1、Designation: E2656 10Standard Practice forReal-time Release Testing of Pharmaceutical Water for theTotal Organic Carbon Attribute1This standard is issued under the fixed designation E2656; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revi
2、sion, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 This practice establishes an approach to the real-timerelease testing (RTRT) of pharmaceutical water
3、 based on thetotal organic carbon (TOC) attribute using on-line total organiccarbon (OLTOC) instrumentation that is in agreement withcurrent regulatory thinking.1.2 This practice is harmonized with or supports the con-cepts of relevant ASTM International Committee E55 onManufacture of Pharmaceutical
4、 Products standards, ICH Har-monized Tripartite Guidelines, the US FDAPAT Guidance, andUS FDA Pharmaceutical cGMPs.1.3 This practice does not provide general guidance infor-mation for pharmaceutical procedures that are consideredstandard practice in the pharmaceutical industry. This practiceprovides
5、 specific guidance for non-standardized procedures.1.4 This practice does not address the users various internalprocedures for risk, change, or quality management systems.The overall project effort associated with this practice shall beproportional to the overall risk of failing the pharmaceuticalwa
6、ters TOC concentration specification.1.5 This practice does not purport to establish how tocomply with pharmacopeias. The RTRT methodology selectedmust assure compliance with the users current requiredpharmacopeias. However, compliance with pharmacopeia TOCmethods is not necessarily sufficient to me
7、et current regulatoryexpectations for RTRT.1.6 This practice does not purport to substitute for or replacecompendial bioburden testing requirements. It is strictly appli-cable to the TOC attribute of water quality.1.7 This standard does not purport to address all of thesafety concerns, if any, assoc
8、iated with its use. It is theresponsibility of the user of this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2E2281 Practice for Process and Measurement CapabilityIndic
9、esE2363 Terminology Relating to Process Analytical Tech-nology in the Pharmaceutical IndustryE2500 Guide for Specification, Design, and Verification ofPharmaceutical and Biopharmaceutical ManufacturingSystems and EquipmentE2537 Guide for Application of Continuous Quality Verifi-cation to Pharmaceuti
10、cal and Biopharmaceutical Manufac-turingD4839 Test Method for Total Carbon and Organic Carbonin Water by Ultraviolet, or Persulfate Oxidation, or Both,and Infrared DetectionD5173 Test Method for On-Line Monitoring of CarbonCompounds in Water by Chemical Oxidation, by UV LightOxidation, by Both, or b
11、y High Temperature CombustionFollowed by Gas Phase NDIR or by Electrolytic Conduc-tivityD5904 Test Method for Total Carbon, Inorganic Carbon,and Organic Carbon in Water by Ultraviolet, PersulfateOxidation, and Membrane Conductivity DetectionD5997 Test Method for On-Line Monitoring of Total Car-bon,
12、Inorganic Carbon in Water by Ultraviolet, PersulfateOxidation, and Membrane Conductivity DetectionD6317 Test Method for Low Level Determination of TotalCarbon, Inorganic Carbon and Organic Carbon in Water byUltraviolet, Persulfate Oxidation, and Membrane Conduc-tivity Detection1This practice is unde
13、r the jurisdiction of ASTM Committee E55 on Manufac-ture of Pharmaceutical Products and is the direct responsibility of SubcommitteeE55.03 on General Pharmaceutical Standards.Current edition approved Aug. 1, 2010. Published October 2010. DOI: 10.1520/E2656-10.2For referenced ASTM standards, visit th
14、e ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959,
15、United States.2.2 Pharmacopoeia Documents:ICH Q2 (R1) Validation of Analytical Procedures: Text andMethodology3ICH Q7 Good Manufacturing Practice Guide for ActivePharmaceutical Ingredients3ICH Q8 (R1) Pharmaceutical Development3ICH Q9 Quality Risk Management3ICH Q10 Pharmaceutical Quality System3ISO
16、 15839 Water Quality On-line Sensors/AnalyzingEquipment for Water: Specifications and PerformanceTests4JP Chapter Test for Total Organic Carbon5Ph. Eur. Chapter Total Organic Carbon in Waterfor Pharmaceutical Use6US FDA PAT Guidance Guidance for Industry: PAT AFramework for Innovative Pharmaceutical
17、 Development,Manufacturing, and Quality Assurance7US FDA Pharmaceutical cGMPs Pharmaceutical cGMPsfor the 21st Century A Risk-Based Approach7US FDA Procedures and Methods Validation Guidance forIndustry: Analytical Procedures and Methods ValidationChemistry, Manufacturing, and Controls Documentation
18、7USP Chapter Total Organic Carbon (TOC)8USP Chapter Validation of Compendial Proce-dures8USP Chapter Verification of Compendial Proce-dures8USP Chapter Water for Pharmaceutical Purposes8USP Guidance Analytical Instrument Qualifica-tion83. Terminology3.1 For definitions of terms specific to this stan
19、dard, refer tothe Terminology sections of Practice E2281, TerminologyE2363, and Guide E2500. Refer to ICH Q2 (R1) for methodvalidation terminology.4. Summary of Practice4.1 This practice provides the user with sufficient guidancefor developing the scientific and risk-based information nec-essary to
20、make informed decisions on the implementation,continuous verification, and continuous improvement of asystem to provide the real-time release testing of pharmaceu-tical water using on-line total organic carbon (RTRT-OLTOC)instrumentation that meets pharmaceutical water TOC specifi-cations. This guid
21、ance is based on Practice E2281, Terminol-ogy E2363, and Guide E2500 standards as well asICH Q2 (R1), ICH Q7, ICH Q8 (R1), ICH Q9, and ICH Q10guidelines. The following steps are required to meet theobjectives of this practice.4.1.1 Technical EvaluationEvaluate and understand watersystems, TOC measur
22、ement technologies, and the relatedregulatory requirements.4.1.2 Risk AssessmentPerform quality risk analysis on theprospective RTRT system designs to establish the samplinglocations representative of the point-of-use.4.1.3 Data QualityEnsure the quality of the data from theTOC measurement system is
23、 suitable for the intended use inthe water RTRT system. Ensure equivalency/consistency todata from existing TOC measurement systems used to releasewater to the TOC attribute, if they exist.4.1.4 Implementation StrategiesDevelop process to as-sure successful implementation of RTRT.4.1.5 Continuous Ve
24、rification ProceduresDevelop qualitycontrol strategies to ensure consistent system performance.4.1.6 Continuous Process ImprovementAssess and imple-ment process improvement practices.5. Significance and Use5.1 Pharmaceutical water is the most common componentor ingredient used in pharmaceutical and
25、biopharmaceuticalmanufacturing. Acceptable purity of the water is important tothe quality of the final pharmaceutical product. TOC concen-tration is a key indicator and attribute of the purity of this waterand also an important monitor of the overall performance of thewater purification system. TOC
26、analysis is the measurement ofall the covalently bound carbon present in the water, notincluding carbon in the form of carbon dioxide (CO2), bicar-bonate icon (HCO3), or carbonate ion (CO32), and is reportedas the mass of organic carbon per volume.5.2 Application of this practice provides pertinent
27、informa-tion to make informed decisions on the release of watermeeting pharmaceutical TOC concentration specifications.6. Procedure6.1 Technical Evaluation:6.1.1 The overall project scope shall be proportional to theassociated risk of exceeding the pharmaceutical water TOCconcentration specification
28、s. Knowledge and understanding ofthe TOC concentration in the water system, the OLTOCmeasurement system technology performance, and the phar-maceutical water system design shall be acquired to minimizerisk, ensure correct quality decisions, and maximize return oninvestment (USP Chapter and (1-7)9).
29、TOC measure-ment technologies are referenced in Test Methods D4839,D5173, D5904, D5997, and D6317.6.1.2 Technical assessments should be conducted to evalu-ate and develop a low-risk, science-based RTRT-OLTOC3Available from International Conference on Harmonisation of TechnicalRequirements for Regist
30、ration of Pharmaceuticals for Human Use (ICH), ICHSecretariat, c/o IFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20,Switzerland, http:/www.ich.org.4Available from International Organization for Standardization (ISO), 1, ch. dela Voie-Creuse, Case postale 56, CH-1211, Geneva 20, Switzerland,
31、http:/www.iso.ch.5Available from Japanese Pharmacopoeia (JP), Standards Division, Office ofCompliance and Standards, Pharmaceuticals and Medical DevicesAgency (PMDA),Shin-kasumigaseki Building, 3-3-2, Kasumigaseki, Chiyoda-ku, Tokyo 100-0013,Japan, http:/www.std.pmda.go.jp.6Available from European P
32、harmacopoeia (Ph. Eur.), 7 alle Kastner, CS 30026,F67081 Strasbourg, France, http:/www.pheur.org.7Available from Food and Drug Administration (FDA), 5600 Fishers Ln.,Rockville, MD 20857, http:/www.fda.gov.8Available from U.S. Pharmacopeia (USP), 12601 Twinbrook Pkwy., Rockville,MD 20852-1790, http:/
33、www.usp.org.9The boldface numbers in parentheses refer to a list of references at the end ofthis standard.E2656 102system design. Knowledge of related information from avail-able sources should be used to understand, interpret, andimplement the results of the technical assessments. Informationon gen
34、eral and specific RTRT-OLTOC system design consid-erations, performance characteristics, and validation should befound in published documents and texts (8-15).6.1.3 For existing water purification systems, the usershould assess historical, current, and potential organic contami-nation. Evaluation of
35、 potential organic contamination shouldbe based on a realistic assessment of water system design andcomponents to determine the probability of a specific or abroad spectrum of organic contaminants reaching the waterdistribution system. The user should consult with TOC instru-mentation vendors to det
36、ermine if the TOC measurementsystem will meet the requirements of the intended applicationin light of any organic contamination assessment.6.1.4 For new water purification systems, the presence ofpotential problematic compounds in the pharmaceutical watersystem shall be addressed during the design a
37、nd qualificationand validation activities and correction/mitigation/preventiveactions shall be implemented accordingly.6.1.5 TOC measurement system technology assessmentsshall be achieved by meeting regulatory guidance requirementson analytical procedure verifications and validations(ICH Q2 (R1), US
38、P Chapter , and US FDA Proceduresand Methods Validation). The requirements shall depend on theuse of the data and the intended use of the instrumentation.6.1.5.1 Legal USA Requirements and Verification ofUSP Chapter The use of USP Chapter TOC islegally recognized to meet the requirements for testing
39、 theTOC attribute in pharmaceutical water. The users of US-P Chapter TOC are not required to validate this method,but they shall verify it is suitable under actual conditions ofuse. The user shall understand that Section 501(b) of the UnitedStates Food, Drug, and Cosmetic Act (the Act) legally recog
40、-nizes the analytical procedures in the United StatesPharmacopeia/National Formulary (USP/NF) for purposes ofdetermining compliance with this Act (US FDA Proceduresand Methods Validation). The USA federal regulation CFR211.194(a)(2) states: the suitability of a compendial analyticalprocedure must be
41、 verified under actual conditions of use.Users shall use USP Chapter , ICH Q2 (R1), or equiva-lent to verify compendial procedures.6.1.5.2 The procedure for validation and verification of theTOC analytical method shall depend on the analytical proce-dure classification in ICH Q2 (R1), USP Chapter ,o
42、rthe US FDA Procedures and Methods Validation. The mea-surement of the TOC attribute in water shall be classified as animpurity test. Under impurity tests are two additional classifi-cations, quantitative and limit test. For each of these, there arerecommended lists of validation tests to perform. A
43、ll pharma-copeia TOC test methods are limit tests. Limit testing producesonly a pass or fail output as graphically represented by Fig. 1.To control, trend, and monitor on-line systems and to releasewater in real time using quantitative data, the analytical methodrequires the use of quantitative data
44、, so the analytical methodshall be validated to the requirements of quantitative tests (USFDA PAT Guidance). Quantitative data use is graphicallyrepresented in Fig. 2. Classifications and recommended testsare shown in Table 1. Additional helpful information can befound in ISO 15839.6.1.5.3 The US FD
45、A considers “real-time release to becomparable to Alternative Analytical Procedures” and the USRegulation CFR 211.165 requires that the accuracy, sensitivity,specificity, and reproducibility of the alternative analytical testmethods or procedures used for process control purposes bevalidated and doc
46、umented appropriately (US FDA PAT Guid-ance and US FDA Procedures and Methods Validation).6.2 Risk Assessment:6.2.1 If the TOC concentration data is to be used in aquantitative way for trending, process control, or processstatistical analysis, a statistical assessment of the processperformance shoul
47、d be done to estimate the risk of the processfailing the specification requirement. This information shouldFIG. 1 “Information Poor” Limit Test OutputE2656 103be used in the project implementation phase to understand andimprove, if necessary, the combined performance of the waterpurification system
48、and the TOC measurement system. Thesestatistical assessments should be used for communicating thelevel of process control for both regulatory inspection and toascertain the continued performance of the TOC impurityremoval and measurement system. See Fig. 3 and Fig. 4 for agraphical presentation of a
49、 process with high and low prob-ability of failure.6.2.2 The placement and connection of the OLTOC instru-mentation to the water system should be based on a riskassessment (USP Chapter and (9), as outlined inICH Q9, or an engineering assessment. The user shall use goodengineering design practices and follow cGMP requirements(ISO 15839 and (1-3, 5, 9, 11). The OLTOC measurementlocation shall represent the quality of the sample as measuredat the points-of-use (POU). Water at the POU shall meet theTOC concentration specification. Sample frequency frompoints-o
