Total organic carbon (TOC), O.I., USP 643, EP 2.2.44

Total Organic Carbon (TOC) Analysis is used to establish the amount of organic compounds in purified water, medical device extracts, or rinses. Total organic carbon analysis is used to determine if purified water meets the specifications according to the United States Pharmacopeia (USP). This test can also be used as a process control to monitor the performance of unit operations comprising water purification and distribution systems. Organic carbon molecules can be introduced into the water from purification and distribution system materials and from biofilm growing in the system. Extracts from medical devices can be analyzed for TOC to determine cleaning material residuals. TOC analysis can also be used in cleaning validations for pharmaceutical applications. Swabs or rinses from pharmaceutical production equipment can be analyzed by TOC to prove the effectiveness and consistency in the cleaning of the production equipment.

Study Outline

The determination of total organic carbon (TOC) is performed by the wet oxidation method on an OI Analytical Total Organic Carbon Analyzer. The sample is injected into the instrument where it is acidified and purged of inorganic carbon. Sodium persulfate is added and this oxidant quickly reacts with organic carbon in the sample at 100°C to form carbon dioxide. The carbon dioxide from the oxidized organic carbon is purged from the solution and detected by a non-dispersive infrared (NDIR) detector that has been calibrated to directly display the mass of carbon dioxide detected. This mass is proportional to the mass of TOC in the sample.

For medical devices, TOC analysis is a relatively straightforward and inexpensive method for validating a cleaning process and for performing routine monitoring of residual levels once the validation is complete. Samples are extracted in a known amount of purified water, and the extract is analyzed on the instrument.

In order for TOC to be a suitable analysis technique, first it must be established that a substantial amount of organic carbon is contained in the target compound(s).  The carbon present must also be oxidizable under the TOC test conditions, and adequate water solubility of the target compound(s) must be demonstrated.  Even some essentially insoluble organic residues may be removed by water extraction and analyzed by TOC.

A TOC analysis is quantitative but not qualitative.  In other words, TOC does not identify or distinguish among different compounds containing oxidizable carbon.  Therefore, a manufacturer should limit the amount of background carbon (i.e. carbon from sources other than the target compounds) as much as possible.  Any established limits for the target compounds must be corrected for background carbon.

When possible, it is recommended that the extraction efficiency be determined.  There are two techniques which can be used to determine extraction efficiency: (1) spike recovery; and (2) exhaustive extraction.

• The spike recovery technique uses positive controls which contain a known level of contamination.  The positive controls are created at Nelson Laboratories, Inc. (NLI) using clean devices which are spiked with a known amount of the target residue(s). The sponsor must provide NLI with samples of the target residue(s).  Spike recovery positive controls only need to be extracted once.  Dilutions may be required to ensure that the amount of carbon in the extract may be accurately quantified.
• The exhaustive extraction technique uses positive controls which contain an unknown level of contamination.  The positive controls are normally created by exposing devices to the regular manufacturing processes but then not subjecting them to the cleaning process being validated.  These are “real-life” positive controls.  Exhaustive extraction positive controls should be extracted until no significant increase in the cumulative residue level is detected upon re-extraction, or until the amount extracted is less than 10% of what was detected in the first extraction.  Dilutions may be required to ensure that the amount of carbon in the extract may be accurately quantified.

One advantage of TOC is that a level has been established for purified water which represents a great target level for residual analysis.  The United States Pharmacopeia (USP) and European Pharmacopeia (EP) both require purified water to contain approximately or lower than 500 parts per billion (ppb) of TOC.  This represents a defensible standard level because it would be hard for a regulatory agency to justify a cleaning level for a device lower than that required for purified water.  By coupling TOC analysis with a conductivity/pH analysis (also required for purified water testing), device extracts may also be analyzed for any ionized species such as acids, bases, or salts.

Sample Requirements

Minimum sample size for liquids = 40 mL vial put in a VOA bottle with a Teflon® septa.

Recommended replicates = 2

Nelson Laboratories provides VOA bottles with a Teflon® septa for purchase plus shipping charges.  After sampling, the bottles should be wrapped in bubble wrap or placed in a container with packing peanuts and shipped overnight, preferably refrigerated.

For devices, sampling is the responsibility of the sponsor.  It is recommended that test devices be taken in random groupings from different lots, if available.  It is the responsibility of the sponsor to determine the number of devices that need to be tested to establish known reproducibility.

Devices may be pooled or tested individually; it is recommended that pooled devices be of the same type and size.

Nelson Experts:

• Brent Torgensen 801-290-7846, 800-826-2088

Sample Requirements

Minimum sample size for liquids = 40 mL vial put in a VOA bottle with a Teflon® septa.

Recommended replicates = 2

Nelson Laboratories provides VOA bottles with a Teflon® septa for purchase plus shipping charges.  After sampling, the bottles should be wrapped in bubble wrap or placed in a container with packing peanuts and shipped overnight, preferably refrigerated.

For devices, sampling is the responsibility of the sponsor.  It is recommended that test devices be taken in random groupings from different lots, if available.  It is the responsibility of the sponsor to determine the number of devices that need to be tested to establish known reproducibility.

Devices may be pooled or tested individually; it is recommended that pooled devices be of the same type and size.