Total organic carbon (TOC) and conductivity data are used in various applications to demonstrate equipment cleanliness, purified water chemical purity, process understanding, and process control. Not only do these analyses offer numerous quality and efficiency gains within a process but monitoring CGMP equipment and pharmaceutical grade water systems is mandated by regulatory organizations around the world, including the FDA.
This article will cover the basics of TOC and conductivity monitoring by focusing on common questions from the industry:
- What is total organic carbon and what are the different methodologies for measuring TOC?
- What are the TOC and conductivity regulatory requirements for CGMP equipment and pharmaceutical grade water systems?
- Is measuring TOC suitable for all compounds, APIs, excipients, and detergents?
- What are the best practices when performing TOC and conductivity analysis in the lab, online, or at-line?
What is Total Organic Carbon and What are the Different Methodologies for Measuring TOC?
Total organic carbon and conductivity analysis aids in detecting chemical impurities in pharmaceutical grade water systems and process equipment. These quality attributes provide insight into the degree of process control and overall quality for those systems and equipment. Organic molecules can be introduced into water in a variety of ways: from source water, from purification and distribution system materials, from biofilm growing in a system, and from packaging of sterile and nonsterile waters. Understanding the comprehensive cleanliness of water and equipment allows manufacturers to consistently deliver safe, high quality drug products.
There are a variety of methodologies used for total organic carbon monitoring. When choosing a technology, it is important to ensure the technology is fit for purpose and satisfies user and regulatory requirements for accuracy, precision, specificity, quantitative data, and other important validation requirements. At the very least, an instrument must have a limit of detection (LOD) of at least 50 ppb and be able to discern inorganic carbon from the CO2 produced from the oxidation of organic molecules when monitoring pharmaceutical grade water per USP <643>. The instrument must be able to pass a system suitability verification, as well as numerous other apparatus requirements, as outlined and defined in USP <643>.
Many TOC technologies work by oxidizing organic molecules using UV or chemical oxidation and measuring the resulting CO2. Using membrane conductometric technology ensures accurate reporting by separating the CO2 produced from the oxidation of organics relative to interfering ionic compounds. Sensor technology cannot detect these interferences and can lead to false reporting and validation issues when attempting to demonstrate requirements such as specificity or linearity with various detergents, degradants, APIs, and excipients. It is prudent to determine if a monitoring program requires quantitative or qualitative data. For example, cleaning validation is not a limit test, so the technology used needs to provide quantitative data that can be used to make important quality decisions throughout the entire range of use.
What are the TOC and Conductivity Regulatory Requirements for CGMP Equipment and Pharmaceutical Grade Water Systems?
USP <643> Total Organic Carbon and USP <645> Conductivity are the applicable United States compendia. Other parts of the world have their own compendia, such as Japanese Pharmacopoeia (JP) and European Pharmacopoeia (EP). Routine testing chapters are often harmonized from compendia to compendia but that is not always the case. It is important to assess each applicable compendium in the markets intended for distribution. For example, JP and USP <643> are harmonized to an extent but JP has an additional requirement to challenge the TOC system with SDBS where the USP does not. These nuances are important to be aware of and comply with when using TOC to monitor purified water systems and cleaning validation programs.
When looking to validate TOC methodology, ICH Q2 (R1) should be referenced for requirements. Similarly, when looking to qualify the instrument itself, USP <1058> Qualifying Analytical Instruments, should be referenced for the highest degree of confidence in instrumentation, methodology, and validation.
Is Measuring TOC Suitable for All Compounds, APIs, Excipients, and Detergents?
Total organic carbon testing is a non-specific test method. Rather than detecting a single analyte of interest, TOC analysis gives a comprehensive understanding of purity and cleanliness. A wide variety of compounds can be detected with satisfactory recovery. While many different compounds can be recovered from detergents and degradants to APIs and excipients, it is necessary to demonstrate this with robust recovery studies during method development and validation. Water soluble compounds can be analyzed using TOC analysis with little to no method variation. Compounds that do not readily solubilize in water can still be detected using small adjustments such as agitation, pH, or temperature. The SUEZ applications team can help with these types of development and validation activities.
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Total organic carbon and conductivity are great ways to assess chemical purity and general cleanliness of equipment. In water systems, TOC and conductivity can give important insight into the chemical purity of the water. Furthermore, these quality attributes can demonstrate a continuous state of validation and control.
In cleaning validation, TOC, inorganic carbon, and conductivity viewed together can provide an all-inclusive understanding of cleanliness. Rather than looking for a single API, using TOC and conductivity data together encompasses APIs, detergents, degradants, and excipients that would otherwise go undetected. Whether using TOC and conductivity for pharmaceutical grade water monitoring or for cleaning verification and validation of equipment, choosing technology and consumables that are fit for purpose gives manufacturers confidence in the accuracy and reliability of data.
What are the Best Practices When Performing TOC and Conductivity Analysis in the Lab, Online, or At-Line?
Best practices can start upstream of analysis with proper sampling, training, and materials. Sampling can vary from analyst to analyst, so extensive training should be conducted and documented to limit sample variability, especially when using swabbing techniques for cleaning validation. Swab recovery can yield inconsistent results, so training should be conducted in a manner to limit discrepancies as much as possible.
When sampling and testing for TOC and conductivity, it is important to avoid interfering chemicals that could contaminate the sample. Other samples such as bioburden may be taken concurrently so things like IPA or other cleaning agents should not be used when taking TOC and conductivity samples. Another common sampling error is using unsuitable sample vials. Traditional borosilicate glass vials can leach interfering ions into the sample, causing higher conductivity values. Permeable seals on the vials will also contribute to contamination from atmospheric CO2. SUEZ can help assess vial needs based on applications to ensure sample integrity.
Another best practice is determining a system suitability and verification procedure and frequency that is justifiable and risk based. While performing system suitability and conductivity verification is required by the USP, an explicit frequency is not prescribed. System suitability assesses relative recovery of two compounds, sucrose and benzoquinone, and is required to be performed on some frequency which should be determined internally based on risk of failure. It is worth noting that this is not an accuracy verification but rather relative recovery. While not obligatory for regulatory compliance, it is good practice to run a single point verification at, or near, points of interest to verify accuracy.
When using chemical oxidation for TOC analysis, establishing and validating appropriate flow rates is good practice for consistent and defendable methodology. Some technologies offer auto-reagent features to determine flow rates for each individual sample. This feature can be very useful in method development, especially with unknown TOC levels. However, when running routine procedures and protocols, it is best practice to have these flow rates established and constant. For purified water, UV oxidation is adequate as the TOC is usually very low. Using excess oxidation chemicals can cause air bubbles in the flow path, leading to aberrant results. When analyzing cleaning validation samples, higher TOC levels are generally expected and therefore, it is recommended to determine the appropriate amount of chemical oxidation. This can be done using an auto-reagent feature then validating the chosen flow rates during method validation.
Why is TOC Important?
TOC and conductivity are metrics that manufacturers must monitor to comply with regulations, but compliance is only the beginning. TOC and conductivity are essential to meeting regulatory requirements, but they also allow you to go beyond compliance and achieve optimization and control. Validated, trusted, and quantitative data allow for predicting trends, identifying OOS and OOT results, and making important quality decisions. TOC and conductivity data help facilitate improved process understanding, process control, and product quality. In addition, TOC can be used in a variety of applications to increase efficiency and reduce resources with automation. When using accurate and reliable technology, TOC is a valuable tool. Learn how it can help improve your process by contacting SUEZ.
Author Biography
Michelle Neumeyer is the Life Sciences Product Applications Specialist for the Sievers line of Analytical instruments at SUEZ – Water Technologies & Solutions. Previously, Michelle worked in Quality at Novartis and AstraZeneca, ensuring compliant water systems, test methods and instrumentation. Michelle has a B.A. from University of Colorado, Boulder in Molecular, Cellular and Developmental Biology.