1、Designation: E2656 16Standard 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 U.S. FDA PAT Guidance,and U.S. 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 practicepro
5、vides 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 pharmaceuti
6、calwaters 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
7、to meet 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,
8、associated 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 Capability and Performance
9、MeasurementE2363 Terminology Relating to Process Analytical Technol-ogy 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 Ph
10、armaceutical and Biopharmaceutical Manu-facturingD4839 Test Method for Total Carbon and Organic Carbon inWater by Ultraviolet, or Persulfate Oxidation, or Both, andInfrared DetectionD5173 Guide for On-Line Monitoring of Total OrganicCarbon in Water by Oxidation and Detection of ResultingCarbon Dioxi
11、deD5904 Test Method for Total Carbon, Inorganic Carbon, andOrganic Carbon in Water by Ultraviolet, PersulfateOxidation, and Membrane Conductivity DetectionD5997 Test Method for On-Line Monitoring of TotalCarbon, Inorganic Carbon in Water by Ultraviolet, Persul-fate Oxidation, and Membrane Conductivi
12、ty DetectionD6317 Test Method for Low Level Determination of TotalCarbon, Inorganic Carbon and Organic Carbon in Waterby Ultraviolet, Persulfate Oxidation, and Membrane Con-ductivity Detection2.2 Pharmacopoeia Documents:ICH Q2 (R1) Validation of Analytical Procedures: Text andMethodology3ICH Q7 Good
13、 Manufacturing Practice Guide for ActivePharmaceutical Ingredients3ICH Q8 (R2) Pharmaceutical Development31This practice is under the jurisdiction of ASTM Committee E55 on Manufac-ture of Pharmaceutical and Biopharmaceutical Products and is the direct responsi-bility of Subcommittee E55.03 on Genera
14、l Pharmaceutical Standards.Current edition approved Nov. 1, 2016. Published November 2016. Originallyapproved in 2010. Last previous edition approved in 2010 as E2656 10. DOI:10.1520/E2656-16.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at ser
15、viceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.3Available from International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use (ICH), ICHSecretariat, c/o IFPMA, 15
16、 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20,Switzerland, http:/www.ich.org.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States1ICH Q9 Quality Risk Management3ICH Q10 Pharmaceutical Quality System3ISO 15839 Water Quality On-line Sensor
17、s/AnalyzingEquipment for Water: Specifications and PerformanceTests4JP Chapter Test for Total Organic Carbon5Ph. Eur. Chapter Total Organic Carbon in Waterfor Pharmaceutical Use6U.S. FDA Part 11 Guidance Guidance for Industry: Part 11,Electronic Records; Electronic Signatures Scope andApplication7U.
18、S. FDA PAT Guidance Guidance for Industry: PAT AFramework for Innovative Pharmaceutical Development,Manufacturing, and Quality Assurance7U.S. FDA Pharmaceutical cGMPs Pharmaceutical cGMPsfor the 21st Century A Risk-Based Approach7U.S. FDA Procedures and Methods Validation Guidance forIndustry: Analy
19、tical Procedures and Methods ValidationChemistry, Manufacturing, and Controls Documentation7U.S. FDA Process Validation Guidance Guidance for Indus-try: Process Validation: General Principles and Practices7USP Chapter Total Organic Carbon (TOC)8USP Chapter Validation of Compendial Procedures8USP Cha
20、pter Verification of Compendial Proce-dures8USP Chapter Water for Pharmaceutical Purposes8USP Guidance Analytical Instrument Qualification83. Terminology3.1 For definitions of terms specific to this standard, refer tothe Terminology sections of Practice E2281, TerminologyE2363, and Guide E2500. Refe
21、r 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 make informed decisions on the implementation,continuous verification, and continuous improvement
22、 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 guidance is based on Practice E2281, Terminol-ogy E2363, and Guide E2500 standards as well asICH Q2 (
23、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 measurement technologies, and the relatedregulatory requirements.4.1.2 Risk AssessmentPerform quality r
24、isk 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 suitable for the intended use inthe water RTRT system. Ensure equivalency/consistency todata fro
25、m 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 Verification ProceduresDevelop qualitycontrol strategies to ensure consistent system performance.4.
26、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 biopharmaceuticalmanufacturing. Acceptable purity of the water is important tothe quality of the
27、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 analysis is the measurement ofall the covalently bound carbon present in the water, notincluding
28、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 informa-tion to make informed decisions on the release of watermeeting pharmaceutical TOC concent
29、ration 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 specifications. Knowledge and understanding ofthe TOC concentration in the water system, the OLTOCmeasurement
30、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). TOC measure-ment technologies are referenced in Test Methods D4839,D5904, D5997, and D6317, and G
31、uide D5173.6.1.2 Technical assessments should be conducted to evalu-ate and develop a low-risk, science-based RTRT-OLTOCsystem design. Knowledge of related information from avail-able sources should be used to understand, interpret, andimplement the results of the technical assessments. Informationo
32、n general and specific RTRT-OLTOC system designconsiderations, performance characteristics, and validationshould be found in published documents and texts (8-15).4Available from International Organization for Standardization (ISO), 1, ch. dela Voie-Creuse, Case postale 56, CH-1211, Geneva 20, Switze
33、rland, 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 Eur
34、opean Pharmacopoeia (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,
35、 http:/www.usp.org.9The boldface numbers in parentheses refer to a list of references at the end ofthis standard.E2656 1626.1.3 For existing water purification systems, the usershould assess historical, current, and potential organic contami-nation. Evaluation of potential organic contamination shou
36、ldbe 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 determine if the TOC measurementsystem w
37、ill 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 and qualificationand validation activi
38、ties 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), USP Chapter , and U.S. FDA Proce-dures
39、and Methods Validation). The requirements shall dependon the use of the data and the intended use of the instrumen-tation.6.1.5.1 Legal U.S. Requirements and Verification ofUSP Chapter The use of USP Chapter TOC islegally recognized to meet the requirements for testing theTOC attribute in pharmaceut
40、ical water. The users ofUSP Chapter TOC are not required to validate thispractice, but they shall verify it is suitable under actualconditions of use. The user shall understand that Section501(b) of the U.S. Food, Drug, and Cosmetic Act (the Act)legally recognizes the analytical procedures in the U.
41、S.Pharmacopeia/National Formulary (USP/NF) for purposes ofdetermining compliance with this Act (U.S. FDA Proceduresand Methods Validation). The U.S. Federal Regulation CFR211.194(a)(2) states: the suitability of a compendial analyticalprocedure must be verified under actual conditions of use.Users s
42、hall 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 , orthe U.S. FDA Procedures and Methods Validation
43、. The mea-surement of the TOC attribute in water shall be classified as animpurity test. Under impurity tests are two additionalclassifications, quantitative and limit test. For each of these,there are recommended lists of validation tests to perform. Allpharmacopeia TOC test methods are limit tests
44、. Limit testingproduces only a pass or fail output as graphically representedby Fig. 1. To control, trend, and monitor on-line systems and torelease water in real time using quantitative data, the analyticalmethod requires the use of quantitative data, so the analyticalmethod shall be validated to t
45、he requirements of quantitativetests (U.S. FDA PAT Guidance). Quantitative data use isgraphically represented in Fig. 2. Classifications and recom-mended tests are shown in Table 1. Additional helpful infor-mation can be found in ISO 15839.6.1.5.3 The U.S. FDA considers “real-time release to becompa
46、rable to Alternative Analytical Procedures” and the U.S.Regulation 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 documented appropriately (U.S. FDA PAT Gui
47、d-ance and U.S. 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 should be done to estimate the risk of t
48、he processfailing the specification requirement. This information shouldbe used in the project implementation phase to understand andimprove, if necessary, the combined performance of the waterFIG. 1 “Information Poor” Limit Test OutputE2656 163purification system and the TOC measurement system. The
49、sestatistical 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 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 practi
