Method for the quality-assessed metering of a metering fluid, and pipetting device designed to carry out the method

Abstract

The present invention relates to a method for the quality-assessed metering by means of a pipetting device (10), the method comprising the following steps: - carrying out a metering process by moving a pipetting plunger (30), - recording the time curve of the working-gas pressure (44, 54) in a pipetting channel (12) during the metering process, - comparing the curve of the working-gas pressure (90) on the basis of the recorded time curve of the working-gas pressure (44, 64) with a predetermined target pressure value range (54, 74), and - outputting a quality assessment of the metering process on the basis of the result of the comparison step. According to the invention, in order to improve the quality assessment, the control device (38) carries out the following further steps while the pipetting channel (12) is filled exclusively with working gas as fluid: - carrying out corrective-pressure determination by moving the pipetting plunger (30), and - measuring a pressure of the working gas in the pipetting channel (12) as a corrective pressure during the corrective-pressure determination, wherein, prior to the comparison step, the control device (38) corrects the time curve of the working-gas pressure (44, 64) recorded during the metering process on the basis of the corrective pressure measured during the, so that the comparison step is carried out using the corrected time curve (90) of the working-gas pressure.

Description

[0001]66478P WO Hamilton Bonaduz AG - 1 - Method for the quality-assessed dosing of a dosing liquid and pipetting device, designed to carry out the method Description The present invention relates to a method for the quality-assessed dosing of a dosing liquid by means of a pipetting device, wherein the pipetting device comprises: - a pipetting channel at least partially filled with a working gas, - a pipetting piston movably received in the pipetting channel in order to change a pressure of the working gas in the pipetting channel by a piston movement, - a pipetting opening through which dosing liquid can flow in order to change the amount of fluid received in the pipetting channel, - a piston drive in order to drive the pipetting piston to move along the pipetting channel, - a pressure sensor in order to detect the pressure of the working gas in the pipetting channel, - a control device for storing and processing data, as well as forControl of the piston drive, wherein the method comprises the following steps: - Carrying out a dosing process by moving the pipetting piston and thereby changing the pressure of the working gas in the pipetting channel and thereby changing the amount of dosing liquid taken up in the pipetting channel, - Recording a temporal profile of the pressure of the working gas in the pipetting channel during the dosing process, - Comparing a profile of the working gas pressure based on the recorded temporal profile of the working gas pressure with a predetermined pressure setpoint range, and - Outputting a quality assessment of the dosing process depending on the result of the comparison step. Such a method and a pipetting device adapted for its implementation are known from WO 02 / 073215 A2. In the known method, a 66478P WO Hamilton Bonaduz AG - 2 - pressure setpoint range is defined by a curve of an upper pressure limit and by a curve of aThe lower pressure limit is specified. The setpoint pressure range is determined in advance in the laboratory for a pipetting device type and for a dosing liquid or class of dosing liquid and is stored in a data memory of the pipetting device's control unit. Essentially, the lower pressure limit curve corresponds to the upper pressure limit curve and is merely shifted towards lower pressures. If the recorded temporal pressure profile of the working gas in the pipetting channel during the dispensing process runs completely between the upper pressure limit and the lower pressure limit for a relevant period of time, which can, for example, be the period of a movement of the pipetting piston caused by the dispensing process, the dispensing process is assessed as good or OK. However, if the recorded temporal pressure profile of the working gas in the pipetting channel leaves the setpoint pressure range, theDosing process is assessed as faulty, whereby a distinction can also be made between different possible sources of error depending on the location and direction of the deviation from the pressure setpoint range. It has been found that the pipetting channels of even identical pipetting devices differ due to manufacturing tolerances. This leads to a scattering of the values ​​of temporal pressure profiles recorded during a dispensing process, even though each individual dispensing process has run without errors. To avoid false-negative quality assessments of dispensing processes, the pressure setpoint range can be selected to be sufficiently large. However, this increases the risk of false-positive quality assessments, since deviations from the norm during a dispensing process would then have to be particularly significant to cause an enlarged pressure setpoint range above the upper pressure limit or below the lower pressure limit.This problem is massively aggravated in practice, especially because, for reasons of the highest possible process hygiene, the section of the pipetting channel wetted by the dosing liquid during dispensing is formed by an exchangeable and generally only once-used pipette tip. By exchanging disposable pipette tips, the pipetting channel of a pipetting device can change its dispensing characteristics with each pipette tip in the sense of an interaction between the pipetting channel and the working gas during a dispensing process. Thus, nominally identical pipetting devices not only differ from one another in terms of their dispensing characteristics, but the dispensing characteristics themselves are not constant, but change over the operating life of the respective pipetting device. Even if a difference in dispensing characteristics incould be corrected in any way, this correction can become unusable or even harmful during the further operation of the pipetting device due to changes in the pipetting channel. EP 2037283 A1 discloses a piston-driven dosing device for dosing a dosing liquid. A pressure sensor detects the pressure of the working gas in the pipetting channel. If, during dispensing, the pressure in the pipetting channel exceeds a predetermined threshold value, an analysis module of the device detects the pipetting opening as blocked. The threshold value is determined using a standard device with a reference dosing liquid. The standard device is essentially constructed in the same way as the working dosing device used to feed an analysis device. However, despite being identical in design, the pressure sensors exhibit fluctuations in their sensitivity of up to30%. As a result, an identical process, performed once on the standard device and again on the working dosing device, can each lead to pressure sensor signals that can differ by up to 30% at the same process progress point. In order to make the signals of the working dosing device comparable with those of the standard device, for example with the threshold value determined there, EP 2037 283 A1 teaches the use of a correction factor, which is applied to the signals of the working dosing device. The correction factor corresponds to the ratio of the sensitivity of the pressure sensor in the standard device to that of the working dosing device. By multiplying the signal of the pressure sensor of the working dosing device by the correction factor, this signal is corrected to the signal level of the standard device. It is readily apparent that the pressure sensor signals from EP2037283 A1 is not applicable to differences between the working dosing device and the standard device that change during the operating period of a working dosing device, or that such time-varying differences can only be corrected by repeated, complex comparative dosing. WO 2016 / 025849 A1 discloses a method for testing the integrity of a pipetting tip on a pipetting device. For this purpose, WO 2016 / 025849 A1 teaches aspirating gas into a pipetting tip coupled to a pipetting device and determining a maximum and minimum pressure value during a predetermined aspiration period. Based on the determined maximum and minimum pressure values, a pressure range of the pipetting tip is determined, limited by the maximum and minimum pressure values. The pressure range is limited to a predetermined upper threshold value and a predetermined lower threshold value.compared. If the determined pressure value range lies between the upper and lower threshold values, the executing device assesses the pipetting tip as functioning correctly; otherwise, the pipetting tip is discarded. Based on the method described above, the object of the present invention is to provide a technical teaching which, given the above-described value variations of recorded temporal profiles of the pressure of the working gas in the pipetting channel, makes it possible to increase the accuracy of the quality assessment of the performed dispensing process. The present invention achieves this object in that the control device carries out the following additional steps while the pipetting channel is essentially filled exclusively with working gas as a fluid: 66478P WO Hamilton Bonaduz AG - 5 - - The control device carries out a correction pressure determination process. For this purpose, it controls the piston driveand moves the pipetting piston. This movement of the pipetting piston causes a change in the pressure of the working gas in the pipetting channel. Depending on the direction of movement of the pipetting piston, working gas is aspirated into the pipetting channel and / or dispensed from the pipetting channel. - During the correction pressure determination process, the control device uses the pressure sensor to detect the pressure of the working gas in the pipetting channel. The pressure thus detected is a correction pressure in the further process. To increase the accuracy of the assessment of the quality of the dispensing process, the control device corrects the temporal progression of the working gas pressure recorded during the dispensing process, based on the correction pressure of the working gas recorded during the correction pressure determination process, before the comparison step. The comparison step is thus carried out with the corrected temporal progression of the working gas pressure. An advantage of thisThe advantage of the method according to the invention is that the correction pressure is determined on the same pipetting channel with which the dispensing process is carried out. Thus, a correction pressure is determined which exactly represents the pipetting channel whose dispensing behavior is relevant for assessing the quality of the dispensing process carried out. A portion of the pipetting channel is never reached by dispensing liquid, even during dispensing processes with large dispensing volumes, but is always filled only with working gas. The working gas moved during the correction pressure determination process very accurately reflects the characteristics of the pipetting channel's interaction with the working gas for this area of ​​the pipetting channel, which is always filled only with working gas during operation of the pipetting device. A portion of the area of ​​the pipetting channel which is always filled only with working gas is, when using interchangeable pipetting tips, separated from the respectiveThe pipette tip itself is formed, which is never completely filled with dosing liquid during dispensing processes. 66478P WO Hamilton Bonaduz AG - 6 -. In particular, if a filter is arranged in the replaceable pipette tip through which the working gas flows during the dispensing process, the filter is located in the area of ​​the pipette tip that is always filled with working gas and, on the other hand, the filter contributes particularly significantly to the individual characteristics of the respective pipette tip and thus of the currently used pipette channel of the pipetting device in its interaction with the working gas. It is easy to understand, especially for these filters, that the filters have a specific filter characteristic in order to retain certain undesirable components in the working gas. This filter characteristic can be achieved by a specific pore size in the filter material of the filter, whereby the distribution of differentPore ​​sizes in the filter can be subject to a relatively large stochastic variation. Thus, pipette tips can have filters that have essentially the same filtering effect, but which influence the pressure of the working gas generated by the movement of the pipette piston differently during a dispensing process. The filter in the pipette tip mentioned is merely a particularly clear example of the different interactions of nominally identical pipette tips with the working gas in the pipette channel. Other effects, such as dimensional differences of pipette tips usually manufactured by injection molding due to permissible manufacturing tolerances or different thermal expansions due to different operating temperatures, can also influence the interaction of the pipette channel with the working gas during a dispensing process, as can temporary condensate deposits.on wall sections of the pipetting channel. The presented method is therefore particularly advantageous for filter-bearing pipetting tips, but not only for these. The individual influences of the pipetting channel can be determined in temporal proximity to the actual dispensing process by the above-mentioned steps carried out in addition to the already known method and can be corrected by taking into account the pressure curve indicating the quality of the dispensing process. 66478P WO Hamilton Bonaduz AG - 7 - The best possible correction can be achieved with the least possible effort by ensuring that the correction pressure determination process differs as little as possible from the subsequent dispensing process. A key difference, namely the presence of dispensing liquid in the pipetting channel during the dispensing process, in contrast to the pipetting channel filled exclusively with working gas during the correction pressure determination process, isHowever, a correspondence between the correction pressure determination process and the dispensing process can be achieved by moving the pipetting piston in the same direction of movement during the correction pressure determination process as during the dispensing process. Therefore, if the dispensing process essentially involves aspiration of dosing liquid, the correction pressure during the correction pressure determination process is preferably determined during a movement of the pipetting piston in the aspiration direction. The same applies mutatis mutandis to a dispensing process as a dispensing process. In principle, it is possible to repeat the piston movement of the dispensing process during the correction pressure determination process "dry," i.e., with a pipetting channel filled only with working gas, with an identical stroke and identical piston acceleration and speed, and to record the temporal progression of the pressure of the working gas during theThe correction pressure determination process can then be recorded as the correction pressure. The time profile of the working gas pressure determined during the dispensing process can then be corrected by the time profile of the working gas pressure determined during the counterpressure determination process. Although this procedure promises high correction accuracy, it significantly impairs the productivity of the pipetting device. Higher productivity of the pipetting device with sufficiently accurate correction can be achieved by moving the pipetting piston at a constant speed during the correction pressure determination process and recording the correction pressure of the working gas during the movement phase of constant speed. The time profile of the working gas pressure during the dispensing process can then be corrected with this constant value of the correction pressure.The accuracy of this simplified method lies in detecting a quasi-static state, in the sense of an unaccelerated state of the working gas, by detecting the correction pressure during the constant movement speed of the pipetting piston. This is because the pipetting piston is also moved at a constant speed during a phase of the dispensing process between phases of acceleration and deceleration of the pipetting piston. Thus, the simplified correction pressure determination process sufficiently accurately replicates the dispensing process carried out with the same pipetting channel. A further increase in productivity or minimization of any impairment of the productivity of the pipetting device due to the correction pressure determination process can be achieved by moving the pipetting piston at a different speed during the correction pressure determination process than during the dispensing process. The pipetting piston is preferably moved at a different speed duringof the correction pressure determination process at a higher speed, in particular at a higher constant speed, than during the dispensing process. For this purpose, a data relationship can be stored in a data memory for a particular type of pipetting channel used, in particular a pipetting tip, which links different correction pressures with different piston speeds. Such a data relationship can have been previously determined for the individual types of pipetting tips or pipetting channels in the laboratory. The type of pipetting channel can be determined by its length, its flow cross-section, its sequence of different flow cross-sections, etc., and generally by its shape. The type of a pipetting tip can be determined by its shape and its nominal pipetting volume. Surprisingly, the applicability of a data relationship which links different piston speedsspeeds, regardless of whether the pipette tip has a filter or not. The filter does have a significant influence on the interaction of the pipette tip with the working gas moving within it. However, the correction pressures of filter-bearing pipette tips at different piston speeds behave in approximately the same way as the correction pressures of otherwise identical, but filterless pipette tips at the same different piston speeds. 66478P WO Hamilton Bonaduz AG - 9 - If only the ratio of the two correction pressures is important when converting a correction pressure determined at the first piston speed to a correction pressure expected to occur at a second piston speed different from the first, the ratios of the correction pressures of filter-bearing and filterless pipette tips differ, otherwise nominallyidentical pipetting tips only insignificantly, so that a data relationship that was determined for a pipetting tip type only for filter-bearing pipetting tips can also be used for filterless pipetting tips of the same type, i.e., the same shape and the same nominal pipetting volume. Therefore, the control device preferably determines an expected correction pressure associated with the piston speed of the dispensing process based on the correction pressure actually recorded at the piston speed of the correction pressure determination process using the aforementioned data relationship. Furthermore, the control device then corrects the temporal profile of the working gas pressure recorded during the dispensing process with the expected correction pressure. For example, a predetermined value can be stored in the data memory retrievable by the control device for the respective type of pipetting channel used, i.e., in particular, the pipetting tip.A data context must be stored that links a constant piston speed vK with the correction pressure pkorr determined during a piston movement at this piston speed. The suffix "kalib" indicates that the correction pressure belongs to the data context. The data context can be a table, a characteristic map, or, and this is preferred, a functional context. The following then applies to a first piston speed 1vK: ) ! " " # % $ &' $ ( = *+ ), - . Eq.1 It has been found that a linear relationship between the constant piston speed vK and the corresponding correction pressure pkorr, as can be obtained by linear regression based on measurement points obtained at different piston speeds, sufficiently accurately represents the relationship between piston speed and correction pressure. The following applies in general to the ratio of two correction pressures determined at different piston speeds: 9+ . The quotient8 9+7: ; . from Eq. 2 can be determined solely from the previously determined data context. The quotient can be simplified as >?) < "%&'( which links the correction pressures determined at different piston speeds 1vK and 2vK according to the previously determined data relationship. For the linear relationship mentioned above, which is preferred due to its simplicity, the following applies: However, pipetting channels, especially their pipetting tips, are always subject to manufacturing tolerances, which lead to differing dimensions between nominally identical pipetting channels, especially pipetting tips. Therefore, identical piston speeds on nominally identical pipetting channels can lead to different correction pressures. This also applies to the pipetting channels used in the laboratory to determine the data correlation compared to the pipetting channels used for the respective dispensing process and thus for the respective correction pressure determination process associated with the dispensing process.Here, however, the inventors have discovered that, while pipetting channels of the same design can deliver different values ​​for the detected correction pressure at the same piston speed, the correction pressures determined at different piston speeds, regardless of their specific value, always have the same relationship to one another with sufficient accuracy. Therefore, if the correction pressure determination process is always carried out at the same first piston speed, while the dispensing process is carried out with a different second piston speed, the following applies: or > The suffix "dos" indicates that the correction pressure belongs to the dispensing process; the index "2" indicates that it is assigned to the piston speed 2vK used during the dispensing process. The suffix "KE" indicates that the correction pressure was determined during the correction pressure determination process. The index "1" indicates that this determination was made using the piston speed 1vK. Thus, the expected correction pressure at the second piston speed can be determined with sufficient accuracy simply from the correction pressure actually measured at the first piston speed using the data relationship mentioned above. This works even if Equation 1 for a pipetting channel type, in particular for a pipetting tip type, was determined only for a filter-bearing or only for a filterless variant of this type, but the other variant of the same type is now used for the dispensing device.The ratio quotient in equations 4 and 4a, which essentially determines the conversion, differs essentially the same for one and the same type of pipette channel or pipette tip, for filtered and filterless variants, or differs only to an extent that is negligible for the accuracy assessment. Since, of all the causes contributing to the variation in the pressure of the working gas during the dispensing process in a pipette channel, a filter or filter element in the pipette channel, particularly in the pipette tip, makes the greatest contribution to the variation, the method can only be carried out on pipette channels with filters, particularly pipette tips.The above-described correction of an effect largely caused by a filter in the pipetting channel by subtracting an individual correction pressure from the temporal progression of the working gas pressure recorded during a dispensing process can be approximately understood as subtracting the effect on the working gas pressure achieved by the filter from the recorded progression of the working gas pressure. Tests have shown, for example, that the effect of a filter in the pipetting channel is a factor of 20 or more greater than the effect of other sources of interference on the working gas pressure in the pipetting channel. Consequently, the described correction approximates the recorded temporal progressions of the working gas pressure during a dispensing process with filter-bearing pipetting channels to those temporal progressions carried out with nominally identical, but filterless pipetting channels.According to a preferred development of the present invention, the same pressure setpoint ranges can therefore be used for nominally identical pipetting channels, in particular nominally identical pipetting tips, regardless of whether the pipetting channels, in particular the pipetting tips, have a filter or not. A pressure setpoint range is always assigned to a specific quantity of dosing liquid to be dispensed and to a specific dosing liquid or class of dosing liquid. This represents a considerable simplification in everyday dispensing operations. Due to the significant influence of the designated filters on the pressure of the working gas, this simplification can even be used if only the dispensing processes carried out with filter-bearing pipetting tips are corrected according to the method, while the dispensing processes carried out with filterless pipetting tips are not.66478P WO Hamilton Bonaduz AG - 13 - To achieve productivity gains or to minimize productivity losses, as already explained above, the piston speed of the correction pressure determination process is preferably higher than the piston speed of the dispensing process. The correction pressure determination process is preferably carried out at the highest possible piston speed for the respective design of the pipetting channel, in particular for the respective pipetting tip used. The piston speed during the correction pressure determination process is preferably at least in the range of 90% to 100% of the maximum possible piston speed for the respective design of the pipetting channel.If the design of the pipetting channel does not place an upper limit on the applicable piston speed, the correction pressure determination process is preferably carried out with a piston speed in the range of 90% to 100% of the maximum possible piston speed of the pipetting device. Alternatively, the piston speed can be selected so high that the resulting flow of working gas in the pipetting channel is just laminar and does not turn into turbulent flow. This piston speed can be determined in advance in the laboratory for each type of pipetting tip. In case of doubt, the term "piston speed" refers to the constant piston speed occurring during the correction pressure determination process and during the dispensing process.In the unlikely event that two or more different constant piston speeds occur during the specified processes, the highest occurring constant piston speed is the piston speed specified above. In principle, the correction pressure can be an absolute pressure of the working gas in the pipetting channel. To simplify the correction of the time profile of the pressure of the working gas during the dispensing process, the correction pressure is the same pressure type as the pressure of the working gas. Since the time profile of the pressure of the working gas, which is recorded during the dispensing process, is usually a differential pressure between the absolute pressure of the working gas and the absolute pressure of the surrounding atmosphere, the correction pressure is preferably also a differential pressure 66478P WO Hamilton Bonaduz AG - 14 - between the ambient pressure of the pipetting channel and the absolute pressure of the working gas in the pipetting channel.The correction step can then particularly easily comprise reducing the temporal profile of the working gas pressure recorded during the dispensing process by the amount of the correction pressure. For example, the correction pressure can simply be subtracted from the temporal profile of the working gas pressure during the dispensing process. Thus, the temporal profile of the working gas pressure during the dispensing process is adjusted for effects that occur during piston movement in the pipetting channel, regardless of whether or not dosing liquid is dispensed using the pipetting channel. In principle, the pipetting channel can be a rigid tube. For reasons of the highest possible process hygiene, it is preferred that the pipetting channel has a body channel with a coupling formation for temporarily coupling a pipetting tip. The method discussed here then preferably comprises coupling a pipetting tip to the body channel.The body channel and the pipette tip coupled to it then together form the pipette channel of the pipette device. To ensure that the correction pressure is determined for the pipette tip with which the dispensing process is also carried out, the correction pressure determination process is preferably carried out after the pipette tip has been coupled. In principle, it does not initially matter whether the correction pressure determination process is carried out before or after the dispensing process. However, especially during aspiration processes, the correction pressure determination process can be carried out with high accuracy immediately after coupling a new pipette tip on a clean pipette tip that is unaffected by residues of dispensing liquid. The correction pressure determination process is therefore preferably carried out before the dispensing process.During the dispensing process, the control device can record the temporal progression of the working gas pressure throughout the entire dispensing process, i.e., from the start of the piston movement or shortly before until the working gas pressure returns to a constant value after the piston movement has stopped again. However, to assess the quality of the dispensing process performed, it may be sufficient if the control device only corrects the temporal progression of the working gas pressure recorded during the dispensing process until the end of the pipetting piston movement. After the end of the pipetting piston movement, only pressure equalization processes and the decay of any vibrating column of dispensing liquid take place in the pipetting channel, which, however, generally has no significant influence on the quality of the previous dispensing process.Likewise, while further simplifying the process without loss of accuracy in assessing the quality of the dispensing process, it may be sufficient to begin a correction of the temporal progression of the working gas pressure recorded during the dispensing process only at a point in time within a time interval whose duration is no more than 10%, preferably no more than 5%, of the movement duration of the pipetting piston during the dispensing process and which includes the point in time at which the dispensing liquid, driven by the piston movement, begins to flow through the pipetting opening. The aforementioned end of the pipetting piston movement can be readily determined from the operating data of the control device or the pipetting device.In contrast to the end of the pipetting piston's movement, the beginning of the flow of dosing liquid through the pipetting opening is not the direct operation of a component of the pipetting device, but merely a consequence of it. However, the beginning of the flow of dosing liquid through the pipetting opening is clearly visible in the recorded temporal profile of the working gas pressure as a kink or a spontaneous change in the gradient of the pressure curve, so that this point in time at which the flow movement begins can also be determined clearly. This is explained in more detail below using the exemplary embodiment.According to the assessment method already known from the prior art, the present assessment method with pressure correction also provides that the control device outputs a positive quality assessment if the comparison step shows that the working gas pressure profile, preferably the time profile of the working gas pressure corrected by the correction pressure, lies entirely within the predetermined pressure setpoint range within a predefined section. Alternatively, or preferably additionally, it can be provided that the control device outputs a negative quality assessment if the comparison step shows that the working gas pressure profile, preferably the time profile of the working gas pressure corrected by the correction pressure, lies outside the predetermined pressure setpoint range within a predefined section.The quality assessment can be output via light signals, text output on a monitor and / or on printer paper, voice output, acoustic signals, and the like. Alternatively, or preferably additionally, the control device can mark the faulty pipetting in pipetting protocols and / or repeat the faulty dispensing process with a new pipette tip. In case of doubt, the control device initiates or immediately performs the aforementioned process steps. The latter applies in particular to the comparison step and the correction step.In accordance with the above, the present invention further relates to a pipetting device comprising: - a pipetting channel at least partially filled with a working gas, - a pipetting piston movably received in the pipetting channel in order to change a pressure of the working gas in the pipetting channel by a piston movement, - a pipetting opening through which dosing liquid can flow in order to change the amount of fluid received in the pipetting channel, - a piston drive for driving the pipetting piston to move along the pipetting channel, - a pressure sensor for detecting the pressure of the working gas in the pipetting channel, and - a control device for storing and processing data, and for controlling the piston drive, wherein the control device is designed to carry out a method as described and further developed above.The above description of the 66478P WO Hamilton Bonaduz AG - 17 - method also serves to describe the pipetting device designed to carry out this method. The concrete design for carrying out this method is generally in the control device of the pipetting device. The control device generally comprises a data memory and at least one integrated circuit. Sensor signals, for example from the pressure sensor, can be stored in the data memory. In addition, an operating program for operating the pipetting device can be stored in the data memory. The control device can be formed by several cooperating partial control devices. Likewise, the data memory can comprise several partial data memories.Since the method presented here achieves its particular advantage when the variability of the characteristics of the pipetting channel in interaction with the working gas is particularly great due to the exchange of different pipetting tips, the pipetting channel of the pipetting device preferably has a body channel with a coupling formation for temporarily coupling a pipetting tip. The coupling formation can be a coupling nozzle, which can be inserted into a corresponding longitudinal end-side counter-coupling formation, for example in the form of a sleeve or socket section of the pipetting tip. Therefore, the pipetting device preferably has a pipetting tip that can be coupled to the coupling formation as part of the pipetting channel, wherein the pipetting tip has a counter-coupling formation complementary to the coupling formation."Complementary" should not be understood as a necessarily negative shape to the coupling formation as a positive shape. The counter-coupling formation is sufficiently complementary to the coupling formation if, after insertion into the counter-coupling formation, the coupling formation is arranged in a suitable and gas-tight manner within the counter-coupling formation. The body channel and the pipetting tip coupled to it then jointly form the pipetting channel of the pipetting device. Due to the particular value of the method described above for correcting fluctuations in the characteristics of a filtered pipetting tip in conjunction with moving working gas, the pipetting tip preferably not only has the pipetting opening in the conventional manner, but also preferably has a porous filter in a section between the pipetting opening and the counter-coupling formation.According to the above explanation, the pipetting device can even be designed to correct only recorded temporal profiles of the working gas pressure of dispensing processes that were carried out with filter-bearing pipetting tips. The pipetting device or its control device can use the same pressure setpoint range to assess the quality of a dispensing process for dispensing one and the same amount of one and the same dispensing liquid, once for filter-bearing and once for filterless pipetting tips of nominally the same design. The present invention will be explained in more detail below with reference to the accompanying drawings. They show: Fig. 1 a roughly schematic view of a pipetting device according to the invention, designed to carry out the method according to the invention, Fig.1 during a dispensing process, without correction of the pressure curve, Fig. 4 is a roughly schematic representation of predetermined data relationships of constant speed of the piston of the pipetting device of Figure 1 and correction pressures of the working gas recorded in the pipetting channel, and 66478P WO Hamilton Bonaduz AG - 19 - Fig. 5 is a roughly schematic representation of a family of time profiles of pressure of the working gas in the pipetting channel of the pipetting device of Figure 1, each corrected by an individually determined correction pressure.In Figure 1, an embodiment of a pipetting device according to the invention is generally designated 10. The pipetting device 10 comprises a pipetting channel 12 extending along a channel axis K. The pipetting channel 12 is designed in several parts and comprises a body channel 14 fixed to the pipetting device and having a coupling formation 16. The pipetting channel 12 further comprises an exchangeable pipetting tip 18 coupled to the coupling formation 16. The pipetting tip 18 comprises a counter-coupling formation 20 at its longitudinal end coupled to the coupling formation 16 and comprises a pipetting opening 22 at its other longitudinal end. The pipetting opening 22 opens the pipetting tip 18 to a receiving volume 24 into which dosing liquid, for example the dosing liquid 25, can be received through the pipetting opening 22 and from which dosing liquid 25 can be dispensed through the pipetting opening 22.A filter element 26 is accommodated in an area of ​​the pipetting tip 18, which during normal pipetting operation is always filled only with a working gas, such as air. The filter element 26 can be formed from a fiber tangle and / or a sintered particle material and / or an open-cell foam with a predetermined porosity. The body channel 14 itself is in turn formed from several parts. In a section 28 of the body channel 14 located further away from the coupling formation 16 along the channel axis K, a pipetting piston 30 is movably accommodated along the channel axis K.Connected to the section 28 of the body channel 14 accommodating the pipetting piston 30 is another section 32 of the body channel 14, which has a narrower channel cross-section than the section 28 accommodating the pipetting piston 30, 66478P WO Hamilton Bonaduz AG - 20 - so that the pipetting piston 30 cannot leave the section 28 toward the coupling formation 16. A pressure sensor 34 is arranged in the section 32 and is designed to detect the pressure of the working gas in the pipetting channel 12. The body channel 14 is always filled only with working gas. The pipetting tip 18 is also always filled only with working gas, from its counter-coupling formation 20 to the pipetting opening 22 and beyond the filter element 26. During normal operation, the pipetting tip 18 is filled either with working gas or with dosing liquid 25 from the pipetting opening 22 in the axial direction towards the counter-coupling formation 20.During normal pipetting operation, the pipetting tip 18 is filled with dosing liquid 25 up to its maximum nominal volume. Apart from the working gas and dosing liquid, there are no other fluids in the pipetting channel 12. The pipetting piston 30 is coupled to a piston drive 36, by which the pipetting piston 30 can be driven to move along the channel axis K in section 28 of the pipetting channel 12. The piston drive 36 can be a conventional mechanical drive, such as a spindle drive, or can be a linear motor drive in which the pipetting piston 30 forms a permanent-magnet rotor. The piston drive 36 is connected to a control device 38 for signal transmission, so that the control device 38 can control the piston drive 36 to achieve movement of the pipetting piston 30.The piston drive 36 can transmit data indicating the current position of the pipetting piston 30 in the pipetting channel 12 to the control device 38 via a connecting line. The control device 38 comprises a plurality of integrated circuits 40 and a plurality of data memories 42, in which sensor data can be stored and read out, and in which predetermined data relationships and operating programs can be stored. As is already known from WO 02 / 073215 A2, the pressure of the working gas in the pipetting channel 12 during an aspiration process and during a dispensing process exhibits a characteristic temporal profile, which can be used to check the quality of the dispensing process being performed, be it an aspiration process or a dispensing process.Figure 2 shows an example and rough schematic of the time course of an – uncorrected – pressure of the working gas in the pipetting channel 12 during an aspiration process. Figure 3 shows an example and rough schematic of the time course of an – uncorrected – pressure of the working gas in the pipetting channel 12 during a dispensing process. In Figure 2, the time course of the pressure of the working gas in the pipetting channel 12 during an aspiration process is shown as a solid line 44, as detected by the pressure sensor 34. The pressure of the working gas is shown as a differential pressure with respect to the ambient pressure. The aspiration process begins at an empty pipetting tip 18 at a differential pressure with respect to the ambient pressure of 0 Pa. At approximately point 46, the pipetting piston 30 begins to move, which is why the pressure of the working gas in the pipetting channel 12 initially drops steeply.At point 48, the negative pressure in the receiving chamber 24 of the pipette tip 18 is so great that dosing liquid 25 begins to flow into the receiving chamber 24 through the pipette opening 22. The pipette piston is moved at a constant speed. The inflowing dosing liquid 25 ensures a less rapid pressure drop of the working gas in the pipette channel 12. The pressure of the working gas in the pipette channel 12 drops approximately linearly with time until the end of the pipette piston's movement at point 50. After the end of the pipette piston's movement, dosing liquid 25 continues to flow into the receiving chamber 24, driven by the still-existing negative pressure in the pipette channel 12 and in particular in the receiving chamber 24 of the pipette tip 18.In the absence of further movement of the pipetting piston 30, this subsequent flow of dosing liquid 25 leads to a rapid reduction of the negative pressure of the working gas relative to the ambient pressure in the pipetting channel 12 until an equilibrium is reached between the negative pressure of the working gas still existing as a holding pressure in the pipetting channel 12 and the quantity of 66478P WO Hamilton Bonaduz AG - 22 - dosing liquid 25 taken up into the pipetting channel 12. Since the inflowing dosing liquid 25 ceases to flow upon reaching the equilibrium state, the thus delayed liquid column can continue to oscillate in the receiving space 24 of the pipetting tip 18, which is shown in curve 44 as a decaying pressure fluctuation in the region 52. The curve 44 of the time course of the working gas in the pipetting channel 12 is a curve of a successful aspiration process which has run without errors.It runs entirely within a pressure setpoint range 54, which indicates the permissible values ​​of the pressure of the working gas in the pipetting channel 12 at any time during the aspiration process for the aspirated quantity and type of dosing liquid 25. The pressure setpoint range 54 is limited towards higher pressures by a dashed curve 56, which represents an upper limit of the pressure setpoint range 54. Likewise, the pressure setpoint range 54 is limited towards lower pressures by a dashed curve 58, which represents a lower limit of the pressure setpoint range 54. As long as the temporal progression of the recorded pressure of the working gas in the pipetting channel 12 during a dosing process, here during an aspiration process, runs between the upper limit 56 and the lower limit 58, the aspiration process is considered error-free.If the temporal progression of the recorded pressure of the working gas leaves the pressure setpoint range 54, the aspiration process is considered to be faulty. Depending on where and how the recorded temporal progression of the pressure of the working gas leaves the pressure setpoint range 54, different causes of the error can be inferred. In this regard, reference is made to the description already given in WO 02 / 073215 A2. If the temporal progression of the pressure of the working gas falls below the lower limit 58, for example, this may be due to a blockage in the pipetting opening 22. If the temporal progression exceeds the upper limit 56, this may be due, for example, to undesired foam formation in the dosing liquid 25 or to an aspiration process that was carried out for too short a time.66478P WO Hamilton Bonaduz AG - 23 - Pipetting devices 10 with pipetting channels 12 of the same design, in particular with pipetting tips 18 of the same design, can lead to different pressure profiles of the working gas pressure in the pipetting channel 12 when the piston movement of the pipetting piston 30 for aspiration of the same amount of the same dosing liquid occurs in an essentially identical manner due to manufacturing tolerances that occur, in particular of the pipetting tip 18 and, within this, in particular of the filter element 26. The dotted lines 60 and 62 shown in Figure 2 indicate, by way of example and in a rough schematic manner, an upper limit (line 60) and a lower limit (line 62) of the scatter of the recorded temporal profile of the working gas pressure.To avoid false-negative assessments of the quality of the aspiration process, the pressure setpoint range 54 must be selected to be large enough for the specified scatter that the entire scatter range of the recorded temporal progression of the working gas pressure lies within the pressure setpoint range 54. However, such a wide pressure setpoint range 54 increases the risk of false-positive assessments of the quality of the aspiration process. The same applies to the dispensing process shown schematically in Figure 3. The temporal progression of the pressure of the working gas in the pipetting channel 12 during the dispensing process is shown by the solid line 64. At 66, the movement of the pipetting piston 30 begins, and at 68, dosing liquid 25 begins to exit the receiving chamber 24 through the pipetting opening 22.At 70, the movement of the pipetting piston ends, and the overpressure of the working gas in the pipetting channel 12 relative to the ambient pressure drops suddenly. The pressure level of the working gas at the end of the dispensing process is determined by the amount of dosing liquid remaining in the receiving chamber 24. The control device 38 preferably sets the pressure value supplied by the pressure sensor 34 to zero at the beginning of a dispensing process, so that the pressure values ​​supplied during the dispensing process indicate the deviation from the mandatory initial value of zero. Setting to zero corresponds to shifting the curve 64 along the ordinate such that the curve 64 begins at zero. The pressure value established at the end of a dispensing process is therefore positive. This represents a holding pressure in order to keep the residual amount of dosing liquid remaining in the receiving chamber 24 in the pipette tip 18.Since less dosing liquid 25 is taken up into the receiving chamber 24 at the end of the dispensing process than at the beginning, the holding pressure, as a negative differential pressure, is lower in magnitude at the end of the dispensing process but higher in pressure value than at the beginning of the dispensing process. By setting the pressure value supplied by the pressure sensor 34 at the beginning of the dispensing process to zero, the recorded dispensing pressure curve 64 is shifted towards more positive values, which is why the holding pressure is positive at the end of the dispensing process. The control device 38 can also, in an analogous manner, shift the pressure value supplied by the pressure sensor 34 to the zero point of the ordinate at the beginning of an aspiration process, i.e., set it to zero. The pressure setpoint range for the temporal progression of the working gas pressure during a dispensing process is indicated by 74 in Figure 3.Analogous to the pressure setpoint range 54 for the aspiration process, the pressure setpoint range 74 for the dispensing process is defined by a dashed upper limit 76 and a dashed lower limit 78. The scatter of recorded pressure values ​​of the working gas pressure during a dispensing process caused by realized manufacturing tolerances, despite the use of nominally identical pipetting tips and a nominally identical body channel 14 for dispensing an identical amount of an identical dosing liquid, is again indicated in Figure 3 by dotted lines, namely by a dotted upper limit 80 and a dotted lower limit 82 of the scatter range.As in the case of the aspiration process, false-negative quality assessments of a dispensing process can only be avoided by selecting a correspondingly large pressure setpoint range 74, whereby an increase in the pressure setpoint range 74 also increases the risk of undesirable false-positive quality assessments. 66478P WO Hamilton Bonaduz AG - 25 - To avoid the aforementioned scatter in the working gas pressure values, the control device 38, after coupling a new pipette tip 18 and before the first dosing of dosing liquid with the newly coupled pipette tip 18, carries out a correction pressure determination process in which the pipette piston is moved at a constant speed with the pipette channel 12 completely filled with working gas only. The pressure of the working gas in the pipetting channel 12 prevailing during the piston movement at constant speed is recorded by the pressure sensor 34 and stored in the data memory 42.To avoid productivity losses, the pipetting piston 30 is moved at the highest possible piston speed during the correction pressure determination process. In pipetting devices, the piston speed is advantageously specified as the volume swept by the moving pipetting piston per unit of time, for example, in the unit µl per second (µl / s). For the pipetting device 10, the highest possible piston speed is 500 µl / s. With this constant piston speed, the pipetting piston 30 is moved in the aspiration direction, and the pressure of the working gas prevailing in the pipetting channel 12 is measured as a differential pressure relative to the ambient pressure. This detected correction pressure is, for example, -350 Pa. The subsequent aspiration process performed with the same pipetting tip 18 is not carried out at 500 µl / s, but only at a piston speed of 200 µl / s.To convert the correction pressure actually recorded at a higher piston speed to a correction pressure expected at the actual piston speed of the dispensing process, a data relationship shown in Figure 4 is stored in the data memory 42 of the control device 38. More precisely, a data relationship 84 for an aspiration and another data relationship 86 for a dispensing with the respective pipette tip 18 are stored in the data memories 42. The data relationships were determined in advance on a pipetting device identical in construction to the pipetting device 10, for a body channel 14 nominally identical to the body channel 14, and for a pipette tip 18 nominally identical to the pipette tip 18.Since the permissible manufacturing tolerances for the pipette tip 18 used to determine the data context 84 for aspiration were realized in a different way than for the pipette tip 18 actually coupled during the correction pressure determination process, a correction pressure of -318 Pa is stored in the data context 84 for the piston speed of 500 µl / s. This is lower in magnitude than the correction pressure of -350 Pa determined during the correction pressure determination process. However, the inventors have discovered that for identically constructed pipette tips 18 or for identically constructed pipette channels 12, the correction pressures determined at different piston speeds always behave the same to one another, regardless of their respective absolute value.In data context 84, a correction pressure of -125 Pa is stored for the piston speed of 200 µl / s actually used during the dosing process. Using equations 4 and 4a mentioned in the introduction to the description, the correction pressure expected during the aspirating dosing process following the correction pressure determination process can be determined as ?. )>NO%P > ! " C # # $ D $ = HIJKLM A ?Q)RPO%This results in an expected correction pressure of -137.6 Pa for the aspirating dosing process carried out between points 48 and 50 with an essentially constant piston speed of 200 µl / s. The temporal profile of the pressure of the working gas recorded during the aspirating dosing process is corrected, i.e. reduced, by this correction pressure. Since both the temporal profile of the pressure of the working gas during the aspiration process and the expected correction pressure have a negative sign, the reduction of the temporal profile of the pressure of the working gas by the expected correction pressure leads to an absolute reduction in the profile of the working gas pressure by the correction pressure. For a dispensing process, the procedure is analogous mutatis mutandis, but using the data context 86 for a dispensing process. For the aspiration process of Fig.2, it may be sufficient to correct the curve 44 of the working gas pressure only between points 48 and 50. For the dispensing process of Fig. 3, it may be sufficient to correct the curve 64 of the working gas pressure only between points 68 and 70. Since, with the correction pressure determination process described above, an individual correction value can be determined for the pipetting channel 12 performing the dispensing process in each case, and in particular for the pipetting tip 18 coupled to it, the scatter of the recorded temporal profile of the working gas pressure corrected by the correction value can be significantly reduced. In Figure 5, a family of temporal profiles corrected by the respective correction values ​​is shown with a solid line 90. Their scatter is negligible.As a result, the pressure setpoint range 54 can be defined as a new pressure setpoint range 54', which is considerably more narrowly defined than the pressure setpoint range 54 of Figure 2, without increasing the number of false-negative quality assessments. However, the more narrowly defined pressure setpoint range 54' significantly reduces the risk of undesirable false-positive quality assessments of aspiration processes. The same applies mutatis mutandis to dispensing processes. Thus, the accuracy of the quality assessment of the dispensing process performed can be considerably improved by the correction process presented here, based on a correction pressure determined individually using a pipetting channel 12 filled exclusively with working gas. Since the correction pressure can be determined at very high piston speeds, the improvement in quality assessments can be achieved with only very minimal loss of productivity.

Claims

66478P WO Hamilton Bonaduz AG - 28 - Claims 1. A method for the quality-assessed dosing of a dosing liquid (25) by means of a pipetting device (10), wherein the pipetting device (10) comprises: - a pipetting channel (12) at least partially filled with a working gas, - a pipetting piston (30) movably received in the pipetting channel (12) in order to change a pressure of the working gas in the pipetting channel (12) by a piston movement, - a pipetting opening (22) through which dosing liquid (25) can flow in order to change the amount of fluid received in the pipetting channel (12), - a piston drive (36) for driving the pipetting piston (30) to move along the pipetting channel (12), - a pressure sensor (34) for detecting the pressure of the working gas in the pipetting channel (12), - a control device (38) for storing and processing of data, as well as for controlling the piston drive (36),wherein the method comprises the following steps: - carrying out a dosing process by moving the pipetting piston (30) and thereby changing the pressure of the working gas in the pipetting channel (12) and thereby changing the amount of dosing liquid (25) taken up in the pipetting channel (12), - detecting a temporal profile of the pressure of the working gas (44, 54) in the pipetting channel (12) during the dosing process, - comparing a profile of the working gas pressure (90) based on the detected temporal profile of the working gas pressure (44, 64) with a predetermined pressure setpoint range (54, 74), and - outputting a quality assessment of the dosing process depending on the result of the comparison step, characterized in that the method comprises the following further steps, wherein the control device (38) carries out the further steps while the pipetting channel (12) is filled substantially exclusively with working gas filled with fluid:, 66478P WO Hamilton Bonaduz AG - 29 - - Carrying out a correction pressure determination process by moving the pipetting piston (30) and thereby changing the pressure of the working gas in the pipetting channel (12) and thereby aspirating working gas into the pipetting channel (12) and / or dispensing working gas from the pipetting channel (12), and - Detecting a pressure of the working gas in the pipetting channel (12) during the correction pressure determination process as a correction pressure, wherein the control device (38) carries out the following further step before the comparison step: Correcting the time profile of the working gas pressure (44, 64) detected during the dispensing process on the basis of the correction pressure of the working gas detected during the correction pressure determination process, so that the step of comparing with the corrected time profile (90) the working gas pressure. 2.Method according to claim 1, characterized in that during the correction pressure determination process, the pipetting piston (30) is moved in the same direction of movement as during the dosing process.

3. Method according to claim 1 or 2, characterized in that during the correction pressure determination process, the pipetting piston (30) is moved at a constant movement speed, and the correction pressure of the working gas is detected during the movement phase of constant movement speed. 4.Method according to one of the preceding claims, characterized in that during the correction pressure determination process the pipetting piston (30) is moved at a different speed than during the dosing process, wherein in a data memory (42) for a respectively used type of pipetting channel (12) a data relationship (84, 86) is stored which links different correction pressures with different piston speeds, wherein the control device (38) proceeds from the piston speed of the correction pressure. 66478P WO Hamilton Bonaduz AG - 30 - an expected correction pressure associated with the piston speed of the dispensing process is determined from the correction pressure actually detected during the determination process based on the data context (84, 86), and the temporal profile of the working gas pressure (44, 64) detected during the dispensing process is corrected with the expected correction pressure.

5. Method according to one of the preceding claims, characterized in that the piston speed of the correction pressure determination process is higher than the piston speed of the dispensing process.

6. Method according to one of the preceding claims, characterized in that the correction pressure is a differential pressure between the ambient pressure of the pipetting channel (12) and the absolute pressure of the working gas in the pipetting channel (12). 7.Method according to one of the preceding claims, characterized in that the correcting step comprises a reduction in the temporal profile of the working gas pressure detected during the dosing process by the correction pressure.

8. Method according to one of the preceding claims, characterized in that the pipetting channel (12) has a body channel (14) with a coupling formation (16) for temporarily coupling a pipetting tip (18), the method comprising coupling a pipetting tip (18) to the body channel (14), the correction pressure determination process being carried out after the coupling of the pipetting tip (18).

9. Method according to one of the preceding claims, characterized in that the correction pressure determination process is carried out before the dosing process. 66478P WO Hamilton Bonaduz AG - 31 - 10. The method according to one of the preceding claims, characterized in that the control device (38) corrects the temporal profile of the working gas pressure detected during the dosing process only until the end of the movement of the pipetting piston (30).

11. The method according to one of the preceding claims, characterized in that the control device (38) outputs a positive quality assessment if the comparison step shows that the profile of the working gas pressure (90) lies entirely within the predetermined pressure setpoint range (54') within a predefined section, and / or that the control device (38) outputs a negative quality assessment if the comparison step shows that the profile of the working gas pressure (90) lies outside the predetermined pressure setpoint range (54') within a predefined section. 12.A pipetting device (10), comprising: - a pipetting channel (12) at least partially filled with a working gas, - a pipetting piston (30) movably received in the pipetting channel (12) in order to change a pressure of the working gas in the pipetting channel (12) by a piston movement, - a pipetting opening (22) through which dosing liquid (25) can flow in order to change the amount of fluid received in the pipetting channel (12), - a piston drive (36) for driving the pipetting piston (30) to move along the pipetting channel (12), - a pressure sensor (34) for detecting the pressure of the working gas in the pipetting channel (12), and - a control device (38) for storing and processing data, and for controlling the piston drive (36), characterized in that the control device (38) is designed to carry out a method according to one of the preceding claims. 66478P WO Hamilton Bonaduz AG - 32 - 13. Pipetting device (10) according to claim 12, characterized in that the pipetting channel (12) has a body channel (14) with a coupling formation (16) for temporarily coupling a pipetting tip (18).

14. Pipetting device (10) according to claim 13, characterized in that the pipetting device (10) has a pipetting tip (18) that can be coupled to the coupling formation (16), wherein the pipetting tip (18) has a counter-coupling formation (20) complementary to the coupling formation (18).

15. Pipetting device (20) according to claim 14, characterized in that the pipetting tip (18) has the pipetting opening (22), wherein the pipetting tip (18) has a porous filter (26) in a section between the pipetting opening (22) and the counter-coupling formation (20).

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