Jim Knows Best | Pharmaceutical Waters Industry Expert
Shailesh from India asks:
We are using Hach Anatel PAT 700 TOC Analyzer in new purified water system. But even after hot water sanitization at 80 degrees, the TOC values don't go down to 1500 ppb.
Thank you for contacting us with your question regarding high TOC readings. A new system can take a little time to rinse up and deliver the expected water quality. I will try and provide some possible causes for the high readings, but I also have some questions regarding the installation and system. Are you also observing high conductivity readings, if so that would lead me to believe the system is continuing to rinse up. At what point of the PW system are you measuring TOC, on the return line to the storage tank from the distribution loop, on the feed line to the storage tank after purification or at some other point in the purification process? If you are measuring at the beginning of the purification process then high readings could be expected. If the high readings are after the purification system or on the distribution piping then the high readings are unexpected. Has the Hach Anatel system recently been calibrated? Was the purified water system flushed and operated for a period of time before connecting the TOC analyzer? If not, it could have become contaminated with organics in the new system and piping.
To check the accuracy of the TOC analyzer you have installed you could bring in a portable TOC system and compare the readings. If the portable shows a lower reading then the Hach Anatel system might have a technical issue. If the readings are high on both units then your system may have a purification process that is not operating properly.
Ramil from the Philippines asks:
What do you think are the sanitation approaches that work (or don't) for Pharmaceutical Water Systems and why?
In regards to sanitization of Pharmaceutical Water systems, the most commonly used method is heat sanitization: raising the water temperature of the distribution loop to above 82 degrees C for a period of time, normally a minimum of half an hour, but many pharma companies heat for over an hour. This is normally performed on a Pure Water (PW) system. A hot Water for Injection (WFI) loop would not require this because the system is always heated and self-sanitizing. In a WFI system the temperature must reach approximately 75 degrees C at the end of the distribution loop to ensure that heat penetrates all the surfaces of valves, manifolds and distribution points. The other method that is popular is the use of ozone to sanitize, as it requires less energy and is very effective at destruction of biofilm and sanitization. The last method that has been commonly used in the past is chemical sanitization, but that is discouraged today because many chemicals are not that effective, requiring long contact time and lengthy rinse periods after use which wastes large volumes of water.
Swapnil from India asks:
Can one online TOC meter monitor two to three loops of TOC and intermittently at some time interval record samples? Can the different loop be of purified water and water for injection?
A TOC system could monitor multiple loops, but it would require the installation of a sample line sequencer to provide the water samples at programmed intervals. Using a TOC analyzer in this manner does create a number of challenges. The first is ensuring that the data being reported is not a mix of two water samples. Secondly, if a water sample not being tested remains stagnant in a sample line, then it would not be a real-time picture of the water being distributed in the WFI or PW loop. Lastly, the distance from the different loops to the analyzer would providedelayed analysis of the actual water quality. An alternative method would be to install a TOC analyzer on the critical water loop, usually the WFI loop, and then either install a second analyzer on the PW loop or use a portable TOCunit (450TOC) to perform TOC checks on the other loops at a scheduled sampling period.
Ajoy from Malaysia asks:
We have installed a new purified water system generation plant. We tried to analyze TOC online using GE SIEVERS CHECKPOINT PHARMA, GE RL 500, HACH ANATEL PAT700, etc. Checkpoint gives a pass result (< 500 ppm) from the water generation end but increases to > 500 ppm after circulation in the distribution loop. Same thing happened with PAT 700 but GE RL 500 and M9 provide pass results even after water circulation in the distribution loop. Question is why Checkpoint is showing confusing results. It’s widely used in the pharma industry and hence there is no reason why we cannot use it. Do you have some opinion? We are an API producer from Malaysia.
The measurement basis for all the on-line TOC systems for pure water is differential conductivity and each of the systems you have tested use that method, but also have some differences in the final measurement and calculation of the TOC value. In your message you state that all the systems show TOC levels below the Pharmacopeia limit of 500ppb after the Purified Water generation system, but the Checkpoint and Hach systems show readings above 500ppb after distribution. Are the systems all measuring the water as an at-line measurement, in other words a sample line that feeds directly into the instrument? If you are collecting samples to test off-line, sample container, sampling method and environmental (airborne) contaminants will impact the TOC readings. The TOC readings can also be affectedby any compound that is added or in the distribution loop. Have you performed a sanitization procedure on your distribution loop and if so, did the TOC readings change after the sanitization?
You specifically asked about the variation in the readings from the Checkpoint and why you could not use it for testing. If the Checkpoint is showing readings above the allowed limit, I would be concerned about using it for validating the Purified Water especially because the measurement point that is recommended for reporting water quality is on the return line of the distribution loop. You state that the Checkpoint is widely used in the Pharma industry and our experience is that we do not see the Checkpoint used by many Pharma companies on their Purified Water or Water for Injection systems. Our industry experience has shown that the Checkpoint will consistently measure at a significantly higher TOC level than other on-line systems.
If you are looking to use a TOC system that is less expensive and is as accurate as the Sievers RL 500 or M9, you may want to consider evaluating the METTLER TOLEDO Thornton 450TOC Portable Analyzer or the 5000TOCi Analyzer.
Jordi from Spain asks:
I have a question about TOC of pure vapor. We have a pure water vapor generator (200 L) which produces pure vapor for our installation. The water used is purified water, which undergoes weekly controls to assure its quality. We analyze TOC of the vapor by condensing the vapor in one liter glass bottles (laboratory) previously depyrogenated at 250ºC / 2 hours. We are obtaining results greater than 500 ppb (450 to 800 ppb are typical values).Our vapor generator is used 2 days a week and is stopped for the rest of the week. The chamber of the vapor generator remains half full (100 L approx.).Before we take the sample for TOC, the generator is usually working for half an hour with steam passing though the point of use for at least five minutes before the sample is taken. The sample once condensed is passed to a smaller 50 ml TOC tube and sent for analysis. We have results within a few hours a taking the sample.We need to lower the TOC but cannot see an obvious way to proceed.Is this problem a common one?I feel it is related to the sampling protocol we use, but as I am not familiar with other sampling methods, I cannot be certain.Could it be related to the number of days the water stays in the generator between uses?
Regarding your question about the TOC value of your pure steam condensate and sampling technique, there are several specific areas I would look at to reduce the TOC value of the samples. The sampling technique and the containers used for the sampling can certainly impact the TOC and increase the value. The glass bottles are being de-pyrogenated but they may still have a residue on the glass. When filling the bottles you should do so with the water from the sample port and then discard that sample. Do these three times to rinse the bottle with the water to be sampled. The same rinsing technique should be done with the TOC sample tubes you are using: fill, rinse, and discard three times. What is the material of the TOC sample tubes is it plastic or glass?
The pure water from the generator will quickly absorb any organic vapors in the air and therefore you should limit the exposure of the water to the atmosphere. As the steam undergoes the phase change from steam vapor to water and begins to cool, the absorption rate will actually increase.
The water left in the chamber of the condenser will be absorbing any atmospheric contaminants the entire time it is sitting in the chamber and I would recommend that the chamber be drained between operating periods.
What is the source water to your pure steam generator? Is it city drinking water or is it being supplied from a purified water system? If it is city water and there is no pretreatment, you should consider installing a GAC (Granular Activated Carbon) cartridge on the feed water line. If the organics are in the feed water then they are being carried over as the pure steam is being generated. If the steam is being cooled too quickly the volatile organics in the feed water are not being vented to atmosphere and are being carried into the condensate, some steam should be permitted to escape from the condenser vent.
To determine if the high TOC value is coming from the sampling technique and containers or is in the steam condensate, you could have a portable TOC system brought in for a demonstration. The portable TOC analyzer would be connected to the sampling line and you would know immediately your TOC value. The METTLER TOLEDO Thornton 450TOC is recommended for this specific application and would assist you in determining the actual TOC value and the possible source.
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.
Pawel from Poland asks:
What is the best temperature for PW in a distribution loop in order to prevent microbiological growth?
The short answer is to keep a PW distribution system above 66˚ C. This has proven to be an effective temperature in the control and prevention of microbial growth. However, periodic sanitization practices and good system design also contribute to microbial control and temperature alone should not be the only consideration.
The control or prevention of microbial growth in a PW system is normally achieved with a regular sanitization procedure. If a PW system exhibits zero or low growth with regular microbial tests then continued operation at your current temperature with frequent sanitization would control growth. Periodic sanitization of the distribution system with temperatures of at least 80˚ C will kill the biofilm and floating organisms but will not remove any established biofilm.
In addition, to control microbial growth in a PW distribution system the flow should be constant and turbulent if possible, and any dead legs need to be minimized or eliminated.
The design of a PW distribution system should be reviewed to ensure that good design features are incorporated, some of which include, a sloping design that permits complete draining when required, material compatibility for thermal sanitization, and possible inclusion of periodic ozone sanitization or in-line 254-nm UV.
“Why should you make a temperature compensated conductivity measurement?”
For process control.
Conductivity measurement is affected by water temperature. 25°C is recognized by the pharmaceutical industry worldwide as a standard reference temperature. By compensating conductivity measurements of pure and ultrapure waters to this reference temperature, the pharmaceutical water system will be under full process control.
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"How can I set my conductivity alarms based on pharmacopeia conductivity limits?"
Global pharmacopeias publish their conductivity limits based on uncompensated conductivity at specific temperatures. This makes it difficult to set specific operating limits because uncompensated conductivity changes with temperature. Therefore, if you wish to set alarms based on pharmacopeia regulations, you can use a transmitter that has the pharmacopeia's conductivity limits pre-programmed in its firmware. Then, you can simply choose how far below the limit (based on a percentage) you want the alarm to activate and set the setpoint accordingly. The transmitter does the calculation and readjusts the setpoint based on the water temperature.
|Learn about the multi-parameter M800 transmitter|
“Is conductivity testing required for Clean in Place (CIP) of a vessel?”
There is no requirement to test for conductivity or TOC during the cleaning of a vessel. However, testing conductivity and TOC should be conducted during the final rinse procedure for a vessel. The recommendation is that the quality of the effluent water in the final rinse should equal the quality of the water used during manufacturing: quality in, quality out. If you use PW or WFI in the vessel during manufacturing, then the final rinse should have the same quality requirements for conductivity and TOC.
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“Is it a requirement to perform on-line and off-line testing for conductivity of a pharmaceutical water system?”
Calibration of TOC analyzers and conductivity sensors without removing them from the water system
“Can you perform calibration of TOC analyzers and conductivity sensors without removing them from the water system?"