Gary Rhodes, Analytical Associate Laboratory Supervisor
Total Organic Carbon (TOC) testing measures the amount of carbon present in a water sample and is conducted based on USP 643 requirements. Chemical impurities can enter water from various sources, including:
- Source water used for pharmaceuticals (such as injectables)
- Packaging for sterile and non-sterile water
- Purification systems
- Processing equipment
This test serves as a key quality indicator, as organic carbon in water can promote microbial growth and signal potential contamination, posing risks to patient safety.
While a connection exists between TOC levels and microbial activity, a direct numerical correlation does not exist. Therefore, TOC measurements should not be used as a substitute for endotoxin or microbiological control testing.
TOC Test Method
ARL utilizes a Shimadzu TOC-LCSH, High-Sensitivity Analyzer to conduct the TOC test method. TOC is measured by injecting a volume of the sample into a combustion tube containing an oxidation catalyst heated to 680°C. The sample is burned in the tube, converting it into carbon dioxide, which is then measured by the non-dispersive infrared (NDIR) gas analyzer. This measurement is compared to a standard solution prepared from Sucrose at the specified limit to determine the amount of carbon in mg/L.
While this measurement quantifies the amount of carbon in the sample, it does not identify the specific contaminant. USP has established acceptance criteria for carbon content, ensuring that materials meeting these specifications are deemed suitable for their intended pharmaceutical application. If it does not meet requirements, further analysis and/or investigation is required to determine the source and identity of the contamination.
Definition and Limits
USP 643 sets limits for Bulk Water and Sterile Water. Bulk Water is defined as Purified Water, Water for Injections, Water for Hemodialysis, and the condensate of Pure Steam. The limit for carbon contained in samples of these waters is 0.5 mg/L or 500ppb of carbon.
Sterile Water is defined as Sterile Water for Injection, Sterile Purified Water, Sterile Water for Irrigation, Sterile Water for Inhalation, and any specific monograph that references Sterile Water. These waters are derived from Purified Water or Water for Injections; therefore, they have been determined to be compliant with the Bulk Water requirements before being stored and sterilized in their container. The limits for carbon contained in samples of these waters are dependent on the nominal container volume, as stated below.
USP 643 - Table 1. TOC Limit Based on Container Volume
Nominal Container Volume (mL) | Limit 1 (L1) (mg/L of carbon) | Limit 2 (L2) (mg/L of carbon) |
≤5 | 32.00 | 48.00 |
>5 and ≤100 | 24.00 | 36.00 |
>100 | 8.00 | 12.00 |
Other Applications for TOC Testing
In addition to testing water, TOC is used for cleaning validations. It is suitable for testing direct surfaces and rinse water. However, TOC does not identify which compounds contain oxidizable carbon. Any carbon detected is attributed to the target compound(s) and compared to a set limit. If testing for a specific compound, contact ARL to discuss a residual drug cleaning validation study.
Resources:
- USP643 Total Organic Carbon
- Shimadzu TOC-L Series Manual
- FDA Guidance for Q&A on Current Good Manufacturing Practice Requirements - Equipment
- Total Organic Carbon Testing - Back to Basics: American Pharmaceutical Review