation.

There is a suction-side linear area. This is the area in which a suction-side roll of the peristaltic pump is engaged with the hose and no roll re-engages the hose. In the suction-side linear region, the angle of rotation is proportional to the volume delivered on the intake side.

Furthermore, there is a pressure-side linear region, in which the angle of rotation is proportional to the volume delivered on the pressure side. The pressure-side role of the peristaltic pump is engaged with the hose and no role is out of engagement with the hose.

It is understood that the pressure-side linear region of the characteristic curve is out of phase with the suction-side linear region of the characteristic curve.

In a peristaltic pump, at certain phase angles, the rollers of the impeller go into engagement and out of engagement at other phase angles. At least one roller is engaged at any one time, the pump is never "open." A roller pump therefore theoretically has no slippage, ie no deviation between the angle of rotation and the delivered quantity.

When a roller is re-engaged, the volume of tubing inserted into the pump decreases, and as a roller disengages, the volume increases again. As a result, the pumping capacity, ie the volume delivered per rotation angle, is not constant. The pump "pulsates." This pulsation occurs on both the suction and discharge sides of the pump.

This non-linear characteristic both on the pressure and on the suction side of the peristaltic pump is detrimental to the dosing accuracy, which is particularly disadvantageous when both main components in quite large quantities and micro quantities are to be metered with a single peristaltic pump.

A review of each dosing step is improved according to an embodiment of the invention, even at micro quantities, that the amount of a Dosing step in the target container transferred liquid is calculated taking into account the pressure-side characteristic of the pump power of the peristaltic pump.

During or after each dosing step, the target container is weighed, thus checking the amount of each transferred liquid. For this check based on the weight of the target container according to this embodiment of the invention but not the calculated amount of the source container withdrawn amount of liquid used, but it is calculated taking into account the pressure-side characteristic of the peristaltic pump, which amount of liquid was transferred to the target container.

If this calculated quantity in the target container of transferred liquid coincides with the result of the weighing of the target container, the respective dosing step can be considered correct. On the other hand, if the results do not agree or lie outside a predetermined tolerance range, an error can be caused by the system, e.g. on a display.

Depending on the nature and significance of the difference between the calculated and weighed amount, the user of the system, for example by display on a display, be prompted to discard the target container and fill a new target container and / or to calibrate the system.

In conventional systems for the preparation of parenteral nutrition can be checked with an accurate load cell, although at the end of the filling, ie after completion of all dosing, whether the increase in weight of the target container coincides with the target amount of individual components to be dosed.

However, at least for micro quantities, a sufficiently accurate evaluation of each individual metering step is fundamentally not possible on account of the pressure-side non-linear characteristic curve.

On the other hand, by taking into account the pressure-side characteristic, in particular when metering in micro quantities, a check of the individual metering step can be carried out by weighing the target container even at micro-quantities. This increases the assurance that the composition of the medicinal preparation meets the requirements.

In a further development of the invention, the amount of liquid to be taken from the respective source container is used to calculate the required rotation of the pump wheel on the basis of the suction-side characteristic curve of the peristaltic pump.

About the rotation of the peristaltic pump, in particular about the angle and the number of revolutions of an impeller of the peristaltic pump, the amount of liquid taken from the respective source container can be calculated calculated at each dosing step. On the basis of the predetermined amount of liquid to be removed, the pump is thus controlled and the required angle of rotation is calculated for a dosing step. In the dosage and thus in the control of the peristaltic pump at each dosing is not assumed in this embodiment of the invention of a constant flow rate, but it is based on a previously determined and stored characteristic, the suction side existing fluctuation of the pump power is calculated, which improves the dosing accuracy.

According to a further embodiment of the invention, which also serves to increase the metering accuracy, the peristaltic pump for metering from at least one source container is brought into a position such that the entire metering from this source container takes place in a region with a linear characteristic.

This embodiment of the invention is based on the finding that the dosage of micro quantities is also possible with a peristaltic pump with high accuracy if during the entire metering step the peristaltic pump is moved exclusively in the region with a linear characteristic.

It is understood that for this purpose, the amount of liquid to be metered in this metering step must be so small that the entire liquid to be dispensed can be promoted in an angular range of the impeller of the peristaltic pump by this does not leave the linear range. In order to be able to determine the angle in which an impeller of the peristaltic pump is located, the peristaltic pump preferably comprises a rotary encoder.

Preferably, the peristaltic pump is brought into a position in which the suction-side characteristic of the peristaltic pump is linear. In the dosage of micro quantities, especially the amount of liquid taken from the source container is critical, and therefore, the linear region of the peristaltic pump present on the suction side is used in order to dose the withdrawn amount as precisely as possible. In order to bring the peristaltic pumps into the desired position, ie the region with a linear characteristic curve, liquid can be taken from a source container other than that from which the metering is to take place. In particular, to move the impeller, for example to the beginning of the suction-side linear region, as the source container, a swelling container having the above-described universal liquid (Ul) can be used. While the pump operates in the non-linear range, so medium is taken from the source container with universal fluid.

In the region of the linear characteristic, it is preferred to deliver a small amount with a volume of less than 10 ml, preferably less than 5 ml, particularly preferably less than or equal to 3 ml, during a metering step.

If the volume which can be conveyed in the linear region during a single metering step is insufficient, it is also provided according to an embodiment of the invention to remove liquid from a source container in a plurality of metering steps, the hose pump being moved to the beginning of a linear region between these individual metering steps ,

In the metering steps, in which the main components of the medical preparation are transferred and in which the metering accuracy plays a less important role, the peristaltic pump can be operated in a conventional manner, ie during the respective metering step, both the non-linear and the linear region of the suction and / or pressure-side characteristic of the peristaltic pump. According to a further embodiment of the invention, the sequence of different liquids in the inlet of the target container is taken into account in order to include the density of the liquids during the checking during weighing. This embodiment of the invention is based on the recognition that the accuracy of the check is increased at each dosing step by taking into account the density, ie the specific weight of the respective liquid transferred to the target container. In particular, in the dosage of micro quantities, it may be that after removal of a predetermined amount of liquid from a source container, the liquid does not arrive directly in the target container, but is initially in the transfer set, for example, in the tube inserted in the hose pump. The liquid that is in front of this liquid in the transfer set and that is now pressed into the target container may have a different density. Therefore, only the weight gain of the target container can not be used as a sufficiently accurate measure of the transferred amount.

In this calculation, theoretically, the inlet of the target container is subdivided into sections, each containing liquid of a different density.

Preferably, taking into account the pressure-side characteristic of the peristaltic pump, it is now possible to predict which liquid or liquids will be introduced into the target container during a metering step.

This principle is based on the consideration that all liquids taken from the source containers ultimately arrive in the target container. Since the volume of the distance from the source container or from the valve, from which the liquid of the respective source container flows into the valve unit, to the source container located on the balance is known, it can be calculated which liquid or which liquids arrives at a dosing in the target container or Arrive.

The volume is determined by the valve unit from the position of the respective valve of the source container, and the guided through the hose pump hose connecting the valve unit with the target container. When checking the respective metering step by weighing the target container is therefore not based on the density of the withdrawn at the respective metering liquid, but the density of the liquid or liquids, which are introduced into the target container. Due to the volume of the feed and the peristaltic pump, the density of the introduced liquid may differ at least at the beginning of the metering step.

It is understood that the liquids arranged in an inlet and / or in a hose of the peristaltic pump are not exactly separated from one another according to this calculation model, but rather that different liquids are mixed in the area of the boundary surface. However, it has been shown that these mixing effects can be neglected in general or in an approximation. When dosing micro quantities, it can also lead to occlusions that are difficult to detect on the system side. For example, if the hose leading from a source container to the peristaltic pump is clogged, the peristaltic pump will still deliver fluid to the target container at a small amount, especially less than 3 ml since the flexible tubing of the transfer set may contract. Now, if the valve is opened to another source container, then the tube relaxes by this sucks liquid from the other source container. Under certain circumstances, this effect may result in the total quantity checked by weighing the target container being correct at the end of all dosing steps, but a single micro amount may be in the wrong dosage or not at all.

In a further development of the invention, the delivery rate of the peristaltic pump is therefore checked by means of a flow sensor. Preferably, the flow sensor is arranged on the suction side. In particular, a flow sensor may be provided in which a hose of the transfer set is inserted.

Such flow sensors are known. It has been found that these are not suitable for accurately determining the flow rate even at very low flow rates. In the case of a blockage or in the case of a non-opening valve of the transfer set such a high deviation from a setpoint can be determined via the flow sensor, however, that it can be concluded that the flow rate to the current theoretical flow rate of the pump is not plausible.

The procedure can then be aborted and the user of the system informed about an error message.

In one embodiment of the invention, a bubble sensor (Bubble Detector) is used to check in an inlet in the target container that no bubbles are conveyed in the hose

This bubble sensor, which may for example be designed as an ultrasonic sensor, is preferably located on the pressure side to the peristaltic pump. It is in particular a sensor in which the tube of a transfer set can be inserted.

In the event of bubbles above a threshold, the procedure may also be stopped and the user informed of an error message.

In a preferred embodiment of the invention, the metering factor of the peristaltic pump is determined in an upstream calibration step by weighing a target container. The metering factor is the volume which is conveyed when delivering a certain liquid, in particular when pumping water, at a certain speed of the impeller and at a full pump revolution. The metering factor depends, among other things, on tolerances of the hose inserted into the pump. This metering factor can be calibrated during commissioning of the system when filling a target container in order to adapt the activation of the peristaltic pump to a newly used transfer set.

It is provided in particular that when commissioning the plant for producing the medical preparation, a first target container is used, which is subsequently discarded, a so-called "waste bag." This waste bag is connected by means of the transfer set and they become the ones venting all leading hoses leading tubes, each by a required amount of liquid is removed.

To determine the metering factor, liquid, preferably water, is conveyed into the waste bag, thereby determining the metering factor. After discarding the waste bag now this metering factor is used for the calculation of the pumped by the pump at further dosing steps amount.

It is understood that the metering factor is in turn to be set in relation to the above-described consideration of the non-linear region of the suction-side and pressure-side characteristic of the peristaltic pump.

Furthermore, the pumping capacity of a peristaltic pump depends inter alia on the medium to be delivered, in particular on the viscosity of the liquid to be delivered. This dependence can, as it is provided in one embodiment of the invention, also be taken into account in the calculation of the quantities delivered.

For water, a flow factor of 1, 0 can be used, for other media, such as glucose, this flow factor takes on higher values, for example values up to 1, 1. This can be taken into account in the calculation of the quantities produced, in particular the quantities of main components produced, by including the flow factor in the calculation of the volume delivered.

Another aspect of the invention relates to a method for producing a medical preparation, wherein a liquid is transferred from a plurality of source containers by means of a peristaltic pump in a target container.

According to the invention, during manufacture of the medical preparation, when a pump wheel of the peristaltic pump rotates at least one complete revolution, the metering factor of the peristaltic pump is calibrated.

The invention thus provides that the metering factor of the peristaltic pump is not only determined initially when the system is put into operation, but that, if possible, the metering factor is also checked during regular operation of the system, ie during the manufacture of medical preparations, and possibly new is calibrated. It is provided in particular that, in addition to an initial calibration by determining the metering factor, there are a plurality of, preferably at least three, further determinations of the metering factor during the duration of use of a transfer set. Preferably, this in-service calibration is performed when a sufficient amount of universal liquid or water is transferred to the target container since the flow factor of this general liquid is always 1.0 so that no error due to a different flow factor is included in the calibration. The calibration during operation is preferably carried out with delivery of the same liquid as was used to initially determine the metering factor using the waste bag.

Particularly preferably, the calibration is made during operation only when the transfer set is flushed with universal fluid, the inlet of the target container thus has no sections in which another liquid is.

Since only fluid with the same density and the same viscosity is pumped during the entire calibration process, a higher calibration accuracy is achieved.

The above-described method steps according to the invention can be implemented by means which are correspondingly designed or suitable for carrying out the described method steps. These facilities can be part of a system.

In the scope of the invention is therefore also a plant for producing a medicinal preparation, in particular a plant for the production of parenteral nutrition, comprising a peristaltic pump and a system for carrying out a method according to the invention described above.

The process according to the invention can be carried out in particular by means of the plant according to the invention. The system with the system according to the invention is in particular designed for carrying out the method according to the invention. Brief description of the drawings

The object of the invention will be explained below with reference to the drawings Fig. 1 to Fig. 1 1, using an exemplary embodiment.

Fig. 1 shows a perspective view of a plant for the preparation of a medicinal preparation, as used for the inventive method. Fig. 2 is a detail view of the peristaltic pump.

Referring to Fig. 3, the characteristic of a peristaltic pump will be explained with reference to an embodiment. 4a to 4c are detailed views of the valve unit of the plant for the preparation of a medical preparation together with hoses.

FIGS. 5a and 5b show, with reference to a flowchart, the method steps in an exemplary embodiment of the method according to the invention.

Fig. 6 is a detail view of the plant for preparing a medical preparation, in which flow sensor and bubble sensor can be seen.

Fig. 7 is a schematic representation of the inflow of the target container, on the basis of which the calculation of the amount transferred to the target container will be explained.

Fig. 8 is a flowchart for explaining the check of each metering step by weighing the target container. Fig. 9 is a flow chart for explaining the calculation of the weight of the liquid transferred to the target container.

Fig. 10 is a flow chart for explaining control of the bubble sensor. FIG. 11 is a flow chart to explain control of the flow sensor. FIG.

Detailed description of the drawings

Fig. 1 shows a plant 1 for the preparation of a medical preparation.

The plant 1 for the production of a medical preparation comprises a plurality of source containers 2, which are only partially shown in this view. In particular, in this illustration those source containers are not shown, which comprise the main components of the medicinal preparation, as well as the container which is filled with universal liquid. In particular, these containers can be remotely remote, e.g. be hung on a hook attached to a rail. Evident is designed as an infusion bag target container 3, which is arranged on a balance 4. Through the balance 4, the amount of liquid transferred to the target container 3 can be checked during operation of the system 1.

In order to take the system 1 into operation, a transfer set is used, which comprises a valve unit 5 and hoses 14, 15, with which the valve unit 5 is connected to the one with the target container 3 and the other with the source containers 2.

When preparing a medical preparation, a valve of the valve unit 5 is opened via the system 1 in each case during a dosing step, so that liquid can be pumped from exactly one source container 2 into the target container 3.

To promote the liquids, the plant 1 here has a single peristaltic pump 6, by means of which liquids from all the source containers 2 can be pumped into the target container 3.

The system 1 further has a display 7, which is designed for example as a touch screen, by means of which the user can program the system 1, and in particular can select a program by means of which a target container 3 is filled with a predetermined composition of components. The system includes an electronic control (not shown), via which the peristaltic pump 6 is controlled and which is connected to the balance 4.

Fig. 2 is a detail view of the peristaltic pump 6. The pump 6 is here preferably provided as a roller pump.

It can be seen that the peristaltic pump 6 has an impeller 8 with two rollers 9. The tube to be inserted is not shown in this view. It is understood that the method according to the invention can also be carried out with a peristaltic pump with a different number of rollers, in particular with a peristaltic pump comprising three rollers (not shown).

If a hose (not shown) is inserted into the hose pump 6, the hose pump has an inlet 10 and an outlet 11. In the position of the impeller 8 shown here, both rollers 9 are in engagement with the hose.

It is understood, however, that when the rollers 9 move from the outlet 1 1 to the inlet 10, these are partly out of engagement with the hose. This results in both the suction side, so on the side of the inlet 10, as well as the pressure side, ie on the side of the outlet 1 1, a non-linear characteristic of the pump power, the peristaltic pump 6 pulsates.

Preferably, the amount of the delivered liquid in a full revolution between 5 and 50 ml.

In order to be able to dose precisely micro quantities, ie quantities which are in the lower ml range, preferably the peristaltic pump 6 is moved by turning the impeller 8 into a position in which the respective micro quantity is completely metered in the at least suction side linear region of the peristaltic pump 6 can be.

For this purpose, the peristaltic pump comprises a rotary encoder (not shown).

In the illustrated here position of the impeller 8, a roller 9 is just past the inlet 10 and now in engagement with the inserted tube. It is advisable to bring the peristaltic pump 6 for metering a micro amount in the position shown here, in order then to be able to meter the micro amount completely in the region of the suction-side linear characteristic of the peristaltic pump 6. The pressure-side and suction-side characteristic is shown in FIG.

The phase angle p is divided into 1600 units, which are plotted on the x-axis. These 1600 steps represent one complete revolution of the pump. The differential flow, ie the volume delivered per rotation angle unit, for the peristaltic pump 6 is plotted on the y-axis.

The dashed curve represents the pressure-side differential flow and the dotted curve represents the suction-side differential flow.

It can be seen that the characteristic curves are constant over wide ranges, ie areas with a linear characteristic curve are present.

Each characteristic has however two break-ins. On the suction side these are the phase angles at which one of the two rollers is newly engaged (p = 700 and p = 1500). In these areas, the volume of the tube of the peristaltic pump in the vicinity of the suction-side connection is reduced. The suction power of the pump is reduced.

On the pressure side, the burglaries are in the areas where a roll goes out of engagement. The hose of the hose pump returns to its original shape. The hose increases its volume and the delivery rate of the pump is reduced on the pressure side.

For the exact dosage, in particular a micro amount, the funded volume of the suction side is relevant. All liquid that is removed in the respective dosing step the source container, finally reaches the target container. It is therefore crucial that in each dosing step, the correct volume is taken from the suction side. When dosing a so-called micro amount, according to one aspect of the invention, in a dosing step, liquid is now conveyed only in one of the two linear regions of the suction side of the pump. For this purpose, the peristaltic pump is preferably placed at the beginning of the next linear region of the suction side prior to the beginning of the metering step under pumps universal liquid. In this example, these positions are approximately at p = 50 and p = 850. In this way, micro quantities can be precisely dosed with a single peristaltic pump.

The suction-side characteristic of the peristaltic pump is used according to another aspect of the invention to more accurately calculate the amount of liquid taken from the source container.

Thus, even with dosing steps that take place in the non-linear region of the peristaltic pump, the suction-side characteristic of the peristaltic pump can be used to calculate the quantities of the withdrawn liquid.

It is therefore taken into account in the calculation that the suction-side flow rate of the peristaltic pump is not linear.

On the basis of the characteristic curve Ds, the phase angle p2 is determined, so that

the volume to be dispensed results. Where p1 is the position of the impeller at the beginning of the dosing step and p2 is the position after the dosing step. The size Vs is the volume to be taken from the source container.

The pressure-side characteristic curve of the pump can in turn be used to check in an improved way by weighing the target container, if the actually taken amount corresponds to the calculated quantity.

For this purpose, the volume of liquid entering the target container is calculated. Next, the mass of the. Based on the known density of the delivered liquid calculated incoming fluid. To determine the volume of liquid arriving in the target container, the characteristic Dd of the pressure side is used.

The characteristics preferably determined by empirical measurements may e.g. stored as approximate formulas or as a simple value table to calculate the suction and pressure side pumping power as a function of the phase angle. In particular, the characteristics can be determined by measurement and then approximated by an empirical formula. The calculations in the plant then take place using the empirical formula or a table of values.

FIG. 4a is a perspective view of the valve unit 5 used for the plant for manufacturing a medical preparation. FIG.

The valve unit 5 comprises a plurality of inlets 12, which are connected via hoses 15 with the source containers (2 in Fig. 1). By way of valves (not shown) integrated in the valve unit 5, a hose 15, by means of which fluid is withdrawn from a source container, can be selectively connected to a hose 14 which is arranged on the outlet 13 of the valve unit 5. The hose 14 further includes a portion which is inserted into the hose pump.

In Fig. 4b, the ends of the tubes 15 are shown for connection of the source container. Evident are the connections 22 for the source containers, which are formed in this exemplary embodiment as a Luer lock connection with a connected spike.

Fig. 4c shows the hose 14, which forms the outlet of the valve unit 5 and at the same time the inlet of the target container. You can see the connection 23 for the target container. The valve unit 5 shown here, together with the hoses 14, 15 and their terminals 22, 23, the transfer set, which is used for the operation of the system.

This transfer set is preferably designed as a disposable component and is replaced regularly. Due to this configuration, the come to transferring liquids on the way from the source container to the target container only with components of the transfer set in contact.

With reference to the flowchart according to FIGS. 5 a and 5 b, a method according to the invention for producing a medical preparation will be explained by means of an exemplary embodiment.

First, the transfer set described above is used to connect the source containers. Next, a so-called "waste bag" is inserted as a target container, that is, a container which is not intended to be used as intended for applying a medical preparation, but which is discarded after preparing the system.

The entire transfer set together with hoses is doing with universal fluid (Ul), z. As isotonic water, filled and each valve is opened so long that the tubes (15 in Fig. 4a, b), which lead to the source containers filled and bubble-free.

Then, the metering factor of the peristaltic pump can be determined by weighing the waste bag when pumping universal fluid. The changing due to particular tolerances of the hose used pumping power of the peristaltic pump is now calibrated by determining this metering factor.

The waste bag is then discarded and the first target container, which is to be filled with a medicinal preparation, can be connected.

In this embodiment, first a micro amount is to be dosed in a first dosing step. Therefore, in step 5. the impeller is spent in an area with suction side linear characteristic, wherein during the introduction of the impeller in this position initially universal fluid is conveyed.

Now a micro amount can be completely removed in the suction side linear region of the characteristic of the pump to the source container. Each individual dosing step, including the step of dosing a micro amount, is checked by weighing the target container.

In this case, the density of the liquid transferred into the target container is taken into account by calculating which liquid or which liquids are located in the feed of the target container during transfer of the micro amount in step 5 and are transferred into this.

Furthermore, when checking by weighing, taking into account the pressure-side characteristic of the peristaltic pump, it is possible to calculate as accurately as possible which volume was transferred to the target container during the respective metering step. This volume does not always match due to the phase-shifted characteristics of suction side and pressure side. Then, a main component of the medical preparation is metered taking into account the suction-side characteristic of the peristaltic pump. In contrast to the dosage of micro quantities, the hose pump is also operated in the non-linear range when dosing the main components. In the calculation of the source container withdrawn amount of the respective main component, the suction-side characteristic of the peristaltic pump but is taken into account in order to accurately predict the volume taken on the suction side can.

Also, the arithmetic check of the source container taken for a main component amount is made taking into account the density of the transferred into the target container liquid and taking into account the pressure-side characteristic of the peristaltic pump.

Both when dosing micro quantities and when dosing main constituents, a flow factor which is dependent on the type, in particular on the viscosity, of the pumped liquid is also a further factor in the calculation of the volume of the conveyed liquid. Water is assigned a flow factor of 1.0, with viscous components such as glucose solutions, the flow factor changes significantly. It has been shown that a general consideration of the flow factor is sufficient in dependence on the liquid taken out in each dosing step, since a viscosity-related influence of the pumping capacity is present primarily due to the constriction present at the connection of the source container (eg spike).

The weight added to the target container at a dosing step can be calculated in detail as follows:

Vs is the volume to be dosed during a dosing step. This corresponds to the volume of the suction side to which a source container is connected. p1 is the position of the impeller before the metering step, in particular the end position of a previous metering step or the beginning of the linear range in which the impeller has been previously rotated. p2 is the calculated position of the impeller after the dosing step, ie the result of the calculation for the rotational angle of the pump in the dosing step.

F is the flow factor, ie the correction factor for the respective viscosity of the medium.

Ds (p) is the characteristic of the suction side (constant) and p is the phase of the pump impeller.

The phases p1 and p2 can differ by several revolutions.

The flow factor F is thus a correction for an additional slip of the pump by water increased viscosity. The volume to be dispensed is in particular set higher by a factor of F than in the case of water.

Almost all media used for medicinal preparation have the same or higher viscosity than water. Media with a lower viscosity are very rare. Consequently, as a rule, F> = 1. The volume expected on the pressure side, by means of which the weight of the quantity of liquid delivered to the target container during a dosing step is calculated, is:

This calculated weight is used to check the respective dosing step via weighing.

Vd is the volume expected on the pressure side, ie the volume of liquid which is conveyed in the dosing step into the target container located on the balance.

Dd (p) is characteristic of the pressure side (constant). The flow factor F is not included in the calculation of the volume delivered on the pressure side, since the "slip of the pump is not conveyed. The expected mass increase G on the balance is then:

G = Vd * p with the density P of the pumped medium.

P is therefore the specific weight of the liquid transferred to the target container during a dosing step, ie, first of all the liquid already present in the feed of the target container. If several different liquids are transferred to the target container during a dosing step, the specific weight of the liquids is set in relation to their quantity. As a next step, additional micro quantities or further main constituents are fed in further metering steps. Steps 5 to 9 can therefore be repeated until all the desired components are in the target container.

It is understood that the steps 5. to 7., So the dosage of a micro amount, as well as the steps 8 and 9, so the dosage of a main component, are also interchangeable, so can be made in different order. At the end of each filling operation, the transfer set is rinsed with universal liquid and, if appropriate, the desired residual quantity of universal liquid is fed to the target container.

It is envisaged, for example, to use this rinsing phase, in which the impeller of the peristaltic pump rotates by more than one full revolution, in order to redetermine the dosing factor of the peristaltic pump during operation by weighing the target container. The dosing factor can thus be recalibrated during operation. This can change, for example, by the fact that the elasticity and shape of the tube inserted into the peristaltic pump changes.

After completion of all dosing steps and rinsing of the transfer set, the target container can be removed and a new target container can be connected.

It is understood that all steps shown here except for the connection of the source and target containers and the starting of the system preferably run automatically. FIG. 6 is a further detailed illustration of FIG. 1. FIG. To recognize is in turn the target container 3. Further to recognize is a valve unit. 5

The hose, not shown here, which connects the valve unit 5 with the target container 3, and which is inserted in particular into the peristaltic pump, is first inserted into a flow sensor 16.

About the flow sensor 16, the suction-side flow in the hose is measured and the flow rate of the peristaltic pump can be checked for plausibility. If, for example, there is a blockage in the area of the valve unit or at the connection of a source container, the suction-side flow rate will decrease in such a way that an error can be detected by means of the flow sensor 16. In particular, when dosing a micro amount, the tube will first contract also in the area of the flow sensor 16, with the result that the detected flow can be reduced and a blockage can be concluded. The electronic control can then generate an error message and be displayed to the user. The flow sensor 16 is preferably designed as an ultrasonic sensor. In particular, at low flow rates, such a sensor is generally not accurate enough to be able to determine the amount of the suction side funded fluid alone sufficiently accurate via the flow sensor.

Preferably, therefore, the flow sensor is used solely to control such that when exceeding a threshold value of the difference of calculated capacity of the peristaltic pump and resulting calculated flow rate against the flow rate determined by the flow sensor, an error is assumed.

On the pressure side, the tube is inserted into a bubble sensor 17. It is an ultrasonic sensor that detects bubbles and shuts off the system above a certain threshold and indicates an error to the user.

FIG. 7 is a schematic illustration of the hose 14 connecting the valve unit 5 to the target tank 3. In this embodiment, three series-connected valve units are shown, but this has no influence on the basic principle. The three valve units 5 shown here can just as well be combined to form a single valve unit.

By means of the valve unit 5, the feed to a source container is opened at each dosing step, so that liquid from the source container via the respective valve of the valve unit can first enter the valve unit and then into the hose 14.

The tube 14 and the collecting channels 22 of the valve units 5 form a volume into which the liquid taken from the respective source containers is first transferred. For the calculation of the weight of the liquid, which arrives at a metering step in the target container 3, therefore, the density of the liquid withdrawn during the respective metering step is not taken as the basis. Rather, the tube 14 and the collecting channels 24 of the valve units 5 are considered such that different liquids, namely a first liquid 19, a second liquid 20 and a third liquid 21 in different sections of the tube 14 and / or the subsequent collecting channel 24 are. If, for example, a micro amount is metered in, the specific weight of the first liquid 19 is initially taken as the basis. This theoretical "material stack" can improve the accuracy of the verification. In particular, it is possible to check and evaluate each individual dosing step.

Fig. 8 is a flowchart for explaining the check of each metering step by weighing the target container.

At each dosing step, the weight transferred to the target container is calculated as a target weight. This is done, as described above, based on the pressure-side characteristic of the peristaltic pump and the specific gravity of the liquid transferred to the target container.

If the weight determined by the weighing deviates from the calculated weight during weighing of the target container such that a first limit range is not adhered to, which would impair the quality of the medical preparation or which suggests an error, the filling process is aborted and an error message is issued , The user can then correct the error if necessary, insert a waste bag and recalibrate the systems.

Otherwise the filling process will continue.

If the weight determined by means of the weighing is not within a second narrower limit range, which although e.g. indicates inadequate calibration of the plant, but which suggests such a small deviation of the metered amount that it does not affect the quality of the medical preparation, the filling process is continued.

After completing the filling process, however, the user of the system receives a message that the system must be calibrated. Otherwise, the next target container can be inserted after completing the filling process. Fig. 9 is a flowchart for explaining the calculation of the target weight in a metering step. The volume of the liquid introduced is calculated on the basis of the pressure-side characteristic of the peristaltic pump.

It is then determined which liquid or which liquids have entered the target container in the metering step. This is done as described with reference to FIG. 7.

The specific weight of the transferred liquid or liquids can then be used to calculate the target weight. This target weight serves to determine the limit values mentioned in FIG. 8. For example, a first limit range could be defined as a deviation of over 10% and a second limit range as a deviation above 5%.

It is understood that the boundary regions can also be varied depending on the liquid withdrawn in a dosing step, since there are components in which deviations in the amount are more or less critical to the quality of the medicinal preparation.

Fig. 10 is a flow chart for explaining control of the bubble sensor.

About the arranged after the hose pump bubble sensor is continuously monitored, the amount of bubbles in the transferred liquid. In this embodiment, two border areas are provided.

If the amount of bubbles is in a limit range which is unacceptable for the quality of the product produced, the filling process is interrupted and an error message is issued. If a second, narrower limit range is not adhered to, the filling process can continue and the target container can be used as intended, but when the filling process is completed an error message appears indicating that the system must be bled.

Otherwise, the next target container can be inserted after completing the filling process

FIG. 11 is a flow chart to explain control of the flow sensor. FIG.

The flow rate is calculated continuously, preferably on the basis of the suction-side characteristic of the peristaltic pump. In parallel, the flow rate is measured with a flow sensor located upstream of the peristaltic pump.

Measured and calculated flow rates are compared. If there is a deviation above a threshold, in this example 20%, an error (e.g., occlusion) is closed and the filling process is aborted.

An error message informs the user. In order to better localize the error, it is preferable for any error message to indicate to the user the source container (e.g., via a number on a screen) from which liquid was withdrawn upon fault entry.

By the invention, the accuracy in the preparation of a medical preparation using a peristaltic pump and at the same time the security against dosing errors can be improved. LIST OF REFERENCE NUMBERS

1 plant

2 source containers

3 target containers

4 scales

5 valve unit

6 peristaltic pump

7 display

8 impeller

9 roll

10 inlet

1 1 outlet

12 inlet

13 process

14 hose

15 hose

6 flow sensor

17 bubble sensor

18 connection

19 first liquid

20 second liquid

21 third liquid

22 connection

23 connection

24 collection channel

Claims

claims

1 . A method for producing a medical preparation, in particular a parenteral nutrition, wherein from a plurality of source containers (2) liquids are transferred with a peristaltic pump (6) in a target container (3), wherein the target container (3) is weighed in the individual dosing steps and the quantity of liquid transferred to the target container (3) is checked at the individual metering steps.

2. A method for producing a medicinal preparation according to the preceding claim, characterized in that the amount of liquid transferred to the target container (3) is checked at all metering steps.

3. A method for producing a medicinal preparation according to any one of the preceding claims, characterized in that the amount of liquid transferred to a dosing step in the target container (3) is calculated taking into account a pressure-side characteristic of the pump power of the peristaltic pump (6), wherein the calculated Amount compared with the amount determined by the weighing of the target container (3).

4. A method for producing a medical preparation according to any one of the preceding claims, characterized in that the source container (2) removed amount of liquid is calculated taking into account a suction-side characteristic of the pump power of the peristaltic pump (6), wherein the calculated amount with the by the weighing of the target container (3) determined amount is compared.

5. A method for producing a medical preparation according to any one of the preceding claims, characterized in that the sequence of different liquids in an inlet of the target container (3) is taken into account in order to calculate the specific mass of the liquid during the check during weighing.

6. A method for producing a medical preparation according to one of the preceding claims, characterized in that in at least one Dosing a small amount of less than 10 ml, preferably less than 5 ml, more preferably less than or equal to 3 ml is transferred.

7. A method for producing a medical preparation according to one of the preceding claims, characterized in that the peristaltic pump (6) has at least one area with linear and a range with non-linear characteristic of the pump power, wherein for dosing from at least one source container, the peristaltic pump (6 ) is brought into a position so that the entire dosage from the source container (2) takes place in the region with the linear characteristic.

8. A method for producing a medical preparation according to any one of the preceding claims, characterized in that the peristaltic pump (6) is brought into a position in which the suction-side characteristic of the peristaltic pump (6) is linear.

9. A method for producing a medical preparation according to any one of the preceding claims, characterized in that, in order to bring the peristaltic pump (6) in the desired position with a linear characteristic, liquid is removed from another source container, as is to be dosed from the in particular from a source container with universal liquid or water.

10. A process for the preparation of a medicinal preparation according to one of the preceding claims, characterized in that in the region of the linear

Characteristic small amount with a volume of less than 10 ml, preferably less than 3 ml is promoted.

1 1. Method for producing a medical preparation according to one of the preceding claims, characterized in that with a flow sensor

(16) the delivery rate of the peristaltic pump (6) is checked and / or that it is checked with a bubble sensor (17) that there are no bubbles in an inlet to the target container (3).

12. A process for the preparation of a medicinal preparation according to one of

preceding claims, characterized in that the dosing of the Peristaltic pump (6) is determined in an upstream calibration step by weighing a target container (3).

13. A method for producing a medical preparation according to any one of the preceding claims, characterized in that for transferring the

Liquids from the source containers (2) in the target container (3) a transfer set is used, which comprises a valve unit (5), a hose (14) which can be inserted into the peristaltic pump, and a plurality of hoses (15) for connection the source container (2) comprises.

14. A method for producing a medical preparation, in particular according to one of the preceding claims, wherein from a plurality of source containers (2) liquids are transferred by means of a peristaltic pump (6) in a target container (3), wherein at a dosing step from a source container, at which a pump wheel (8) of the peristaltic pump (6) rotates at least one complete revolution, the metering factor of the pump is calibrated.

15. Plant for the preparation of a medicinal preparation, in particular plant for the production of parenteral nutrition, comprising a peristaltic pump and a

System for carrying out a method according to one of the preceding claims.