Total Organic Carbon and Conductivity Testing
Because of the various uses of these waters, microbial requirements are not included in these monographs since this would unnecessarily burden some users with meaningless and/or inconsequential or inappropriate requirements, e.g. water used for many laboratory analyses. Microbial guidelines are provided under the informational chapter Water for Pharmaceutical Purposes <1231> where it states that the user should establish in-house specifications or fitness for use microbial levels above which the water is unsuitable for use.
Alert and Action Levels are process control terms and should be established at levels indicative of the water system trending outside of its normal microbial control range. These levels should be established at levels no higher than, and preferably lower than, those listed in Water for Pharmaceutical Purposes <1231> based on the normal microbial performance trends in your water system. The purpose of Alert and Action Levels is to trigger additional, non-routine, rather than routine microbial control measures. These additional control measures should prevent objectionable levels and types of microorganisms from being present in the water, based on for the water’s use.
USP is silent on a specific answer to this question. It is understood that some manufacturers have their analyses performed by external laboratories – which may take several days or longer. For this reason, there is no time limit.In general, you can wait as long as you want – at your risk. But it is advised to test as soon as practical for the following reasons; 1) when stored, the water purity only degrades over time. Since Purified Water, Water for Injection or the sterile waters are of such high purity, the passage of time does not do anything except potentially degrade the sample due to environmental, ambient, or container factors; and 2) water is typically not produced in batches, but rather it is usually purified, produced, and consumed continuously. The water may have had direct product impact or contact before any lab analysis is executed. Delays in testing only increase the amount of potential product impact – in the event of a failed test.
For lab analyses, samples should be stored in containers that do not adversely impact the test results. This is to prevent false positives and unnecessary investigations. For example, storage of water in a glass container for a few hours is usually good, but storage for a longer time will result in a modest increase in the sample conductivity. This is due to the leaching of sodium silicate from the glass, raising the pH and the water conductivity, and threatening to fail Water Conductivity <645>. In general, clean plastic containers are a better choice for long term storage of samples for Water Conductivity <645> testing. For Total Organic Carbon <643>, there is a similar rationale - many types of non-shedding plastics or glass suffice. In general, storage at ambient or refrigerated temperatures is best for these chemical tests, while refrigerated storage is advised for samples used in microbial testing. Cleanliness of any container is most critical. Due to the very high purity of these waters, fingerprints, soaps, and other residues must be avoided. False positives can result.
These two chapters specifically state that these tests can be performed off-line or on-line. There are benefits and challenges for each approach, and they are described in more detail in these chapters and in Water for Pharmaceutical Purposes <1231>. In general, on-line testing avoids the risk of contamination of off-line samples by humans, containers, or the environment, and it provides immediate analysis and direct opportunities for real-time control, decision and intervention. For example, you can continuously test and accept the water (for these chemical attributes). Conversely, you can prevent the distribution of the water in the event of a failed test in real time. However, for a facility with multiple types of waters and loops, a centralized lab analysis system may offer a more economical choice. In either case, the water sample must be representative of the water used in production.
There is a "target limit response" of 500 µg of Carbon/L. The true limit is the response of the TOC measurement system to a 500 µg Carbon/L (prepared from sucrose) solution, Rs, corrected for the response to reagent water, Rw. This limit is equal to Rs – Rw. The actual number will vary based upon your reference standard solution, your equipment, background carbon, etc. USP Reference Standards are required for use.
USP General Chapter <643> intentionally says nothing about how often the system suitability test (SST) should be run. The reasoning is that this frequency depends on the stability of the Total Organic Carbon (TOC) instrument response and other factors associated with the water quality and risk. If the TOC of a quality water system is very low, say <20 ppb, then many opt to reduce the frequency of testing due to less risk. The stability of different TOC measurement technologies may vary over extended periods of time. The instrument manufacturer can advise the user on this matter and user experience can also be valuable in determining a suitable frequency. Another factor is the risk of a non-conforming system suitability test result since the Rs-Rw result used in this calculation is the limit response for the instrument, the crucial pass/fail value for the TOC test. If a non-conforming system suitability test is obtained, it implicates the inaccuracy of all TOC test results since the previous successful system suitability test. For this reason, many users choose to perform the system suitability test more frequently than the stability of the TOC instrument response might suggest, just to minimize the impact of a possibly non-conforming result. This is why a typically low TOC water system is at less risk, even with a failed SST. If the SST fails, some remediation is necessary to re-adjust the instrument, replace a lamp, or some other means of instrument improvement. But even a 50% error will have little impact on the past TOC readings (since the readings, even with this error, are so low relative to the Limit). On a high TOC water system, the failure of the SST is possibly more critical. This is up to the risk the user is willing to assume, knowing the historic stability of their instrument and other factors. Therefore, the Total Organic Carbon <643> is silent on the frequency of performing the system suitability test because it is up to the user to decide what is appropriate.
Where USP is silent on storage conditions and the stability of prepared Total Organic Carbon (TOC) reference standard solutions, the solutions should be 1) prepared fresh or 2) used within the expiry if procured from 3rd party supplier or 3) used within a timeframe determined by stability studies. In all cases, USP Reference Material is specified. Several factors can influence the stability of the reference standard solutions. These include temperature, light, oxygen, microbial decomposition, and adsorption to the container surface. The developments of turbidity, additional color, or performance variability relative to freshly prepared solutions are indicators of instability. Most of the suppliers of solutions specify expiry dates. But as a practical matter, concentrated reference standard solutions of Sucrose last 3-6 months, and analogous solutions of 1, 4 Benzoquinone (pBQ) last about 2 months, assuming they are stored at appropriate temperatures in appropriate containers and protected from light (for pBQ). It is recommended to use refrigeration since this slows down solution degradation, and reduces microbial growth, particularly in the sucrose solution.
In Stage 3, a neutral electrolyte (KCl) is added to increase the ionic strength and accurately measure the pH of the solution. If the ionic strength of the solution is not increased, the pH measurement will be highly unstable and inaccurate. So KCl is added to make a valid pH measurement as a part of the Water Conductivity <645> - Stage 3 test. The increase in the ionic strength is needed so that there is minimal concentration gradient across the pH electrode diaphragm/junction. A large concentration gradient results in a lack of equilibrium and unstable pH response.
There is no need to perform stages 1 and 2 in order. You can go directly to Stage 2 if offline testing in preferred - you do not have to fail stage 1 first.
The cell constant accuracy must be ±2% of the certified value, not the nominal value.
In general, any material that does not impact the conductivity in any appreciable way is suitable. Many plastic containers including PTFE, HDPE, LDPE and some polycarbonates are appropriate. Glass containers for immediate testing are appropriate. Regardless of the material, they have to be clean and free of any cleaning reagents such as soaps. Soaps are very conductive.
Yes, this is correct. There has never been a test for nitrates for USP waters. The heavy metals test on USP waters was deleted in 1996. The pH test was deleted in 1998. [Note - There is a pH measurement (not a test) as a part of Stage 3 test for Water Conductivity <645>, but this is still a conductivity limit test]. Note that you cannot fail the former pH specifications of water (pH 5.0 – 7.0) if you pass the conductivity specifications. You also cannot fail the heavy metals test or the nitrate test if you pass conductivity and your water system starts with water compliant with the requirements for one of the drinking waters specified in the monographs (for the US, EU, Japan, or WHO). In some cases, these tests may be required by other pharmacopoeia.