1、Designation: E2898 13E2898 14Standard 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 l
2、ast 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 provides an overview to the risk-based validation of process analytical methods under a process analyticalte
3、chnology (PAT) paradigm for pharmaceuticals and biopharmaceuticals and as such includes guidance on assessing risk to productquality from inappropriate method validation.1.2 This guide builds on existing standards on the topic of validation concentrating on applying such standards to analyticalmetho
4、ds for on-line analysis. In particular, it addresses the validation of at-line, on-line, or in-line PAT measurements and coversboth API and Drug Product (DP) measurements.1.3 The definitions of International Conference on Harmonization (ICH) validation parameters (such as specificity, precision,repe
5、atability, etc.) apply; however, the method of demonstrating the validation parameters may vary from that described in ICHand is discussed.1.4 As consistent with the U.S. Food and Drug Administration (FDA) process validation guidance, this document also brieflycovers ongoing assurance that the metho
6、d remains in a validated state during routine use.1.5 Equipment and instrument qualification are out of the scope of this guide but will be referenced as inputs to validation ofanalytical methods for PAT applications.1.6 The validation of multivariate prediction models is out of scope but will be re
7、ferenced as inputs to validation of analyticalmethods for PAT applications.1.7 Microbiological methods are out of scope.1.8 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 appropr
8、iate safety and health practices and determine the applicability of regulatorylimitations prior to use.2. Referenced Documents2.1 ASTM Standards:2D3764 Practice for Validation of the Performance of Process Stream Analyzer SystemsD6122 Practice for Validation of the Performance of Multivariate Online
9、, At-Line, and Laboratory Infrared SpectrophotometerBased Analyzer SystemsE1655 Practices for Infrared Multivariate Quantitative AnalysisE1790 Practice for Near Infrared Qualitative AnalysisE2056 Practice for Qualifying Spectrometers and Spectrophotometers for Use in Multivariate Analyses, Calibrate
10、d UsingSurrogate MixturesE2476 Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processesfor Pharmaceutical ManufactureE2500 Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems andEquipm
11、ent1 This guide 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, 2013June 1, 2014. Published December 2013June 2014.
12、Originally approved in 2013. Last previous edition approved in 2013 as E2898 13. DOI: 10.1520/E2898-13.10.1520/E2898-14.2 For referencedASTM standards, visit theASTM website, www.astm.org, or contactASTM Customer Service at serviceastm.org. For Annual Book of ASTM Standardsvolume information, refer
13、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 depict all chang
14、es 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 19428-2959. Uni
15、ted States1E2617 Practice for Validation of Empirically Derived Multivariate CalibrationsE2629 Guide for Verification of Process Analytical Technology (PAT) Enabled Control SystemsE2656 Practice for Real-time Release Testing of Pharmaceutical Water for the Total Organic Carbon Attribute2.2 ICH Stand
16、ards:3Q2(R1) Guidance on Validation of Analytical Procedures: Text and MethodologyQ7 Good Manufacturing Practice Guide for Active Pharmaceutical IngredientsQ9 Quality RiskICH Quality Implementation Working Group Points to Consider (R2) ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementationdated 6 Decem
17、ber 20112.3 Other Standards:ASME BPE2009 BioProcessing Equipment Standard4FDA Guidance for Industry Process Validation: General Principles and Practices5ISO 14971 Medical DevicesApplication of Risk Management to Medical Devices6ISO 15839 Water QualityOn-line Sensors/Analysing Equipment for WaterSpec
18、ifications and Performance Tests6ISO/IEC Guide 51 Safety AspectsGuidelines for Their Inclusion in Standards6USP Acoustic Emission 73. Terminology3.1 Definitions:3.1.1 acceptance criteria, ncriteria that a system or component shall satisfy to be accepted by a user or other authorized entity.3.1.2 at-
19、line measurements, nmeasurement in which the sample is removed, isolated from, and analyzed in close proximityto the process stream.3.1.3 categorical data, nmeasurement output that has distinct and predetermined output options (for example, pass/fail, 1/0,red/yellow/green, and on/off) and is typical
20、ly nonnumeric in nature.3.1.4 continuous data, nnumerical information or output having any values within a given range.3.1.5 discrete data, nnumerical information for which a limited set of values are allowed within a given range.3.1.6 in-line measurements, nmeasurement in which the sample is not re
21、moved from the process stream, which may be eitherinvasive or noninvasive.3.1.7 off-line measurements, nmeasurement in which the sample is removed, isolated from, and analyzed in an area remotefrom the manufacturing process.3.1.8 on-line measurements, nmeasurement in which the sample is diverted fro
22、m the manufacturing process and may bereturned to the process stream.3.1.9 process analytical technology (PAT) application, nthe installation/utilization of a measurement system, for designing,analyzing, and controlling manufacturing through timely measurements (that is, during processing) of critic
23、al quality andperformance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality.3.1.10 qualification, naction of proving and documenting that equipment or ancillary systems are properly installed, workcorrectly, and are fit for their intended purpo
24、se.3.1.10.1 DiscussionQualification is part of validation, but the individual qualification steps alone do not constitute process validation. FDA/ICH Q7A3.1.11 qualitative, adjtype of method whereby a classification (such as pass/fail) is generated for the attribute or parametermeasured.3.1.11.1 Dis
25、cussionThe method output may be descriptive rather than numerical.3 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 195, 1211 Geneva 20, Switzerland, h
26、ttp:/www.ich.org.4 Available from American Society of Mechanical Engineers (ASME), ASME International Headquarters, Two Park Ave., New York, NY 10016-5990, http:/www.asme.org.5 Available from Food and Drug Administration (FDA), 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, http:/www.fda.go
27、v.6 Available from International Organization for Standardization (ISO), 1, ch. de la Voie-Creuse, CP 56, CH-1211 Geneva 20, Switzerland, http:/www.iso.org.7 Available from U.S. Pharmacopeia (USP), 12601 Twinbrook Pkwy., Rockville, MD 20852-1790, http:/www.usp.org.E2898 1423.1.12 quantitative, adjty
28、pe of method whereby a numerical value or result is generated for the attribute or parametermeasured.3.1.13 reference sample, nsubstance of established quality used as a reference standard for the method validation.3.1.13.1 DiscussionThe reference sample may be a reference standard (primary or secon
29、dary) and may be commercial or development material forwhich the value of its relevant parameter or attribute has been established. E16553.1.14 risk, ncombination of the probability of occurrence of harm and the severity of that harm. ISO/IEC Guide 51, ICHQ93.1.15 risk analysis, nthe estimation of t
30、he risk associated with the identified hazard. ICH Q93.1.16 risk assessment, na systematic process of organizing information to support a risk decision to be made within a riskmanagement process. Consisting of identification hazards and the analysis and evaluation of risks associated with exposure t
31、o thosehazards. ICH Q9, ISO 149713.1.17 verification, nsystematic approach to demonstrate that manufacturing systems, acting singly or in combination, are fitfor intended use, have been properly installed, and are operating correctly.3.1.17.1 DiscussionThis is an umbrella term that encompasses all t
32、ypes of approaches to assuring systems are fit for use such as qualification,commissioning and qualification, verification, system validation, or other validation. There is recognition that the word verificationis used in conjunction with validating process systems and that the word validation is us
33、ed for analytical methods.3.2 Acronyms:3.2.1 ICHInternational Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals forHuman Use3.2.2 LODlimit of detection3.2.3 LOQlimit of quantification3.2.4 PATprocess analytical technology3.2.5 RTRT real time release testing3.2
34、.6 DOEdesign of experiments4. Significance and Use4.1 This guide supports the principles of Guide E2500 and extends these principles to validation of analytical methods for PATapplications. The ongoing process of method validation is graphically represented in Fig. 1, which shows the life cycle of t
35、heFIG. 1 Life Cycle for the Validation of Analytical Method for PAT ApplicationsE2898 143validation of analytical methods for PAT applications. Prerequisites for validation are the identification of the measurementrequirements and development of a method to meet those requirements.4.2 The method ris
36、k assessment also takes into account the stage in the product life cycle at which the measurements are beingmade and how the resulting data will be used. The integration of these considerations in the risk assessment facilitates thedetermination of the level of validation necessary to ensure that th
37、e method is fit for purpose.4.3 Changes may occur during the product life cycle necessitating identification of changes to the measurement requirementsand method update and revalidation. Procedures should be established to evaluate the continued suitability of the process analyticalmethod.4.4 Additi
38、onal informative examples can be found in Practices D3764, D6122, E1655, E1790, E2056, E2617and, E2617andE2656 that address validation of methods and models. Other useful standards include ASME BPE2009, ISO 14971, ISO 15839,and USP Acoustic Emission .5. Significance and Use5.1 Guidance documents for
39、 the validation of off-line, laboratory-based analytical methods frequently have requirements thatcannot be satisfied when applied to at-line, on-line, and in-line analytical methods for PAT applications. This guide providesguidance for the validation of at-line, on-line, or in-line analytical metho
40、ds for PAT applications.Additionally, this guidance shouldbe used in conjunction with Guide E2629 when the PAT measurement is an integral part of a process control system.5.2 The documentation required for validation necessary to demonstrate that the analytical method is fit for purpose for theinten
41、ded application at the stage of the product life cycle may be determined by assessing the risks to quality. The documentationrequirements for validation is determined by risk assessment and will depend on the intended use. For example, a process analyticalmethod used during the development stage for
42、 research purposes may have little or no requirements for documenting validationcompared to a method that is being used during the commercial manufacturing stage of the product life cycle to support qualitydecisions about the product. Similarly, the documentation requirements for validation of a met
43、hod that is being used during themanufacturing stage of the product life cycle to support the quality decision about the product may differ from those listed in ICHQ2(R1). These differences in documentation requirements for validation will depend on the level of criticality of the risk of theapplica
44、tion.6. Procedure6.1 Inputs to Validation:6.1.1 There are a number of inputs to the risk assessment process such as establishing the measurement need, determining theintended purpose, establishing the measurement system, and developing the process analytical method.6.1.2 Defining the Intended Purpos
45、e of the ApplicationThis includes the design intent of the application and the level of therisk associated with the use of the specific application. This is defined well in the ICH Quality Implementation Working GroupPoints to Consider (R2). While the ICH guide discusses levels of as they apply to m
46、odeling, the same principle applies to thevalidation of analytical methods for PAT applications.6.1.2.1 Low-Impact ApplicationsThese are applications that are typically used to support product and process development.This level would include activities of low risk such as gathering information on a
47、process, method feasibility, process andformulation optimization, and other similar activities.6.1.2.2 Medium-Impact ApplicationsIncluded in this category are applications that assure quality, but are not measurement ofproduct quality. Examples of this may include many development measurements that
48、are used to establish design space and otherin process measurements of CQAs that may have another release test for the attribute. Other examples may include measurementsthat can be used for control, but the data is not used specifically for release.6.1.2.3 High Impact ApplicationsThese are applicati
49、ons that fall into the Real Time Release Testing (RTRT) category. Thisis the application that incorporates the measurement to insure product quality by control of the process or is a substitute for aspecification test such as product assay or is replacement for dissolution.6.1.3 Establishing the PAT Measurement SystemMeasurement system qualification is out of scope for this guide and isreferenced here as an input. The extent of the hardware and software qualifications is linked to the purpose of the application. Referto Guide E2500,ASME BP
