USP <643> “Total Organic Carbon”

 

What is USP <643> and why does it matter?

USP <643> is a general chapter in the United States Pharmacopeia that provides guidance on measuring total organic carbon (TOC) in pharmaceutical waters. It provides a standardized method for measuring TOC, ensuring that pharmaceutical water meets the required purity standards. By measuring TOC, pharmaceutical manufacturers can detect contamination or determine quality and purity of the water used in the manufacturing process, all of which can impact product quality and safety. TOC serves as one of a pair of essential chemical limit tests for validating chemical control in water purification systems. It is used in conjunction with USP <645> Water Conductivity testing, which specifically measures ionic contaminants, to ensure water quality standards are met.

Who is impacted by USP <643>?

Some of the industries and sectors impacted by USP <643> are:

• Pharmaceutical and biopharmaceutical manufacturers, including research and development and ingredient manufacturers

• Medical device manufacturers
• Contract testing and quality control laboratories
• Water purification system and instrument manufacturers
• Some healthcare and veterinary facilities

Note: This list is not exhaustive.

USP <643> guidance and regulation overview

The chapter provides guidance on TOC measurement technologies and methodologies. While it does not endorse specific processes or technologies, it does require that methods are able to discriminate between inorganic and organic carbon. This discrimination can be achieved either by indirect measurement - determining inorganic carbon and subtracting it from total carbon - or by direct measurement - purging inorganic carbon before oxidation. TOC testing can be performed either online or as an off-line laboratory test.

The guidance also clarifies that TOC measurements, while capable of detecting organic materials that could support microbial growth, cannot substitute for endotoxin testing or microbiological control methods. Although organic carbon may function as a potential nutrient source for microorganisms, TOC levels do not directly correlate with microbiological activity in a quantifiable way.

USP <643> for bulk purified water

For bulk purified water, the chapter outlines requirements that include:

• Instrumentation with detection limit of ≤ 0.05 mg/L (0.05 ppm)
• Use of reagent water with TOC level of ≤ 0.10 mg/L
• Preparation procedures for containers and labware to reduce or prevent contamination

System suitability testing is used to demonstrate the suitability of the instrument for TOC monitoring. Users must determine the frequency of system suitability based on the criticality of application and process risk assessment. The regulation defines an easy-to-oxidize solution (USP Sucrose Rs) and hard-to-oxidize solution (USP 1,4-Benzoquinone Rss) in order to show instrument suitability across a range of compounds. It should be noted, good manufacturing practices (GMP) are important for accuracy of solution preparation, as improperly prepared solutions could contribute to suitability failures and lead to additional investigations.

USP <643> for sterile waters derived from bulk purified water

For sterile water, USP <643> establishes more stringent limits and testing requirements, such as water for injection (WFI) or ingredient water as part of inhalation or irrigation products. Since these products have direct access to the bloodstream or respiratory system, the risks associated with contamination are significantly higher. Organic contaminants in these products could lead to severe adverse reactions, infections, or toxic responses. Additionally, organic compounds in these waters could interact with drug products, potentially affecting their stability, efficacy, or safety. Image Link The chapter details more stringent instrument detection limits for sterile waters and includes specific procedures for sample handling and testing. It also provides guidance for preparing system suitability and standard solutions for each category of container volume.

Read More: Changes to USP <643> Total Organic Carbon in Sterile Water

Download now: USP <643> Sterile Water Testing Protocols: Implementing TOC Analysis for USP Compliance

USP <643> for sampling, instrumentation, procedures, and system suitability

The chapter details requirements for sampling, including proper container preparation, procedures for collecting representative samples, and sample handling.

Instrumentation requirements include regular demonstration of instrument suitability, specific detection limit requirements for both bulk and sterile water, and options for both online and off-line testing.

Procedures must be detailed and documented to include step-by-step testing and calculations for calibration, system suitability and sample analysis.

System suitability requirements include the use of specified reference standards, calculation of response efficiency, acceptance criteria as well as requirements for periodic verification of system performance.

Read More: FAQs: What’s the difference between a TOC sensor and a TOC analyzer?

Download Now: Comparison of TOC Analyzers and Sensors for Pharmaceutical TOC Applications 

USP <643> and process verification

Process verification involves:

• Demonstration of system suitability testing with an 85-115% response efficiency
• Use specified reference standards (USP 1,4-Benzoquinone RS, and USP Sucrose RS)
• Periodic demonstration of instrument suitability
• Reagent water control must use water with TOC level ≤ 0.10 mg/L for bulk water testing and may require conductivity testing to ensure method reliability Sample container choice and preparation must document cleaning procedures and verification so as not to introduce contamination

Download now: Selecting the Best TOC Sample Vial for Your Application

USP <643> does not make specific recommendations for the following:

• Process development: Organizations must ensure that sampling is truly representative of water quality
• Location: Testing can be performed either online, at-line, or in a laboratory
• Instrumentation: The choice should be based on suitability, manufacturing process, and intended use

Facilities must balance efficiency and other operational demands when implementing USP <643> guidelines, making compliance uniquely challenging for every organization.

Read More: What’s the difference between a TOC sensor and a TOC analyzer?

Download now: Best Practice for Analyzing Compendia Water Samples for USP <643> and <645>

We can support you with USP <643> compliance

Working with experienced partners who specialize in TOC testing and water system monitoring can help address any challenges you have when implementing USP <643>, as well as USP <645> Conductivity Testing. On the one comment on the 643 piece, I think I can correct the sentence to - Our experts can provide guidance on selecting appropriate instrumentation, applying proper testing procedures, and establishing effective SOPs for documentation and compliance.

After selecting suitable and compliant technology, comprehensive instrument qualification and method validation must be completed before data can be used for making quality decisions. Our industry-leading expertise ensures you are supported with thorough method validation and deployment strategies. With decades of specialized experience, we have refined these processes to meet the most stringent regulatory requirements while maintaining operational efficiency.

Modern efficiency improvements now enable dual testing of TOC and conductivity for compliance with USP <643> and <645> from a single sample using specialized vials that prevent ionic leaching and CO2 contamination. This approach enhances sample integrity while reducing analysis time compared to traditional methods. Additionally, many facilities have adopted online water monitoring for real-time testing (RTT), eliminating the need for manual sampling and streamlining the QC process. This implementation of process analytical technology (PAT) provides immediate measurement of quality attributes and demonstrates process control in a validated state, particularly when using compatible membrane conductometric technology.

Contact us for more information about TOC compliance, transitioning to real-time testing, or improving efficiency of USP <643> TOC testing.