ASTM E2968-2014 Standard Guide for Application of Continuous Processing in the Pharmaceutical Industry《制药工业连续工艺应用的标准指南》.pdf

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1、Designation: E2968 14Standard 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 r

2、evision. 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 continu

3、ous processing 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

4、Most of the 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 beha

5、vior and dynamics in 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 Th

6、e values stated in SI 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-pria

7、te safety and health practices 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-ceutica

8、l Manufacture and ControlE2537 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

9、 Pharmaceutical Development, 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 timedistribut

10、ion (RTD) which is non zero and 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 w

11、ill not result in an equivalent stepchange 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 Pharma

12、ceutical Products and is the direct 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.

13、org, orcontact ASTM Customer Service at serviceastm.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.C

14、opyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States1and 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 stat

15、eA process is in a controlled statewhen it is: (1) Under Process 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

16、of the product or theprocess, or both, predicts or detects a change 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 val

17、ues). 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 strategy which is in-tended t

18、o eliminate drift or deviation in a specific productattribute away from the target (Setpoint) by means of:(1) Measuring the attributes of material leaving a processoperation,(2) Comparing the measured values with target (Setpoint)values for the attributes, and(3) Using a process model containing app

19、ropriate processdynamics in order to calculate revised Setpoint values for therelevant process conditions.3.2.3.2 feed forward controla control strategy which mea-sures either: (1) specific critical attributes of materials as theyenter a specific process, or (2) other upstream factors (forexample, f

20、low rates, temperature, etc.), and uses this informa-tion in combination with an appropriate process model toadjust the Setpoint of the process conditions in order to reducethe impact of the upstream change on the quality of thematerial leaving the process step.3.2.3.3 multivariate model based contr

21、olmeasurements ofone or more product attributes and process conditions are usedin a model of the process to determine the process conditionsrequired to achieve the correct product quality.3.2.4 continuous processa process where, during normaloperation, raw materials are continuously fed into the sys

22、tem atthe same time as acceptable product is continuously removedfrom the system.3.2.4.1 Discussion(1) In a continuous process, the degreeof transformation of any specific quantity of material from aninitial condition into the subsequent condition is a function ofthe process parameters applied and e

23、ither:(a) The position of the material as it flows through theprocess,(b) The duration that the material has been within theprocess, or(c) A combination of both (a) and (b).(2) A continuous process may be operated to transform apre-defined quantity of material into a pre-defined physicalquantity of

24、product which is then subjected to a dispositiondecision. The size of the resulting lot is predefined by theamount of starting material (with the option to divert certainamount of material taken from online control), and this iscomparable to conventional discrete or batch manufacturingoperations.(3)

25、 Alternatively a continuous process may be operatedwith an infiniterun-time, in which quantities of product aredefined during the operation of the process in a flexible way,based on principles of science and risk (for example, as anyentity produced in a certain time, or containing a certain lotof a

26、starting material), and subjected to a dispositiondecision.(4) A process consisting of a series of interconnected unitoperations or transformations can be considered to becontinuous even if it also contains transformations of definedquantities of material which, when viewed at a particularscale of s

27、crutiny or level of detail, might be considered to becomposed of a sequence of individual discrete events.(5) During periods of startup, shutdown or processing ofsmall quantities of material, or both (for example, fordevelopment/experimental or clinical studies), it is possiblethat not all unit oper

28、ations within a continuous productionline will be in normal or steady state conditions at the sametime. For example: the first unit operation could already beshut down while the material is processed further in subse-quent unit operations. This condition should not automati-cally invalidate the defi

29、nition of the process as representativeof normal continuous operation; however care must be takento understand the impact of this mode of operation onproduct quality.3.2.5 normal operationbehavior of the process which canbe expected or predicted, or both, based on an understanding ofthe process. Unf

30、orced variability in the process or productwhich can be expected, predicted and characterized statisticallyor predictable variability, or both, which is forced by anexternal stimulation may be considered as normal operation.3.2.6 plug flow processa process with a residence timedistribution (RTD) whi

31、ch approaches zero.3.2.6.1 DiscussionFor example, in an idealized plug flowprocess a step change of the quantity, quality, or identity of theinput materials is, after a defined time, directly and equallyreflected by a step change in the output.3.2.7 process control setpointa process control Setpoint

32、 isa specific target value for a process parameter or productattribute which is used by a dynamic control system. Thedynamic process control system will determine what correctivecontrol action to apply in order to try to bring the specificparameter or attribute closer to the Setpoint value.3.2.7.1 D

33、iscussionA Setpoint may be specified togetherwith upper and lower target values such that corrective controlaction may be reduced once the value is within the target range.A target range specified by upper and lower target values onlyhas no explicit specified Setpoint value and hence correctiveproce

34、ss control action is often suspended once the parameter orattribute is within the target range.E2968 1423.2.8 process disturbancean un-requested and un-controlled change in a measured or unmeasured parameterwhich has the effect of changing the process conditions orproduct quality (that is, a short-t

35、erm transient condition).3.2.9 process time constanta measure of the rate at whichthe process can change from steady state operation at onecondition to steady state operation at another condition.3.2.10 quasi-steady stateconditions where some indi-vidual process parameters are consistently varying i

36、n time butwith a set pattern of variation (for example, compression forcein a tablet press). In this guide, quasi-steady state conditionsare considered equivalent to steady state conditions.3.2.11 recipe-based process control systeman automatedcontrol system which maintains specific process paramete

37、rs atpre-specified fixed values (that is, according to a predeterminedrecipe) without adjustment of process parameters based oneither measurement and feedback of product quality attributesor measurement and feed-forward of input material qualityattributes or upstream conditions.3.2.12 steady stateco

38、nsistent operation over a period oftime where all relevant process parameters and product quali-ties are not subject to variation outside of a defined range ofvalues.3.2.12.1 Discussion(1) A steady state condition by itselfdoes not directly imply that the defined targets are correct withrespect to a

39、chieving acceptable product quality.(2) Steady state implies only that the process is not subjectto significant variance with respect to time.(3) Achieving or maintaining acceptable product qualitymay require an adjustment of target values and hence atransition between two steady state conditions.3.

40、2.13 transient conditionsconditions where the process isdisturbed from steady state or is in transition between onesteady state condition to another (that is, the process conditionsor product quality are not in steady state or quasi-steady state).Transients may be due to either external disturbances

41、 orintentional changes in the selected operating conditions.3.2.14 residence timethe time that process material is in aspecific process environment/vessel/unit operation.3.2.15 residence time distribution (RTD)a measure of therange of residence times experienced by material passingthrough a specific

42、 process environment/vessel/unit operation.Hence in a process where the RTD is not zero a quantity ofmaterial which all enters the process at the same time mayleave at different times and hence is not all resident in theprocess for the same time. The RTD can be used to characterizethis difference in

43、 residence time and hence understand howchanges to the process or materials will propagate through theprocess.3.2.16 Under Process Controlbehavior of the processwhen it responds in a predictable way to the actions of thecontrol system and is able to achieve and maintain operation ata specific proces

44、s control Setpoint or Setpoints.3.2.16.1 DiscussionPhysical or chemical limitations mayprevent a process from responding to the process controlsystem (for example, control valve already wide open) andhence under such conditions the process might be considered tobe not fully Under Process Control. In

45、 such a situation (forexample, transient conditions, start up and shutdown), the plantmay be considered to be Under Process Control if the ProcessControl Setpoints are managed such that the process is notconstantly operated at its limits.4. Significance and Use4.1 Although some continuous processing

46、 is used in thepharmaceutical industry (for example, purified waterproduction, inherently continuous individual unit operationssuch as dry granulation and compression), these operations aregenerally operated in isolation and do not deliver the potentialbenefits of an integrated continuous manufactur

47、ing operation.The FDA Guidance for Industry PAT document specificallyidentifies that the introduction of continuous processing may beone of the outcomes from the adoption of a science-basedapproach to process design.4.2 This guide does not:4.2.1 Suggest that continuous production is suitable for the

48、manufacture of all pharmaceutical products.4.2.2 Provide guidance on issues related to the safe opera-tion of a continuous process or continuous processing equip-ment. It is the responsibility of the user of this standard toestablish appropriate health and safety practices and determinethe applicabi

49、lity of regulatory limitations prior to use.4.2.3 Recommend particular designs or operating regimesfor continuous manufacturing.4.3 Appendix X1 includes a table comparing the character-istics of continuous and discrete or batch processes.5. Operation of Continuous Manufacturing Systems5.1 Operational Considerations:5.1.1 In order to successfully introduce continuousprocessing, due consideration should first be given to theoverall operation and support of the system during the lifecycleof the plant and product, for example:5.1.1.1 Considerations for process