ASTM E2500-20

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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: E2500 − 13 E2500 − 20
Standard Guide for
Specification, Design, and Verification of Pharmaceutical
and Biopharmaceutical Manufacturing Systems and
Equipment
This standard is issued under the fixed designation E2500; 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 is applicable to all elements of pharmaceutical and biopharmaceutical manufacturing systems including: facility
good manufacturing practice (GMP) utility equipment, process equipment, supporting utilities, associated process monitoring and
control systems, and automation systems that have the potential to affect product quality and patient safety.
1.2 For brevity, these are referred to throughout the rest of this guide as manufacturing systems.
1.3 This guide may also be applied to laboratory, information, and medical device manufacturing systems.
1.4 This guide is applicable to both new and existing manufacturing systems. The approach may be used for the implementation
of changes to existing systems, and their continuous improvement during operation. systems.
1.5 This guide is applicable throughout the life-cycle of the manufacturing system from concept to retirement.
1.6 This standard does not address employee health and safety, environmental, or other non-GxP regulations. 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 safety, health, and healthenvironmental practices and determine the applicability of
regulatory limitations prior to use.
1.7 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:
E2363 Terminology Relating to Process Analytical Technology in the Pharmaceutical Industry
E2474 Practice for Pharmaceutical Process Design Utilizing Process Analytical Technology (Withdrawn 2020)
E2475 Guide for Process Understanding Related to Pharmaceutical Manufacture and Control
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of
Subcommittee E55.03 on General Pharmaceutical Standards.
Current edition approved Nov. 1, 2013Oct. 1, 2020. Published November 2013November 2020. Originally approved in 2007. Last previous edition approved in 20122013
as E2500 – 07 (2012). 13. DOI: 10.1520/E2500-13.10.1520/E2500-20.
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’sstandard’s Document Summary page on the ASTM website.
The last approved version of this historical standard is referenced on www.astm.org.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E2500 − 20
E2476 Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes
for Pharmaceutical Manufacture
E2537 Guide for Application of Continuous Process Verification to Pharmaceutical and Biopharmaceutical Manufacturing
E2629 Guide for Verification of Process Analytical Technology (PAT) Enabled Control Systems
E3051 Guide for Specification, Design, Verification, and Application of Single-Use Systems in Pharmaceutical and Biophar-
maceutical Manufacturing
2.2 Other Publications:
EU GMP Annex 15 Qualification and Validation
FDA Guidance for Industry Process Validation: General Principles and Practices
ICH Q8 Pharmaceutical Development
ICH Q9 Quality Risk Management
ICH Q10 Pharmaceutical Quality System
ICH Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)
Pharmaceutical cGMPs for the 21st Century —A — A Risk-Based Approach
3. Terminology
3.1 Definitions—For definitions of terms used in this guide, refer to Terminology E2363.
3.1.1 acceptance criteria—criteria, n—the criteria that a system or component must satisfy in order to be accepted by a user or
other authorized entity.
3.1.2 commissioning, n—a planned, managed and documented approach to the setting to work, start-up, regulation and adjustment,
and installation/ operation/ performance verification necessary to bring equipment, automation and systems to a fully operational
state meeting safety and end-user requirements.
3.1.3 design reviews—reviews, n—planned and systematic reviews of specifications, design, and design development and
continuous improvement changes performed as appropriate throughout the life-cycle of the manufacturing system. Design reviews
evaluate deliverables against standards and requirements, identify problems, and propose required corrective actions.
3.1.4 manufacturing systems—systems, n—elements of pharmaceutical and biopharmaceutical manufacturing capability, including
manufacturing systems, facility equipment, process equipment, supporting utilities, associated process monitoring and control
systems, and automation systems, that have the potential to affect product quality and patient safety.
3.1.5 qualification, n—a systematic approach to confirming that manufacturing systems, acting singly or in combination, are
suitable (fit) for intended use with respect to patient safety and product quality. Qualification begins with defining suitability for
use in a particular manufacturing context, typically based on process and quality risk control strategy, and ends with formal
acceptance and release for manufacturing followed by life-cycle continuous improvement.
3.1.6 subject matter experts (SMEs)—(SMEs), n—individuals with specific expertise and responsibility in a particular area or field
(for example, quality unit, engineering, automation, development, operations, and so forth).
3.1.7 verification—verification, n—a systematic approach to verify that manufacturing systems, acting singly or in combination,
are fit for intended use, have been properly installed, and are operating correctly. 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.broad umbrella term that includes specific actions to confirm, with a high degree of assurance, that a particular
fabrication, configuration, installation, operation, or performance specification has been satisfied and is suitable for its intended
purpose. Verification actions can be of a variety of types, including physical inspection, structural or functional test, document
review, performance monitoring, etc. Commissioning and qualification activities are types of verification.
4. Summary of Guide
4.1 This guide describes a risk-based and science-based approach to the specification, design, verification and verificationquali-
fication of manufacturing systems and equipment that have the potential to affect product quality and patient safety.
Available from Food and Drug Administration (FDA), 5600 Fishers Ln., Rockville, MD 20857, http://www.fda.gov.
Available from International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH Secretariat, c/o
IFPMA, 15 ch. Louis-Dunant, 9, chemin des Mines, P.O. Box 195, 1211 Geneva 20, Switzerland, http://www.ich.org.
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4.2 This guide describes a systematic, efficient, and effective way ofapproach to ensuring that manufacturing systems and
equipment are fit for intended use, and that risk to product quality, and consequently to patient safety, are effectively managed to
the extent that these are affected by such systems and equipment. This approach provides an effective methodology for qualifying
pharmaceutical and biopharmaceutical equipment, systems, facilities and associated automation.
4.3 The overall objective is to provide manufacturing capability to support defined and controlled processes that can consistently
produce product meeting defined patient safety and quality requirements.
4.4 The approach described within this guide also supports continuous process capability improvements and enables innovation
such as the implementation of Process Analytical Technology (PAT).process analytical technology (PAT) and single-use systems
(SUSs). See Guides E2476 and E2629 for further guidance on risk assessment and verification of PAT systems. See Guide E3051
for guidance on SUSs.
4.5 The main elements of this guide are:
4.5.1 The underlying key concepts that should be applied,
4.5.2 A description of the specification, design, and verification process, andprocess and their relationship to qualification, and
4.5.3 A description of the required supporting processes.
5. Significance and Use
5.1 Application of the approach described within this guide is intended to satisfy international regulatory expectations in ensuring
that manufacturing systems and equipment are fit for intended use, for example, qualified, and to satisfy requirements for design,
installation, operation, and performance.
5.2 The approach described in this guide applies concepts and principles introduced in the FDA initiative, Pharmaceutical cGMPs
for the 21st Century—A Century — A Risk-Based Approach.
5.3 This guide supports, and is consistent with, the framework described in ICH Q8, ICH Q9, ICH Q10, and ICH Q11.
5.4 This guide is designed to conform with FDA, EU, and other international regulations regarding equipment and facility
suitability for use and qualification.
5.5 This guide may be used independently or in conjunction with other Committee E55 standards published by ASTM
International.
6. Key Concepts
6.1 This guide applies the following key concepts:
Risk-Based Approach
Science-Based Approach
Critical Aspects of Manufacturing Systems
Quality by Design
Good Engineering Practice
Subject Matter Experts
Use of Vendor Documentation
Continuous Process Improvement
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Risk-based Approach
Science-based Approach
Critical Aspects of Manufacturing Systems
Quality by Design
Good Engineering Practice
Subject Matter Expert
Use of Vendor Documentation
Continuous Process Improvement
6.2 Risk-basedRisk-Based Approach:
6.2.1 Risk management should underpin the specification, design, and verification process, and be applied appropriately at each
stage.
6.2.2 Two primary principles of quality risk management are identified in ICH Q9:
6.2.2.1 The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the
patient.
6.2.2.2 The level of effort, formality and documentation of the quality risk management process should be commensurate with the
level of risk.
6.2.3 These principles should be applied to specification, design, and verification of manufacturing systems.
6.2.4 The scope and extent of quality risk management for specification, design, and verification activities and documentation
should be based on the risk to product quality and patient safety.
6.3 Science-basedScience-Based Approach:
6.3.1 Product and process information, as it relates to product quality and patient safety, should be used as the basis for making
science- and risk-based decisions that ensure that the manufacturing systems are designed and verified to be fit for their intended
use.
6.3.2 Examples of product and process information to consider include: critical quality attributes (CQAs), critical process
parameters (CPPs), process control strategy information, and prior production experience.
6.4 Critical Aspects of Manufacturing Systems:
6.4.1 Critical aspects of manufacturing systems are typically functions, features, abilities, and performance or characteristics
necessary for the manufacturing process and systems to ensure consistent product quality and patient safety. They should be
identified and documented based on scientific product and process understanding.
6.4.2 For brevity, these are referred to throughout the rest of this guide as critical aspects.
6.4.3 Verification activities should focus on these specifically include (though not be limited to) these critical aspects of
manufacturing systems and should be documented. The verification process is defined in 7.4. Commissioning is comprised of all
verification activities. Qualification includes those verification activities that center on items determined to be critical aspects
6.5 Quality by Design:
6.5.1 Quality by design concepts should be applied to ensure that critical aspects are designed into systems during the specification
and design process. The critical aspects of the design and associated acceptance criteria should be documented. This will typically
require that a risk assessment be performed in conjunction with the development of specifications to identify risks to be mitigated
as well as CQA to be achieved.
6.5.2 Assurance that manufacturing systems are fit for intended use should not rely solely upon verification after installation, but
be achieved by a planned and structured verification approach applied throughout the system life cycle.
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6.6 Good Engineering Practice:
6.6.1 Good Engineering Practiceengineering practice (GEP) should underpin and support the specification, design, and verification
activities.
6.6.2 Good Engineering Practice GEP is defined as those established engineering methods and standards that are applied
throughout the life cycle to deliver appropriate and effective solutions.
6.6.3 Examples of Good Engineering Practices GEPs include:
6.6.3.1 Specification, design, and installation activities should take full account of all applicable requirements, including GxP,
safety, health, environmental, ergonomic, operational, maintenance, recognized industry standards, and other statutory require-
ments.
6.6.3.2 Adequate provisions related to quality should be included in specification, design, procurement, and other contractual
documents.
6.6.3.3 Life-cycle documentation covering planning, specification, design, verification, installation, acceptance, and maintenance
should be produced.
6.6.3.4 An appropriate degree of oversight and control should be achieved by suitableof the construction, installation, and
verification of execution, construction and installation activities.equipment, systems, and facilities should be achieved.
6.7 Subject Matter Experts:
6.7.1 Subject matter experts SMEs are defined as those individuals with specific expertise and r
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