EP3429546B1 - Method for preparing a medical preparation - Google Patents

Description

field of invention

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

Background of the Invention

Preparations for parenteral nutrition are manufactured specifically for the patient, for example in pharmacies or clinics. These are mixtures of different

Basic nutrients, trace elements and vitamins, possibly together with a drug, which are transferred individually into an infusion bag.

So-called TPN compounders (TPN = Total Parenteral Nutrition) are used for this. Systems known from practice and available on the market, such as the ^MultiComp® system from Fresenius, include a computer-controlled pump unit, by means of which the components of the composition are transferred from various source containers to a target container on a scale.

The safety requirements when producing such medicinal preparations are high. In particular, a high degree of accuracy in the dosing of all components should be ensured.

The target container can be weighed to check the dosage. A compounding system in which the target container is weighed is in the document U.S. 5,697,407 described.

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

object of the invention

In contrast, the invention is based on the object of providing a method for producing a medicinal preparation in which precise dosing of the individual components of a medicinal preparation is made possible by means of a peristaltic pump and in which precise monitoring of the dosage is also 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 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.

Liquids are taken from a number of source containers and transferred to a target container using a peristaltic pump. The peristaltic pump is a displacement pump in which the medium to be pumped is pushed through the hose by external mechanical deformation of a hose. For this purpose, the hose pump preferably has a pump wheel with rollers, with which the hose is compressed.

The production of the medicinal preparation is automated, with the user of the system used for the method being able to enter the composition desired in the target container or to select it from a database with a plurality of recipes.

A defined quantity of liquid is removed from the individual source containers in a predetermined sequence, also referred to below as the "dosing step". After completion of all dosing steps provided for a target container, a "filling process" is finished by definition.

There may be components that are not allowed to come into direct contact or only come into contact with each other in a certain order.

As stated at the outset, such a medicinal preparation typically consists of main components that are supplied in relatively large amounts, and so-called "micro-amounts" that can contain, in particular, vitamins, minerals or drug components.

For the transfer, a transfer set designed as a disposable component is preferably used, which includes the hose that is inserted into the hose pump. The transfer set also includes connection hoses for the source container and a connection for the target container. Furthermore, the transfer set preferably includes 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 open during each individual dosing step. Liquid is therefore only ever taken from one source container.

In addition to the main components of the medicinal preparation and the micro-amounts, there is a so-called universal liquid, also known as a "universal ingredient" (UI), in every preparation. This liquid is allowed to come in direct contact with any other ingredient without undesired side effect and is used in any preparation in a relatively large amount, especially to make up the preparation to the desired total amount. Preferably, the universal liquid is mostly isotonic water.

According to the invention, the target container is preferably weighed at each individual dosing step and the quantity of liquid transferred into the target container is thus checked at each individual dosing step.

All dosing steps are preferably checked by weighing the target container, ie also the dosing steps of micro-amounts of less than 10 ml, preferably less than 5 ml, particularly preferably less than or equal to 3 ml.

The preferred embodiments of the invention described below relate to measures for increasing the dosing accuracy and/or the accuracy when checking the individual dosing steps.

The peristaltic pump used for the method has a range with a linear characteristic and a range with a non-linear characteristic of the pump output.

Under an area with a linear characteristic, the angular range of an impeller is understood in which the pump capacity, i.e. the volume compared to the Angle of rotation of an impeller of the peristaltic pump is constant. The conveyed volume is proportional to the angle of rotation.

There is a linear area on the intake side. This is the area where a suction-side roller of the peristaltic pump engages the hose and no roller re-engages the hose. In the linear range on the suction side, the angle of rotation is proportional to the volume conveyed on the suction side.

There is also a linear range on the pressure side, in which the angle of rotation is proportional to the volume conveyed on the pressure side. The pressure-side roller of the peristaltic pump is engaged with the hose and no roller disengages from the hose.

It goes without saying that the pressure-side linear range of the characteristic curve is phase-shifted with respect to the suction-side linear range of the characteristic curve.

In a peristaltic pump, the rollers of the impeller engage at certain phase angles and disengage at other phase angles. At least one roller is engaged at all times, the pump is never "open". Theoretically, a roller pump therefore has no slippage, i.e. no deviation between the angle of rotation and the quantity pumped.

When a role re-engages, the volume of tubing inserted into the pump decreases, when a role disengages, the volume increases again. As a result, the pump performance, i.e. the volume delivered per angle of rotation, 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 side and on the suction side of the peristaltic pump is disadvantageous for the dosing accuracy, which is particularly disadvantageous if both main components in quite large quantities and also micro quantities are to be dosed with a single peristaltic pump.

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

During or after each dosing step, the target container is weighed and the amount of liquid transferred is checked. According to this embodiment of the invention, this check based on the weight of the target container is not based on the calculated amount of liquid removed from the source container, but rather the amount of liquid transferred into the target container is calculated, taking into account the pressure-side characteristic of the peristaltic pump.

If this calculated amount of liquid transferred into the target container agrees with the result of the weighing of the target container, then the respective dosing step can be regarded as correct. If, on the other hand, the results do not match or if they are outside a specified tolerance range, an error can be shown on the system side, e.g. on a display.

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

In conventional systems for the preparation of parenteral nutrition, a precisely working load cell can be used at the end of the filling process, i.e. after all dosing steps have been completed, to check whether the increase in weight of the target container corresponds to the target quantity of the individual components to be dosed.

However, at least in the case of micro quantities, a sufficiently precise assessment of each individual dosing step is fundamentally not possible due to the non-linear characteristic curve on the pressure side.

On the other hand, by considering the pressure-side characteristic, particularly when dosing micro quantities, the individual dosing step can also be checked for micro quantities by weighing the target container.

This increases the certainty that the composition of the medicinal preparation corresponds to the specifications.

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

The amount of liquid removed from the respective source container can be determined in a calculated manner in each dosing step via the rotation of the peristaltic pump, in particular via the angle and the number of revolutions of a pump wheel of the peristaltic pump. Based on the specified amount of liquid to be removed, the pump is controlled and the required angle of rotation for a dosing step is calculated.

According to this embodiment of the invention, a constant delivery rate is not assumed during dosing and thus when controlling the peristaltic pump in each dosing step;

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

This embodiment of the invention is based on the knowledge that the dosing of micro quantities is also possible with a hose pump with high accuracy if the hose pump is moved exclusively in the area with a linear characteristic curve during the entire dosing step.

It goes without saying that the quantity of liquid to be metered in this metering step must be so small that the entire liquid to be metered can be conveyed in an angular range of the pump wheel of the peristaltic pump by not leaving the linear range.

In order to be able to determine the angle at which an impeller of the peristaltic pump is positioned, the peristaltic pump preferably includes a rotary encoder.

The peristaltic pump is preferably brought into a position in which the suction-side characteristic curve of the peristaltic pump is linear. When dosing micro-amounts, the amount of liquid taken from the source container is particularly important and the linear range of the peristaltic pump available on the suction side is therefore used to dose the amount taken off as precisely as possible.

In order to bring the peristaltic pumps into the desired position, i.e. the range with a linear characteristic curve, liquid can be taken from a different source container than the one from which dosing is to take place. In particular, a source container with the universal liquid (UI) described above can be used as the source container for moving the impeller, for example to the beginning of the suction-side linear range. While the pump is working in the non-linear range, medium is taken from the source container with universal liquid.

In the area of the linear characteristic curve, a very small amount with a volume of less than 10 ml, preferably less than 5 ml, particularly preferably less than or equal to 3 ml, is preferably delivered during a dosing step.

If the volume that can be conveyed in the linear range during a single dosing step is not sufficient, one embodiment of the invention also provides for liquid to be removed from a source container in several dosing steps, with the peristaltic pump being moved to the beginning of a linear range between these individual dosing steps .

In the dosing steps in which the main components of the medicinal preparation are transferred and in which the dosing accuracy plays a less important role, the peristaltic pump can be operated in a conventional manner, i.e. during the respective dosing step both the non-linear and the linear range of the suction and/or the pressure-side characteristic curve 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 in the check when weighing.

This embodiment of the invention is based on the finding that the accuracy of the check is increased for each dosing step by taking into account the density, ie the specific weight of the respective liquid transferred into the target container.

In particular when dosing micro quantities, it may be the case that after removing a specified quantity of liquid from a source container, the liquid does not reach the target container immediately, but is initially in the transfer set, for example in the hose inserted in the peristaltic pump. The liquid that is in front of this liquid in the transfer set and that is now pressed into the target container can have a different density. Therefore, the increase in weight of the target container alone cannot be used as a sufficiently accurate measure of the amount transferred.

From a theoretical point of view, this calculation divides the inlet of the target container into sections, each of which contains liquid with a different density.

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

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 route from the source container or from the valve, from which the liquid from the respective source container flows into the valve unit, to the source container on the scale is known, it can be calculated which liquid or which liquids arrives in the target container during a dosing step or arrive.

The volume is determined by the valve unit from the position of the respective valve of the source container, as well as the tubing routed through the peristaltic pump that connects the valve unit to the target container.

When checking the respective dosing step by weighing the target container, the density of the liquid removed in the respective dosing step is not used as a basis, but rather the density of the liquid or liquids that are introduced into the target container. The density of the liquid introduced can differ due to the volume of the feed and the peristaltic pump, at least at the beginning of the dosing step.

It goes without saying that the liquids arranged in an inlet and/or in a hose of the hose pump are not separated from one another exactly according to this calculation model, but different liquids mix in the area of the interface. However, it has been shown that these mixing effects can be neglected in general or as an approximation.

When dosing micro quantities, occlusions can also occur, which are difficult to detect on the plant side. If, for example, the tubing leading from a source container to the peristaltic pump is blocked, the peristaltic pump will still deliver liquid to the target container if the volume is small, especially if the volume is less than 3 ml, as the flexible tubes of the transfer set can contract. If the valve to another source container is then opened, the hose relaxes by sucking in liquid from the other source container. Under certain circumstances, this effect can mean that at the end of all dosing steps, the total quantity checked by weighing the target container is correct, but a single micro quantity is completely wrong or not available at all.

In a further development of the invention, the flow rate of the peristaltic pump is therefore checked by means of a flow sensor. The flow sensor is preferably arranged on the suction side. In particular, a flow sensor can be provided, into which a tube of the transfer set is inserted.

Such flow sensors are known. However, it has been found that these are not suitable for precisely determining the flow rate even at very low flow rates.

In the event of a blockage or if the transfer set valve does not open, the flow sensor can detect such a high deviation from a setpoint that it can be concluded that the flow rate is not plausible in relation to the current theoretical delivery rate of the pump.

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

In a development of the invention, a bubble sensor (bubble detector) is used to check in an inlet in the target container that no bubbles are being conveyed in the hose

This bubble sensor, which can be designed as an ultrasonic sensor, for example, is preferably located on the pressure side of the hose pump. In particular, it is a sensor into which the tubing of a transfer set can be inserted.

In the event of the presence of bubbles above a threshold, the process can also be stopped and the user informed of an error message.

In a preferred embodiment of the invention, the dosing factor of the peristaltic pump is determined in a preceding calibration step by weighing a target container.

The dosing factor is the volume that is pumped when pumping a specific liquid, in particular when pumping water, at a specific speed of the impeller and at one full pump revolution. The dosing factor depends, among other things, on the tolerances of the hose inserted in the pump. This dosing factor can be calibrated when the system is started up when a target container is filled, in order to adapt the control of the peristaltic pump to a newly used transfer set.

In particular, it is provided that when the system is started up for the production of the medical preparation, a first target container is used, which is then discarded, a so-called "waste bag". This waste bag ("waste container") is connected using the transfer set and the to all hoses leading to the source containers are vented by removing the amount of liquid required for this purpose.

To determine the dosing factor, liquid, preferably water, is pumped into the waste bag and the dosing factor is determined in the process. After discarding the waste bag, this dosing factor is now used as a basis for calculating the quantity delivered by the pump in further dosing steps.

It goes without saying that the dosing factor is in turn to be set in relation to the above-described consideration of the non-linear range of the suction-side and pressure-side characteristic of the peristaltic pump.

Furthermore, the pump performance of a peristaltic pump also depends, among other things, on the medium to be pumped, in particular on the viscosity of the liquid to be pumped. As provided in one embodiment of the invention, this dependency can also be taken into account when calculating the conveyed quantities.

A flow factor of 1.0 can be used for water; for other media, such as glucose, for example, this flow factor assumes higher values, for example values of up to 1.1. This can be taken into account when calculating the conveyed quantities, in particular the conveyed quantities of main components, by including the flow factor in the calculation of the conveyed volume.

A further aspect of the invention relates to a method for producing a medicinal preparation, in which a liquid is transferred from a plurality of source containers into a target container by means of a hose pump.

According to the invention, the dosing factor of the hose pump is calibrated during the manufacture of the medicinal preparation when a pump wheel of the hose pump rotates at least one full revolution.

The invention therefore provides that the dosing factor of the peristaltic pump is not only determined initially when the system is started up, but that, if this is possible, the dosing factor is also checked and, if necessary, re-determined during regular operation of the system, i.e. when producing medicinal preparations is calibrated.

In particular, it is provided that, in addition to an initial calibration by determining the dosing factor, there are several, preferably at least three, further determinations of the dosing factor during the period of use of a transfer set.

Preferably, this on-line calibration is performed when a sufficient quantity of universal liquid or water is transferred to the target container, since the flow factor of this universal liquid is always 1.0, so that no flow factor variation error is introduced into the calibration. The calibration during operation is preferably carried out when the same liquid is pumped as was used to initially determine the dosing factor using the waste bag.

The calibration is particularly preferably only carried out during operation when the transfer set has been rinsed with a universal liquid, ie the inlet of the target container does not have any sections in which there is another liquid.

Since only liquid with the same density and the same viscosity is pumped during the entire calibration, greater accuracy is achieved during calibration.

The method steps according to the invention described above can be implemented by devices that are appropriately designed or suitable for carrying out the method steps described. These devices can be part of a system.

The scope of the invention therefore also includes a system for producing a medicinal preparation, in particular a system for producing parenteral food, comprising a peristaltic pump and a system for carrying out a method according to the invention described above.

The method according to the invention can be carried out in particular by means of the system according to the invention. The plant with the system according to the invention is designed in particular to carry out the method according to the invention.

Brief description of the drawings

• Fig. 1 zeigt eine perspektivische Ansicht einer Anlage zur Herstellung einer medizinischen Zubereitung, wie sie für das erfindungsgemäße Verfahren verwendet wird.
• Fig. 2 ist eine Detailansicht der Schlauchpumpe.
• Bezugnehmend auf Fig. 3 soll die Kennlinie einer Schlauchpumpe anhand eines Ausführungsbeispiels erläutert werden.
• Fig. 4a bis 4c sind Detailansichten der Ventileinheit der Anlage zur Herstellung einer medizinischen Zubereitung nebst Schläuchen.
• Fig. 5a und Fig. 5b zeigen anhand eines Flussdiagramms die Verfahrensschritte bei einem Ausführungsbeispiel des erfindungsgemäßen Verfahrens.
• Fig. 6 ist eine Detailansicht der Anlage zur Herstellung einer medizinischen Zubereitung, in welcher Flusssensor und Blasensensor zu erkennen sind.
• Fig. 7 ist eine schematische Darstellung des Zulaufs des Zielbehälters, anhand welcher die Berechnung der in den Zielbehälter transferierten Menge erläutert wird.
• Fig. 8 ist ein Flussdiagramm, anhand dessen die Überprüfung jedes Dosierschrittes durch Wiegen des Zielbehälters erläutert wird.
• Fig. 9 ist ein Flussdiagramm, anhand dessen die Berechnung des Gewichts der in den Zielbehälter transferierten Flüssigkeit erläutert wird.
• Fig. 10 ist ein Flussdiagramm, anhand dessen die Kontrolle über den Blasensensor erläutert werden soll.
• Fig. 11 ist ein Flussdiagramm, anhand dessen die Kontrolle über den Flusssensor erläutert werden soll.

The subject of the invention shall be explained in the following, referring to the drawings Figures 1 to 11 , are explained using an exemplary embodiment.

• 1 shows a perspective view of a plant for the production of a medicinal preparation as used for the method according to the invention.
• 2 is a detailed view of the peristaltic pump.
• Referring to 3 the characteristic curve of a peristaltic pump is to be explained using an exemplary embodiment.
• Figures 4a to 4c are detailed views of the valve unit of the plant for the production of a medicinal preparation together with hoses.
• Figure 5a and Figure 5b use a flow chart to show the method steps in an exemplary embodiment of the method according to the invention.
• 6 is a detailed view of the plant for the production of a medicinal preparation, in which flow sensor and bubble sensor can be seen.
• 7 is a schematic representation of the inflow of the target container, on the basis of which the calculation of the quantity transferred into the target container is explained.
• 8 Fig. 12 is a flowchart used to explain verification of each dosing step by weighing the target container.
• 9 Fig. 12 is a flow chart for explaining the calculation of the weight of the liquid transferred to the target container.
• 10 Fig. 12 is a flow chart for explaining the bubble sensor control.
• 11 Fig. 12 is a flowchart for explaining flow sensor control.

Detailed description of the drawings

1 shows a system 1 for the production of a medicinal preparation.

The system 1 for producing a medicinal preparation comprises a large number of source containers 2, which are only partially shown in this view. In particular, those source containers are not shown in this representation, which contain the main components of the medicinal preparation, as well as the container that is filled with universal liquid. In particular, these containers can be hung remotely from the system, e.g. on a hook attached to a rail.

A target container 3 embodied as an infusion bag can be seen, which is arranged on scales 4 . The amount of liquid transferred to the target container 3 can be checked via the scales 4 during operation of the system 1 .

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

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

In order to convey the liquids, the system 1 has a single peristaltic pump 6 here, by means of which liquids can be pumped from all the source containers 2 into the target container 3 .

The system 1 also 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, select a program by means of which a target container 3 is filled with a predetermined composition of components.

The system includes an electronic controller (not shown) via which the peristaltic pump 6 is controlled and which is connected to the scale 4 .

2 Figure 12 is a detailed view of the peristaltic pump 6. The pump 6 is preferably provided here as a roller pump.

It can be seen that the hose pump 6 has a pump wheel 8 with two rollers 9 . The hose to be inserted is not shown in this view.

It goes without saying that the method according to the invention can also be carried out using a hose pump with a different number of rollers, in particular using a hose pump which has three rollers (not shown).

If a tube (not shown) is inserted into the tube pump 6 , the tube 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.

However, it is understood that when the rollers 9 move from the outlet 11 to the inlet 10, they are partly disengaged from the hose. This results both on the suction side, ie on the side of the inlet 10, and on the pressure side, ie on the side of the outlet 11, a non-linear characteristic curve of the pump output, the peristaltic pump 6 pulsates.

Preferably, the amount of liquid delivered is between 5 and 50 ml per full revolution.

In order to be able to precisely meter micro-amounts, i.e. amounts in the lower ml range, the hose pump 6 is preferably brought into a position by rotating the pump wheel 8 in which the respective micro-amount is metered completely in the linear range of the hose pump 6, at least on the suction side can be.

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

In the position of the impeller 8 shown here, a roller 9 has just passed the inlet 10 and is now in engagement with the inserted hose.

It makes sense to bring the peristaltic pump 6 into the position shown here for dosing a micro-amount, in order then to be able to meter the micro-amount completely in the region of the linear characteristic curve of the peristaltic pump 6 on the suction side.

The pressure-side and suction-side characteristics are in 3 shown.

The phase angle p is divided into 1600 units, which are plotted on the x-axis. These 1600 steps represent one full revolution of the pump.

The differential flow, ie the delivered volume per unit of angle of rotation, for the hose pump 6 is plotted on the y-axis.

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

It can be seen that the characteristic curves are constant over wide areas, i.e. there are areas with a linear characteristic curve.

However, each characteristic shows two dips. On the suction side, these are the phase angles at which one of the two rollers re-engages (p=700 and p=1500). In these areas, the volume of the hose of the peristaltic pump is reduced in the vicinity of the suction-side connection. The suction power of the pump is reduced.

On the pressure side, the dips are in the areas where a roller comes out of engagement. The tubing of the peristaltic pump returns to its original shape. The hose increases in volume and the delivery rate of the pump is reduced on the pressure side.

The pumped volume on the suction side is relevant for the exact dosing, especially of a micro quantity. All liquid that is taken from the source container in the respective dosing step ultimately reaches the target container. It is therefore crucial that the correct volume is removed from the suction side in each dosing step.

According to one aspect of the invention, when dosing a so-called micro quantity, liquid is only pumped in one of the two linear areas of the suction side of the pump in a dosing step.

For this purpose, before the start of the dosing step, the peristaltic pump is preferably set to the beginning of the next linear range of the suction side while pumping universal liquid. In this example, these positions are around p=50 and p=850.

In this way, even micro quantities can be precisely dosed with a single peristaltic pump.

According to a further aspect of the invention, the suction-side characteristic curve of the peristaltic pump is used to more precisely calculate the quantity of liquid removed from the source container.

In this way, the characteristic curve on the suction side of the hose pump can also be used for dosing steps that take place in the non-linear range of the hose pump in order to calculate the quantities of liquid removed.

The calculation takes into account that the suction-side flow rate of the peristaltic pump is not linear.

das zu dosierende Volumen ergibt. Dabei ist p1 die Position des Pumpenrades am Beginn des Dosierschrittes und p2 die Position nach dem Dosierschritt. Die Größe Vs ist das dem Quellbehälter zu entnehmende Volumen.The phase angle p2 is determined using the characteristic curve Ds, so that $$\mathit{vs}={\displaystyle {\int }_{p1}^{\mathrm{<figure-callout\; id="2"\; label="p"\; filenames="imgf0001.png"\; state="\{\{state\}\}">p</figure-callout>}2}\mathit{Ds}\left(p\right)\mathit{dp}}$$

the volume to be dosed 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 variable 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 whether the quantity actually removed corresponds to the calculated quantity.

To do this, the volume of the liquid entering the target container is calculated. Next, based on the known density of the pumped liquid, the mass of incoming liquid calculated. The characteristic curve Dd of the pressure side is used to determine the volume of the liquid arriving in the target container.

The characteristic curves, which are preferably determined by empirical measurements, can be stored, for example, as approximate formulas or as a simple table of values, in order to calculate the suction-side and pressure-side pump 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 system are then carried out using the empirical formula or a table of values.

Figure 4a Fig. 14 is a perspective view of the valve unit 5 used for the medicinal preparation manufacturing plant.

The valve unit 5 comprises a large number of inlets 12, which are connected to the source containers (2 in 1 ) get connected. Valves (not shown) integrated in the valve unit 5 can selectively connect a hose 15 , by means of which liquid is removed from a source container, to a hose 14 which is arranged on the outlet 13 of the valve unit 5 .

The hose 14 also has a section which is inserted into the hose pump.

In Figure 4b the ends of the hoses 15 for connecting the source container are shown. The connections 22 for the source container can be seen, which in this exemplary embodiment are in the form of a Luer lock connection with an attached spike.

Figure 4c shows the tube 14, which forms the outlet of the valve unit 5 and at the same time the inlet of the target container. Connection 23 for the target container can be seen. The valve unit 5 shown here forms, together with the hoses 14, 15 and their connections 22, 23, the transfer set, which is used to operate the system.

This transfer set is preferably designed as a disposable component and is regularly replaced. Because of this design come to Transferred liquids only come into contact with components of the transfer set on their way from the source container to the target container.

Referring to the flow chart according to Figure 5a and Figure 5b a method according to the invention for the production of a medicinal preparation is to be explained using an exemplary embodiment.

First, the transfer set described above is used to connect the source containers. A so-called “waste bag” is also inserted as the target container, ie a container which is not intended to be used as intended for applying a medicinal preparation, but which is discarded after the system has been prepared.

The entire transfer set including hoses is filled with a universal liquid (UI), e.g. B. isotonic water, and each valve is opened long enough to allow the tubing (15 in Fig. 4a, b ) leading to the source tanks are filled and free of bubbles.

Then the dosing factor of the peristaltic pump can be determined by weighing the waste bag when pumping universal liquid. The pump performance of the hose pump, which changes due in particular to tolerances in the hose used, is now calibrated by determining this dosing 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 exemplary embodiment, a micro-amount is to be dosed in a first dosing step.

Therefore, in step 5, the impeller is brought into an area with a linear characteristic curve on the suction side, with universal fluid first being conveyed while the impeller is brought into this position.

A micro-quantity can now be removed from the source container completely in the linear range of the pump's characteristic curve on the suction side.

Each individual dosing step, including the step of dosing a micro-quantity, is checked by weighing the target container.

The density of the liquid transferred into the target container is taken into account by calculating which liquid or which liquids are in the inlet of the target container when the microquantity is removed in step 5 and are transferred into it.

Furthermore, during the check by weighing, also taking into account the pressure-side characteristic curve of the peristaltic pump, it is calculated as exactly as possible which volume was transferred to the target container in the respective dosing step. This volume does not always match due to the phase-shifted characteristics of the suction side and pressure side.

A main component of the medicinal preparation is then dosed, taking into account the suction-side characteristic curve of the peristaltic pump. In contrast to dosing micro quantities, the peristaltic pump is also operated in the non-linear range when dosing the main components.

However, when calculating the quantity of the respective main component removed from the source container, the suction-side characteristic curve of the peristaltic pump is taken into account in order to be able to precisely predict the volume removed on the suction side.

The mathematical verification of the quantity taken from the source container for a main component is also carried out taking into account the density of the liquid transferred to the target container and taking into account the pressure-side characteristic curve of the peristaltic pump.

Both when dosing micro quantities and when dosing main components, a flow factor, which is dependent on the type, in particular the viscosity, of the liquid being pumped, is preferably included as a further factor in the calculation of the volume of the pumped liquid. A flow factor of 1.0 is assigned to water; the flow factor changes significantly in the case of viscous components such as glucose solutions.

It has been shown that a general consideration of the flow factor depending on the liquid withdrawn in each dosing step is sufficient, since there is a viscosity-related influence on the pump capacity primarily due to the bottleneck (e.g. spike) present at the connection to the source container.

• Vs ist das bei einem Dosierschritt zu dosierende Volumen. Dieses entspricht dem Volumen der Saugseite, an welcher ein Quellbehälter angeschlossen ist.
• p1 ist die Position des Pumpenrads vor dem Dosierschritt, insbesondere die Endstellung eines vorherigen Dosierschrittes oder der Beginn des linearen Bereiches, in welchen das Pumpenrad vorher gedreht wurde.
• p2 ist die berechnete Position des Pumpenrads nach dem Dosierschritt, also das Ergebnis der Berechnung für den Drehwinkel der Pumpe bei dem Dosierschritt.
• F ist der Flussfaktor, also der Korrekturfaktor für die jeweilige Viskosität des Mediums.
• Ds(p) ist Kennlinie der Saugseite (Konstante) und p die Phase des Pumpenrades.

The weight added to the target container at a dispense step can be calculated in detail as follows: $$f\ast \mathit{vs}={\displaystyle {\int }_{p1}^{\mathrm{<figure-callout\; id="2"\; label="p"\; filenames="imgf0001.png"\; state="\{\{state\}\}">p</figure-callout>}2}\mathit{Ds}\left(p\right)\mathit{dp}}$$

• Vs is the volume to be dosed in one dosing step. This corresponds to the volume of the suction side to which a source tank is connected.
• p1 is the position of the impeller before the dosing step, in particular the end position of a previous dosing step or the start of the linear range in which the impeller was previously rotated.
• p2 is the calculated position of the impeller after the dosing step, i.e. the result of the calculation for the rotation angle of the pump in the dosing step.
• F is the flow factor, i.e. 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 impeller.

The phases p1 and p2 can differ by several revolutions.

The flow factor F is therefore a correction for an additional slippage of the pump due to increased viscosity compared to water. In particular, the volume to be dosed is set higher by a factor of F than with water.

Almost all media used for a medicinal preparation have the same or higher viscosity than water. Media with a lower viscosity are very rare. Consequently, F >= 1 usually applies.

The volume expected on the pressure side, which is used to calculate the weight of the liquid quantity conveyed into the target container during a dosing step, is: $$\mathit{Vd}={\displaystyle {\int }_{p1}^{\mathrm{<figure-callout\; id="2"\; label="p"\; filenames="imgf0001.png"\; state="\{\{state\}\}">p</figure-callout>}2}\mathit{dd}\left(p\right)\mathit{dp}}$$

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

Vd is the volume expected on the pressure side, i.e. the volume of liquid that is pumped into the target container on the scale during the dosing step.

Dd(p)is characteristic of the pressure side (constant). The flow factor F is not included in the calculation of the volume pumped on the pressure side, since the "slip" of the pump is not pumped.

mit der Dichte P des geförderten Mediums.The expected increase in mass G on the scale is then: $$G=\mathit{Vd}\ast \rho$$

with the density P of the pumped medium.

P is therefore the specific gravity of the liquid transferred into the target container during a dosing step, ie initially the liquid that is already present in the inlet of the target container. If several different liquids are transferred to the target container during a dosing step, the specific gravity of the liquids is set in relation to their quantity.

As a next step, further micro-amounts or further main components are added in further dosing steps. Steps 5 to 9 can therefore be repeated until all the desired components are in the target container.

It goes without saying that steps 5 to 7, ie the dosing of a micro-amount, and steps 8 and 9, ie the dosing of a main component, are also interchangeable, ie can be carried out in a different order.

At the end of each filling process, the transfer set is rinsed with universal liquid and, if necessary, the desired residual amount of universal liquid is fed to the target container.

It is intended, for example, to use this rinsing phase, in which the impeller of the peristaltic pump rotates more than one full revolution, to re-determine 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, because the elasticity and shape of the hose inserted into the hose pump changes.

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

It goes without saying that all the steps presented here, with the exception of connecting the source and target containers and starting the system, are preferably automated.

6 is another detail of the 1 . The target container 3 can again be seen. A valve unit 5 can also be seen.

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

The flow rate in the hose on the suction side is measured via the flow sensor 16 and the delivery capacity of the hose pump can thus 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 throughflow on the suction side will be reduced to such an extent that an error can be detected by means of the flow sensor 16 . In particular when dosing a micro-amount, the tube will initially also contract in the area of the flow sensor 16, with the result that the detected flow rate is reduced and a blockage can be concluded. An error message can then be generated via the electronic control and 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 quantity of liquid conveyed on the suction side with sufficient accuracy using the flow sensor alone.

The flow sensor is therefore preferably used solely for monitoring such that an error is assumed if the difference between the calculated pump capacity of the peristaltic pump and the resulting calculated flow rate compared to the flow rate determined by the flow sensor exceeds a threshold value.

The hose is placed in a bubble sensor 17 on the pressure side. This is an ultrasonic sensor that detects bubbles and switches off the system from a certain threshold value and displays an error to the user.

7 FIG. 12 is a schematic representation of the hose 14 connecting the valve unit 5 to the target container 3. FIG. In this exemplary embodiment, three valve units connected in series are shown, but this has no effect on the basic principle. The three valve units 5 shown here can just as easily be combined into a single valve unit.

The inlet to a source container is opened by means of the valve unit 5 for each dosing step, so that liquid can flow from the source container via the respective valve of the valve unit first into 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 initially transferred.

The calculation of the weight of the liquid which arrives in the target container 3 in a dosing step is therefore not based on the density of the liquid removed in the respective dosing step. Rather, the tube 14 and the collecting channels 24 of the valve units 5 are considered in such a way that different liquids, namely a first liquid 19, a second liquid 20 and a third liquid 21 are located in different sections of the tube 14 and/or the subsequent collecting channel 24.

If, for example, a micro-amount is dosed, the specific weight of the first liquid 19 is initially taken as a basis.

This theoretical "material stack" ("material arrangement") can improve the accuracy of the check. In particular, it is possible to check and evaluate each individual dosing step.

8 Fig. 12 is a flowchart used to explain verification of each dosing step by weighing the target container.

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

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

Otherwise the filling process is continued.

If the weight determined by weighing is not within a second, narrower limit range, which indicates, for example, insufficient calibration of the system, but which indicates that the deviation in the dosed quantity is so small that it does not impair the quality of the medicinal preparation, the filling process is continued.

However, once the filling process is complete, the user of the system receives a message that the system needs to be calibrated.

Otherwise, the next target container can be inserted after the filling process is complete.

9 FIG. 12 is a flow chart used to explain the calculation of the target weight in a dosing step.

The volume of the liquid introduced is calculated using the pressure-side characteristic of the peristaltic pump.

It is then determined which liquid or liquids has or have reached the target container in the dosing step. This is done as with reference to 7 was described.

The target weight can then be calculated from the specific weight of the transferred liquid or liquids.

This target weight is used to determine the in 8 mentioned limit values. For example, a first limit range could be defined as a deviation of more than 10% and a second limit range as a deviation of more than 5%.

It goes without saying that the limit ranges can also be varied as a function of the liquid removed during a dosing step, since there are components for which deviations in quantity are more or less critical for the quality of the medicinal preparation.

10 Fig. 12 is a flow chart for explaining the bubble sensor control.

The amount of bubbles in the transferred liquid is continuously monitored by the bubble sensor located after the peristaltic pump.

Two boundary areas are also provided in this embodiment.

If the amount of bubbles is in a limit range that is unacceptable for the quality of the product being manufactured, the filling process is interrupted and an error message is displayed.

If a second, narrower limit range is not complied with, the filling process can be continued and the target container can be used as intended, but an error message appears when the filling process is complete, stating that the system must be vented.

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

11 Fig. 12 is a flowchart for explaining flow sensor control.

The flow rate is continuously calculated, preferably on the basis of the suction-side characteristic curve of the peristaltic pump.

At the same time, the flow rate is measured with a flow sensor arranged on the flow side in front of the peristaltic pump.

Measured and calculated flow velocities are compared.

If there is a deviation above a threshold value, in this example 20%, an error (e.g. occlusion) is assumed and the filling process is aborted.

The user is informed of an error message.

In order to be able to localize the error better, the source container is preferably displayed to the user (e.g. via a number on a screen) in the event of any error message, from which liquid was taken when the error occurred.

With the invention, the accuracy in the manufacture of a medicinal preparation using a peristaltic pump and at the same time the security against dosing errors can be improved.

Reference List

• 1 plant
• 2 source containers
• 3 target containers
• 4 scales
• 5 valve unit
• 6 peristaltic pump
• 7 displays
• 8 impeller
• 9 roll
• 10 entry
• 11 outlet
• 12 inflow
• 13 Expiration
• 14 hose
• 15 hose
• 16 flow sensor
• 17 bubble sensor
• 18 connection
• 19 first liquid
• 20 second liquid
• 21 third liquid
• 22 connection
• 23 connection
• 24 collector channel

Claims (14)

1. A method for producing a medical preparation, in particular parenteral nutrition, wherein liquids are transferred using a peristaltic pump (6) from a plurality of source containers (2) into a target container (3), wherein the target container (3) is weighed during the individual metering steps and the quantity of liquid transferred into the target container (3) is thus checked during the individual metering steps, characterised in that
   the sequence of different liquids in an inflow of the target container (3) is taken into account in order to factor in the specific mass of the liquid when checking during weighing.
2. The method for producing a medical preparation according to the preceding claim, characterised in that the quantity of liquid transferred into the target container (3) is checked during all metering steps.
3. The method for producing a medical preparation according to any one of the preceding claims, characterised in that the quantity of liquid transferred into the target container (3) during a metering step is calculated taking into account a pressure-side characteristic curve of the pump output of the peristaltic pump (6), wherein the calculated quantity is compared with the quantity determined by weighing the target container (3).
4. The method for producing a medical preparation according to any one of the preceding claims, characterised in that the quantity of liquid removed from a source container (2) is calculated taking into account a suction-side characteristic curve of the pump output of the peristaltic pump (6), wherein the calculated quantity is compared with the quantity determined by weighing the target container (3).
5. The method for producing a medical preparation according to any one of the preceding claims, characterised in that a very small quantity of less than 10 ml, preferably of less than 5 ml, particularly preferably of less than or equal to 3 ml, is transferred in at least one metering step.
6. The method for producing a medical preparation according to any one of the preceding claims, characterised in that the peristaltic pump (6) has at least one region with linear and one region with non-linear characteristic curve of the pump output,
   wherein, in order to meter from at least one source container, the peristaltic pump (6) is brought into a position such that the entire metering from the source container (2) takes place in the region with the linear characteristic curve.
7. The method for producing a medical preparation according to any one of the preceding claims, characterised in that the peristaltic pump (6) is brought into a position in which the suction-side characteristic curve of the peristaltic pump (6) is linear.
8. The method for producing a medical preparation according to any one of the preceding claims, characterised in that, in order to bring the peristaltic pump (6) into the desired position with linear characteristic curve, liquid is removed from a source container other than that from which metering is to be carried out, in particular from a source container with universal liquid or water.
9. The method for producing a medical preparation according to any one of the preceding claims, characterised in that a very small quantity with a volume of less than 10 ml, preferably less than 3 ml, is delivered in the region of the linear characteristic curve.
10. The method for producing a medical preparation according to any one of the preceding claims, characterised in that a flow sensor (16) is used to check the delivery rate of the peristaltic pump (6) and/or in that a bubble sensor (17) is used to check that there are no bubbles in an inflow to the target container (3).
11. The method for producing a medical preparation according to any one of the preceding claims, characterised in that the metering factor of the peristaltic pump (6) is determined in a preceding calibration step by means of weighing a target container (3).
12. The method for producing a medical preparation according to any one of the preceding claims, characterised in that, in order to transfer the liquids from the source containers (2) into the target container (3), a transfer set is used which comprises a valve unit (5), a hose (14), which is insertable into the peristaltic pump, and a plurality of hoses (15) for connecting the source containers (2).
13. The method for producing a medical preparation according to any one of the preceding claims, wherein the metering factor of the pump is calibrated in a metering step from a source container, in which an impeller (8) of the peristaltic pump (6) rotates for at least one full revolution.
14. An installation for producing a medical preparation, in particular an installation for producing parenteral nutrition, comprising a peristaltic pump, characterized by a system for carrying out a method according to one of the preceding claims 1 to 13.

Images