There were days when taking a water sample once in a day from the PW/WFI distribution loop and analysing it at the lab would satisfy the auditors about water quality. But, nowadays the expectation of auditors is increasing and they expect online monitoring of the PW/WFI loop with higher sample frequency to ensure that quality is being monitored.
Although the frequency of the online monitoring is not mentioned, based on risk calculations we can fix the minimum frequency of monitoring. It could be anywhere between 15 minutes to one hour, based on the capacity of generation, user points consumption, storage tank etc.
Once the online analyser is being installed in line it gives some total organic carbon (TOC) data which needs to be validated and co-related to offline measurements. In the market there are two online TOC measurement systems available: Sensors (fast, less accurate, less stable) and Analysers (slow, more accurate, more stable). Most of the online analysers (95 per cent) used in UPW applications is conductivity based as it has proven to be most suitable for these applications. The detector can be a direct conductivity, membrane conductivity or dynamic end point detection by single sensor differential conductivity methods. As the direct conductivity method is more of a sensing technology it needs more calibration, possibly every six months. Whereas the membrane conductivity and the dynamic endpoint detection by single sensor differential conductivity methods are more stable with a calibration stability of one year.
Calibration of TOC analyser used in UPW water is known to be critical due to its low level of detection (4ppb-500ppb). It has some significance based on which technology you are using and how stable it is. As far as compendial requirement for Pharmacopeia is concerned, the TOC analyser used in pharma manufacturing process should be tested and challenged with System Suitability Test (SST) to ensure the unit is between the required specification range (85 per cent = RE =115 per cent). The frequency of SST again depends on the risk analysis of the technology used to measure the capability of the water system to deliver stable quality of water. These tests are offline tests and need to be done with external standards. Calibration of the system is key for a good response from the instrument with high degree of accuracy. And during calibration, the
system made to correct itself to the standard value.
We need standards for calibrating a TOC analyser. These standards are made from chemicals like sucrose or Potassium Hydrogen Phthalate (KHP). Sucrose is a very common chemical where as KHP is a more stable compound. These chemicals are diluted with a specific dilution ratio to achieve a particular concentration. It is always good to have the multipoint calibration method to ensure that the system is in perfect line. The points can be chosen between operating range and analyser range. A typical concentration used for calibrating the online TOC is 250 ppb, 500ppb, 750 ppb and blank. These concentration as carbon can be made easily in the QC laboratories by using sucrose. However, we recommend using NIST traceable readymade standards as this affects the TOC value during routine analysis.
Some analysers have in-built offline sampling and some do not. Those that do not have an offline sampling system need to attach a separate module called calibration KIT. Mostly high end analysers will have the option of offline sampling then you can directly introduce the standards one by one so that calibration can be done. There are certain analysers available which have multiple offline PORT so that all the standards can be introduced at once to perform a fully automatic calibration. The analyser runs the standards one by one and calculates the drifts with the internal algorithm and stores it in the calibration parameter. At the end of the calibration process the analyser will ask either to accept the new calibration constant or reject it, if you accept it, take the new calibration constants and replace it with older one, if you reject the test then it keeps the older constants only.
It is always advisable to run validation/ verification standards of known concentration and check the response with new calibration constants after calibration. Once it is an accepted criteria then the analyser should be taken forward to the next step. If not, calibration should be repeated.
System Suitability Test (SST)
This is a compendial requirement of Pharmacopeia. TOC is a non-specific method but there are many other technologies available which can be used in the detection of the same. Rather than qualifying all the technology individually, Pharmacopeia has made this test mandatory to not only qualify the technology or instrument but also to validate the analysed samples.
This test is done to challenge the capability of the analytical method used for TOC analysis by testing it against the easiest and hardest (difficult) oxidised chemicals. Prepare a 500ppb as C of standards by using sucrose and 1-4 Benzoquinone and by getting it analysed. Then, get the response efficiency calculated from the analysed values of the above standards. If it falls between 85 per cent to 115 per cent, then it passes this test.
RE = 100 [(rss–rw) / (rS–rw)].
- Using ultra pure water, prepare standards of 500ppb as C by adding sucrose and 1-4 Benzoquinone by proper dilution.
- First, analyse the blank water and denote the result as Rw
- Next, analyse the sucrose standards and denote the result
- Then, analyse the 1-4 Benzoquinone standards and denote the result as Rss
- Manually calculate the RE with above formula and ensure it falls in between 85 per cent to 115 per cent.
- The SST results of the analyser certify intactness of the analytical methodology and also certify that the components present in the analyser are working satisfactory. At the same time, this also validates the result produced in past.
As these standards have to be introduced to the analyser, a smart online TOC analyser should have an offline sample introduction system in built or it needs to be arranged externally in case of economic TOC analysers. All the calculations are in-built. Most of the tests need multiple standards, for example; multipoint calibration needs four vials, SST needs three vials, accuracy needs four vials etc. There are certain analysers available in which you can introduce all the vials at a time and can run a fully automatic calibration/ SST/ validation.
Skytech Systems (India)
401, Siddheshwar Arcade,
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Thane (W) – 400615
Tel: +91-22-4153 3342
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