1、Designation: E2629 11Standard Guide forVerification of Process Analytical Technology (PAT) EnabledControl Systems1This standard is issued under the fixed designation E2629; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year o
2、f 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 the verification of process analyti-cal technology (PAT) enabled control systems using a scienc
3、e-and risk-based approach. It establishes principles for determin-ing the scope and extent of verification activities necessary toensure that the PAT-enabled control system is fit for purpose,properly implemented, and functions as expected.1.2 In this guide, a PAT-enabled control system is consid-er
4、ed to be the system that adjusts the manufacturing processusing timely measurements (that is, during processing) ofattributes of raw and in-process materials to determine re-sponses that assure the process remains within specifiedboundaries and minimizes variability in the output material.The overal
5、l aim of the PAT-enabled control system is to ensureproduct quality. The PAT-enabled control system of a manu-facturing process provides the capability to determine thecurrent status of the process and drive the process to ensure theoutput material has the desired quality characteristics. Thecontrol
6、 system should be able to respond to process variationsin a timely manner, providing corrections that ensure that theprocess follows the desired process trajectory to reach thedesired outcome. PAT-enabled control systems may use pro-cess models based on first principles understanding or empiri-cal m
7、odels derived from experimental investigations or both.In addition to automated controls, a PAT-enabled controlsystem may include components where there is manual inter-vention.1.3 Principles described in this guide may be appliedregardless of the complexity or scale of the PAT-enabledcontrol system
8、 or whether applied to batch or continuousprocessing, or both.1.4 The principles described in this guide are applicable toa PAT-enabled control system and also to its componentsubsystems. This guide does not cover the requirements forcontinuous quality verification of the overall process, whichare c
9、overed in Guide E2537.1.5 For information on science- and risk-based approachesin the pharmaceutical industry, reference should be made toICH Q8(R2), ICH Q9, and ICH Q10. For guidance on PATsystems in the pharmaceutical industry, reference should bemade to FDA Guidance for IndustryPAT and FDA Guidan
10、cefor IndustryProcess Validation.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 practices and determine the applica-bility of regulatory limitat
11、ions prior to use.2. Referenced Documents2.1 ASTM Standards:2E122 Practice for Calculating Sample Size to Estimate,With Specified Precision, the Average for a Characteristicof a Lot or ProcessE2363 Terminology Relating to Process Analytical Tech-nology in the Pharmaceutical IndustryE2476 Guide for R
12、isk Assessment and Risk Control as itImpacts the Design, Development, and Operation of PATProcesses for Pharmaceutical ManufactureE2500 Guide for Specification, Design, and Verification ofPharmaceutical and Biopharmaceutical ManufacturingSystems and EquipmentE2537 Guide for Application of Continuous
13、 Quality Verifi-cation to Pharmaceutical and Biopharmaceutical Manufac-turing2.2 Other Standards:ICH Q2(R1) Validation of Analytical Procedures: Text andMethodology3ICH Q8(R2) Pharmaceutical Development3ICH Q9 Risk Management31This guide is under the jurisdiction of ASTM Committee E55 on Manufacture
14、of Pharmaceutical Products and is the direct responsibility of Subcommittee E55.02on PAT System Implementation and Practice.Current edition approved April 15, 2011. Published May 2011. DOI: 10.1520/E2629-11.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer
15、 Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.3Available from International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use (ICH), ICHSecretariat
16、, c/o IFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20,Switzerland, http:/www.ich.org.1Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959, United States.ICH Q10 Pharmaceutical Quality System3FDA Guidance for IndustryPAT A Framework for Inno-vat
17、ive Pharmaceutical Development, Manufacturing andQuality Assurance4FDA Guidance for IndustryProcess Validation GeneralPrinciples and Practices43. Terminology3.1 DefinitionsSee also Terminology E2363 for other PATterms.3.1.1 attribute, ncharacteristic or inherent quality or fea-ture. (E2363)3.1.2 con
18、trol model, nprocedure or mathematical expres-sion (algorithm) that uses the outputs of the process modelcombined with any other data inputs required to calculatevalues for the critical control parameters for the process; it usesinput data from the process to generate an actionable commandor command
19、s that are issued to the control system.3.1.2.1 DiscussionThe control model may define whatactions to take when specific attribute values are detected. Thecontrol model may be complex or simple, for example, it maybe predictive, as in the case of model-based control (MBC) inwhich it is desired to ma
20、nage the operation of the process alonga particular trajectory; it may be a single proportional integralderivative (PID) loop controller; or it may be anything inbetween.3.1.3 control system, nsystem that responds to inputssignals from the process, its associated equipment, otherprogrammable systems
21、 or an operator or both, and generatesoutput signals causing the process and its associated equipmentto operate in the desired manner.(Perrys Handbook of Chemical Engineering5)3.1.4 measurement system, nsystem of sensors, instru-ments, and/or analyzers that collects signals generated bypassive or ac
22、tive interaction with process material or processequipment and converts those signals into data.3.1.5 parameter, nmeasureable or quantifiable character-istic of a system or process. (E2363)3.1.6 process model, nmathematical expression (algo-rithm) that uses data from the measurement system(s) (input
23、sto the process model) to calculate the value of one or more ofthe process material attributes (outputs from the processmodel) at the time the measurement was taken.3.1.6.1 DiscussionThe process model typically will haveto handle sets of orthogonal or nonorthogonal attributes. Themathematical algori
24、thm will ideally represent first-principleunderstanding of the process being modelled. However, whensufficient first-principles understanding is unavailable, an em-pirical model may also be used.3.2 Acronyms:3.2.1 CCPCritical control parameter3.2.2 CPPCritical process parameter3.2.3 CQACritical qual
25、ity attribute3.2.4 CQVContinuous quality verification3.2.5 FDAFood and Drug Administration3.2.6 ICHInternational Conference on Harmonization ofTechnical Requirements for Registration of Pharmaceuticalsfor Human Use3.2.7 ISAInternational Society of Automation3.2.8 LODLimit of detection3.2.9 MBCModel-
26、based control3.2.10 MVAMultivariate analysis3.2.11 PATProcess analytical technology3.2.12 PIDProportional integral derivative3.2.13 PPProcess parameter3.2.14 QAQuality attribute4. Summary of Practice4.1 To aid reader understanding, a diagram of the data flowsin a PAT-enabled control system is shown
27、in Fig. 1.4.2 Fig. 2 shows how the quality attributes (QAs), noncriti-cal as well as critical, are fed into the control model via theprocess model. Each process has process parameters (PPs).Based on process understanding, some PPs are held static andothers are subject to dynamic adjustment. Some of
28、the PPsdirectly or indirectly impact critical quality attributes (CQAs)and these PPs are called critical process parameters (CPPs).When the CPPs (which may be fixed or adjustable) aredynamically adjusted as a result of information generated bythe process and control models, they are called critical
29、controlparameters (CCPs). Revised CCP settings are transmitted inreal time to the manufacturing equipment where they changethe conditions of manufacture for the product.5. Significance and Use5.1 This guide supports the principles of Guide E2500 andextends these principles to the verification of PAT
30、-enabledcontrol systems.5.2 This guide clarifies what is important for verification ofPAT-enabled control systems. Such systems are often complexand require multidisciplinary and cross-functional teams toachieve optimum results. This guide provides a common basisfor understanding requirements for al
31、l involved disciplinessuch as control engineering, development, manufacturing, andprocess validation.6. Principles To Be Considered for Verification of PAT-Enabled Control Systems6.1 Verification should be science and risk based. Qualityrisk management should drive the verification process. Practice
32、E2476 provides additional guidance on risk assessments forPAT systems.6.2 Verification should use the most efficient and effectivemethod available to achieve the specified results, choosingfrom, for example, simulation, testing, first principle modeling,or other approaches or combinations of these.6
33、.3 Verification should cover the range over which themanufacturing process is intended to operate. This will includeall those ranges in which it is necessary that the control systemwill be able to bring the process back into its intendedoperating range.4Available from Office of Training and Communic
34、ation, Division of DrugInformation, HFD-240, Center for Drug Evaluation and Research, Food and DrugAdministration, 5600 Fishers Lane, Rockville, MD 20857, http:/www.fda.gov.5Perrys Handbook of Chemical Engineering, see BPCSBasic Process ControlSystem, McGraw Hill, 2007.E2629 1126.4 Verification of t
35、he control systems should always in-clude verification of the system as a whole. It may also includeverification of individual system components.6.5 The verification process should confirm that relevantquality attributes will be controlled concurrently.6.6 Verification should ensure that the control
36、 system isstable throughout the range of operation.6.7 Each component of the PAT-enabled control systemshould generate outputs with sufficient frequency, accuracy,and precision to make the necessary level of process controlpractical, meaningful and value-added.6.8 Process and control models and the
37、control systemshould be verified as applicable to the scale of manufacture atwhich they will be used.6.9 All stages of the verification should be appropriatelydemonstrated and clearly documented in accordance withrelevant requirements.7. Verification Process for PAT-Enabled Control Systems7.1 The ve
38、rification of PAT-enabled control systems shouldbe science and risk based and normally consists of three stages,as follows. These stages are then expanded further in thissection:FIG. 1 Data Flows for a PAT-Enabled Control SystemFIG. 2 Relationship between Quality Attributes and the Control SystemE26
39、29 1137.1.1 Verification planning,7.1.2 Testing and confirmation, and7.1.3 Continued verification.7.2 The extent of verification of PAT-enabled control sys-tems and the detail of documentation will vary on a case-by-case basis. Prior knowledge of the process and experience ofthe PAT control system w
40、hen available should be consideredand appropriate risk assessment used to help quantify theextent of verification needed.7.3 Verification PlanningThe verification plan should de-scribe aspects such as the scope, strategy, stakeholders, andboundaries of the system undergoing verification and if there
41、 isa need for process data to be communicated to subsequent unitprocesses (for example, feed forward). The verification planincludes three important elements: technical assessment (see7.3.1), sensitivity analysis (see 7.3.2), and acceptance criteria(see 7.3.3).7.3.1 Technical Assessment:7.3.1.1 Perf
42、orm a technical assessment of the process con-trol strategy and its capability to deliver the desired final orintermediate product attributes. The purpose of this assessmentis to:(1) Ensure the link to product attributes is understood andclear,(2) Understand the ranges over which process parametersn
43、eed to be controlled, and(3) Ensure that the defined control strategy has beencorrectly implemented.7.3.1.2 The following are examples of factors that could beconsidered for inclusion in the technical assessment:(1) Meeting the final product attributes or CQAs;(2) Meeting the intermediate product at
44、tributes;(3) Establishing equipment and operational robustness,repeatability and reproducibility, and accuracy (including pro-cess equipment and measurement equipment);(4) Understanding feedback sensitivity and response speed(damping);(5) Understanding any external conditions affecting theprocess an
45、d operator interventions;(6) Variability in quality of the input material to thePAT-controlled process;(7) Level of understanding in the process and controlmodels;(8) Novelty and complexity of the overall PAT-enabledcontrol system. Systems that are copies of, use elements of, orare scale-ups of exis
46、ting control systems may require lesstesting for verification, provided data are available and theimpact of the novelty and complexity on the process can beestablished; and(9) Focus the verification testing steps on the elements ofthe PAT-enabled control system that have the potential toinduce the m
47、ost system variability (such as through a riskassessment process).7.3.1.3 An example might be if there was significant vari-ability in incoming materials. In this case, more extensivetesting of the PAT-enabled controls may be appropriate. Alter-natively, when there is a high degree of confidence in
48、theprocess capability of the upstream steps (for example, they arein a state of statistical process control), then less challengingtests may be appropriate.7.3.2 Sensitivity Analysis:7.3.2.1 Sensitivity of the process to the variation in theperformance of the components of the PAT-enabled controlsys
49、tem should be considered and analyzed where and whenappropriate. The actual performance of the PAT-enabled con-trol system should be analyzed in relation to these consider-ations.7.3.2.2 The PAT-enabled control system typically consistsof inputs, processing, and outputs in which the importance ofvariation in a single component is a function not only of themagnitude of variation but also of the properties of the overallcontrol system. As such, some components may have a greaterimpact (and, thus, potentially pose greater risk) than others.Components in
