The key to effectively detecting pharmaceutical water using an M9 analyzer with conductivity options includes:

According to USP<645>, 'Stage 1 conductivity can be tested offline in a suitable container'.¹A suitable container for synchronous testing refers to a container that does not affect the TOC or conductivity of the sample when in contact with it. Tests have shown that, with the use of correct sampling techniques, the Sievers DUCT bottle body, cap, and gasket can withstand up to 5 days,It will not make a significant contribution to the TOC and conductivity of the sample.^2,3

When using M9 analyzer to analyze pharmaceutical water, the samples should be tested multiple times to obtain good statistical robustness and detection stability. When using M9 analyzer to detect TOC and conductivity, it is recommended to repeat the detection no less than 4 times, and one of the detections should be discarded. The original conductivity and temperature are used to detect the conductivity in the first stage, so there is no need to choose a compensation algorithm. The M9 analyzer provides the original conductivity, temperature, and temperature compensation values. For pharmaceutical water, the original conductivity and temperature should be reported. The acceptance criteria should be determined based on Table 1 in the chapter "USP<645>Stage 1- Temperature and Conductivity Requirements". According to the measured temperature, the corresponding conductivity value is the conductivity limit of pharmaceutical water.¹

Figure 1: Method conditions

Set the flow rates of acid and oxidant required for detecting pharmaceutical water with TOC below 500 ppb to 1.0 μ L/min (acid) and 0.0 μ L/min (oxidant), respectively. This flow rate can ensure the oxidation of carbon in the UV reactor while avoiding excessive oxidation of the sample.

Another method is to use an optional Inorganic Carbon Remover (ICR). If the detection value of inorganic carbon (IC) increases by about 10 times or is greater than the TOC detection value, it is recommended to use an inorganic carbon remover to improve the stability and accuracy of TOC detection.^4,5

If the first stage conductivity test fails, please conduct the second stage test according to USP<645>.

Challenge instruments and methods with known standards to provide credibility for each test. Determine the frequency of testing through risk assessment, and confirm the nominal performance of the method on the analyzer using TOC system suitability standards and conductivity confirmation standards. Using standard samples that meet the acceptance criteria can ensure that the analysis of unknown water samples meets the pharmacopoeial requirements for pharmaceutical grade production water.^1,6

Although the pharmacopoeia does not specify the frequency of confirmation, it stipulates that production units should regularly use conductivity confirmation standards and system suitability standards to confirm methods. The frequency of confirmation should be determined by assessing the risks and potential impacts of each process. Risk management requires clear definition and evaluation of all variables and their impact on the process. Factors that must be considered include frequency of use of standard samples, sampling time, system suitability or risk of confirmation failure, possibility of out of specification (OOS) results, time constraints, etc. As USP<643>and<645>do not specify frequencies, each production unit is responsible for developing robust process flows and procedures to manage process risks. It is important to use conductivity confirmation standards and system suitability standards at a practical and reasonable frequency, while also meeting the requirements of USP<643>and<645>.

In order to minimize the differences in standard samples, we recommend using standard samples and sample bottles produced by Sievers analyzer to obtain certified standard samples with consistent concentrations. The applicability standards and conductivity confirmation standards of the Sievers system listed in Table 1 have shown good performance. If you use the standard samples in Table 1, you can obtain OOS investigation support from Sievers analyzer. If your sample, system suitability, or confirmation fails, the quality assurance team of Sievers analyzer will investigate and resolve internal variation factors and on-site instrument performance failures for you, and discuss the investigation results in the fault analysis report.

Due to the sensitivity and low acceptable concentration of the offline detection method for the first stage conductivity, many users use a Sievers M9 TOC analyzer specifically for offline detection of TOC and conductivity⁷If the same M9 analyzer is used to detect pharmaceutical water and non pharmaceutical water (i.e. clean validation samples), additional operational steps are required to minimize cross contamination when switching between the two samples. These additional steps depend on the type of non pharmaceutical water to be analyzed. For precautions regarding such operations, please refer to technical document UPW 07-10.⁸Please maintain and confirm the Sievers analyzer according to its operation and maintenance manual to achieve optimal performance.

By adopting the correct sampling techniques, method conditions, and reasonable confirmation frequency, the accuracy of the TOC and conductivity detection results of the Sievers M9 analyzer can be ensured. The best practices outlined in this article can help you accurately detect TOC and conductivity while meeting pharmacopoeia requirements.