Total Organic Carbon and Conductivity Testing
USP 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 accuracy 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 <643> is silent on the frequency of performing the system suitability test because it is up to the user to decide what is appropriate.
There is a "target limit response" of 500 µg of Carbon. The true limit is the response of the TOC measurement system to a 500 µg of 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.
Where USP is silent on storage conditions and the stability of prepared Total Organic Carbon (TOC) reference standard solutions, the solutions should be prepared fresh; or used within the expiry if procured from a third party supplier; or used within a timeframe determined by stability studies. In all cases, USP Reference Material is specified. Several factors can influence the stability of reference standard solutions. These factors 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 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 because 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 membrane. A large concentration gradient results in a lack of equilibrium and unstable pH response.
There is nothing in <643> that says how often to run the system suitability test. You need to run the system suitability periodically. The frequency would depend on the quality of water and typical results of system suitability testing. Once the limit has been established (Rs–Rw) from your last system suitability test, you would then determine the frequency for system suitability testing.
Because of the various uses of these waters, microbial requirements are not included in these monographs because this would unnecessarily burden some uses with meaningless and/or inconsequential or inappropriate requirements (e.g laboratory water). Microbial guidelines are provided under the non-mandatory informational General Chapter <1231> Water for Pharmaceutical Purposes. We recommend that you implement Alert and Action Levels no higher than, and preferably lower than, those listed in General Chapter <1231> Water for Pharmaceutical Purposes 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 the water’s use.
Is further information available for the PDG-harmonized General Chapters <61> Nonsterile Products- Microbial Enumeration Tests and <62>: Microbiological Examination of Nonsterile Products- Tests for Specified Microorganisms?
Yes, additional FAQs on these chapters are available in the Harmonization section of the web site.