Examining The Role Of TOC Analyzers In The Pharmaceutical .

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S him adzu S cientific Ins trum ents , 7102 Riverwood Drive, Columbia, MD 21046Tel: 800.477.1227/410.381.1227; Fax: 410.381.1222; www.ssi.shimadzu.comExamining the Role of TOC Analyzers inthe Pharmaceutical LaboratoryTotal Organic Carbon (TOC) analyzers are utilized across a wide range of industries for suchmeasures as process and water quality control, experimental research, and EPA compliance. Withinthe pharmaceutical industry, they serve vital roles in the manufacturing process. From inspectionsof the water used in drug manufacture (ultrapure water) to evaluation of cleaning effectiveness(cleaning validation), TOC analyzers are essential instruments in the pharmaceutical laboratory toensure compliance with applicable regulations.Ensuring ComplianceCompliance with regulations must be maintained throughout the different processes, which can begrouped under three general categories:1) Preparation (includes processing and innovation)2) Production3) Waste DischargeThroughout such processes, it is required to use pharmaceutical quality water, monitor thepharmaceutical water used, and achieve the required cleaning level to avoid any crosscontamination. For these steps, the FDA does not recommend any one specific analytical technique.In fact, the FDA states that any “Specific” or “Non-Specific” analytical technique can be used, aslong as the technique provides results that prove its ability to detect any contaminants that wouldaffect the quality of the water used1.Several specific and non-specific analytical techniques can be utilized to monitor the pharmaceuticalwater used and achieve the required cleaning validation.A “Specific” technique is defined as one that identifies the concentration of a specific chemicalwithin the analyzed sample. A “Non-Specific” technique identifies the presence of all the chemicalsin the analyzed sample, i.e. a cumulative representation of the effect of all the chemicals presentwithin the sample.

During the cleaning processes, pharmaceutical water and different cleaning agents are used.Different analytical methods can be used to identify these agents, drug residue, and excipients. Themethod used depends on whether a specific chemical within the residue must be monitored, or acumulative study of all of the chemicals within the residue must be determined. The following tablepresents some of the available specific and non-specific techniques that can be used.Analy tical MethodS pecificMethodAdv antagesDis adv antagesTOCNOBroad spectrum analysis with low leveldetection, and requires minimal samplepreparation. Quantitative analyticalmethodHPLCYESHighly specific with moderate to highsensitivity, quantitative methodRequires long analysis timeand is very expensive toolTLCYESHighly specific with moderate to highsensitivity, and fairly expensiveVisual endpoint notquantitative and require longtime sample preparationCONDUCTIVITY(Not TOC Method)NORapid and inexpensive analysisNon-specific with limitedsensitivitySPECTROPHOTOMETRICYES/NOModerate to high specificity, highsensitivity, and used as screeningmethodNot quantitativeNon-Specific MethodTOC Analysis as a Non-Specific Analytical TechniqueTOC analysis is a “Non-Specific” analytical method. TOC is not only used in the cleaning validationprocess, but also for the monitoring of the pharmaceutical water used within the cleaning processand for the preparation of drugs. TOC can measure the active compounds, excipients, cleaningagents, and water system organics within the sample. As a result, TOC is a “Non-Specific” tool thatprovides an accurate result representing all of the chemicals under study within the sample, in afew minutes. The following table compares the detection capability of TOC to other techniques.Detection CapabilityAnaly tical MethodDrug Res idueEx ricYES/NOYES/NOConductivity(Not TOC Method)Cleaning AgentYESYESSeveral pharmaceutical waters exist, including Purified Water (PW) and Water for Injection (WFI).PW is used for the cleaning process as well as in the preparation of drugs that do not enter into theblood stream2. As a result, PW must be maintained under certain chemical purity levels, but need

not be biologically ultra-pure. The TOC acceptable level for PW should be less than or equal to 500ppb.WFI, on the other hand, is used in the production of intravenous drugs, i.e. drugs that enter theblood stream, and in the cleaning validation process of specific systems2. WFI must be maintainedunder the same chemical and biological purity levels of the PW. In addition, WFI must undergoother tests to determine bacteria count and endotoxin content, to achieve a more stringentbiological purity level. WFI’s TOC level must be maintained at 500 ppb or less.TOC analysis for either the cleaning validation processes or monitoring of pharmaceutical water canbe measured using different organic carbon analyzers. The analyzer identifies the carbon levelspresent in the sample by oxidizing the carbon present to carbon dioxide, and consecutivelydetecting the carbon dioxide produced3. Results for TOC can be either reported as TOC or NPOC(non-purgeable organic carbon)3,4. TOC within a sample consists of purgeable organic carbon(POC), volatile carbon, and NPOC (hard to volatilize carbon). According to the USP, “the amount ofPOC in pharmaceutical water is negligible and can be discounted”4; therefore, TOC can bereported as NPOC and vice versa.Several oxidation and detection methods can be used in conjunction with each other to accomplishthe carbon analysis. Use of any of the combined oxidation/detection methods depends on thepreference of the user, required detection levels, oxidation and detection method, matrix of thesample, characteristics of the sample, and/or sample type (solid or liquid). The table below indicatesthe different oxidation and detection methods (X denotes possible and available combinations)Detection MethodOxidation MethodNDIRDetection MethodCONDUCTOMETRICTOC INSTRUMENTSNon-Dispersive InfraredXCOMBUSTIONCatalytic / High TemperatureXXXXXXWET CHEMICALPersulfateUV/PersulfateHeated PersulfateHeated UV/PersulfateHeated UVUVXTITANIUMPhotocatalytic OxidationMembraneDirectXXXXX

ApplicationsFollowing are examples illustrating the use of TOC analyzers in the pharmaceutical lab.Cleaning ValidationQuality control and product safety are paramount in the manufacture of pharmaceutical products.The effective removal of residues in pharmaceutical production lines is a crucial prerequisite forproduction. A properly cleaned system prevents contamination and, consequently, the adulterationof the produced drug. This is especially important in the production of active agents in batchprocesses, as the system is used for different products and contamination of the next product mustbe prevented. Cleaning validation confirms the effectiveness of a cleaning procedure and assuresthat no residues remain.To verify standards are met, pharmaceutical companies often use HPLC systems. However, whensample preparation requires the use of solvent extraction or enrichment, HPLC can becomecomplicated and time consuming. In contrast, measurement with a TOC analyzer does not requiresample preparation. Therefore, the quantity of drug residues can be quickly and easily detected.For cleaning validation using a TOC analyzer, the following 3 methods are available.(1) Rinse sampling – TOC measurement method(2) Swab sampling – aqueous extraction – TOC measurement method(3) Swab sampling – direct combustion carbon measurement methodFor the purpose of this article, the swab sampling – direct combustion carbon measurementmethod will be examined.The Swab Sampling – Direct Combustion method consists of wiping a fixed area of theequipment surface with the swab material, and the residues adhering to the material are physicallycollected and analyzed using a direct combustion carbon measurement system. The swab materialwith adhering residue is merely placed in the sample boat, and the carbon content is measureddirectly by the TOC analyzer in combination with a solid sample combustion unit.Quick, accurate measurement can be conducted even when there are insoluble compounds, bakedon residues or encrustations that cannot be easily removed via a rinsing solution. No special pretreatment procedures are required to extract residues from the swab.In order to evaluate this method, residue measurement samples were created by applying varioustypes of pharmaceutical products and their constituents to stainless steel pots. The aqueous andnon-aqueous substances that were used are listed in the table below.

Substance NameTranexamic acidAnhydrous caffeineIsopropylantipyrineNifedipineGentashin ointmentRinderon ointmentSolubility in lubleSolvent used Solution he aqueous and non-aqueous substances were dissolved in water and ethanol or acetone,respectively, and the solution concentrations were adjusted to 2000 mgC/L ( carbon concentrationof 2000 mg/L). Each residue substance measurement sample consisted of a 5 cm2 area on thesurface of a pot to which a volume of 100 µL of each solution was applied and dried. Thus, theamount of carbon in the sample at each application site was 200 µg.Among these, Gentashin ointment (aminoglycoside antibiotic) and Rinderon ointment(corticosteroid) were prepared based on determination of their carbon concentrations using theTOC analyzer equipped with a solid sampling module.To evaluate the rate of recovery of the different types of substances using the swab sampling –direct combustion method, we used the quartz glass filter paper swab material to wipe the sampleoff the sample adhering to the stainless steel pot, placed the swab in the sample boat, andconducted TC measurement. Some of the measurement data, representing each of the sampletypes: 1) water soluble (Tranexamic Acid (top left)), 2) water insoluble (Isopropylantipyrine (topright)), and 3) water insoluble ointments (Gentashin Ointment (bottom left)), are shown infollowing figure.Measurement ConditionsAnalyzer:Total Organic Analyzer TOC-LCPH SolidSample Combustion Unit (IC circuit bypassusing system with cell switching valve set)(Shimadzu, Columbia, MD)Cell length:Short cellSSM carrier gas:400 mL/min oxygen gasMeasurement item:TCCalibration curve:1-point calibration curve using 1% C glucoseaqueous solutionSwab material:Advantec quartz glass paper QR-100 (diameter45 mm) heat-treated at 600 C for 15 minutes

Since the carbon content in each of the residue measurement samples is 200 µg, the TC valuewould be 200 µg if all of the sample were wiped off. For the blank, measurement was conductedin the same way by wiping the stainless pot, which had no sample applied. The measured blankvalue was subtracted from each TC value, and then compared to the theoretical value of 200 µg todetermine the rate of recovery. The results are shown below. A high recovery rate of about 100%was obtained for all the substances, regardless of whether they were water-soluble or waterinsoluble.Substance NameBlankTranexamic acidAnhydrous caffeineIsopropylantipyrineNifedipineGentashin ointmentRinderon ointmentTOC Value [µC]0.00202201210212200209Recovery Rate, [TC Value – Blank / Theoretical Value]101%100%105%106%100%104%When using the Rinse Sampling – TOC Measurement and the Swab Sampling – Water Extraction –TOC Measurement methods, substances that do not easily dissolve in water were found to includethose that had both high and low recovery rates5. It is thought that this may be due to differencesin the strength with which the substances adhere to the stainless steel pot. Accordingly, it isprobable that residue evaluation using these methods would be difficult for substances with lowrecovery rates.In contrast, high recovery rates were obtained for all the substances when using the SwabSampling – Direct Combustion method, regardless of whether the substances were water-solubleor water-insoluble, thereby permitting residue evaluation. Therefore, this method is considered tobe the most effective measurement method for conducting cleaning validation, especially whenmultiple compounds are being manufactured in the same vat.Measuring Samples Per USP 643 The United States Pharmacopoeia has established guidelines for determining system suitability andestablished the acceptance of Water For Injection (WFI) purposes and Purified Water (PW) (USPMethod 643 ).Shimadzu’s TOC-LC*H analyzer is perfectly adapted to meet the requirements of USPMethod 643 . The TOC-LC*H analyzer utilizes 680 C heat and platinum catalyst to provide alower maintenance instrument with a detection limit of 0.0040 mg per liter.USP 643 In the system suitability test, the response from a solution of sucrose, a relatively easily oxidizedcompound, is compared to the response from 1,4 benzoquinone, a more difficult compound tooxidize. The response of the reagent water is subtracted from each response to yield a correctedresponse.

The requirement for passing the system suitability test is to obtain results for the control standard(1,4 BQ) minus the reagent water that are within /- 15% of the sucrose standard minus thereagent water as shown in equation 1.%R [(rss-rw) / (rs-rw)] * 100(equation 1)Table 1 - Key to equation 1Rss1,4-Benzoquinone (area counts)rsSucrose (area counts)rwReagent Water (area counts)%RPercent Recovery (%)Samples are acceptable for Purified Water (PW) or Water For Injection (WFI) if equation 2 issatisfied.(Sample Area Counts) (rs-rw)(equation 2)ProcedureFirst 25.0 mg of glucose was accurately weighed out and brought to 100 mL with purified water;this yields a 100 mg per liter carbon solution. 0.5 mL of this solution was then diluted to 100 mLyielding a 0.5 mg per liter carbon solution. This was used as the high standard for calibration.Standard AnalysisPrepared System Suitability Standards were purchased from Shimadzu. The standards wereanalyzed on the Shimadzu TOC-LC*H. The instrument parameters are shown in Table 2.Table 2 - ParametersAnalysisNPOCInjection Volume816 μLSparge Time1.50 minutesSparge gas flow150 mL / min.Acid added3.0%Injections3Max injections5Carrier gas flow150 mL / min.Standard ResultsTable 3 - ResultsStandardMean Area Countsrw8.51rs43.50rss43.63

System Suitability%R [(rss-rw) / (rs-rw)] * 100(equation 1)%R [(43.63-8.51) / (43.50-8.51)] * 100 100.4 % (equation 3)According to the requirements outlined by USP, the Shimadzu TOC-LC*H is suitable for the analysisof Purified Water and Water For Injection. 1,4-Benzoquinone is more difficult to oxidize thansucrose, therefore it is used as a system suitability solution. As shown in table 3 the area counts arevery similar, and the recovery was 100.4%, validating the instrument’s ability to accurately measureTOC in the ranges of 0.5000 mg per liter TOC.ConclusionAs shown, TOC analyzers play a valuable role in the pharmaceutical laboratory, in both the drugdevelopment and manufacturing processes. When the right equipment is used, the TOC analyzerenables a laboratory to be safer, cleaner, and more productive.References1. Weitzel, S. Critical Process Cleaning and Cleaning Validation, CFPA 20062. USP 29, 1231 USP/NF The Official Compendia of Standards. U.S. Pharmacopeia.Webcom Limited: Toronto, Canada.3. TOC-V CPH/CPN & TOC-Control V Software User Manual. Shimadzu Corporation: Process &Environmental Instrumentation Division. Japan, Kyoto, 2001.4. USP 29 643 . USP/NF The Official Compendia of Standards. U.S. Pharmacopeia. WebcomLimited: Toronto, Canada.5. Shimadzu Application Note, Cleaning Validation by TOC Analyzer, No. pdfS HIMADZU Corporationwww.shimadzu.com/an/For Research Use Only. Not for use in diagnostic procedures.The contents of this publication are provided to you “as is” without warranty of any kind, and are subject to change withoutnotice. Shimadzu does not assume any responsibility or liability for any damage, whether direct or indirect, relating to theuse of this publication.S HIMADZU SCIENTIFIC INS TRUMENTS7102 Riverwood Drive, Columbia, MD 21046, USAPhone: 800-477-1227/410-381-1227, Fax: 410-381-1222URL: www.ssi.shimadzu.com ShimadzuCorporation, 2012

TOC Analysis as a Non-Specific Analytical Technique TOC analysis is a “Non-Specific” analytical method. TOC is not only used in the cleaning validation process, but also for the monitoring of the pharmaceutical water used within the cleaning process and for the preparation of drugs. T

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