Total Organic Carbon (TOC) testing is an established USP test procedure that is an indirect measure of organic molecules present in pharmaceutical water measured as carbon. This method is referenced in USP <661.1> (Plastic Materials of Construction) and USP <661.2> (Plastic Packaging Systems for Pharmaceutical Use). In this article, we will explore the use case of TOC testing at CS Analytical, fundamentals of TOC testing, describe the instrumentation used, and outline some of the key procedural steps involved in the testing process.
At CS Analytical, TOC testing is primarily conducted in compliance with USP <661.1> (Plastic Materials of Construction) and USP <661.2> (Plastic Packaging Systems for Pharmaceutical Use). USP <661.1> focuses on plastic materials that are used in the manufacture of pharmaceutical packaging systems. It applies to materials that do not come into direct contact with drug products but may still be part of the packaging structure. TOC testing is performed to ensure that the plastic materials meet purity and safety standards before they are used in drug packaging systems.
In contrast, USP <661.2> applies to plastic components that do come into direct contact with drug products, such as containers, closures, and drug delivery systems. TOC testing is performed to ensure that the finished plastic components do not release harmful substances (ex. chemicals, organic compounds) into the drug product, potentially affecting its safety, efficacy, or stability.
TOC testing works by oxidizing these organic molecules in the sample solution to produce carbon dioxide (CO2). The CO2 is then measured, and its concentration is used to calculate the organic carbon content in the sample. This process provides an efficient way to detect organic contaminants, which is particularly valuable information in the pharmaceutical manufacturing industry.
At CS Analytical, we use the Suez M9 TOC Analyzer with an Autosampler, which consists of several key components to ensure accurate and efficient testing. The Sample Inlet System includes a dual pump and sample line that connects the sample to the analyzer for on-line sampling. The Chemical Reagent System introduces the necessary reagents, using syringe pumps to deliver them into the sample for oxidation. The heart of the oxidation process is the UV Reactor, where a spiral quartz tube wrapped around a UV lamp facilitates the breakdown of organic compounds into CO2. The CO2 Measurement Module is responsible for detecting the CO2 produced during oxidation, using quartz conductivity cells and a dual conductivity signal processor to provide precise data. Additionally, the Fluids Module manages the sample pumps and DI water loop, while the Electronics subsystem controls the system and provides a touch panel display for easy operation. The integration of the Sievers Autosampler further automates the sample collection, ensuring higher throughput and consistency in results. Through these components, the analyzer accurately measures the organic carbon content in prepared sample test solutions ensuring compliance with USP standards and maintaining high-quality control in pharmaceutical manufacturing.
The preparation of samples for TOC testing depends on the method. For USP <661.1>, solution preparation involves extracting organic materials from plastic materials. First, 25 g of the test material is placed in a borosilicate glass flask with a ground-glass neck. 500 mL of purified water is added, and the mixture is boiled under reflux conditions for 5 hours. After boiling, the solution is cooled, filtered through a sintered-glass filter, and collected in a 500 mL volumetric flask. The flask is then filled to volume with purified water, creating Solution S1, which must be used within 4 hours of preparation.
For USP <661.2>, the procedure involves extracting organic compounds from plastic packaging systems. The packaging system is filled to its nominal capacity with purified water, sealed (using either the normal closure or an inert closure), and then heated in an autoclave. The temperature is maintained at 121 ± 2°C for 30 minutes. If the container deteriorates at this temperature, alternative heating conditions are applied, such as heating at 100 ± 2°C for 2 hours or at 70 ± 2°C for 24 hours, depending on the material’s tolerance. After cooling, the packaging system is emptied, and the liquid collected is labeled Solution C1.
Both USP 661.1 and 661.2 prepared sample solutions will undergo TOC instrumental analysis, by running the prepared blank and sample solutions on the Suez M9 TOC Analyzer with an Autosampler. The results will be recorded and confirmed according to USP acceptance criteria. For 661.2 the specification states that the difference in TOC concentrations between Solution C1 and a suitable blank is NMT 32mg/L (ppm) for containers ≤5 mL; NMT 24 mg/L (ppm) for containers >5 and ≤100mL; and NMT 8 mg/L (ppm) for containers >100 mL. For 661.1 the specification reads the difference between the sample and blank TOC concentrations is NMT 5 mg/L.
To summarize, in the pharmaceutical industry, TOC testing is essential to ensure the integrity and safety of packaging systems. By accurately measuring the organic carbon content in materials, TOC testing helps identify potential contaminants that could jeopardize the quality, efficacy, and stability of pharmaceutical products. As a contract laboratory specializing in container packaging testing, CS Analytical plays a pivotal role in supporting pharmaceutical manufacturers. We help ensure that all packaging systems meet regulatory standards, maintain product safety, and comply with the requirements of USP <661.1> and USP <661.2>. With our advanced TOC testing capabilities and extensive industry knowledge, we provide thorough, reliable, and timely testing services that help our clients meet their quality assurance goals.