FAQ

In this section we would like to summarize and answer the most frequently asked questions.

For a better overview, we have divided these into 5 groups:

Number of found questions:  

Prospective

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  • What advantages does the online measurement offer?

    Online measurements provide readings in a short time and allow for more accurate monitoring and, if necessary, control of the process. Frequent manual sampling can be omitted. This reduces the risk of contamination and minimizes the time and effort involved. The resulting concentration / time profile of the cultivation additionally represents a good documentation of the overall process.

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  • Which substances can be measured?

    TRACE C2 allows the simultaneous determination of glucose and lactate with the aid of a selective biosensor.

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  • In which measuring range can I measure glucose and lactate?

    The measuring range for glucose is 0.1 - 40 g/L. Lactate can be measured between 0.05 and 5 g/L.

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  • Are there other applications apart from glucose and lactate?

    Yes, Ethanol and Methanol. In the future, however, more applications will be available.

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  • How do I connect the meter to my bioreactor?

    The TRACE C2 is connected to the reactor via sampling probes. These are available in various diameters and lengths and can be connected to a 25 mm side port or 12/19 mm top plate port as needed. For disposable bioreactors, sampling via probe port is available.

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  • Which sampling options are available?

    You can basically choose between two types of sampling: filtration and dialysis. In  filtration mode cell-free medium is removed from the reactor via a membrane probe and measured using a biosensor. Alternatively, a dialysate can be removed from the bioreactor.

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  • What are the benefits of sampling dialysis?

    Using the dialysis probe, representative samples can be obtained from a bioreactor without having to remove any liquid. This method is therefore very well suited for small volume reactors. With the help of a semipermeable membrane only the low molecular weight substances are separated by diffusion from the medium.

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  • What are the advantages of sampling filtration?

    Filtration allows continuous recovery of a cell-free sample from the bioreactor. The microporous filtration membrane consists of a robust and pressure-resistant plastic body on the filtration probe. This also makes possible the use in very large reactors of several m3 content.

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  • Can I also connect disposable bioreactors?

    With the single use probe, dialysis sampling is available, which is integrated into a reactor port. This disposable sampling is supplied as a sterile kit or can be delivered as part of custom disposable reactors.

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  • Does the meter consume media?

    • No, not in dialysis sampling.
    • Only when using the sampling method filtration medium is consumed. With continuous measurement, approx. 1 mL of medium per minute or 1.5 L per day is required.

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  • What are the consumables of the system?

    A tubing set containig the whole liquid path, all pumps and valves as well as the sensor. This is combined with calibration solutions and transport buffer solution.

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  • How many parameters can the controller read simultaneously?

    The PID is programmed for only one leading parameter. This can be glucose or lactate or ethanol or methanol, depending on the analytical method choosen.

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  • How many external actuators can be controlled by the PID control?

    One device at the same time. We have an internal built-in pump for feeding or alternatively external pumps (like Watson Marlow) can be connected via analog or digital connection.

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  • Can the controller handle reading from other vendors probes?

    No.

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Academic user (University)

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  • Which sampling is best for which microorganisms or cell lines?

    Basically all microorganisms and cell lines can be measured with both types of probes. But especially filamentous fungi often form a highly viscous mass during fermentation. In these cases, the dialysis probe is to be preferred, as it is better suited for highly viscous media.

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  • For how many cultivations can I use the tube set?

    The tube set is a disposable item. The tube set must therefore be replaced after each cultivation or fermentation.

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  • What is the consumption of transport buffer?

    • The supplied transport buffer concentrate (0.5L) gives 10 L transport buffer. It is sufficient for continuous measuring operation for approx. 8 days.
    • The table shows the buffer consumption depending on the interval:

    Dialysis mode

    Interval

    Buffer Consumption

    10 L for:

    min

    µl/min

    ml/h

    ml/d

    h

    d

    1

    835,6

    50,1

    1203,2

    199

    8,3

    5

    835,6

    50,1

    1203,2

    199

    8,3

    10

    614,4

    36,9

    884,7

    271

    11,3

    20

    356,3

    21,4

    513,1

    468

    19,5

    30

    270,3

    16,2

    389,3

    617

    25,7

    60

    184,3

    11,1

    265,4

    904

    37,7

    120

    141,3

    8,5

    203,5

    1179

    49,1

    360

    112,6

    6,8

    162,2

    1480

    61,7

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  • How long are the solutions durable?

    All solutions are stable for 15 months. Diluted solutions are stable for a maximum of 4 weeks. If necessary, sterile filtered and well sealed, the solutions can be used longer.

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  • What is the standard deviation for glucose / lactate measurement?

    The spread of the glucose reading around the mean is less than 1,5% at 4 g/L.
    The spread of the lactate reading around the mean is less than 1,5% at a value of 2g/L.

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  • Can I take measurements offline with the TRACE C2?

    The TRACE C2 is primarily an online meter for continuous measurements. However, individual samples (for example for reference measurements) can also be measured offline.

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  • How long do the enzymatic reagents last?

    Measurements of TRACE C2 and MultiTRACE are based on a biosensor, which is integrated in a preconfigured tubing set. There are no reagents needed, except a transport buffer solution for the transport of the analyte to the biosensor. The buffer is supplied as a concentrate (20x) which gives 10L transport solution. This lasts in continuous operation for 10 days (dialysis mode) or 11 days (filtration mode). The system automatically calibrates itself in customer defined intervalls. We use two calibration standards. Each bottle (500mL) lasts for approx. 120 calibrations. 

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  • What is the temporal resolution of the readout? I have a lot of experience with YSI2700, and found that it requires constant calibration to read samples accurately, which takes time.

    The temporal resolution of the readout is depending on the sampling method. If you use filtration sampling the resolution is one per minute. With dialysis as sampling method the resolution is two minutes. Typically, customers set the system to one calibration per day which is enough to compensate for drifting effects or sensor deterioration. However, the calibration frequency can be increased if required. There is no extra workload since the calibration is fully automated.

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  • Is there a lag in the measurements obtained by TRACE C2, and if not, how are these possible in light of the enzymatic reaction?

    You are right, there is a time lag between sampling and display of result, which is the sum of the following processes:

    a) sample transport (only in filtration method): time during which the medium travels from the reactor to the diffusion module in the tubing set;
    b) accumulation time: time during which the analyte passes the diffusion membrane and accumulates in the holding chamber;
    c) transport of the accumulate to the measurement cell (biosensor) and
    d) passage of the measurement cell and peak detection.

    For the filtration method we have a) = 60s; b) = 30s; c) & d) = 30s adds up to 120s and for dialysis method we have b)=45s and c)&d)=75s adds up to 120 s. As a consequence in filtration mode the signal represents the situation in the reactor 2 minutes ago with an integral of 30 s and  the dialysis method represents the situation in the reactor 2 minutes ago with an integral of 45 s.

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Big Pharma / Biotech (Industry)

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  • What technology available allows measurement of the true bioreactor metabolite environment at the time of measurement? An in culture probe technology or a technology that draws sample directly away from the bioreactor to an analyzer outside the vessel?

    • TRACE C2 offers automated simultaneous glucose/lactate monitoring at frequent intervals (every 1 or 2 minutes). Other analytes available are ethanol or methanol.
    • The measurement principle is based on enzymatic biosensors, thus a true and selective molecular measurement is the basis for every analysis.
    • The analyte is sampled by a probe within the bioreactor and automatically transported to the biosensor. The sensor is located outside the reactor integrated in a tubeset.
    • The sampling technologies that TRACE offers are filtration and dialysis. The respective stainless steel probes are similar to conventional probes for pH or pO2 measurement. Additionally, a dialysis probe for single-use reactors is available.
    • The device is also available as MultiTRACE or C2/M4 for parallel monitoring of up to four bioreactors.

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  • From the technology listed, which poses a greater risk for contamination based on its set-up and use in a GMP environment?

    • Manual sampling and sample drawing always pose greater risk than sampling via sterile membrane probes.
    • TRACE sampling probes for filtration and dialysis have been proven as stable and reliable sampling devices in GMP as well as large scale processes. Due to their aseptic stainless steel design, the probes can be sterilized like conventional probes. Both probes are pressure resistant up to 6 bar (87 psi).
    • A great advantage of the TRACE dialysis sampling technology is that it does not consume any media of the process, making closed loop control available for very small bioreactors.

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  • From a cleaning and sterilization perspective, which technology has the least moving parts or modules for ease and assurance in performing these operations? Which are easier to functionally test and calibrate on the GMP floor?

    TRACE C2 is a small-footprint device that uses preconfigured single-use tubing sets. This renders cleaning unnecessary. The sets come with respective calibration and flushing media, which, when connected to the device, allow for automated calibration and recalibration at customer specified times or intervals.

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  • Which technology allows for the integration of a feedback control loop to automate feed delivery directly to the bioreactor based on in-line glucose readings?

    • TRACE C2 allows for direct feedback control due to an integrated PID controller. With an integrated pump the instrument can directly feed small and medium sized reactors. For larger reactors or high glucose consumption rates larger external pumps (e.g. Watson Marlow 5xx series) can be directly connected via the digital or analog port.
    • Alternatively, if a SCADA system is available for bioreactor control, the measurement results can be instantly transferred via analog (0-10V / 4-20 mA) or via digital (Modbus, OPC) signals.

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  • Which technology is available for use globally and not just available in the US, Japan, and or certain countries or regions? Is global technical support available readily?

    TRACE technology and support is readily available worldwide through a network of established partners like Sartorius, Eppendorf/Dasgip, BlueSens and PROAnalytics.

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  • Which technologies have shown previous use by the literature citations to be used at pilot or GMP scale?

    TRACE technology is in continuous use since 1997 in GMP production of large scale processes at insulin production at Sanofi (former Aventis/Hoechst). Several other customers use the technology in their GMP facilities, however, since this is mostly confidential, there are only few publications available. Contact to reference customers will be given by TRACE on demand.

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  • I have a 4-fold fermenter system, can I connect the TRACE C2 to it or do I need an analyzer for each fermenter?

    Yes, you can use the MultiTRACE or TRACE M4 as a peripheral to the C2.

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  • Can the transport solution penetrate into my fermenter medium during sampling with the dialysis probe and thus impair the fermentation?

    When using the dialysis probe, the transport solution as such cannot penetrate into the fermentation medium. Since the dialysis membrane is permeable to very small molecules, individual ions from the solution can penetrate into the fermentation medium. The transport solution contains only physiological salts. On request, we will provide our customers with a material certificate of the solution.

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First time user

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  • How often should I take measurements?

    If you want to perform a control based on the measured values, you should adapt the measuring frequency to the dynamics of your process. With the filtration, 60 measurements per hour and dialysis 30 measurements per hour are possible, which can also track fast microbial processes very well. For slow growth processes (e.g., cell cultures), perhaps 2 measurements per hour may be sufficient for control.

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  • I run a cell cultivation over several weeks and only need a current reading every 4-6 hours, is it worth an online measurement?

    TRACE C2 can be set to any time interval so that even large measurement intervals are possible. Here, too, the automatic measurement is worthwhile, especially at night and at weekends, when there is little personnel available for manual sampling.

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  • How are the measured values displayed and stored?

    The measured values are displayed graphically using the supplied PC software and saved in text form. Parallel to this, the current measured values are available as analog signals (0..10 V, 0..20 mA and 4..20 mA).

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  • How long does the sensor last?

    The sensor is integrated into the disposable tubing set and will be replaced with it. The lifetime of the sensor is at least 5000 measurements. In continuous operation, at least 14 days can be covered.

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  • How is the device calibrated?

    The device calibrates itself at freely selectable intervals. The calibration standards provided are automatically measured. It is also possible to trigger the calibration manually if necessary, or to do without it altogether.

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  • How often do I have to calibrate?

    As a rule, one calibration per day is sufficient. We recommend a more frequent calibration in strongly changing environmental conditions (for example, temperature differences day / night). At large time intervals (e.g., measurement every 6 hours), calibration may also be performed prior to each measurement.

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  • Which calibration solutions should I choose?

    Select the concentrations of the two calibration standards so that the concentration range that is important for you (for example for controls) is between these concentrations. Higher concentrations are usually still determined sufficiently good, but with less accuracy.

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Experienced user

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  • I start my cultivation with a high glucose value (for example 20 g / L) and would like to control later in the lower concentration range. Is this possible?

    It is possible in principle to start with high glucose concentrations and control them in the lower concentration range. In this case, it is recommended to calibrate with two low standards (e.g., 4 g / L and 0.5 g / L glucose). The course of the high glucose concentrations will then be recorded, but the measured values in this area will deviate from the actual values. In the control area, however, the measured values will then be recorded exactly.

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  • Can I connect the TRACE C2 to a process control system?

    The device can be connected to a process control system via the analogue outputs on the rear panel. The following outputs are available: 0..10V, 0..20mA and 4..20mA.

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  • Is the TRACE C2 also suitable for industrial scale production?

    Basically, the TRACE C2 is also suitable for industrial scale. It will, however, be necessary to adapt the device to the particular environmental conditions (for example put it in a splash-proof cabinet).

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  • Is steam or dry sterilization possible with the sampling probes?

    • Steam sterilization is possible with both probe types (dialysis and filtration). However, it must be ensured that the respective membrane is wetted with liquid during sterilization.
    • Dry sterilization is not possible due to the high temperature load with either of the two types of probes.

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  • What is the maximum sterilization temperature?

    It is recommended to carry out steam sterilization at 121 ° C and 1 bar overpressure. If higher temperatures are reached by up to 10 ° C in the short term, this is no problem for the membranes.

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  • I have a very viscous medium, which probe is best for that?

    For highly viscous media, the dialysis probe is better suited than the filtration probe. However, it must always be tested whether the dialysis probe is suitable for the viscous medium.

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  • How long can I store a tubeset if I have cleaned it with cleaning solution and then put it in cooling? There are users who do not want to use the device permanently but every now and again.

    When storing after use, 3 factors are crucial:

    1) Disinfection - this is easily done by the cleaning solution. But it is also important that the adapter lines (UNF LUER) are flushed! They will be connected to the tubeset again later and should not be contaminated or blocked. We use the syringe, first with cleaning solution, then water, then air.

    2) Blockage due to crystal formation of buffer residues - ie: wash well and with plenty of dest / deion water (also runs automatically in cleaning mode)

    3) Gluing the silicone or pump hoses - we recommend taking the hoses out of the valve blocks for longer periods of storage. A channel is always closed and the corresponding silicone tubes are glued dry in some cases and have not opened again by itself when re-priming. We did not make any such observations with the pumps, but for safety's sake we could take the cassettes off the axles.

    If the set is so disinfected and rinsed it can simply be left standing. It then dries up slowly and must of course be rinsed again during startup. Maybe after a long break it will take longer to get fit. For a short storage (1 week) that works well several times.

    We would advise against cooling the set. This could rather lead to problems with e.g. condensation and possibly then growth. Dry and room temperature is better.

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  • For one customer, the bioreactors are so far apart that 8 m long probe lines were requested for a MultiTRACE device. Is this fundamentally feasible in terms of metrology and what changes must possibly be made to the parameterization?

    In dialysis mode, probe tubes with lengths of up to 8 m are possible. The measuring time is extended from 2 to 4 minutes. For conversion, however, the device must be sent.

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  • Temperature (Media) - We wanted to run the TRACE C2 with dialysis sampling for both Glucose and Ethanol (2 x Systems) in media that is at about 50°C.

    The higher temperature in the medium is no problem. The signals will be higher and thus the linear range might be lower.

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  • Calibration (error) - We are getting “calibration not plausible” messages – even though the coefficients are in normal range. Are there other success criteria for the no plausible message?

    • Yes, there are other success criteria. If the deviation of three calibration measurements is too high, the system will show you “calibration not plausible”.
    • This deviation can be caused by an old tubing set or if you have a leakage in the tubing set. You have to check your tubing set and the placement of the silicon tubes inside the valves.

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  • Reference (no lactate) - What would you advise is the minimum lactate concentration needed before an accurate reference can be made?

    The higher the lactate concentration is, the higher the signals of the sensor are and the better the referencing will be. For low concentrations I would advise to start referencing only above conc. of 0.2 g/L lactate.

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  • Pressure (Dialysis Probe) - What is the current recommended maximum pressure rating for the dialysis probe?

    • We tested the dialysis mode at 3.5 bar (50.76 psi) pressure in the reactor for test duration of 6 days. The membrane showed no rupture or leakage during that time period (not tested longer).
    • As expected, there is an increase in signal with increase in pressure (approx. 10% per bar). This would be compensated by the reference factor.
    • We tried to perform a burst test, but the membrane did not burst even up to 6 bar (87psi), no matter whether a tubing set is connected to the probe or the probe is left open on the connectors.

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  • Data (Feeding Pump) - I see that Column F (Excel sheet) output ranges from 0.01 to 0.127. What % / analog output does this equate to?

    1 equates to 100%

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  • Which buffer consumption should I expect?

    The table shows the buffer consumption depending on the interval:

    Dialysis mode

    Intervall

    Buffer Consumption

    10 L for:

    min

    µl/min

    ml/h

    ml/d

    h

    d

    1

    835,6

    50,1

    1203,2

    199

    8,3

    5

    835,6

    50,1

    1203,2

    199

    8,3

    10

    614,4

    36,9

    884,7

    271

    11,3

    20

    356,3

    21,4

    513,1

    468

    19,5

    30

    270,3

    16,2

    389,3

    617

    25,7

    60

    184,3

    11,1

    265,4

    904

    37,7

    120

    141,3

    8,5

    203,5

    1179

    49,1

    360

    112,6

    6,8

    162,2

    1480

    61,7

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