Jim Knows Best | Pharmaceutical Waters Industry Expert - METTLER TOLEDO

Jim Knows Best | Pharmaceutical Waters Industry Expert

Calibration of TOC analyzers and conductivity sensors without removing them from the water system


Christopher from Singapore asks:

Can I choose not to calibrate the temperature sensor and electronics of the conductivity analyzer since the temperature compensation is already turned off?

Regarding calibration of the temperature sensor within the conductivity probe and the electronics of the conductivity transmitter, I do not know which pharmacopeia you are following, but being at Novartis I would assume both USP and EP. The answer to your question is in two parts, the first regarding the electronics of the conductivity transmitter and the second concerns the conductivity sensor.

Whether you are using or not using temperature compensation does not affect the calibration requirements. All the global pharmacopeias require the calibration or verification of the conductivity/resistivity measurement circuit in the conductivity transmitter. Verifying the temperature measurement circuit in the transmitter is not required, but is recommended as good practice. If you are using a METTLER TOLEDO Thornton conductivity transmitter, the calibration process is very easy and can be performed using our traceable, digital calibrators.

In regards to the conductivity sensor and temperature, the pharmacopeias requirements state that the temperature device must be accurate to ±2˚C. If you are not using the temperature reading from the conductivity sensor to report the temperature of the water then it would not be required, but you still have to report temperature so an additional temperature sensor located near the conductivity sensor would be required for that reporting. If you do not calibrate the temperature of the conductivity sensor, the accuracy of the conductivity reading could be in question because conductivity is temperature dependent. You can calibrate the conductivity sensor for temperature and conductivity without removing it from the pipe and this is actually the preferred method by the pharmacopeias.

Joao from Brazil asks:

Why do I have high conductivity measure, after R.O. treatment? What can I do to fix this?

The most common reason for higher conductivity, post RO treatment, is carbon dioxide in the processed water. This can occur when the feedwater to the RO is being adjusted with acid to protect the RO membrane. If the pH of the feedwater is lowered too much, you will produce CO2, which passes through the RO membrane raising the conductivity. Test the pH of the feedwater. RO membranes prefer a slightly acidic feedwater, but if you are below 5.6, raise the pH of the feedwater to the range of 6.0 to 6.3 and then test the conductivity of the product water from the RO.

Why are the results (in-line vs. a QC lab) so different? I believe they would be, but sometimes I detect a double...so weird.

Pure water will absorb CO2 from the atmosphere at a very fast rate, especially if the water is at ambient temperature. For example, if the conductivity of the water measured in-line is 0.06 μS and you then proceed to take the sample of the water for off-line testing, the conductivity will increase to 2.1 μS in less than 2 minutes. The best procedure is to measure your conductivity in-line and use that to validate your system. The Global Pharmacopeias are encouraging in-line versus off-line testing because of the variability of off-line testing. This same phenomenon also occurs with TOC testing. A purified water system with in-line testing for TOC may show a value of 20 ppb. That same water when tested off-line could easily have a value of 140 to 300 ppb, depending on sampling technique, sample container and atmospheric contamination. This is why in-line testing is being strongly encouraged by the Pharmacopeias.

What is the recommended method and material (glass/plastic) for collecting samples (for TOC or conductivity tests)? I am trying to validate a PW system and having many difficulties with these tests.

If you are going to perform off-line testing then the sample containers should be cleaned extensively and the material of the container is very important. Glass (borosilicate (Pyrex)) containers could be used but they should not be if they are new (unless they have been cleaned with ultrapure or purified water and also cleaned with dilute nitric or hydrochloric acid). The surface of the glass container, especially when new, will have ions that will leach into the water changing your test results. It would be best to use either polypropylene or PFDF container. These will also have to be cleaned with Ultrapure or Purified water. When you use the container to obtain a sample, you should fill it and empty it with the water you are going to be testing for a minimum of three times before taking the final sample. Once again, we would recommend that you perform the validation of conductivity and TOC with in-line instruments as your results will more accurately reflect the quality of the water and you will not experience the variability that can occur with off-line testing.

Mezghiche from Algeria asks:

I have TOC on-line, but the calibration is very difficult because the standard solutions are not available locally and the expiration date is very short - 15 days. To get them within 15 days from the country it is developed in, to our country is practically impossible, so we decide to stop working with TOC and use an EU pharmacopeia test called "oxidizable substance" to monitor TOC; this test is done by a QC lab. Is my justification acceptable by auditors and experts?

The challenge of obtaining short shelf life SST and/or calibration solutions in a suitable time frame can be difficult. The pharmacopeias require the use of ‘fresh’ solutions, but they do not define the term ‘fresh’, which is why a lot of solutions have such a short shelf life. The SST and calibration solutions produced by METTLER TOLEDO Thornton have a shelf life of 45 days, but even that time period can present a challenge logistically.

In regards to your specific question and the use of the oxidizable substance (OS) test for TOC, let me first provide you with some background history. The OS test was the standard test for oxidizable impurities (mostly organic impurities) in Purified Water (PW) and Water for Injection (WFI) prior to 1996. In 1996, the USP replaced all of the wet chemical tests (OS, chloride, sulfate, calcium, ammonia, etc.) with conductivity and TOC. Two years later, the EP introduced TOC. Whether or not you can continue to use the OS test is dependent on the water type you are producing and the pharmacopeia you are following. 

If you are producing WFI, you are not permitted to use the oxidizable substance test and this applies to all of the major global pharmacopeias. No exceptions. If you are producing PW and are following the European Pharmacopeia (EP), Chinese Pharmacopeia (ChP), or the Indian Pharmacopeia (IP), then you are permitted to use either TOC or the oxidizable substance test, though this is likely change to a TOC-only test in the future. If you are producing PW and following the USP or JP, you are not allowed to use the oxidizable substance test and must use a TOC instrument. Included below is a summary of the TOC test requirements for the major global pharmacopeia organizations.

AttributeUSP 37EP 8.0JP 16ChPIP
TOC (mg/L) Purified Water - PW0.50.5 (Optional) (Optional)
TOC (mg/L) Water for Injection - WFI0.
Oxidizable Sub (/100 mL) Not dectable Option to TOCNot dectable


Timothy from Lancaster, PA asks:

1. Is it acceptable (for calibration) to be performed on-line by comparing to a standard placed in a side stream?

Yes, an on-line calibration with comparison to a standard sensor in a side-stream is permitted and in fact approved and accepted by USP, EP and other pharmacopeias.

2. Is off-line calibration of the sensor and measuring circuit still required?

If the calibration procedure is followed for the on-line system there is no requirement to perform an off-line calibration. When performing the on-line calibration the procedure is as follows; 1. Verify temperature measurement circuit of transmitter. 2. Verify the resistance/conductance circuit of the transmitter. 3. Compare temperature measurement of on-line sensor to standard sensor if within ±2˚C, no adjustment is required, otherwise adjustment of the temperature calibration factors using the protocols of the sensor calibration functions. 4. Compare the conductivity reading of the on-line sensor versus the standard sensor, if within ±2%, no adjustment is required, otherwise, adjust the cell constant based on the manufacturer's recommendation.

3. What tolerance is required for the loop?

There is no specified loop tolerance, but if you perform a system verification the new recommended limit for a side-by-side comparison is 5%.

Timothy from Lancaster, PA follows up with: 

I’d just like to get some clarification. To summarize your response below; the on-line calibration consists of verification of the transmitter temperature and resistance/conductance circuits along with verification of the sensor temperature and conductivity versus a standard. I’m clear on that part. However, I’m not clear on how to apply the conductivity tolerances. I understand the sensor conductivity must be adjusted if it exceeds ± 2% versus the standard. Is the ± 2% considered to be an adjustment limit or is it the calibration tolerance? I think my confusion lies with the system verification tolerance of ± 5%. Which tolerance, ± 2% or ± 5%, is considered the calibration failure limit that would cause the water quality to come into question? The USP verbiage doesn’t make this clear so I’m hoping you can help me to understand the intended meaning of the requirements.

The system verification statement was added about 5 or 6 years ago and was initially stated at 20%. This has been changed in the recent edition of the USP to 5%. The system verification is recommended, but not required by the USP and it is intended for use when the sensor is calibrated independently from the measurement electronics (transmitter). It does not apply and is not needed for the following situations: 1) Thornton digital conductivity sensors (since the measurement circuit is directly attached to the sensor) and 2) analog conductivity sensors that are calibrated with the same measurement electronics (transmitter) as the transmitter in operation.

Regarding the 2% versus 5% question, the 2% is the tolerance for the conductivity measurement of the sensor versus a reference sensor or the stated value of a conductivity solution. The 2% represents the calibration or verification tolerance that is permitted without any required adjustment, unless your own SOP requires a tighter tolerance.

Cell constant (value and its accuracy) is linear with conductivity (measurement and error). If the conductivity reading does not match the actual reference conductivity reading (within 2%), then cell constant adjustment is required. If ≤2%, no adjustment is required.

Also, technically, if >2%, then the question of water purity comes into play, but it is mostly a theoretical point. Suppose your water is 1.10 µS/cm at 25°C and your cell constant required a 5% adjustment (up), then the actual water was 1.10 µS/cm * 1.05 = 1.155 µS/cm, still very far from 1.3 µS/cm at 25 °C. All you need to do is adjust the reading by the same percentage as the cell constant change to see the impact. Since everyone operates well below the <645> limits, this is only a theoretical issue, not a practical issue.

Our recommendation for Thornton sensors is the following: If your reading differs by >2% but ≤ 5%, then make the adjustment. If the sensor differs by >5%, clean the sensor and recalibrate. Because conductivity is temperature dependent, an accurate temperature calibration should within ±2˚C.

“Can you perform calibration of TOC analyzers and conductivity sensors without removing them from the water system?”

Yes, you can!

TOC instruments and conductivity sensors must be calibrated. The ability to do this while they are on-line, as opposed to having to remove them and perform the calibration off-line or ship them to another location, is a significant benefit and time saver.

Download the related PRO Insight

"What are the requirements for pH and temperature for bulk Water for Injection (WFI) or bulk Purified Water (PW)?"

There is no specific requirement for either parameter. The owner of the water system must determine if a specific temperature is needed for their process. Temperature is required to be measured to determine the appropriate conductivity limit as specified in USP <645> Stage 1 test. WFI and PW have a pH at or near 7 because of its purity. When removed from the process piping, the pH will be lower due to the absorption of CO2. There is no specific pH requirement either, unless you are performing the USP <645> Stage 3 test.

Download our free guide to read more about WFI and PW requirements

“Is TOC testing required for Pure Steam?”

The regulations require that the condensate of Pure Steam be tested for TOC, conductivity and endotoxins, the same as for WFI. The Pure Steam must have no added substances and microbial testing is unnecessary due to the lethal properties of pure steam. The steam is NOT lethal to endotoxins.

Learn about continuous, on-line TOC analyzers


David from Mexico asks:

What is the best method for calibration of conductivity sensors?

The global pharmacopeias have all harmonized on the calibration methods for conductivity. Stating which is best is difficult, but I can share with you the method that is currently recommended for conductivity measurement systems in Purified or Water-For-Injection systems.

There are two aspects to a conductivity calibration, the first is the transmitter electronics and the second is the actual sensor. Verification and calibration of the transmitter electronics are performed first and the requirements are the same regardless of which method you use for the sensor.

Transmitter requirements:

  • Temperature measurement circuit should be verified.
  • Reports uncompensated conductivity or resistivity.
  • Display resolution of 0.1 uS/cm minimum.  1 uS/cm resolution is unacceptable.
  • Verify performance resistance/conductance circuit to ±0.1 uS/cm by replacing sensor with traceable precision (0.1%) resistor. For example: 100 kohm resistor with 0.1 cm-1 cell constant should display 1.0 ± 0.1 uS/cm.

After the transmitter electronics have been verified and calibrated, then the sensor is calibrated. This can be performed in one of three ways.

Sensor requirements:

The sensor can be removed from the water system, though this can add errors or issues with the calibration, or the sensor can be calibrated in the water system.

The temperature is compared to a reference temperature device or another calibrated reference sensor.

  • The temperature accuracy of the sensor is always performed first. Sensor temperature measurement must be accurate to within ± 2°C.

After the temperature accuracy of the sensor is verified, then the cell constant or conductivity measurement is verified. This step can be performed with the sensor removed from the water system or performed with the sensor in the system. 

  • The sensor cell constant must be known and accurate to within ± 2%.

If the sensor is removed, the solution used to verify the conductivity can either be a certified conductivity solution from a national standards body or the solution can be prepared following the ASTM D1125 procedure. Note some cautions regarding the above procedures: by removing the sensor from the water system the sensor can get dented, scratched or contaminated. Remember, any solution you put the sensor into will not be as clean as the water in your water system. Additionally, if you purchase low conductivity solutions these are not stable in the atmosphere and if they are 'stabilized' solutions they may contain alcohol or oil to stabilize the solution. If you prepare the solution following ASTM D1125 then the solution will have a conductivity of 146.93 µS/cm. It is stable in the atmosphere but at a much higher conductivity than the water in your system.

The next method which is approved and currently recommended by the pharmacopeia is to leave the sensor in the water system and calibrate in-line.

You would connect a reference conductivity loop to the water system at a sample point in proximity to the sensor being tested. You verify/calibrate the meter and then with water flowing to the reference sensor you allow the temperature to equilibrate and then compare the reference sensor temperature to the sensor being calibrated. After the temperature accuracy is verified, you then measure the conductivity and if the sensor under test is within 2% of the reference sensor, calibration is complete. The significant advantage of this method is that you have not removed your sensor from a validated water system and you are calibrating in the same quality of water that you use in your process. A final note regarding calibration - it is a single point calibration for pharmaceutical waters.

The three methods:

  • Sensor is calibrated using certified solutions from a national body
  • Sensor is calibrated in a solution prepared to a specific conductivity (ASTM D1125) standard
  • Sensor is calibrated against another reference-calibrated sensor usually from the same manufacturer.




“Is it a requirement to perform on-line and off-line testing for conductivity of a pharmaceutical water system?”

Conductivity measurement
Conductivity measurement


“Why should you make a temperature compensated conductivity measurement?”

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