ASTM E2898-20a

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it may not be technically possible to adequately depict all changes accurately, ASTM recommends that users consult prior editions as appropriate. In all cases only the current version
of the standard as published by ASTM is to be considered the official document.
Designation: E2898 − 20 E2898 − 20a
Standard Guide for
Risk-Based Validation of Analytical Methods for PAT
Applications
This standard is issued under the fixed designation E2898; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
1. Scope
1.1 This guide provides an overview to the risk-based validation of process analytical methods under a process analytical
technology (PAT) paradigm for pharmaceuticals and biopharmaceuticals and as such includes guidance on assessing risk to product
quality from inappropriate method validation.
1.2 This guide builds on existing standards on the topic of validation concentrating on applying such standards to analytical
methods for on-line analysis. In particular, it addresses the validation of at-line, on-line, or in-line PAT measurements and covers
both drug substance and drug product (DP) measurements.
1.3 The definitions of International Council for Harmonisation (ICH) validation parameters (such as specificity, precision,
repeatability, etc.) apply; however, the method of demonstrating the validation parameters may vary from that described in ICH
and is discussed.
1.4 As consistent with the U.S. Food and Drug Administration (FDA) process validation guidance, this document also briefly
covers ongoing assurance that the method 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 of
analytical methods for PAT applications.
1.6 The validation of multivariate prediction models is out of scope but will be referenced as inputs to validation of analytical
methods for PAT applications.
1.6.1 The validation of any analytical model used in the PAT method is essential to the validation of the PAT method but, the
details of the model validation process is out of scope. See term model validation,3.1.7.
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 responsibility
of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of
regulatory limitations prior to use.
1.9 This international standard was developed in accordance with internationally recognized principles on standardization
established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued
by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
2. Referenced Documents
2.1 ASTM Standards:
D3764 Practice for Validation of the Performance of Process Stream Analyzer Systems
D6122 Practice for Validation of the Performance of Multivariate Online, At-Line, and Laboratory Infrared Spectrophotometer
Based Analyzer Systems
E1655 Practices for Infrared Multivariate Quantitative Analysis
E1790 Practice for Near Infrared Qualitative Analysis
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of
Subcommittee E55.01 on Process Understanding and PAT System Management, Implementation and Practice.
Current edition approved May 15, 2020June 1, 2020. Published June 2020. Originally approved in 2013. Last previous edition approved in 20142020 as E2898 – 14.20.
DOI: 10.1520/E2898-20.10.1520/E2898-20A.
For referenced ASTM standards, visit the ASTM website, www.astm.org, or contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM Standards
volume information, refer to the standard’s Document Summary page on the ASTM website.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E2898 − 20a
E2056 Practice for Qualifying Spectrometers and Spectrophotometers for Use in Multivariate Analyses, Calibrated Using
Surrogate Mixtures
E2476 Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes
for Pharmaceutical Manufacture
E2500 Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and
Equipment
E2617 Practice for Validation of Empirically Derived Multivariate Calibrations
E2629 Guide for Verification of Process Analytical Technology (PAT) Enabled Control Systems
E2656 Practice for Real-time Release Testing of Pharmaceutical Water for the Total Organic Carbon Attribute
E2891 Guide for Multivariate Data Analysis in Pharmaceutical Development and Manufacturing Applications
2.2 ICH Standards:
ICH Quality Implementation Working Group Points to Consider (R2) ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation
dated 6 December 2011
Q2(R1) Guidance on Validation of Analytical Procedures: Text and Methodology
Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
Q9 Quality Risk
2.3 Other Standards:
ASME BPE2019 BioProcessing Equipment Standard
FDA Guidance for Industry Process Validation: General Principles and Practices
ISO 14971 Medical Devices—Application of Risk Management to Medical Devices
ISO 15839 Water Quality—On-line Sensors/Analysing Equipment for Water—Specifications and Performance Tests
ISO/IEC Guide 51 Safety Aspects—Guidelines for Their Inclusion in Standards
PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, Guidance for Industry,
September 2004
USP Acoustic Emission <1005>
3. Terminology
3.1 Definitions:
3.1.1 acceptance criteria, n—criteria that a system or component shall satisfy to be accepted by a user or other authorized entity.
3.1.2 at-line measurements, n—measurement in which the sample is removed, isolated from, and analyzed in close proximity
to the process stream.
3.1.3 categorical data, n—measurement output that has distinct and predetermined output options (for example, pass/fail, 1/0,
red/yellow/green, and on/off) and is typically nonnumeric in nature.
3.1.4 continuous data, n—numerical information or output having any values within a given range.
3.1.5 discrete data, n—numerical information for which a limited set of values are allowed within a given range.
3.1.6 in-line measurements, n—measurement in which the sample is not removed from the process stream, which may be either
invasive or noninvasive.
3.1.7 model validation, n—the process of testing a calibration model with validation samples to determine bias between the
estimates from the model and the reference method, and to test the agreement between estimates made with the model and the
reference method as defined in Guide E2891.
3.1.8 off-line measurements, n—measurement in which the sample is removed or isolated from the immediate manufacturing
process stream, and analyzed in an area remote from the manufacturing process.
3.1.9 on-line measurements, n—measurement in which the sample is diverted from the manufacturing process and may be
returned to the process stream.
3.1.10 process analytical technology (PAT) application, n—the installation/utilization of a measurement system, for designing,
analyzing, and controlling manufacturing through timely measurements (that is, during processing) of critical quality and
performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. PAT
Available from International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), ICH Secretariat, Route de Pré-Bois, 20,
P.O Box 1894, 1215 Geneva, Switzerland, https://www.ich.org.
Available from American Society of Mechanical Engineers (ASME), ASME International Headquarters, Two Park Ave., New York, NY 10016-5990, http://
www.asme.org.
Available from U.S. Food and Drug Administration (FDA), 10903 New Hampshire Ave., Silver Spring, MD 20993, http://www.fda.gov.
Available from International Organization for Standardization (ISO), ISO Central Secretariat, Chemin de Blandonnet 8, CP 401, 1214 Vernier, Geneva, Switzerland,
https://www.iso.org.
Available from U.S. Pharmacopeial Convention (USP), 12601 Twinbrook Pkwy., Rockville, MD 20852-1790, http://www.usp.org.
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3.1.11 qualification, n—action of proving and documenting that equipment or ancillary systems are properly installed, work
correctly, and are fit for their intended purpose.
3.1.11.1 Discussion—
Qualification is part of validation, but the individual qualification steps alone do not constitute process validation. FDA/ICH Q7A
3.1.12 qualitative, adj—type of method whereby a categorical outcome (such as pass/fail) is generated for the attribute or
parameter measured.
3.1.12.1 Discussion—
The method output may be descriptive rather than numerical.
3.1.13 quantitative, adj—type of method whereby a numerical value or result is generated for the attribute or parameter
measured.
3.1.14 reference sample, n—representative substance of established quality used as a reference standard for the method
validation.
3.1.14.1 Discussion—
The reference sample may be a reference standard (primary or secondary) and may be commercial or development material for
which the value of its relevant parameter or attribute has been established. E1655
3.1.15 risk, n—combination of the probability of occurrence of harm and the severity of that harm. ISO/IEC Guide 51, ICH
Q9
3.1.16 risk analysis, n—the estimation of the risk associated with the identified hazard. ICH Q9
3.1.17 risk assessment, n—a systematic process of organizing information to support a risk decision to be made within a risk
management process. Consisting of identification hazards and the analysis and evaluation of risks associated with exposure to those
hazards. ICH Q9, ISO 14971
3.1.18 verification, n—systematic approach to demonstrate that manufacturing systems, acting singly or in combination, are fit
for intended use, have been properly installed, and are operating correctly.
3.1.18.1 Discussion—
This is an umbrella term that encompasses all types 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 verification
is used in conjunction with validating process systems and that the word validation is used for analytical methods.
3.2 Acronyms:
3.2.1 ICH—International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
3.2.2 LOD—limit of detection
3.2.3 LOQ—limit of quantification
3.2.4 PAT—process analytical technology
3.2.5 RTRT —real time release testing
3.2.6 DOE—design of experiments
4. Significance and Use
4.1 This guide supports the principles of Guide E2500 and extends these principles to validation of analytical methods for PAT
applications. The ongoing process of method validation is graphically represented in Fig. 1, which shows the life cycle of the
validation of analytical methods for PAT applications. Prerequisites for validation are the identification of the measurement
requirements and development of a method to meet those requirements.
4.2 The method risk assessment also takes into account the stage in the product life cycle at which the measurements are being
made and how the resulting data will be used. The integration of these considerations in the risk assessment facilitates the
determination of the level of validation necessary to ensure that the method is fit for purpose.
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FIG. 1 Life Cycle for the Validation of Analytical Method for PAT Applications
4.3 Changes may occur during the product life cycle necessitating identification of changes to the measurement requirements
and method update and revalidation. Procedures should be established to evaluate the continued suitability of the process analytical
method and to make appropriate recommendations to update the process analytical method for the intended use during the product
life cycle.
4.4 Additional informative examples can be found in Practices D3764, D6122, E1655, E1790, E2056, E2617, and E2656; and
Guide E2891 that address validation of methods and models. Other useful standards include ASME BPE2019, ISO 14971, ISO
15839, and USP Acoustic Emission <1005>.
5. Significance and Use
5.1 Guidance documents for the validation of off-line, laboratory-based analytical methods frequently have requirements that
cannot be satisfied when applied to at-line, on-line, and in-line analytical methods for PAT applications. This guide provides
guidance for the validation of at-line, on-line, or in-line analytical methods for PAT applications. Additionally, this guidance should
be 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 the
intended application at the stage of the product life cycle may be determined by assessing the risks to quality. The documentation
requirements for validation is determined by risk assessment and will depend on the intended use. For example, a process analytical
method used during the development stage for research purposes, may be important for pharmaceutical innovation and
pharmaceutical research and development, but may not carry the same level of validation documentation requirements compared
to a method that is being used during the commercial manufacturing stage of the product life cycle to support quality decisions
about the product. Similarly, the documentation requirements for validation of a method that is being used during the
manufacturing stage of the product life cycle to support the quality decision about the product may differ from those listed in ICH
Q2(R1). These differences in documentation requirements for validation will depend on the level of criticality of the risk of the
application.
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6. Procedure
6.1 Inputs to Validation:
6.1.1 There are a number of inputs to the risk assessment process such as establishing the measurement need, determining the
intended purpose, establishing the measurement system, establishing the measurement interface, measurement location,
measurement frequency, validation of any analytical models used in the method, and developing the process analytical method.
6.1.2 Defining the Intended Purpose of the Application—This includes the analytical target profile, the application and the level
of the risk associated with the use of the specific application. This is defined well in the ICH Quality Implementation Working
Group Points to Consider (R2). While the ICH guide discusses levels of as they apply to modeling, the same principle applies to
the validation of analytical methods for PAT applications.
6.1.2.1 Low-Impact Applications—These 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 process, method feasibility, process and
formulation optimization, and other similar activities where no control decisions are made.
6.1.2.2 Medium-Impact Applications—Included in this category are applications that assure quality, but are not the only measure
of product quality. An example Examples of this may include many development measurements that can be used for control
decisions, but the measurements are confirmed later in the process, and the process data is not used specifically for release. are
used to establish design space and other in process measurements of CQAs that may have another release test for the attribute.
Other examples may include measurements that can be used for control, but the control decisions but the measurement is verified
downstream, and the process data is not used specifically for release.
6.1.2.3 High Impact Applications—These are applications that fall into the measurement of product quality category such as
control decisions for Real Time Release Testing (RTRT). This is the application that incorporates the measurement to insure
product quality by control of the process or is a substitute for a specification test such as product assay or is replacement for
dissolution.
(1) It is important to recognize that the level of impact of the applications is categorized by low, medium, and high for ease
of documentation and practical purpose. In reality, situation may arise that the initial categorization of the impact level of the
analytical method of PAT application may change, due to new information available or situation change which leads to risk
categorization change.
6.1.3 Establishing the PAT Measurement System—Measurement system qualification is out of scope for this guide and is
referenced here as an input. The extent of the hardware and software qualifications is linked to the purpose of the application. Refer
to Guide E2500, ASME BPE2019, and other appropriate standards for process qualification and validation reference material. The
qualification should be summarized, documented, and approved before initiating the validation process.
6.1.4 Planning and Development of the Analytical Method for PAT Applications—The process analytical method development
document should state the need and purpose of the method to be developed as previously defined in 6.1.2 including sampling and
instrument interface development considerations. Aspects that should be considered and documented include:
6.1.4.1 Attributes or parameters to be measured.
6.1.4.2 Measurement mode—at-line, on-line, or in-line.
6.1.4.3 Choice of the instruments and the interface.
6.1.4.4 Sampling requirement for the measurement (sampling should be handled in accordance with scientifically justified and
representative analytical sampling procedures and may evolve throughout the method life cycle):
• Static or dynamic sampling,
• Frequency of sampling and speed at which the measurement result is obtained,
• Number of sampling points,
• Location of sampling points, and
• Size/amount of the batch to be sampled (scientifically justified and representative analytical sampling plan should be
developed).
(1) It should be recognized that representative sampling could be challenging, especially for dynamic sampling under process
environment. Noise from dynamic process stream, possible artifacts from material which is stagnate on the measurement interface
or measuring pathway, and measurement instrument’s signal to noise ratio, etc., should be taken into consideration when
developing dynamic sampling strategy.
6.1.4.5 Determination/understanding of the sources of process variation and measurement robustness requirements.
6.1.4.6 Fit for purpose in terms of precision and accuracy.
6.1.5 Method Output Requirements:
6.1.5.1 Qualitative versus quantitative;
6.1.5.2 Discrete, continuous, or categorical;
6.1.5.3 Trajectory/trending versus single value; and
6.1.5.4 Understanding of process and environmental conditions.
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6.1.6 Risk Assessment—A risk assessment should be performed to identify the fo
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