1、Designation: E 2537 08Standard Guide forApplication of Continuous Quality Verification toPharmaceutical and Biopharmaceutical Manufacturing1This standard is issued under the fixed designation E 2537; the number immediately following the designation indicates the year oforiginal adoption or, in the c
2、ase of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon (e) indicates an editorial change since the last revision or reapproval.1. Scope1.1 This guide describes Continuous Quality Verification(CQV) as an approach to process vali
3、dation where manufac-turing process (or supporting utility system) performance iscontinuously monitored, evaluated and adjusted (as necessary).It is a science-based approach to verify that a process is capableand will consistently produce product meeting its predeter-mined critical quality attribute
4、s. CQV is similarly described asContinuous Quality Assurance (U.S. FDA) and ContinuousProcess Verification (ICH Q8).1.2 Pharmaceutical and biopharmaceutical product manu-facturing companies are required to provide assurance that theprocesses used to manufacture regulated products result inproducts w
5、ith the specified critical quality attributes of strengthidentity and purity associated with the product safety, andefficacy. Process validation is a way in which companiesprovide that assurance.1.3 With the knowledge obtained during the product life-cycle, a framework for continuous quality improve
6、ment will beestablished where the following may be possible: (1) riskmitigated, (2) process variability reduced, (3) process capabil-ity enhanced, (4) process design space defined or enhanced,and ultimately (5) product quality improved. This can enable anumber of benefits that address both complianc
7、e and opera-tional goals (for example, real time release, continuous processimprovement).1.4 The principles in this guide may be applied to drugproduct or active pharmaceutical ingredient/drug substancepharmaceutical and biopharmaceutical batch or continuousmanufacturing processes or supporting util
8、ity systems (forexample, TOC for Purified Water and Water for Injectionsystems, and so forth).1.5 The principles in this guide may be applied during thedevelopment and manufacturing of a new process or product orfor the improvement and/or redesign of an existing process.1.6 Continuous quality verifi
9、cation may be applied to manu-facturing processes that use monitoring systems that providefrequent and objective measurement of process data. Theseprocesses may or may not employ in-, on-, or at-line analyzers/controllers that monitor, measure, analyze, and control theprocess performance. The associ
10、ated processes may or may nothave a design space.1.7 This guide may be used independently or in conjunctionwith other proposed E55 standards to be published by ASTMInternational.2. Referenced Documents2.1 ASTM Standards:2E 2363 Terminology Relating to Process Analytical Tech-nology in the Pharmaceut
11、ical Industry2.2 Other Publications:ICH Q8 Pharmaceutical Development (Step 4 version), 10November 20053ICH Q9 Quality Risk Management (Step 4 version), 9November 20053Pharmaceutical cGMPs for the 21st Century A Risk-Based Approach4Guidance for Industry, PAT A Framework for InnovativePharmaceutical
12、Development, Manufacturing and QualityAssurance43. Terminology3.1 For definitions of terms used in this guide, refer toTerminology E 2363.4. Significance and Use4.1 Application of the approach described within this stan-dard guide applies science-based concepts and principlesintroduced in the FDAini
13、tiative Pharmaceutical cGMPs for the21st Century.4.2 This guide supports, and is consistent with, elementsfrom ICH Q8 and ICH Q9.1This guide is under the jurisdiction of ASTM Committee E55 on Manufactureof Pharmaceuticals Products and is the direct responsibility of SubcommitteeE55.03 on General Pha
14、rmaceutical Standards.Current edition approved Jan. 1, 2008. Published February 2008.2For referenced ASTM standards, visit the 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
15、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 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20,Switzerland, http:/www.ich.org.4Available from Food and Dru
16、g Administration (FDA), 5600 Fishers Ln.,Rockville, MD 20857, http:/www.fda.gov.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.4.3 According to FDA Guidance for Industry, PAT, “Withreal time quality assurance, the desired quality at
17、tributes areensured through continuous assessment during manufacture.Data from production batches can serve to validate the processand reflect the total system design concept, essentially support-ing validation with each manufacturing batch.” In other words,the accumulated product and process unders
18、tanding used toidentify the Critical Quality Attributes (CQAs), together withthe knowledge that the risk-based monitoring and controlstrategy will enable control of the CQAs, should provide theconfidence needed to show validation with each batch. This isas opposed to a conventional discrete process
19、validationapproach.5. Key Concepts5.1 This guide applies the following key concepts: (1)science-based approach, (2) quality by design, (3) product andprocess understanding, (4) quality risk management, and (5)continuous improvement.5.2 Science-based Approach:5.2.1 Product and process information, as
20、 it relates toproduct quality and public health, should be used as the basisfor making science- and risk-based decisions that ensure that aproduct consistently attains a predefined quality at the end ofthe manufacturing process.5.2.2 Examples of product and process information toconsider include: Cr
21、itical Quality Attributes (CQAs), CriticalProcess Parameters (CPPs), control strategy information, andprior production experience.5.3 Quality by Design:5.3.1 Quality by design concepts may be applied in thedesign and development of a product and associated manufac-turing processes to ensure critical
22、 quality attributes can beaccurately and reliably predicted (for example, for materialsused, process parameters, manufacturing, environmental andother conditions).5.3.2 Quality by design, when built into an organizationsquality system, provides a framework for the transfer ofproduct and process know
23、ledge from drug development to thecommercial manufacturing processes for launch, post-development changes, and continuous improvement. It is thisknowledge which enables the organizational understandingthat is required for effective risk management and decisionexcellence. Continuous quality verificat
24、ion can only beachieved if systems exist to capture and codify this knowledgeinto actionable elements for process monitoring and control aspart of the quality systems framework.5.4 Product and Process Understanding:5.4.1 Product and Process understanding accumulates dur-ing the development phase and
25、 continues throughout thecommercialization phase of the product lifecycle. In thedesired state, “A process will be considered well understoodwhen (1) critical sources of variability are identified andexplained; (2) variability is managed by the process; and (3)product quality attributes can be accur
26、ately and reliably pre-dicted over the design space established for materials, processparameters, manufacturing, environmental, and other condi-tions.” (FDA Guidance for Industry, PAT)5.4.2 A focus on product and process understanding canreduce the burden for validating systems by providing moreopti
27、ons for justifying and verifying systems intended to moni-tor and control biological, physical, and/or chemical attributesof materials and processes.5.5 Quality Risk Management:5.5.1 Quality risk management approaches should be usedas a proactive means to identify potential quality issues duringprod
28、uct development and manufacturing to further ensure thehigh quality of the drug product to the patient.5.5.2 Quality risk management can, for example, help guidethe setting of specifications and process parameters for drugmanufacturing, assess and mitigate the risk of changing aprocess or specificat
29、ion.5.5.3 Risk management should be an ongoing part of thequality management process and the output/results of the riskmanagement process should be reviewed to take into accountnew knowledge and experience.5.6 Continuous Improvement:5.6.1 Improved process understanding provides opportuni-ties for fu
30、rther risk mitigation by optimizing process designand control.5.6.2 Comprehensive statistical process data analysis maybe used to provide the rationale for justifying changes tomeasurement, control, and testing requirements along withassociated specifications for each product.6. Continuous Quality V
31、erification Process6.1 Overview:6.1.1 Continuous learning and quality verification occursover the lifecycle of a product and should include the followingaspects:6.1.1.1 Product understanding and process understanding,6.1.1.2 Continuous quality monitoring and control,6.1.1.3 Process performance evalu
32、ation,6.1.1.4 Acceptance and release, and6.1.1.5 Continuous process improvement.6.1.2 Manufacturers should have a comprehensive andmodern quality systems in place. Robust quality systems willpromote process consistency by integrating effectiveknowledge-building mechanisms into routine operations.6.1
33、.3 Science-based approaches should be applied at eachstage of the process.6.1.4 Quality risk management should be applied at eachstage of the process.6.2 Product and Process Understanding:6.2.1 In a modern quality systems manufacturing environ-ment, the significant characteristics of the product bei
34、ngmanufactured should be defined from design through the fulllifecycle to retirement, and appropriate levels of control shouldbe exercised over all changes.6.2.2 Process characterization studies performed duringprocess development establish initial process knowledge.6.2.3 Further process characteriz
35、ation studies performedduring scale-up establish further understanding of the processand control requirements. Risk assessments to define andjustify the final CPPs and CQAs may be an iterative process asthe understanding of the process increases.E25370826.2.4 This information is documented in summar
36、y docu-ments (for example, product and process development report,formulation development summary or process knowledge re-port). Here Critical Process Parameters (CPP) are identified inorder to meet the Critical Quality Attributes (CQA). These aredefined, justified, and documented.6.2.5 For existing
37、 processes, commercial experience andhistorical data provide further process knowledge and under-standing.6.2.6 The use of conventional data collection plans, processcontrol charts, production record data, and modern processanalytical technology systems during manufacture will allowfor the collectio
38、n and further analysis of real- or near-time data.6.2.7 The use of multivariate data analysis approaches inconjunction with knowledge management systems can allowthe identification of product variation and process controlvariables that are critical to product quality and processperformance.6.2.8 Ris
39、ks to product quality may be identified, assessedand mitigated by the identification and establishment of criticalprocess parameters whereby the critical quality attributes areassured. Results from risk assessments will provide input to theprocess control strategy. Knowledge gained from similar pro-
40、cesses and equipment performance may be leveraged inprocess risk management.6.3 Continuous Quality Monitoring and Control:6.3.1 A quality systems approach calls for the manufacturerto develop procedures (based on product and process under-standing) that monitor, measure, analyze, and control theproc
41、ess performance (including analytical methods and/orstatistical techniques).6.3.2 A process control strategy should be developed anddocumented. The strategy will describe the elements necessaryto assure the process is valid and suitable for commercializa-tion; the plan for monitoring, measuring, ana
42、lyzing, andadjusting (if necessary) the critical aspects of manufacturingsteps/unit operations; and how this plan will ensure processperformance and product quality. The measurement frequencyshould be sufficient to identify process excursions related tocritical quality attributes.6.3.3 The process c
43、ontrol strategy may document or refer-ence the following:6.3.3.1 The steps/unit operations included in the scope ofthe control strategy document.6.3.3.2 The critical quality attributes, critical quality param-eters, intended operating ranges that need to be monitored andcontrolled, and acceptance cr
44、iteria as determined through thequality by design approach.6.3.3.3 The facility environment and equipment operatingparameters.6.3.3.4 The associated methods, accuracy, and frequency ofmonitoring and control to facilitate timely feedback/feed for-ward and appropriate corrective action and preventive
45、action.6.3.3.5 Process measurement and data collection techniquesmay allow for the collection and further analysis of real- ornear-time data, for example, of in-process and/or final productCQAs, process end-points, and CPPs.6.3.3.6 Consideration of raw materials and component vari-ability, in-proces
46、s testing, end product testing, and evaluationrequired to demonstrate the performance of the process.6.4 Process Performance Evaluation:6.4.1 Continuous quality verification requires documenta-tion or records including a decision as to the validated state.Collectively these documents will provide th
47、e necessary evi-dence to show that the process operates in a validated state, andthe ongoing monitoring, control, and analysis provides assur-ance that the process continues to operate in a state of control.A decision as to the fitness for use should be in place prior tocommercialization.6.4.2 Ongoi
48、ng process monitoring data will provide anopportunity to conduct an evaluation of process performance toconfirm that the process is performing as intended.6.4.3 The process performance evaluation may include thefollowing:6.4.3.1 A review of the manufacturing data for CPPs andCQAs against the accepta
49、nce criteria.6.4.3.2 An evaluation of the process performance, for ex-ample using process capability analysis. If statistical processcapability analysis is used, it should include an assessment ofprocess controls and parameters that are critical to productquality.6.4.3.3 A conclusion whether the process is consideredvalidated and recommendations for any modifications to theprocess understanding (for example, CPPs, Design Space) orcontrol strategy based on the increased process understandingacquired during the performance evaluation.6.4.3.4 A recommendation on the appropriate frequ
