HK1067407B - Method and device for evaluating a liquid dosing process - Google Patents

Description

The present invention relates to methods and devices for the assessment of a liquid dosing process in a pipette at least partially filled with a gas.

Fluid dosing is a common practice in chemical, pharmaceutical, medical and human biology processes. Many of these dosing processes are part of a manufacturing process to produce pharmaceutical or medical active substances and medicinal products or contribute to the medical diagnosis of diseases. Unrecognized incorrect fluid dosing can therefore lead to numerous products that are valuable, critical or even dangerous to the health of living organisms, especially humans. However, even in clinical or operational settings, the risk of mis-dose is always limited and only when the dosing is not adequately controlled and the risks of mis-dose are still limited, is it realized that the risks of mis-dose are limited.

It is therefore of great importance to be able to assess the error-free performance of liquid dosing operations as early as possible with the greatest possible certainty.

For example, for an aspiration process, i.e. for the absorption of a liquid, and for a dispensation process, i.e. for the release of a liquid, various methods for evaluating a liquid dosing process during pipetting are known from the state of the art.

In an aspiration process, the pipette tip is first immersed in the liquid to be absorbed, which locks a volume of gas in a liquid intake space bounded by a pipette tip opening, a pipette tip inner wall and a plunger and separates it from the surrounding gas volume, so that the gas volume in the pipette tip remains approximately constant, i.e. excluding evaporation and condensation processes. An intake movement of the pipette tip from the pipette tip increases the volume of the closed gas pressure through the pipette, which increases the pressure of the gas in the liquid intake chamber. The pressure difference between the gas intake velocity of the liquid in the pipette and the flow velocity of the gas in the liquid intake chamber is due to a change in the flow velocity of the gas through the pipette.

The known methods for assessing a liquid dosing process are to monitor whether the gas pressure in the liquid intake chamber falls below a predetermined limit.In some cases, in addition to falling below a limit, the rate of change in the pressure of the gas contained in the liquid intake chamber is also observed, i.e. it is checked whether the gas pressure in the liquid intake chamber changes by a predetermined amount in a predetermined time.This test can be done graphically by comparing the slope of a pressure-time curve with a predetermined slope or analytically by comparing the corresponding pressure-time values.

The dispensing operation, in which the volume of a volume of gas trapped between a liquid being absorbed and the pipette plunger is reduced by a sliding movement of the pipette plunger on the pipette opening, shall be assessed accordingly as described above.

The disadvantage of this state-of-the-art method is that the assessment of whether the liquid dosing process has been error-free or not is based on only a few measurements, which are usually taken at the beginning of the dosing process. An error that occurs after the gas pressure limit is reached is no longer covered by this method. Such an error may occur, for example, when the pipette tip is blocked by a solid in the liquid during the pipette tip opening when liquid is flowing into the pipette tip. This may be the case for blood dosing, for example, when there are clotted components in the liquid blood.

WO 92/08545 A1 describes a method for assessing a liquid dosing process divided into a variety of sub-dosages, whereby after each sub-dosage, the gas pressure is measured in a line leading to a pipette tip at a stationary piston and compared with upper and lower threshold values, which in turn give a range following a set curve, to check whether or not a measurement point is within the set range.

WO 98/53325 A1 describes a method of liquid dosing in which the pressure of a liquid in a pipette-connected line is continuously monitored for the time the pipette-piston is moving. It describes the possibility of comparing a pressure profile obtained with a pre-determined pressure profile in order to assess the dosing process.

EP 0 982 593 A1 is a device for monitoring pipetting from one liquid to another liquid, which is illuminated by a detector.

A method for monitoring pipetting operations is known from EP 0 990 909 A1 in which four pressure values are measured during a dosing operation with pressure sensors and compared with threshold values.

The present invention is intended to describe a theory which enables the practitioner to perform liquid dosing operations as quickly as possible, while still being able to assess with confidence their success and to detect faulty dosing at an early stage.

The first point of the present invention is that the problem is solved by a method for assessing a liquid dosing process with the characteristics of claim 1.

By recording at least one state size of a medium present in the pipette over substantially the entire duration of the dosing process, information on the filling state of the pipette is available and can be used to assess the state of the pipette for substantially the entire dosing process.

The range of state parameters is defined by a measurement curve, which determines whether the time course of at least one state parameter is within the range of state parameters to assess the dosing process and, depending on the result of the determination, will give an evaluation result, a very easy comparison to make to assess the dosing process reliably.

The range of state parameters to be used may be, for example, an ideal state parameter range with a tolerance specification.

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The state size can be measured in any medium in which the vessel is present. In pipettes, a particularly accurate result can be obtained by measuring at least one state size of the gas in the vessel, since the volume of gas contained in the vessel, unlike the incoming or outgoing liquid, is almost exclusively influenced by the liquid to be dosed and an influence from the surroundings of the vessel is almost excluded.

Another advantage of detecting at least one state size of the gas present in the vessel is that it allows measurements to be made at lower dosage volumes than when measuring the state size of the liquid itself, since the liquid is more subject to adhesion and/or friction interactions with the vessel wall than the gas, which become negligible after a certain minimum volume.

The method of the present invention can be used with any type of gas, i.e. in any type of gas atmosphere. In the simplest and most common case, the dosing operation is carried out in ambient air, so that the vessels are filled with air. However, it is also conceivable that liquids should be dosed whose contact with air or oxygen is not desired. In this case, the method of the present invention can also be used for dosing in an inert or quasi-inert atmosphere, such as argon, nitrogen oxide or carbon dioxide atmosphere.

As already described, the state quantity for measuring hydrostatic pressure in the liquid in the vessel is gas pressure and/or temperature, as in the case of gas pressure measurements in the gas phase, as the gas pressure and/or temperature are used for measuring the gas in the vessel. Since the amount of gas in the vessel, i.e. the gas mass, remains approximately constant in many dosing vessels during the dosing process, but the volume of the gas volume is changed by the movement of a piston, the volume of the gas changes with the pressure and, depending on the dosing process, also the temperature of the gas.

For the purpose of capturing a state quantity, it is sufficient to capture a quantity that changes in a known relationship to the state quantity.

It is advantageous to define the range of state values for at least the entire duration of the liquid dosing process, in which case it is possible to assess the liquid dosing process not only at certain times, but actually at any time during the dosing process.

However, this does not mean that the range of state values is defined only for the duration of the change in the volume of liquid in the vessel. It may also be useful to record the range of state values before and/or after the phase of change in the volume of liquid in the vessel and accordingly extend the range of state values to these periods. Thus, any transport phase between the aspiration phase and the dispensation phase can be monitored, for example for liquid loss due to drip formation and drip loss or even loss of pipette tip.

The precise procedure for recording such upstream and downstream fluid dosing processes is described below by example.

For the sake of maximum clarity and ease of understanding of the assessment results obtained, the range of state parameters may be favourably defined in such a way that the liquid dosing operation is considered error-free as long as the recorded time course of at least one state parameter is within the range of the state parameters and is considered error-free when it is determined that the recorded time course of at least one state parameter is at least partly outside the range of the state parameters.

For example, a pipette opening may be temporarily blocked or narrowed in cross-section by a solid, and the solid is washed away by the incoming or outgoing liquid after a period of stagnation. In this case, for example, the gas pressure inside the pipette tip would drop sharply during an aspiration process (or/and the gas temperature would drop sharply) so that the state size would leave its range of values. After the disturbance is removed, the state size may revert to values within the range of values. However, during the occurrence of the disturbance, uncertain flow ratios at the pipette tip are already defined as defective, and it is then determined that the size of the pipette is outside the range of values defined by the minimum size limit.

A further advantage of the method of the invention is that, in addition to assessing the correct course of the dosing process, it is possible to diagnose the error in the event of its occurrence in terms of its type of error. To this end, it is advantageous that, when the time course of at least one condition quantity is recorded as at least partially outside the condition quantity range, it is determined whether the course of at least one condition quantity is at least partially within at least one error range of a multiple of the error ranges of a condition quantity range outside the condition quantity range.

If the time course of at least one condition value leaves the condition value range, the time course of at least one condition value is in a condition value range outside the condition value range. Different types of errors usually occur at different times and/or lead to different deviations of the condition value from the condition value range. It is therefore possible to divide the condition value values giving the condition value range into at least one error range, preferably a multiple of errors. However, each error range is precisely divided into one error range, or in some cases, a multiple of these errors, and/or to convert them into a multiple of errors.

The upper threshold curve is the threshold curve that limits the threshold curve to higher threshold values. The lower threshold curve is therefore the threshold curve that limits the threshold curve to lower threshold values. The threshold curves can be functions of time and are usually also superior, since the threshold curve usually follows a non-trivial curve. In this case, the time intermediate flow of the curve should be at least one degree below the threshold curve and should be carried out in a simple way, although the time intermediate flow is within the threshold curve and is within the threshold curve.

Alternatively, the determination of whether the time course of at least one state size is within the prescribed state size range of values can also be performed by image processing. An image processing determination method is favoured by the method of the invention insofar as the data bases used in the method, such as the time course of at least one state size, state size range of values and, if desired, a number of error ranges, are particularly suitable for graphical representation and evaluation.

The quality of the assessment of the liquid dosing process obtained by the method of the invention depends to a large extent on the range of state parameters used for the assessment. If the range of state parameters is very broad, there is a risk that already faulty dosing operations will still be considered as error-free. Conversely, a very narrow range of state parameters will carry the risk that error-free dosing operations will be considered as error-free.

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After repeated application of the liquid dosing procedure, provided that each individual dosing procedure has been completed without error, a set of time steps of at least one state size can be obtained, the envelopes of which can be used as the basis for further applications of this liquid dosing procedure as the values of the state size range.

Alternatively, the set of time steps of at least one state quantity can also be aggregated into a reference curve, for example by means of a mean.

The above problem is also solved by a process having the characteristics of claim 6 according to another aspect of the present invention.

According to the method of the present invention, the time course of at least one state quantity can be correlated to determine the degree of agreement of the time course of at least one state quantity with the predefined reference curve by a correlation calculation method and, depending on the result of the calculation, an assessment result can be issued regarding the dosing process. The use of correlation calculation methods makes very accurate comparisons of the time course of at least one state quantity with the predefined reference curve. Furthermore, the correlation calculation method can be performed and a reference curve can be set for certain operating space savings at the time of the detection of the state-scale range of the dose levels required for the current dosing process. The correlation can also be used to reduce the quantity of the correlation factor required for the current dosing rate and to achieve a comparable quality of the correlation.

The correlation method is based on known methods such as the Fast Fourier transform, polynomial regression, regression in general, wavelets and differentiation.

Such correlation calculation methods usually give the degree of agreement between two curves or point courses as a numerical value. For example, the dosing procedure to be examined may be considered to be erroneous if the degree of agreement determined is outside a predetermined range of conformity limits. This comparison of a numerical value with a predetermined range of values allows the assessment result to be obtained quickly, which is particularly important in view of the short time available for industrial dosing procedures.

Furthermore, an error occurring when the degree of conformity is recorded as being outside the prescribed range of conformity values can be examined in more detail by a further diagnostic comparison procedure. In particular, this will determine whether the degree of conformity is within a range of errors from a number of ranges of errors within a range of values outside the range of conformity values. Depending on the range of errors in which the conformity is located, an error statement will be issued. This will make it possible to identify and critically assess a systematic error in the dosing system quickly and reliably.

In order to save further computation time and storage space, it is sufficient for the correlation calculation method to use as input values reference points from the time course of at least one state quantity and the reference curve.

From another point of view, the above problem is also solved by a device as claimed in claim 14.

The time course of at least one state variable may be recorded continuously or in individual measurements at intervals, the interval between two individual measurements being small compared to the total duration of the liquid dosing operation.

The data store stores the preset range of state parameters to be used and the state parameters recorded by the sensor are stored in the data store.

A time series can be formed from a number of individual measurements, for example by assigning to each measurement a state of the machine or vessel characteristic of the dosing operation, e.g. the position of a moving plunger relative to the rest of the vessel.

The device may also include a clock. If desired, the time points associated with a state dimensioning can be stored themselves, either as an alternative or in addition to the above-mentioned machine states. Storage of state dimensions together with the associated recording times or these equivalent machine states is necessary, for example, if the recording of state dimensions by at least one sensor is not done in constant time intervals. If, on the other hand, state dimensions are recorded at constant intervals, the recording of recording times may be omitted, since the recording time is determined from the order of a state parameter position in a series of state dimensions.

The device shall also include a data processing unit trained in accordance with claim 14.

Finally, an output unit is used to output an assessment result, which is obtained by the data processing unit depending on the result of the determination.The output unit may use alphanumeric characters and/or graphic elements such as coloured and/or structured lines and/or surfaces to output the assessment result and, if desired, to display the time course of the condition size and the range of condition size values.

In addition to the state-size-must-have range, the data store may continue to store a number of predefined error ranges, each of which is associated with at least one possible dosing process error, enabling the data processing unit to diagnose the dosing process error (s) in question.

The device for creating the range of values of the state variables may also include an editing unit, which allows, for example, to create a range of values of the state variables from a set of time series of the state variables.

The editing unit may include a related input unit, which may be used to enter numerical values, for example, to define the tolerance ranges around which a time series is widened or narrowed.

Alternatively or in addition to this, the output unit of the device can be a graphic output unit, whereby a range of state values can also be defined graphically via the input unit. This graphic method, in which, for example, the set of time courses of the state size and a range of state values are visible together, represents a particularly simple but yet very effective way of creating a range of state values.

In accordance with the preferred embodiments of the method of the invention described above, the data processing unit can determine whether the time course of at least one state is within the prescribed state-to-value range.

In accordance with another aspect of the present invention, the above-mentioned task is also solved by a device according to claim 19, in which the data processing unit is trained in particular to perform a correlation calculation to determine a degree of agreement of the time course of at least one state quantity with a predefined reference curve as a range of state quantities.

The previously mentioned error ranges that can be stored in the error database for error diagnosis can be, for example, conformity ranges, in which case a specific error or group of errors is assigned to a specific range of conformity values.

It should be explicitly noted here that the two preferred embodiments mentioned above may also be used in combination to increase assurance of assessment for the same dosing procedure.

As already mentioned, the method of the invention for the assessment of a liquid dosing process can be used with any liquids and in any gaseous atmosphere.

It is conceivable that the procedure or device, in addition to a mere assessment, may also initiate or carry out actions in the event of a dosing being considered to be incorrect, such as stopping a particular dosing operation, replacing certain pipette tips, discarding a dosing operation, e.g. aspiration, and repeating that dosing operation.

The present invention is explained in more detail below by means of the accompanying drawings. Fig. 1a-1ePhases of an aspiration process during pipetting,Fig. 2a method for assessing a liquid dosing process according to the state of the art,Fig. 3a graphic representation of the time course of the pressure of a gas present in the liquid intake space of a pipette tip during an aspiration and a dispensing process, a range of state values according to the first preferred embodiment of the invention and the error ranges surrounding the range of values,Fig. 4a flow diagram describing the first preferred embodiment of the invention process,Fig. 5a diagram representing the state of state values of the preferred embodiments of the present invention.

Figures 1a to 1e briefly illustrate, by means of schematic representations, an aspiration process of a liquid during pipetting which is the basis of the present invention.

Figure 1a shows a schematic cross-section of a pipette tip 10 which is moved in the direction of arrow 12 to the liquid level 14a of a liquid 14 and in the liquid intake chamber a pressure sensor 22 is located to detect the pressure of the gas present in the liquid intake chamber 20.

In Figure 1b, the opening 10a of pipette tip 10 has reached the liquid level 14a. This separates the gas in the liquid intake chamber 20 of pipette tip 10 from the ambient air and remains essentially constant, apart from evaporation and condensation.

In Fig. 1c, the pipette tip 10 has reached its point of descent and remains immersed in liquid 14 with the opening 10a. The plunger 16 is now moved in the direction of the arrow 18. Due to friction and surface tension effects, no liquid has yet flowed into the liquid intake chamber 20.

In Figure 1d, it can be seen that the uptake of liquid 14 through pipette tip 10 through the opening 10a has already begun. Then the plunger 16 is stopped (Figure 1d'), so that the volume of the pipette tip 10's fluid intake space 20 is not further increased. However, due to the pressure in the fluid intake space 20 relative to the environment, fluid 14 continues to flow into the fluid intake space 20 until equilibrium is achieved.

In Fig. 1e, the aspiration process is completed. Pipette tip 10 has been removed from liquid 14. In the liquid intake chamber 20 of pipette tip 10 there is a certain volume of liquid 14 which is held there by the downward pressure of the gas trapped between plunger 16 and the liquid volume relative to the surroundings. In addition, friction and adhesion effects between the liquid volume and the wall of pipette tip 10 also contribute to the liquid volume remaining in pipette tip 10.

Figure 2 shows a pressure time diagram of a method for assessing a liquid dosing process using the state of the art method of 30.

The liquid dosing process shall be assessed by determining whether the pressure-time gradient reaches at least a gradient α at least in one section, i.e. whether the rate of change in gas pressure reaches at least one section at a predetermined value proportional to tan α, and/or whether the pressure in the liquid intake space of the pipette tip at the aspiration is below a predetermined limit p. If the pressure-time diagram estimates that the gradient α is reached or/and the limit p. is exceeded in a period close to the start of the aspiration, the aspiration process shall be considered as fault-free. If any of these conditions is not met, the aspiration process shall be considered as fault-resistant.

In Fig. 3 the gas pressure recorded by the pressure sensor 22 during an aspiration operation in the fluid intake chamber 20 of the pipette tip 10 is represented in the time range A by the dotted line 40 in Fig. 3 This time course of the pressure is plotted in a coordinate system.

In this coordinate system, a pressure range 42 is still assigned to a set curve, and outside the pressure range 42 are the fault ranges 44, 46 and 48 below the pressure range 42 and the fault ranges 50, 52, 54, 56 and 58 above the pressure range 42, i.e. higher pressures.

In Fig. 3, time range A, the gas pressure 40 is within the time course 40 of the entire definition range of the pressure limit range 42 and the dosing process considered is therefore considered error-free.

For a better understanding of the time course 40 of gas pressure in the fluid intake chamber 20 of pipette tip 10 of Figures 1a to 1e, a brief explanation is given below:

The process begins at t=0 at ambient pressure p. In the first section 40a, the pressure remains constant. This corresponds to the condition shown in Fig. 1a, where the volume of the fluid intake space 20 remains constant. As soon as the opening 10a of the pipette tip 10 reaches the liquid level 14a, as shown in Fig. 1b, a slight pressure drop initially occurs due to adhesion at the contact of the liquid surface, which is then superimposed by the increasing pressure of the stagnant in the increasingly submerged pipette tip.

At a point corresponding to Fig. 1c, the piston 16 is moved upwards at a constant speed in the direction of arrow 18 with the result that the pressure drops dramatically. This phase of the strong pressure drop, represented by section 40c, ends at point 40d, when liquid begins to flow into liquid chamber 20 of the pipette tip. In the area 40e adjacent to point 40d, a further increase in the volume of the gas-inlet volume contained in the gas-inlet volume 20 caused by the movement of the piston 16 decreases by the volume of liquid liquid in the gas-inlet volume 20, i.e. a dynamic flow of liquid is produced between the gas-inlet and the liquid by the column of gas flow.

The movement of the piston and thus the increase in the volume of the fluid intake space ends at t1 at 40f (Fig. 1d). The underpressure of the gas still present in the fluid intake space 20 relative to the surrounding gas of the pipette tip 10 continues to cause liquid to flow back into the fluid intake space 20, which, as shown in section 40g, causes the volume of the volume of the gas contained in the fluid intake space to rapidly decrease and its pressure to increase accordingly.

At 40h, the pipette tip 10 is already removed from the liquid (Fig. 1e). Shortly before this, the flow of liquid into the pipette tip 10's fluid intake space 20 (Fig. 1d') ends, at 40h, the volume of gas between plunger 16 and the liquid in the fluid intake space 20 is subject to a negative pressure difference Δp, which is directly proportional to the volume of liquid dosed for sufficiently large volumes of liquid.

The individual fault ranges 44, 46, 48, 50, 52, 54, 56 and 58 are bounded by time and pressure values or time pressure values. The pressure limit range 40 is bounded by the lower threshold curve 60 at lower pressures and the upper threshold curve 62 at higher pressures. The lower and upper threshold curves 60, 62 are functions of pressure depending on time and can be determined individually. The different fault ranges can be assigned to the following errors, for example: Error area 44:defective pressure measurementError area 46:pipet opening cloggedError area 48:excessive aspiration timeError area 50:defective pressure measurementError area 52:aspiration and dispensing confused and pipette opening is cloggedError area 54:pipet tip leaksError area 56:aspiration interrupted or air bubbles in the liquidError area 58:too little or no liquid in the pipette tip

In the time zone B of Fig. 3 the time course of the gas pressure, the pressure-duty range and the fault zones surrounding the pressure-duty range are shown in the dispense operation. The dispense operation may, for example, take place after the previously described aspiration operation or after an intermediate transport operation (time zone C). The same elements as in the time zone A of the aspiration process are indicated in the time zone B of the dispense operation with the same but apostrophic reference marks. The fault zones in time zone B are numbered so that the areas with the corresponding error order are indicated with the same but apostrophic reference marks.

The following allocation of error messages and error ranges shall apply: Error area 46':Pipette opening clogged,Error area 48':Dispenser time too long,Error area 52':Aspiration and dispenser confused,Error area 56':Pipette tip or pipette system leaking.

The use of the fault zones is to be understood as follows: for example, if the pipette opening is blocked in a dispenser, the liquid in the pipette tip cannot or only to a limited extent escape from the pipette tip. Due to the sliding motion of the piston during dispensing, which reduces the volume of the liquid intake space of the pipette tip, the volume contained in the pipette tip is compressed. This increases the gas pressure. This causes the pressure to rise over time to the 42' range, exceeding its upper threshold of 62' Lin, and to fall into the 46' error range. This is shown by the 41' B error. This error can be detected not only during the initial phase of the fluid, but also during the second phase of the operation.

In the interim period, pressure monitoring can also be carried out with a slightly increased upward and downward pressure range of 42' to take account of the permissible pressure variations during transport, especially during jerky movements.

In Fig. 4 a flow diagram shows the process of evaluating a liquid dosing operation. At step S1 the pipetting operation, for example the aspiration operation known from time-span A of Fig. 3 begins. At the beginning of the liquid dosing operation, the parameters relevant to the operation are initialized, i.e. a clock is set to zero and started, the pressure detected by a pressure sensor at a detection point is set to zero, as well as the detection point.

In the next step S2, the pressure of the gas in the liquid intake chamber is recorded and the current value of the clock is loaded into the variable terf at the time of the recording.

In the next step S3, the threshold values assigned to the threshold at the time of the data collection are loaded from a memory. USW is the lower threshold of the threshold range (i.e. the value of the lower threshold curve 60 at the time of the threshold of Fig. 3), OSW is the upper threshold. SW1 to SWn are the thresholds separating the individual fault ranges. For example, if the printing is done at the time of the threshold defined in Fig. 3 by line 64, SW1 is the fault range 56 separating the fault range 54 = threshold value and SW2 is the fault range 54 separating the fault range 52 from the threshold value.

In the next step S4 it is checked whether the recorded pressure is equal to or greater than the lower threshold value USW limiting the pressure range to lower pressure values; if this is the case, in the next step S5 it is checked whether the recorded pressure is equal to or less than the upper threshold value OSW limiting the pressure range to higher pressure values; if this is also the case, in a subsequent step S6 it is declared that the operation is correct.

Step S7 is a waiting loop that allows for further printing only after the time interval Δt has elapsed since the last printing.

In step S8 it is checked whether the time limit clockmax for the dosing operation is reached or not. If the time limit is reached, the process ends, if not, the process returns to step S2 and thus returns to a re-measurement of the gas pressure in the liquid intake chamber of the pipette tip.

If in step S4 the pressure recorded is per less than the lower threshold value USW, i.e. the gas pressure time course leaves the pressure range to lower pressure values, then in step S9 the flag F_KI is set to 1. In the next step S10 the flow variable k=1. If the pressure value time course leaves the pressure range to higher pressure values, i.e. if in step S5 the pressure recorded is greater than the upper threshold value OSW, then step S10 is also reached, but the flag F_Kl remains at its initial value of zero.

After the detection of a fault in the liquid dosing process, the following steps are used to diagnose the fault: each fault range is assigned at least one error message. The error messages are defined as a one-dimensional field (= vector), whereby the individual entries in the error message field are assigned to the error ranges in the direction of the pressure, i.e. error message (O) is error 46, error range (1) is error 56, error message (2) is error 54 and error message (3) is error. Accordingly, the one-dimensional error message field contains many different error ranges depending on the number of errors available at a given time.

In step S11 it is now determined whether the recorded pressure per is greater than the k-th threshold. If this is the case, step S12 increases the flow variable k by one and step S13 checks whether or not k already exceeds the maximum number n of threshold values assigned at the time of the test. If k does not exceed the number n, the check of step S11 is carried out again, but with a flow variable increased by one.

However, if k exceeds the value n after the one increase, the pressure value checked shall be in the error range with the highest pressure range and the error message (k), i.e. in the present example error message (3) from error range 52, shall be issued in step S14.

If the check in step S11 shows that the pressure permeable to the SWK threshold is not exceeded, then in step S15 it is checked whether the flag F_KI has the value 1, i.e. whether the time course of the pressure to higher or lower pressure values has broken out of the pressure limit range. If the flag F_KI shows the value zero, i.e. the pressure limit range has been moved to higher pressure values, the error message (k) is issued. However, if the check in step S15 shows that the error message of the flag F_KI has at least the value 1, i.e. the time course of the pressure to lower or higher pressure values has broken out of the pressure limit range, then the error message (D16A) is issued, but the error message may also be transmitted at the end of the pipeline, for example, in case of a pipeline failure, but the error message may be transmitted at the end of the pipeline.

The device in which the process of the invention is performed may be, for example, an electronic data processing device, in particular a personal computer or process controller microcontroller. This data processing device is connected to at least one sensor at the tip of the pipette to record the time course of at least one state size, for example, pressure. The data storage device may be a hard disk, a CD-ROM, a RAM storage device or a memory for a PC connected to the microcontroller. For example, the state size limit range may be stored on a CD-ROM CPU.

The evaluation of the state measurement accompanying the dosing process may be carried out, for example, according to the flow diagram described above, which records a numerical deviation of the momentary measured value from the tolerance range.

The development of state-size range limits for the preferred embodiments of the invention is shown in Figure 5.a. A pressure time diagram (time at the abscissa, pressure at the ordinate) shows a statistically significant set of 70 pressure time courses measured in a dosing procedure with identical operating parameters with identical equipment.

In contrast, Figure 5c shows a reference curve 242 derived from the 70 group, for example by means of the average.

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The degree of conformity is usually a number standardized to have a value between 0 and 1, with 1 being the value for identical conformity. A range of degree of conformity values, for example, ranging from 0.9 to 1, indicates the range for which the degree of conformity values are considered to be error-free for a dosing procedure. A range of values, for example, 0.4 to 0.9, may be used to assume a questionable quality of pipetting, with a case-by-case decision on whether or not to discard the pipette.

Claims (22)

1. Method of evaluating a liquid dosing process in a pipette which is at least partially filled with a gas, preferably with air, in particular an aspiration and/or dispensing process in pipetting, in which process a time characteristic (40, 40') of at least one state variable (p) of a medium present in the pipette is determined substantially over the entire duration of the dosing process and in which it is determined whether the time characteristic (40; 40') of the at least one state variable (p) lies within a predetermined state variable setpoint range (42; 42') following a setpoint curve, wherein an evaluation result (S6, S 14, S 16) is output dependent upon the result of the determination, characterised in that the time characteristic of the at least one state variable (p) is determined during the change in the amount of liquid in the pipette and compared with an associated state variable setpoint range (42; 42').
2. Method according to claim 1, characterised in that the liquid dosing process is evaluated to be incorrect if it is determined that the detected time characteristic (40, 40') pf the at least one state variable (p) lies, at least in sections, outside the state variable setpoint range (42; 42').
3. Method according to either claim 1 or claim 2, characterised in that if at least sections of the time characteristic (40; 40') of the at least one state variable (p) lie outside the state variable setpoint range (42; 42'), it is determined whether the characteristic of the at least sections of the at least one state variable (p) lie in one error range from a plurality of error ranges (44, 46, 48, 50, 52, 54, 56, 58; 46', 48', 52', 56') of a state variable range of values, which lies outside the state variable setpoint range (42; 42'), and an error message is output dependent upon the at least one error range (46') which has been passed through.
4. Method according to any one of the preceding claims, characterised in that the determination as to whether the time characteristic of the at least one state variable (p) lies within the predetermined state variable setpoint range (42; 42') is performed by comparing the characteristic (40, 40') with an upper threshold curve (62; 62') which delimits the state variable setpoint range (42; 42') in the direction of larger state variables and with a lower threshold curve (60; 60') which delimits the state variable setpoint range in the direction of smaller state variable values.
5. Method according to either claim 1 or claim 2, characterised in that the determination whether the time characteristic (40; 40') of the at least one state variable (p) lies within the predetermined state variable setpoint range (42; 42') is carried out by image processing.
6. Method of evaluating a liquid dosing process in a pipette which is filled at least partially with a gas, preferably with air, in particular an aspiration and/or dispensing process in pipetting, in which process a time characteristic (40, 40') of at least one state variable (p) of a medium present in the pipette is determined substantially over the entire duration of the dosing process, and substantially the entire time characteristic (40; 40') of the at least one state variable (p) is compared with a predetermined state variable setpoint range (242) following a set point curve, characterised in that the time characteristic of the at least one state variable (p) is determined during the change in the amount of liquid in the pipette, and compared with an associated state variable setpoint range (242), wherein, by using a correlation calculation method, a degree of correspondence of the time characteristic of the at least state variable (p) is determined with a predetermined reference curve as a state variable setpoint range (242), and wherein an evaluation result is output as a function of the result of the determination.
7. Method according to claim 6, characterised in that the degree of correspondence as an evaluation result is a numerical value, wherein the liquid dosing process is evaluated as incorrect, if the degree of correspondence lies outside a predetermined degree of correspondence setpoint range.
8. Method according to either claim 6 or claim 7, characterised in that if the degree of correspondence is found to lie outside the predetermined degree of correspondence setpoint range, it is determined whether the degree of correspondence lies in an error range from a plurality of error ranges of a degree of correspondence value range that lies outside the setpoint range for degree of correspondence, and in that an error message is output dependent upon the error range in which the degree of correspondence lies.
9. Method according to any one of claims 6 to 8, characterised in that the correlation calculation method uses as interpolation points from the time characteristic of at least one state variable (p) and from the reference curve as the input variable.
10. Method according to any one of the preceding claims, characterised in that the medium is the gas present in the pipette.
11. Method according to any one of the preceding claims, characterised in that the state variable is the pressure (p) and/or the temperature of the medium.
12. Method according to any one of the preceding claims, characterised in that the state variable setpoint range (42; 42'; 242) is defined at least for the entire duration of the liquid dosing process, preferably also for the duration of the interim transport process.
13. Method according to any one of the preceding claims, characterised in that the state variable setpoint range (42; 42'; 242) of a liquid dosing process is based on a plurality of performances (70) of substantially the same liquid dosing process using substantially the same operating parameters.
14. Device for evaluating a liquid dosing process in a pipette which is filled at least partially with gas, preferably with air, using the method according to any one of claims 1 to 5 or 10 to 13, with reference to at least one of claims 1 to 5, wherein the device comprises:

    - at least one sensor which is configured to determine the time characteristic (40; 40') of at least one state variable (p) of a medium present in the pipette, preferably of the gas, during the change in the amount of liquid in the pipette,

    - a data memory for storing a predetermined state variable setpoint range (42; 42'; 242) following a setpoint curve, as well as for storing the state variable values (p) determined by the sensor,

    - a data processing unit which is configured to compare the time characteristic (40; 40') of the at least one state variable (p) during the change in the amount of liquid in the pipette with the predetermined state variable setpoint range (42; 42') and to determine whether the time characteristic (40; 40') of the at least one state variable (p) lies within the predetermined state variable setpoint range (42; 42'), as well as

    - an output unit for issuing an evaluation result (S6, S14, S16) as a function of the evaluation result from the data processing unit.
15. Device according to claim 14, characterised in that further a plurality of predetermined error ranges (44, 46, 48, 50, 52, 54, 56, 58; 46', 48', 52', 56') is stored in the data memory, wherein at least one possible error of the dosing process is assigned to each error range (44, 46, 48, 50, 52, 54, 56, 58; 46', 48', 52', 56').
16. Device according to either claim 14 or claim 15, characterised in that the device further comprises an editing unit for producing a state variable setpoint range.
17. Device according to claim 16, characterised in that the device comprises an input unit connected to the editing unit.
18. Device according to claim 17, characterised in that the output unit is a graphic output unit and a state variable setpoint range can be graphically defined via the input unit.
19. Device for evaluating a liquid dosing process in a pipette filled at least partially with gas, preferably with air, and using the method according to any one of claims 6 to 9 or 10 to 13 and with reference to at least one of claims 6 to 9, wherein the device comprises:

    - at least one sensor which is configured to determine the time characteristic (40; 40') of at least one state variable (p) of a medium present in the pipette, preferably of the gas, during the change in the amount of liquid in the pipette,

    - a data memory for storing a predetermined reference curve (242) as a state variable setpoint range (242), as well as for storing variables determined by the sensor (p),

    - a data processing unit which is configured to compare the time characteristic (40; 40') of the at least one state variable (p) during the change in the amount of liquid in the pipette with the designated state variable setpoint range (242), wherein the data processing unit is further formed to carry out a correlation calculation method to determine a degree of correspondence of the time characteristic of the at least one state variable with the predetermined reference curve as the state variable setpoint range (242),

    - an output unit for issuing an evaluation result (S6, S 14, S16) as a function of the evaluation result from the data processing unit.
20. Device according to claim 19, characterised in that a predetermined degree of correspondence setpoint range is stored in the data memory.
21. Device according to claim 19 and claim 20, characterised in that the data processing unit determines whether the degree of correspondence lies within the predetermined degree of correspondence setpoint range.
22. Pipetting system with an evaluating system according to any one of claims 14 to 18 and/or 19 to 21.