á643ñTOTAL ORGANIC CARBON
Total organic carbon (TOC)is an indirect measure of organic molecules present in pharmaceutical waters measured as carbon.Organic molecules are introduced into the water from the source water,from purification and distribution system materials,and from biofilm growing in the system.TOCcan also be used as a process control attribute to monitor the performance of unit operations comprising the purification and distribution system.
Anumber of acceptable methods exist for analyzing TOC.This chapter does not limit or prevent alternative technologies from being used,but provides guidance on how to qualify these analytical technologies for use as well as guidance on how to interpret instrument results for use as a limit test.TheStandard Solution is a theoretically easy-to-oxidize solution that gives an instrument response at the attribute limit.The analytical technology is qualified by challenging the capability of the instrument using a theoretically difficult to oxidize solution in the system suitability portion of the method.
Analytical technologies utilized to measure TOCshare the objective of completely oxidizing the organic molecules in an aliquot of sample water to carbon dioxide (CO2),measuring the resultant CO2levels,and expressing this response as carbon concentration.All technologies must discriminate between the inorganic carbon,which may be present in the water from sources such as dissolved CO2and bicarbonate,and the CO2generated from the oxidation of organic molecules in the sample.
Two general approaches are used to measure TOC.One approach determines TOCby subtracting the measured inorganic carbon (IC)from the measured total carbon (TC),which is the sum of organic carbon and inorganic carbon:
TOC=TC–IC.
The other approach first purges the ICfrom the sample before any carbon measurement is performed.However,this ICpurging step also purges some of the organic molecules,which can be retrapped,oxidized to CO2,and quantitated as purgeable organic carbon (POC).The remaining organic matter in the sample is also oxidized to CO2and quantitated as nonpurgeable organic carbon (NPOC).In this approach,TOCis the sum of POCand NPOC:
TOC=POC+NPOC.
In pharmaceutical waters,the amount of POCis negligible and can be discounted.Therefore,for the purpose of this methodology,NPOCis equivalent to TOC.

Apparatus Requirements— This test method is performed either as an on-line test or as an off-line laboratory test using a calibrated instrument.The suitability of the apparatus must be periodically demonstrated as described below.In addition,it must have a manufacturer's specified limit of detection of 0.05mg of carbon per L(0.05ppm of carbon)or lower.

Reagent Water— Use water having a TOClevel of not more than 0.10mg per L.[NOTE—Aconductivity requirement may be necessary to ensure method reliability.]

Glassware Preparation— Organic contamination of glassware results in higher TOCvalues.Therefore,use glassware and sample containers that have been scrupulously cleaned of organic residues.Any method that is effective in removing organic matter can be used (see Cleaning Glass Apparatus á1051ñ).UseReagent Water for the final rinse.

Standard Solution— Unless otherwise directed in the individual monograph,dissolve in theReagent Water an accurately weighed quantity of USP Sucrose RS,to obtain a solution having a concentration of about 1.2mg of sucrose per L(0.50mg of carbon per liter).

Test Solution— [NOTE—Use extreme caution when obtaining samples for TOCanalysis.Water samples can be easily contaminated during the process of sampling and transportation to a testing facility.]Collect theTest Solution in a tight container with minimal head space,and test in a timely manner to minimize the impact of organic contamination from the closure and container.

System Suitability Solution— Dissolve inReagent Water an accurately weighed quantity of USP1,4-Benzoquinone RSto obtain a solution having a concentration of 0.75mg per L(0.50mg of carbon per liter).

Reagent Water Control— Use a suitable quantity ofReagent Water obtained at the same time as that used in the preparation of theStandard Solution and theSystem Suitability Solution.

Other Control Solutions— Prepare appropriate reagent blank solutions or other specified solutions needed for establishing the apparatus baseline or for calibration adjustments following the manufacturer's instructions,and run the appropriate blanks to zero the instrument.

System Suitability— Test theReagent Water Control in the apparatus,and record the response,rw.Repeat the test using theStandard Solution,and record the response,rS.Calculate the correctedStandard Solution response,which is also the limit response,by subtracting theReagent Water Control response from the response of theStandard Solution.The theoretical limit of 0.50mg of carbon per Lis equal to the correctedStandard Solution response,rS–rw.Test theSystem Suitability Solutionin the apparatus,and record the response,rss.Calculate the correctedSystem Suitability Solution response by subtracting theReagent Water Control response from the response of theSystem Suitability Solution,rss–rw.Calculate the response efficiency for theSystem Suitability Solution by the formula:
100[(rss–rw)/(rS–rw)].
The system is suitable if the response efficiency is not less than 85%and not more than 115%of the theoretical response.

Procedure— Perform the test on theTest Solution,and record the response,rU.TheTest Solution meets the requirements ifrUis not more than the limit response,rS–rw.This method also can be performed alternatively using on-line instrumentation that has been appropriately calibrated,standardized,and has demonstrated acceptable system suitability.The acceptability of such on-line instrumentation for quality attribute testing is dependent on its location(s)in the water system.These instrument location(s)and responses must reflect the quality of the water used.