1、Designation: E2898 13Standard Guide forRisk-Based Validation of Analytical Methods for PATApplications1This standard is issued under the fixed designation E2898; the number immediately following the designation indicates the year oforiginal adoption or, in the case of revision, the year of last revi
2、sion. 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 provides an overview to the risk-basedvalidation of process analytical methods under a processanalytical technology
3、(PAT) paradigm for pharmaceuticals andbiopharmaceuticals and as such includes guidance on assessingrisk to product quality from inappropriate method validation.1.2 This guide builds on existing standards on the topic ofvalidation concentrating on applying such standards to analyti-cal methods for on
4、-line analysis. In particular, it addresses thevalidation of at-line, on-line, or in-line PAT measurements andcovers both API and Drug Product (DP) measurements.1.3 The definitions of International Conference on Harmo-nization (ICH) validation parameters (such as specificity,precision, repeatability
5、, etc.) apply; however, the method ofdemonstrating the validation parameters may vary from thatdescribed in ICH and is discussed.1.4 As consistent with the U.S. Food and Drug Administra-tion (FDA) process validation guidance, this document alsobriefly covers ongoing assurance that the method remains
6、 in avalidated state during routine use.1.5 Equipment and instrument qualification are out of thescope of this guide but will be referenced as inputs tovalidation of analytical methods for PAT applications.1.6 The validation of multivariate prediction models is outof scope but will be referenced as
7、inputs to validation ofanalytical methods for PAT applications.1.7 Microbiological methods are out of scope.1.8 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
8、and health practices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2D3764 Practice for Validation of the Performance of ProcessStream Analyzer SystemsD6122 Practice for Validation of the Performance of Multi-variate Online, At-Line,
9、 and Laboratory Infrared Spectro-photometer Based Analyzer SystemsE1655 Practices for Infrared Multivariate QuantitativeAnalysisE1790 Practice for Near Infrared Qualitative AnalysisE2056 Practice for Qualifying Spectrometers and Spectro-photometers for Use in Multivariate Analyses, CalibratedUsing S
10、urrogate MixturesE2476 Guide for Risk 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 EquipmentE2617 P
11、ractice for Validation of Empirically Derived Mul-tivariate CalibrationsE2629 Guide for Verification of Process Analytical Technol-ogy (PAT) Enabled Control Systems2.2 ICH Standards:3Q2(R1) Guidance on Validation of Analytical Procedures:Text and MethodologyQ7 Good Manufacturing Practice Guide for A
12、ctive Pharma-ceutical IngredientsQ9 Quality RiskICH Quality Implementation Working Group Points toConsider (R2) ICH-Endorsed Guide for ICH Q8/Q9/Q10Implementation dated 6 December 20111This guide is under the jurisdiction of ASTM Committee E55 on Manufactureof Pharmaceutical Products and is the dire
13、ct responsibility of Subcommittee E55.01on PAT System Management, Implementation and Practice.Current edition approved Nov. 1, 2013. Published December 2013. DOI:10.1520/E2898-13.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org.
14、 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, c/o IFPMA, 15 ch. Louis-Du
15、nant, P.O. Box 195, 1211 Geneva 20,Switzerland, http:/www.ich.org.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States12.3 Other Standards:ASME BPE2009 BioProcessing Equipment Standard4FDA Guidance for Industry Process Validation: GeneralP
16、rinciples and Practices5ISO 14971 Medical DevicesApplication of Risk Manage-ment to Medical Devices6ISO 15839 Water QualityOn-line Sensors/AnalysingEquipment for WaterSpecifications and PerformanceTests6ISO/IEC Guide 51 Safety AspectsGuidelines for TheirInclusion in Standards6USP Acoustic Emission 7
17、3. Terminology3.1 Definitions:3.1.1 acceptance criteria, ncriteria that a system or com-ponent shall satisfy to be accepted by a user or other authorizedentity.3.1.2 at-line measurements, nmeasurement in which thesample is removed, isolated from, and analyzed in closeproximity to the process stream.
18、3.1.3 categorical data, nmeasurement output that hasdistinct and predetermined output options (for example, pass/fail, 1/0, red/yellow/green, and on/off) and is typically nonnu-meric in nature.3.1.4 continuous data, nnumerical information or outputhaving any values within a given range.3.1.5 discret
19、e data, nnumerical information for which alimited set of values are allowed within a given range.3.1.6 in-line measurements, nmeasurement in which thesample is not removed from the process stream, which may beeither invasive or noninvasive.3.1.7 off-line measurements, nmeasurement in which thesample
20、 is removed, isolated from, and analyzed in an arearemote from the manufacturing process.3.1.8 on-line measurements, nmeasurement in which thesample is diverted from the manufacturing process and may bereturned to the process stream.3.1.9 process analytical technology (PAT) application,nthe installa
21、tion/utilization of a measurement system, fordesigning, analyzing, and controlling manufacturing throughtimely measurements (that is, during processing) of criticalquality and performance attributes of raw and in-processmaterials and processes, with the goal of ensuring final productquality.3.1.10 q
22、ualification, naction of proving and documentingthat equipment or ancillary systems are properly installed,work correctly, and are fit for their intended purpose.3.1.10.1 DiscussionQualification is part of validation, butthe individual qualification steps alone do not constituteprocess validation. F
23、DA/ICH Q7A3.1.11 qualitative, adjtype of method whereby a classifi-cation (such as pass/fail) is generated for the attribute orparameter measured.3.1.11.1 DiscussionThe method output may be descrip-tive rather than numerical.3.1.12 quantitative, adjtype of method whereby a numeri-cal value or result
24、 is generated for the attribute or parametermeasured.3.1.13 reference sample, nsubstance of established qualityused as a reference standard for the method validation.3.1.13.1 DiscussionThe reference sample may be a refer-ence standard (primary or secondary) and may be commercialor development materi
25、al for which the value of its relevantparameter or attribute has been established. E16553.1.14 risk, ncombination of the probability of occurrenceof harm and the severity of that harm. ISO/IEC Guide 51,ICH Q93.1.15 risk analysis, nthe estimation of the risk associatedwith the identified hazard. ICH
26、Q93.1.16 risk assessment, na systematic process of organiz-ing information to support a risk decision to be made within arisk management process. Consisting of identification hazardsand the analysis and evaluation of risks associated withexposure to those hazards. ICH Q9, ISO 149713.1.17 verificatio
27、n, nsystematic approach to demonstratethat manufacturing systems, acting singly or in combination,are fit for intended use, have been properly installed, and areoperating correctly.3.1.17.1 DiscussionThis is an umbrella term that encom-passes all types of approaches to assuring systems are fit forus
28、e such as qualification, commissioning and qualification,verification, system validation, or other validation. There isrecognition that the word verification is used in conjunctionwith validating process systems and that the word validation isused for analytical methods.3.2 Acronyms:3.2.1 ICHInterna
29、tional Conference on Harmonization ofTechnical Requirements for Registration of Pharmaceuticalsfor Human Use3.2.2 LODlimit of detection3.2.3 LOQlimit of quantification3.2.4 PATprocess analytical technology3.2.5 RTRT real time release testing3.2.6 DOEdesign of experiments4. Significance and Use4.1 Th
30、is guide supports the principles of Guide E2500 andextends these principles to validation of analytical methods forPAT applications. The ongoing process of method validation isgraphically represented in Fig. 1, which shows the life cycle ofthe validation of analytical methods for PAT applications.4A
31、vailable from American Society of Mechanical Engineers (ASME), ASMEInternational Headquarters, Two Park Ave., New York, NY 10016-5990, http:/www.asme.org.5Available from Food and Drug Administration (FDA), 10903 New HampshireAve., Silver Spring, MD 20993-0002, http:/www.fda.gov.6Available from Inter
32、national Organization for Standardization (ISO), 1, ch. dela Voie-Creuse, CP 56, CH-1211 Geneva 20, Switzerland, http:/www.iso.org.7Available from U.S. Pharmacopeia (USP), 12601 Twinbrook Pkwy., Rockville,MD 20852-1790, http:/www.usp.org.E2898 132Prerequisites for validation are the identification o
33、f the mea-surement requirements and development of a method to meetthose requirements.4.2 The method risk assessment also takes into account thestage in the product life cycle at which the measurements arebeing made and how the resulting data will be used. Theintegration of these considerations in t
34、he risk assessmentfacilitates the determination of the level of validation necessaryto ensure that the method is fit for purpose.4.3 Changes may occur during the product life cycle neces-sitating identification of changes to the measurement require-ments and method update and revalidation. Procedure
35、s shouldbe established to evaluate the continued suitability of theprocess analytical method.4.4 Additional informative examples can be found in Prac-tices D3764, D6122, E1655, E1790, E2056, and E2617 thataddress validation of methods and models. Other useful stan-dards include ASME BPE2009, ISO 149
36、71, ISO 15839, andUSP Acoustic Emission .5. Significance and Use5.1 Guidance documents for the validation of off-line,laboratory-based analytical methods frequently have require-ments that cannot be satisfied when applied to at-line, on-line,and in-line analytical methods for PAT applications. This
37、guideprovides guidance for the validation of at-line, on-line, orin-line analytical methods for PAT applications. Additionally,this guidance should be used in conjunction with Guide E2629when the PAT measurement is an integral part of a processcontrol system.5.2 The documentation required for valida
38、tion necessary todemonstrate that the analytical method is fit for purpose for theintended application at the stage of the product life cycle maybe determined by assessing the risks to quality. The documen-tation requirements for validation is determined by risk assess-ment and will depend on the in
39、tended use. For example, aprocess analytical method used during the development stagefor research purposes may have little or no requirements fordocumenting validation compared to a method that is beingused during the commercial manufacturing stage of the productlife cycle to support quality decisio
40、ns about the product.Similarly, the documentation requirements for validation of amethod that is being used during the manufacturing stage of theproduct life cycle to support the quality decision about theproduct may differ from those listed in ICH Q2(R1). Thesedifferences in documentation requireme
41、nts for validation willdepend on the level of criticality of the risk of the application.6. Procedure6.1 Inputs to Validation:6.1.1 There are a number of inputs to the risk assessmentprocess such as establishing the measurement need, determin-ing the intended purpose, establishing the measurementsys
42、tem, and developing the process analytical method.6.1.2 Defining the Intended Purpose of the ApplicationThis includes the design intent of the application and the levelof the risk associated with the use of the specific application.This is defined well in the ICH Quality ImplementationWorking Group
43、Points to Consider (R2). While the ICH guidediscusses levels of as they apply to modeling, the sameprinciple applies to the validation of analytical methods forPAT applications.6.1.2.1 Low-Impact ApplicationsThese are applicationsthat are typically used to support product and process devel-opment. T
44、his level would include activities of low risk such asgathering information on a process, method feasibility, processand formulation optimization, and other similar activities.6.1.2.2 Medium-Impact ApplicationsIncluded in this cat-egory are applications that assure quality, but are not measure-ment
45、of product quality. Examples of this may include manydevelopment measurements that are used to establish designspace and other in process measurements of CQAs that mayhave another release test for the attribute. Other examples mayinclude measurements that can be used for control, but the datais not
46、used specifically for release.FIG. 1 Life Cycle for the Validation of Analytical Method for PAT ApplicationsE2898 1336.1.2.3 High Impact ApplicationsThese are applicationsthat fall into the Real Time Release Testing (RTRT) category.This is the application that incorporates the measurement toinsure p
47、roduct quality by control of the process or is asubstitute for a specification test such as product assay or isreplacement for dissolution.6.1.3 Establishing the PAT Measurement SystemMeasurement system qualification is out of scope for this guideand is referenced here as an input. The extent of the
48、 hardwareand software qualifications is linked to the purpose of theapplication. Refer to Guide E2500,ASME BPE2009, and otherappropriate standards for process qualification and validationreference material. The qualification should be summarized,documented, and approved before initiating the validat
49、ionprocess.6.1.4 Planning and Development of the Analytical Methodfor PAT ApplicationsThe process analytical method develop-ment document should state the need and purpose of themethod to be developed as previously defined in 6.1.2 includ-ing sampling and instrument interface development consider-ations. Aspects that should be considered and documentedinclude:6.1.4.1 Attributes or parameters to be measured.6.1.4.2 Measurement modeat-line, on-line, or in-line.6.1.4.3 Choice of the instruments and the interface.6.1.4.4 Sampling requirement fo
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