1、Designation: E2537 08E2537 16Standard Guide forApplication of Continuous QualityProcess Verification toPharmaceutical and Biopharmaceutical Manufacturing1This standard is issued under the fixed designation E2537; the number immediately following the designation indicates the year oforiginal adoption
2、 or, in the case of revision, 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 guide describes Continuous QualityProcess Verification (CQV) as an alte
3、rnate approach to process validation wheremanufacturing process (or supporting utility system) performance is continuously monitored, evaluated, and adjusted (asnecessary). It is a science-based approach to verify that a process is capable and will consistently produce product meeting itspredetermin
4、ed critical quality attributes. CQV Continuous Process Verification (ICH Q8) is similarly described as ContinuousQuality Assurance (U.S. FDA) and Continuous Process Verification (ICH Q8). Verification.1.2 Pharmaceutical and biopharmaceutical product manufacturing companies are required to provide as
5、surance that theprocesses used to manufacture regulated products result in products with the specified critical quality attributes of strength identityand purity associated with the product safety,safety and efficacy. Process validation is a way in which companies provide thatassurance.1.3 With the
6、knowledge obtained during the product lifecycle, a framework for continuous quality improvementimprovementswill be established where the following may be possible: (1) risk mitigated,identified, (2) risk mitigated, (3) process variabilityreduced, (3)(4) process capability enhanced, (4)(5) process de
7、sign space defined or enhanced, and ultimately (5)(6) product qualityimproved. This can enable a number of benefits that address both compliance and operational goals (for example, real time release,continuous process improvement).1.4 The principles in this guide may be applied to drug product or ac
8、tive pharmaceutical ingredient/drug substancepharmaceutical and biopharmaceutical batch or continuous manufacturing processes or supporting utility systems (for example,TOC for Purified Waterpurified water and Waterwater for Injectioninjection systems, and so forth).1.5 The principles in this guide
9、may be applied during the development and manufacturing of a new process or product or forthe improvement and/or redesign or redesign, or both, of an existing process.1.6 Continuous qualityprocess verification may be applied to manufacturing processes that use monitoring systems that providefrequent
10、 and objective measurement of process data. data in real time. These processes may or may not employ in-, on-, or at-lineanalyzers/controllers that monitor, measure, analyze, and control the process performance. The associated processes may or maynot have a design space.1.7 This guide may be used in
11、dependently or in conjunction with other proposed E55 standards to be published by ASTMInternational.2. Referenced Documents2.1 ASTM Standards:2E2363 Terminology Relating to Process Analytical Technology in the Pharmaceutical Industry2.2 Other Publications:ICH Q8 (R2) Pharmaceutical Development (Ste
12、p 4 version), 10 November 200520093ICH Q9 Quality Risk Management (Step 4 version), 9 November 200531 This guide is under the jurisdiction of ASTM Committee E55 on Manufacture of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility ofSubcommittee E55.03 on General Pharmaceu
13、tical Standards.Current edition approved Jan. 1, 2008Dec. 1, 2016. Published February 2008January 2017. Originally approved in 2008. Last previous edition approved in 2008 asE2537 08. DOI: 10.1520/E2537-08.10.1520/E2537-16.2 For referencedASTM standards, visit theASTM website, www.astm.org, or conta
14、ctASTM Customer Service at serviceastm.org. For Annual Book of ASTM Standardsvolume information, refer to the standards Document Summary page on the ASTM website.3 Available from International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (IC
15、H), ICH Secretariat, c/oIFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20, Switzerland, http:/www.ich.org.This document is not an ASTM standard and is intended only to provide the user of an ASTM standard an indication of what changes have been made to the previous version. Becauseit may not
16、be technically possible to adequately depict all changes accurately, ASTM recommends that users consult prior editions as appropriate. In all cases only the current versionof the standard as published by ASTM is to be considered the official document.Copyright ASTM International, 100 Barr Harbor Dri
17、ve, PO Box C700, West Conshohocken, PA 19428-2959. United States1ICH Q10 Pharmaceutical Quality System (Step 4 version), June 20083ICH Q8, Q9, and Q10 Questions and Answers (R4), November 20103ICH Q11 Development and Manufacture of Drug Substances (Step 4 version), May 20123Pharmaceutical cGMPsCGMPs
18、 for the 21st Century A Risk-Based Approach4Guidance for Industry, PAT A Framework for Innovative Pharmaceutical Development, Manufacturing and QualityAssuranceAssurance, September 20044Guidance for Industry, Process Validation General Principles and Practices, January 20114Guideline on Process Vali
19、dation for Finished Products Information and Data to be Provided in Regulatory Submissions,February 20145Guidelines for Good Manufacturing Practice, Volume 4 Medicinal Products for Human and Veterinary Use, Annex 15:Qualification and Validation, March 2015 (effective October 2015)6Pharmaceutical Ins
20、pection Co-operation Scheme, Annex 15 Qualification and Validation, April 20157Good Manufacturing Practice, Annex 2 Qualification and Validation, May 2015 (effective December 2015)83. Terminology3.1 For definitions of terms used in this guide, refer to Terminology E2363.4. Significance and Use4.1 Ap
21、plication of the approach described within this standard guide applies science-based concepts and principles introducedin the FDA initiative Pharmaceutical cGMPs FDAs initiative on pharmaceutical CGMPs for the 21st Century. century.44.2 This guide supports, and is consistent with, elements from ICH
22、Q8 and ICH Q9.Q8 Q11 and guidelines from USFDA,European Commission, Pharmaceutical Inspection Co-operation Scheme, and the China Food and Drug Administration.84.3 According to FDA Guidance for Industry, PAT, “With real time quality assurance, the desired quality attributes are ensuredthrough continu
23、ous assessment during manufacture. Data from production batches can serve to validate the process and reflect thetotal system design concept, essentially supporting validation with each manufacturing batch.” In other words, the accumulatedproduct and process understanding used to identify the Critic
24、al Quality Attributes (CQAs), together with the knowledge that therisk-based monitoring and control strategycontrol strategy, will enable control of the CQAs, should provide providing theconfidence needed to show validation with each batch. This is as opposed to a conventionaltraditional discrete pr
25、ocess validationapproach.5. Key Concepts5.1 This guide applies the following key concepts: (1) science-based approach, (2) quality by design, (3) product and processunderstanding, (4) quality risk management, and (5) continuous improvement.5.2 Science-based Approach:5.2.1 Product and process informa
26、tion, as it relates to product quality and public health, should be used as the basis for makingscience- and risk-based decisions that ensure that a product consistently attains a predefined quality at the end of the manufacturingprocess.quality.5.2.2 Examples of product and process information to c
27、onsider include: Critical Quality Attributes (CQAs), Critical ProcessParameters (CPPs), control strategy information, and prior production and development experience.5.3 Quality by Design:5.3.1 Quality by design concepts may be applied in the design and development of a product and associated manufa
28、cturingprocesses to ensure critical quality attributes can be accurately and reliably predicted (for example, for materials used, processparameters, manufacturing, environmental and other conditions).5.3.2 Quality by design, when built into an organizations quality system, provides a framework for t
29、he transfer of product andprocess knowledge from drug development to the commercial manufacturing processes for launch, post-development changes, andcontinuous improvement. It is this knowledge which enables the organizational understanding that is required for effective riskmanagement and decision
30、excellence. Continuous quality Successful continuous process verification can only be achieved ifsystems exist to capture and codify this knowledge into actionable elements for process monitoring and control as part of thequality systems and production framework.5.3.3 Continuous process verification
31、 can be an alternate to traditional process validation.5.4 Product and Process Understanding:4 Available from Food and Drug Administration (FDA), 5600 Fishers Ln., Rockville, MD 20857, http:/www.fda.gov.5 Available from European Medicines Agency (EMA), 30 Churchill Place, Canary Warf, London E14 5EU
32、 United Kingdom, http:/www.ema.europa.eu/ema.6 Available from European Commission (EC), 1049 Brussels, Belgium, http:/ec.europa.eu.7 Available from Pharmaceutical Inspection Co-operation Scheme (PIC/S), 14 Rue du Roveray, 1207 Geneva, Switzerland, http:/www.picscheme.org.8 Available from China Food
33、and Drug Administration, Building #2, 26 Xuanwumen West Street, Xicheng District, Beijing, 100053, P.R. China, http:/.E2537 1625.4.1 Product and Process understanding accumulates during the development phase and continues throughout the commer-cialization phase of the product lifecycle. In the desir
34、ed state, “A process will be considered well understood when (1)criticalcritical sources of variability are identified and explained; (2) variability is managed by the process; and (3) productquality attributes can be accurately and reliably predicted over the design space established for materials,
35、 process parameters,manufacturing, environmental, and other conditions.” (FDA Guidance for Industry, PAT)5.4.2 A focus on product Product and process understanding can reduce the burden for validating systems by providing moreoptions for justifying and verifying systems focusing on aspects that are
36、critical to product quality. Systems are verified that areintended to monitor and control biological, physical, and/or chemical attributes or chemical attributes, or combinations thereof, ofmaterials and processes.5.5 Quality Risk Management:5.5.1 Quality risk management approaches should be used as
37、 a proactive means to identify potential quality issues duringproduct development and manufacturing to further ensure the high quality of the drug product to the patient.5.5.2 Quality risk management can, for example, help guide the setting of specifications and process parameters for drugmanufactur
38、ing, assess and mitigate the risk of changing a process or specification.5.5.3 Risk management should be an ongoing part of the quality management process and the output/results of the riskmanagement process should be reviewed to take into account new knowledge and experience.5.6 Continuous Improvem
39、ent:5.6.1 Improved process understanding provides opportunities for further risk mitigation by optimizing process design andcontrol.5.6.2 Comprehensive statistical process data analysis may analysis, where applicable, should be used to provide the rationalefor justifying changes to measurement, cont
40、rol, and testing requirements along with associated specifications for each product.6. Continuous QualityProcess Verification Process6.1 Overview:6.1.1 Continuous learning and quality verification occurs over the lifecycle of a product and should include the followingaspects:6.1.1.1 Product understa
41、nding and process understanding,6.1.1.2 Continuous process and quality monitoring and control,6.1.1.3 Process performance evaluation,6.1.1.4 Acceptance and release, and6.1.1.5 Continuous process improvement.6.1.2 Manufacturers should have a comprehensive and moderncurrent quality systemssystem in pl
42、ace. Robust processdevelopment and quality systems will promote process consistency by integrating effective knowledge-building mechanisms intoroutine operations.6.1.3 Science-based approaches should be applied at each stage of the process.6.1.4 Quality risk management should be applied at each stag
43、e of the process.6.1.5 A continuous process verification approach may be combined with a traditional validation approach for certain steps ofthe manufacturing process. The entire manufacturing process is thus a hybrid6,7,8 of the two approaches.6.2 Product and Process Understanding:6.2.1 In a modern
44、current quality systems manufacturing environment, environment for new products, the significantcharacteristics of the product being manufactured should be defined from design through the full lifecycle to retirement, andappropriate levels of control should be exercised over all changes.6.2.2 Proces
45、s characterization studies performed during process development establish initial process knowledge.6.2.3 Further process characterization studies performed during scale-up establish further understanding of the process andcontrol requirements. Risk assessments to define and justify the final CPPs a
46、nd CQAs may be an iterative process as theunderstanding of the process increases.6.2.4 This information is documented in summary documents (for example, product and process development report,formulation development summary, or process knowledge report). Here Critical Process Parameters (CPP) are id
47、entified in orderto meet the Critical Quality Attributes (CQA). These are defined, justified, and documented.6.2.5 For existing processes, commercial experience and historical data provide further process knowledge and understanding.6.2.6 The use of conventional data collection plans, process contro
48、l charts, production record data, and moderncurrent processanalytical technology systems during manufacture will allow for the collection and further analysis of real- or near-time data.6.2.7 The use of multivariate data analysis approaches in conjunction with knowledge management systems can allow
49、theidentification of product variation and process control variables that are critical to product quality and process performance.E2537 1636.2.8 Risks to product quality may be identified, assessed and mitigated by the identification and establishment of criticalprocess parameters whereby the critical quality attributes are assured. Results from risk assessments will provide input to theprocess control strategy. Knowledge gained from similar processes and equipment performance may be leveraged in process riskmanagement.6.3 Continuous Process and
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