Use of USP <643> Total Organic Carbon for Cleaning Validation

Purpose and Introduction

This reference document presents the Hyde Analytical Laboratory’s position on the use of the USP <643> [4] compendial method for analysis of cleaning validation or verification samples.

Scope / Background

The USP presents the compendial method for total organic carbon (TOC) within the General Chapters, section <643> [4]. This method is presented as a means for indirectly measuring the amount of organic molecules within pharmaceutical waters by way of analyzing the carbon within those molecules. There are several ways to analyze for organic carbon within an aqueous solvent. The two most popular methods are by chemical oxidiation or thermal combustion of the organic material. Each of the aforementioned methods breaks down the molecules into carbon dioxide, which is then quantitated. The USP does not limit the compendial method to any technology for analysis of organic carbon. As such the USP does not state specific method parameters for the analysis of total organic carbon within water samples. As the USP is does not specify the type of analyzer/analysis used for detection of organic carbon, there are no method parameters stated. Instead the USP presents a method for determining system suitability of the TOC analyzer. The system suitability for TOC analysis is a comparative test between different carbonaceous analytes (sucrose and 1,4-Benzoquinone [BQE]). This test looks at how similar the responses of each analyte are. The system suitability test as specified by the USP does not look at the accuracy of the response for each analyte. This is because the USP for TOC is essentially a limit test not meant for quantitation of carbon. Cleaning validation and verification activities are better suited to a quantitative analytical method.

Results / Discussion

Methods used for the analysis of cleaning samples must consider the analyte of concern (the product or material that poses a risk for carryover to subsequent production runs). During testing for cleaning validation, the analysis verifies or quantitates any carbonaceous materials within the sample. Parameters should be optimized to illicit the strongest response of the analyte of concern. This may include using a diluent that is not WFI, but an acidic or alkaline diluent. The method parameters may also need to be adjusted to overcome higher pH samples. The analyte of concern may be difficult to oxidize requiring modification of parameters to convert the analyte into carbon dioxide. In addition, the higher or lower pH diluents are no longer considered water samples and thusly the compendial method is not appropriate. Per the FDA, “In order for TOC to be functionally suitable … the contaminating material(s) … contains carbon that can be oxidized under TOC test conditions.” (Questions and Answers on cGMP Requirements/ Equipment [1]). Typically, carryover limits allow for a certain quantity of the analyte of concern to be carried over into the next production run without impacting the product or patient safety. This quantity is used for setting the acceptance criteria for cleaning validation/ verification. Normally the allowable carryover is greater than the specification for process water as outlined by the USP (ex, bulk water should return a value less than 500 ppb C). The method within the USP is geared toward the lower levels of carbon that are not expected in the cleaning validation/verification samples which may contain much greater levels of organic carbon. Cleaning validation samples are not testing for the quality or release of the water used during production and therefore it is not appropriate to use a compendial method that was designed for water testing. Cleaning validation sampling is not testing water for water purity but rather for the presence of residual soils remaining after cleaning activities. The FDA expects that manufacturers “determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants.” [2] Again, the expectation of testing for contaminants and not water quality. PDA Tech Report 49 [3] presents that it is acceptable to use the compendial method provided the parameters of the method are adhered to. Although this is correct, Hyde does not recommend using the compendia for TOC analysis regardless if the methods are used within the stated parameters. This is because of the expectation of process trending for cleaning. Trending shall include quantitation of TOC to ensure that cleaning processes remain in control between validation cycles. The compendial method is a limit test not suited for quantitation. In addition, the USP presents a method for system suitability for TOC analyzers. As this method is a comparative test between two analytes at low concentrations and does not evaluate the accuracy of the response, it is also not appropriate on its own to provide evidence that the TOC analyzer is functioning as expected and is suitable for use. Hyde recommends supplementing the USP system suitability testing with bracketing accuracy standards of known concentration that is of similar concentration to the carryover limit or at the upper end of the linear range of the assay.

Conclusions

Hyde does not recommend the use of the compendial method presented in USP general chapter <643> [4] for the analysis of organic carbon for cleaning validation and verification samples. Hyde recommends developing and validating quantitative TOC methods for the detection of the analyte of concern or representative soil using parameters that optimize analyzer response and surface recovery.

References

1. U.S. Food & Drug Administration (FDA) Questions and Answers on Current Good Manufacturing Practice Requirements / Equipment, https://www.fda.gov/drugs/guidances-drugs/questions-and-answers-current-good-manufacturing-practice-requirements-equipment#12
2. U.S. Food & Drug Administration (FDA) Validation of Cleaning Processes (7/93), https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/validation-cleaning-processes-793
3. PDA Technical Report No. 49, Points to Consider for Biotechnology Cleaning Validation
4. USP <643> Total Organic Carbon