ASTM E2474-2014 Standard Practice for Pharmaceutical Process Design Utilizing Process Analytical Technology《使用过程分析技术进行制药工艺设计的标准实施规程》.pdf

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1、Designation: E2474 06E2474 14Standard Practice forPharmaceutical Process Design Utilizing Process AnalyticalTechnology1This standard is issued under the fixed designation E2474; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the y

2、ear 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.INTRODUCTIONProcess design is the systematic conversion of information about needs for a product intoknowledge about how to

3、 manufacture this product. Products and manufacturing processes should bedesigned using science- and risk-based design strategies to manage variation.To attain this goal, integration of Process Analytical Technology (PAT) principles and tools duringprocess design will enhance opportunities to build,

4、 maintain, and expand science- and risk-basedprocess understanding throughout a product lifecycle. The product lifecycle includes the period inproduction as well as development.Process understanding will be the foundation to establish manufacturing (process selection,methodology, implementation, and

5、 practice), process control (real-time control on the basis ofmeasured critical quality attributes), effective risk mitigation, and product release concepts.Process understanding will also enable regulatory strategies in that the level of regulatory scrutinymay reflect the demonstrated level of scie

6、nce- and risk-based process understanding.1. Scope1.1 This practice covers process design, which is integral to process development as well as post-development processoptimization. It is focused on practical implementation and experimental development of process understanding.1.2 The term process de

7、sign as used in this practice can mean:1.2.1 The activities to design a process (the process design), and/oror1.2.2 The outcome of this activity (the designed process).process), or both.1.3 The principles in this practice are applicable to both drug substance and drug product processes. For drug pro

8、ducts,formulation development and process development are interrelated and therefore the process design will incorporate knowledgefrom the formulation development.1.4 The principles in this practice apply during development of a new process or the improvement or redesign of an existingone, or both.1

9、.5 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibilityof the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatorylimitations prior to use.2. Referenced Docu

10、ments2.1 ASTM Standards:2E1325 Terminology Relating to Design of ExperimentsE2475 Guide for Process Understanding Related to Pharmaceutical Manufacture and ControlE2476 Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processesfor Pharmaceutical

11、Manufacture1 This practice is under the jurisdiction of ASTM Committee E55 on Manufacture of Pharmaceutical Products and is the direct responsibility of Subcommittee E55.01 onPAT System Management, Implementation and Practice.Current edition approved Nov. 1, 2006April 1, 2014. Published November 200

12、6April 2014. Originally approved in 2006. Last previous edition approved in 2006 as E2474 06. DOI: 10.1520/E2474-06.10.1520/E2474-14.2 For referencedASTM standards, visit theASTM website, www.astm.org, or contactASTM Customer Service at serviceastm.org. For Annual Book of ASTM Standardsvolume inform

13、ation, refer to the standards Document Summary page on the ASTM website.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 be technically possible to adequately dep

14、ict 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 Drive, PO Box C700, West Conshohocken, PA 19

15、428-2959. United States1E2629 Guide for Verification of Process Analytical Technology (PAT) Enabled Control SystemsE2587 Practice for Use of Control Charts in Statistical Process Control2.2 ReferencedFDA Standards:3FDA Guidance for Industry:Industry PATA Framework for Innovative Pharmaceutical Devel

16、opment, Manufacturing, andQuality Assurance, September 2004ICH Guidance:FDA Guidance for Process Validation ICH Q8 Pharmaceutical Development, Step 4 Document, November2005General Principles and Practices, January 2011ICH Guidance: ICH Q9 Quality Risk Management, Step 4 Document, November 200532.3 I

17、CH Guidance Standards:4ICH Q8 Pharmaceutical Development, Step 4 Document, August 2009ICH Q9 Quality Risk Management, Step 4 Document, November 20053. PAT Process Design Practices3.1 Desired StateIn the desired state of a process, all sources of variation are defined and controlled, and end product

18、variationis minimal. That implies that critical product attributes are controlled to target for all individual units of a product. As a result,processes are capable of consistently supplying, unit to unit and batch to batch, the desired quality.Philosophy and PrinciplesPHILOSOPHY AND PRINCIPLES3.2 P

19、ractice #1: Risk Assessment and MitigationProducts and manufacturing processes should be designed to minimizevariation. Therefore, process design is a means to mitigate the risk of having product units with varying quality. The process designrequires the use of formal risk evaluation methodologies a

20、nd mitigation assessments. See also Guide E2476, ICH Q9, and FDAGuidance for Industry for additional guidance.3.3 Practice #2: Continuous Improvement:3.3.1 Process design starts with the identification of first design options that reflect the desired process state and the desiredproduct attributes.

21、See also FDA Guidance for Process Validation and ICH Q8 for additional guidance.3.3.2 Evaluation of the first and all following design options should follow an iterative process of design improvement.3.3.3 Design improvement is continued post-launch (continuous improvement) to support management of

22、process qualitythroughout the product lifecycle.3.3.4 The iterative approach to continuous process design improvement includes:3.3.4.1 Initiation of the design process based on information about product structure, composition, desired quality attributes, andso forth,3.3.4.2 Definition of initial des

23、ign concepts based on institutional knowledge, intuition, experience, first principles, and so forth,3.3.4.3 Generation of design options,3.3.4.4 Identification of feasible design options from development studies,3.3.4.5 Detailed process development, and3.3.4.6 Design review and learning from experi

24、ence from development or implementation, or both,Design review and learning from experience from development or implementation, or both, where quality risk managementprinciples and methodology are applied on each step, and information and learning is fed-back and fed-forward between all steps.3.4 Pr

25、actice #3: Process Fitness for Purpose:3.4.1 The evaluation of process design options uses risk assessment to establish a process that will consistently deliver thedesired outputs. See also Guide E2476, ICH Q9, FDA Guidance for Industry, and FDA Guidance for Process Validation foradditional guidance

26、.3.4.2 Process fitness should be established regarding:3.4.2.1 Product characteristics, product quality definition.3.4.2.2 Process characteristics, for example, unit operation quality.3.4.2.3 Process systems (for example, control system, measurement system).3.4.2.4 System components (for example, de

27、sign elements, modules, interfaces).3.4.2.5 Commercial fitness for purpose.3.5 Practice #4: Intrinsic Performance Assessment:3.5.1 Processes should be designed with intrinsic process assessments and control systems that are integral components of themanufacturing operations. This approach is fundame

28、ntally different from conventional design approaches that rely on separationof process from process output assessment, for example, by sampling, averaging, and off-line testing.3.5.2 This has the following implications for process design:3 Available from Food and Drug Administration (FDA), 5600 Fish

29、ers Ln., Rockville, MD 20857,10903 New Hampshire Ave., Silver Spring, MD 20993-0002,http:/www.fda.gov.4 Available from International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH Secretariat, c/oIFPMA, 15 ch. Louis-Dunant, P.O. Box

30、 195, 1211 Geneva 20, Switzerland, http:/www.ich.org.E2474 1423.5.2.1 Process steps (unit operations) are evaluated as connected operations, because outputs are inputs for subsequent steps.3.5.2.2 Measurements are focused on assessment(s) of critical quality attributes and/or factors or factors, or

31、both, associatedwith process condition rather than on documenting compliance.3.5.2.3 Measurements are discriminating (to account for the multivariate process nature), rather than averaging (becauseinformation is lost through averaging of data).3.5.2.4 Process performance-based optimization reduces t

32、otal variability (that is, input material, process, and analyticalvariability).3.5.2.5 Process measurements and controls are designed in.3.6 Practice #5: Manufacturing Strategy:3.6.1 There is a mutual relationship between the development of the manufacturing process and the risk mitigation strategy

33、fora given product, as the process is designed to deliver the product with desired attributes. See also Guide E2476, ICH Q9, FDAGuidance for Industry, and FDA Guidance for Process Validation for additional guidance.3.6.2 The design of the manufacturing process should form part of the risk mitigation

34、 strategy for a product. For example, therisks to the patient for a low dose/high potency drug will be different from a high dose drug, and therefore the manufacturingprocess designed in each case will reflect those differences.3.6.3 This has the following implications:3.6.3.1 To achieve unit-to-uni

35、t consistent quality, all material transitions (that is, chemical, physical, or mechanicaltransformations) have to be the same for all units of the product.3.6.3.2 Since process scale is a risk factor, process design should incorporate strategies to mitigate that risk through scaleableor scale-indep

36、endent manufacturing operations. For example, continuous processing technology is an approach to achievescale-independency. Where a process is scaled-up, product quality and process robustness can be assured by measuring thein-process material attributes and critical quality attributes, rather than

37、the machine parameters and using these to ensure endproduct quality.3.7 Practice #6: Data Collection and Formal Experimental DesignExperimental design tools (such as Design of Experiments(DoE) are used to ensure that data is collected throughout the design space in a manner that minimizes the necess

38、ary experimentalload and maximizes the information extracted about the process. Several cycles of such experimental work, each focusing moreclosely on the likely operating area, may be required to establish initial production process conditions. See also TerminologyE1325, Practice E2587, and FDA Gui

39、dance for Process Validation for additional guidance.MethodologyMETHODOLOGY3.8 Practice #7: Multivariate ToolsMultivariate tools are used to generate predicted values for the critical quality attributes,to generate values for factors directly or indirectly linked to process condition, or to generate

40、 qualitative information aboutmaterial. Multivariate tools can be used to understand and control process and product variability.3.9 Practice #8: Process AnalyzersIn-, on-, at-line process analytical tools are used for rapid measurements which can be usedto evaluate material attributes and process p

41、erformance and enable process control.3.10 Practice #9: Process Control:3.10.1 The combination of univariate and multivariate data derived in real-time from the process is used to evaluate effects onprocess critical quality attributes. These in turn are used to evaluate the necessary process paramet

42、ric settings to ensure both thedesired process trajectory and end product quality or desired state. This feedback loop, and any associated feed-forward andfeed-back of data from stage-to-stage, comprises the process control. See also Practice E2587 and Guides E2475 and E2629 foradditional guidance.3

43、.10.2 Process endpoints are based on achieving desired critical quality attributes.E2474 1434. Keywords4.1 design space; desired state; manufacturing; PAT ; PAT; pharmaceutical process design; process analytical technology;process understanding; quality risk managementASTM International takes no pos

44、ition respecting the validity of any patent rights asserted in connection with any item mentionedin this standard. Users of this standard are expressly advised that determination of the validity of any such patent rights, and the riskof infringement of such rights, are entirely their own responsibil

45、ity.This standard is subject to revision at any time by the responsible technical committee and must be reviewed every five years andif not revised, either reapproved or withdrawn.Your comments are invited either for revision of this standard or for additional standardsand should be addressed to AST

46、M International Headquarters. Your comments will receive careful consideration at a meeting of theresponsible technical committee, which you may attend. If you feel that your comments have not received a fair hearing you shouldmake your views known to the ASTM Committee on Standards, at the address

47、shown below.This standard is copyrighted by ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959,United States. Individual reprints (single or multiple copies) of this standard may be obtained by contacting ASTM at the aboveaddress or at 610-832-9585 (phone), 610-832-9555 (fax), or serviceastm.org (e-mail); or through the ASTM website(www.astm.org). Permission rights to photocopy the standard may also be secured from the ASTM website (www.astm.org/COPYRIGHT/).E2474 144