Sydney Jannetta Lead Marketing Specialist SUEZ Water Technologies & Solutions
Introduction
Per USP and other harmonized compendia, conductivity is an important quality metric that must be monitored for product quality and patient safety. The FDA and USP have established conductivity, total organic carbon (TOC), endotoxins, and bioburden as the four critical attributes for water quality assurance for pharmaceutical use. TOC and conductivity are used to ensure the highest level of operational control and process understanding. Consisting of different stages of analysis, conductivity testing allows pharmaceutical companies to maintain and treat their water to confirm purity and suitability for pharmaceutical applications. When combined with TOC analysis, conductivity can provide a complete picture of the water quality and enable companies to get the most out of their testing.
Regulations
USP <645> outlines the three stages of conductivity testing. Analysts must start with Stage 1 conductivity testing, making sure to use a suitable container for offline or online analysis. Using the table provided in USP <645>, analysts determine if the conductivity measurement passes Stage 1. If the sample does not pass Stage 1 conductivity acceptance criteria, additional tests must be performed (Stages 2 and 3) to determine whether the high conductivity is due to intrinsic factors, such as atmospheric CO2, or extraneous ions. Stage 2 conductivity testing is much more prescriptive in the procedural steps that must be taken. The sample must be vigorously agitated while maintaining a temperature of 25 ± 1o C until the change in conductivity is less than 0.1 μS/cm per 5 minutes. Once the conductivity reading is stable, the value must not be greater than 2.1 μS/cm to pass Stage 2. Manual meter and probe Stage 2 conductivity testing can take up to 30 minutes per sample and does not include TOC.
Methods
Traditional conductivity methods using a meter and probe, while compliant, introduce integrity and efficiency weaknesses. For example, meter and probe analysis requires analyst time to manually introduce sample to the probe one sample at a time. This unnecessarily exposes the sample to atmospheric CO2 which can cause over-reporting against Stage 1 limits. This method also lacks automation – allowing for concerns related to sample handling and data transcription – and does not present the opportunity to obtain data other than conductivity. Additionally, manual laboratory testing can take hours of analyst time.
Another method for measuring conductivity consists of using an analyzer with an in-line conductivity cell. This capability offers efficiency and sample integrity gains over other laboratory methods. For example, some analyzers allow for dual TOC and conductivity measurements from one vial. This streamlines sampling resources while generating two data points at one time. With the use of an autosampler and software, efficiency can be maximized to manage over 60 samples with standards at any given time, complete with automated analysis, secure data, audit trails, and configurable reports. By automating simultaneous Stage 1 conductivity and TOC testing, labs realize great efficiency gains while improving sample handling and data management.
Conductivity Verification
USP and other harmonized compendia require conductivity cell constant verification to be performed regardless of the method used (meter and probe or analyzer). A concentration or frequency is not USP and other harmonized compendia require conductivity cell constant verification to be performed regardless of the method used (meter and probe or analyzer). A concentration or frequency is not explicitly stated, but verification on some frequency is compulsory. Many factors can contribute to conductivity instability, one of those being atmospheric CO2. At low levels, standards are more likely to be misreported due to factors such as atmospheric CO2 absorption and desorption, causing unintended bias in measurements. While higher level standards are not immune to impacts from dissolved CO2, the compendial acceptance criteria of ± 2% from the stated value becomes more indicative of the actual instrument performance when using reference materials at higher conductivity levels.
Compendial cell constant verifications are meant to demonstrate suitable conductivity cells based on the guidance set out in USP <645> and other global compendia. USP <645> only states the requirement for verification but does not prescribe frequency or concentration. Many pharmaceutical companies choose to go beyond only the cell constant verification and perform method suitability checks with other concentrations and acceptance criteria determined by process capabilities. These method suitability checks are usually performed closer to the process range of water samples. It is important to distinguish these kinds of checks from a compendial cell constant verification. Method suitability checks are not required by a regulatory body but rather give users confidence that their instrument is suitable for a given method.
Best Practices for Conductivity Testing
Using an analyzer with an in-line conductivity cell and TOC, such as the Sievers M9 TOC Analyzer, is ideal for Stage 1 conductivity testing. Together with Dual Use Conductivity and TOC, or DUCT, vials analyzed with this measurement approach provide accuracy and efficiency for water measurements. DUCT vials are considered a suitable container for simultaneous testing and do not contribute either TOC or conductivity when in contact with the sample. Studies using Sievers DUCT vials, caps, and septa have demonstrated that with good sampling technique, there is no significant TOC or conductivity contribution for up to five days.
Best practices for sampling with DUCT vials are:
- Do not rinse vials prior to use.
- To avoid contamination, do not touch the inside of the vial, cap, or septa.
- Fill the DUCT vial once, completely full, with no headspace and avoid turbulent flow when filling the vial.
- Immediately cap the vial.
- Do not reuse DUCT vials.
Implementing proper sampling technique, method conditions, and justified verification frequencies will ensure a high degree of confidence in TOC and conductivity measurements.
Conclusion
For pharmaceutical manufacturers, the most desirable state for compliance with USP <645> is Stage 1 conductivity testing. It is the simplest to execute, requiring the least time per sample. Automating the testing for USP <645> offers significant time savings as well as increased data integrity and security. Employing combined TOC and USP Stage 1 conductivity testing using the Sievers M9 Lab TOC Analyzer can save companies time and money while simultaneously building quality into their processes. This approach also allows organizations to redirect resources to other operational excellence and lean initiatives. In alignment with the FDA Process Analytical Technology (PAT) Guidance, the Sievers M9 Analyzer with Stage 1 conductivity is also available in a portable configuration for at-line testing or in an online configuration for the ultimate in efficiency.
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