1、Designation:E296814Standard Guide forApplication of Continuous Processing in the PharmaceuticalIndustry1This standard is issued under the fixed designation E2968;the number immediately following the designation indicates the year oforiginal adoption or,in the case of revision,the year of last revisi
2、on.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 introduces key concepts and principles toassist in the appropriate selection,development and operationof continuous process
3、ing technologies for the manufacture ofpharmaceutical products.1.2 Particular consideration is given to the development andapplication of the appropriate scientific understanding andengineering principles that differentiate continuous manufac-ture from traditional batch manufacturing.1.3 Most of the
4、 underlying concepts and principles(forexample,process dynamics and process control)outlined inthis guide can be applied in both Drug Substance(DS)andDrug Product(DP)processes.However it should be recognizedthat in Drug Substance production the emphasis may be moreon chemical behavior and dynamics i
5、n a fluid phase whereasfor drug product manufacture there may be a greater emphasison the physical behavior and dynamics in a solid/powderformat.1.4 This guide is also intended to apply in both the devel-opment of a new process,or the improvement/redesign of anexisting one.1.5 The values stated in S
6、I units are to be regarded asstandard.No other units of measurement are included in thisstandard.1.6 This standard does not purport to address all of thesafety concerns,if any,associated with its use.It is theresponsibility of the user of this standard to establish appro-priate safety and health pra
7、ctices and determine the applica-bility of regulatory limitations prior to use.2.Referenced Documents2.1 ASTM Standards:2E2363 Terminology Relating to Process Analytical Technol-ogy in the Pharmaceutical IndustryE2475 Guide for Process Understanding Related to Pharma-ceutical Manufacture and Control
8、E2537 Guide for Application of Continuous Quality Verifi-cation to Pharmaceutical and Biopharmaceutical Manu-facturingE2898 Guide for Risk-Based Validation of Analytical Meth-ods for PAT Applications2.2 FDA Documents:3FDA Guidance for Industry PAT A Framework for Innova-tive Pharmaceutical Developme
9、nt,Manufacturing,andQuality Assurance(2004)3.Terminology3.1 Definitions:3.1.1 For general definitions,refer to Terminology E2363and Guides E2537 and E2475.3.2 Definitions of Terms Specific to This Standard:3.2.1 back mixed processa process with a residence timedistribution(RTD)which is non zero and
10、potentially significantcompared to the mean residence time.3.2.1.1 DiscussionFor example,in an idealized fully backmixed process quantities of material will be mixed into a singlehomogeneous condition such that a rapid step change in theproperties of inlet material will not result in an equivalent s
11、tepchange in the properties of the output material but will bereflected in a more gradual change.The rate of this change willdepend on the equipment characteristics,residence volume,1This guide is under the jurisdiction of ASTM Committee E55 on Manufactureof Pharmaceutical Products and is the direct
12、 responsibility of Subcommittee E55.01on Process Understanding and PAT System Management,Implementation andPractice.Current edition approved Dec.1,2014.Published April 2015.DOI:10.1520/E2968-14.2For referenced ASTM standards,visit the ASTM website,www.astm.org,orcontact ASTM Customer Service at serv
13、iceastm.org.For Annual Book of ASTMStandards volume information,refer to the standards Document Summary page onthe ASTM website.3Available from Food and Drug Administration(FDA),10903 New HampshireAve.,Silver Spring,MD 20993-0002,http:/www.fda.gov.Copyright ASTM International,100 Barr Harbor Drive,P
14、O Box C700,West Conshohocken,PA 19428-2959.United States1 and the residence time distribution/degree of mixing.A fullyback mixed process may be considered and modeled as one ormore continuously stirred tank reactors(CSTR).3.2.2 controlled stateA process is in a controlled statewhen it is:(1)Under Pr
15、ocess Control,and(2)operatingnormally,such that the measured critical quality attributes ofthe product are within the defined acceptable range.3.2.3 dynamic process control systeman automated con-trol system which monitors the condition of the product or theprocess,or both,predicts or detects a chan
16、ge to the productquality away from a target condition(that is,Setpoint),andthen changes the process conditions during processing in orderto maintain the product quality at the target value(or within thespecified range of target values).Depending on the dynamicsof the process the corrections may be applied immediately as astep change or as a time dependent function(for example,aramp or exponential function).Such real time control systemsmay include for example:3.2.3.1 feedback controla control st
