ASTM E2537-16

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Designation: E2537 − 08 E2537 − 16
Standard Guide for
Application of Continuous QualityProcess Verification to
Pharmaceutical and Biopharmaceutical Manufacturing
This standard is issued under the fixed designation E2537; 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 describes Continuous QualityProcess Verification (CQV) as an alternate approach to process validation where
manufacturing process (or supporting utility system) performance is continuously monitored, evaluated, and adjusted (as
necessary). It is a science-based approach to verify that a process is capable and will consistently produce product meeting its
predetermined critical quality attributes. CQV Continuous Process Verification (ICH Q8) is similarly described as Continuous
Quality Assurance (U.S. FDA) and Continuous Process Verification (ICH Q8). Verification.
1.2 Pharmaceutical and biopharmaceutical product manufacturing companies are required to provide assurance that the
processes used to manufacture regulated products result in products with the specified critical quality attributes of strength identity
and purity associated with the product safety,safety and efficacy. Process validation is a way in which companies provide that
assurance.
1.3 With the knowledge obtained during the product lifecycle, a framework for continuous quality improvementimprovements
will be established where the following may be possible: (1) risk mitigated,identified, (2) risk mitigated, (3) process variability
reduced, (3)(4) process capability enhanced, (4)(5) process design space defined or enhanced, and ultimately (5)(6) product quality
improved. This can enable a number of benefits that address both compliance and operational goals (for example, real time release,
continuous process improvement).
1.4 The principles in this guide may be applied to drug product or active pharmaceutical ingredient/drug substance
pharmaceutical and biopharmaceutical batch or continuous manufacturing processes or supporting utility systems (for example,
TOC for Purified Waterpurified water and Waterwater for Injectioninjection systems, and so forth).
1.5 The principles in this guide may be applied during the development and manufacturing of a new process or product or for
the improvement and/or redesign or redesign, or both, of an existing process.
1.6 Continuous qualityprocess verification may be applied to manufacturing processes that use monitoring systems that provide
frequent and objective measurement of process data. data in real time. These processes may or may not employ in-, on-, or at-line
analyzers/controllers that monitor, measure, analyze, and control the process performance. The associated processes may or may
not have a design space.
1.7 This guide may be used independently or in conjunction with other proposed E55 standards to be published by ASTM
International.
2. Referenced Documents
2.1 ASTM Standards:
E2363 Terminology Relating to Process Analytical Technology in the Pharmaceutical Industry
2.2 Other Publications:
ICH Q8 (R2) Pharmaceutical Development (Step 4 version), 10 November 20052009
ICH Q9 Quality Risk Management (Step 4 version), 9 November 2005
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 Jan. 1, 2008Dec. 1, 2016. Published February 2008January 2017. Originally approved in 2008. Last previous edition approved in 2008 as
E2537 – 08. DOI: 10.1520/E2537-08.10.1520/E2537-16.
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.
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, 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 States
E2537 − 16
ICH Q10 Pharmaceutical Quality System (Step 4 version), June 2008
ICH Q8, Q9, and Q10 Questions and Answers (R4), November 2010
ICH Q11 Development and Manufacture of Drug Substances (Step 4 version), May 2012
Pharmaceutical cGMPsCGMPs for the 21st Century —A Risk-Based Approach
Guidance for Industry, PAT —A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality
AssuranceAssurance, September 2004
Guidance for Industry, Process Validation —General Principles and Practices, January 2011
Guideline on Process Validation for Finished Products —Information and Data to be Provided in Regulatory Submissions,
February 2014
Guidelines for Good Manufacturing Practice, Volume 4 —Medicinal Products for Human and Veterinary Use, Annex 15:
Qualification and Validation, March 2015 (effective October 2015)
Pharmaceutical Inspection Co-operation Scheme, Annex 15 —Qualification and Validation, April 2015
Good Manufacturing Practice, Annex 2 —Qualification and Validation, May 2015 (effective December 2015)
3. Terminology
3.1 For definitions of terms used in this guide, refer to Terminology E2363.
4. Significance and Use
4.1 Application of the approach described within this standard guide applies science-based concepts and principles introduced
in the FDA initiative Pharmaceutical cGMPs FDA’s initiative on pharmaceutical CGMPs for the 21st Century. century.
4.2 This guide supports, and is consistent with, elements from ICH Q8 and ICH Q9.Q8 – Q11 and guidelines from USFDA,
European Commission, Pharmaceutical Inspection Co-operation Scheme, and the China Food and Drug Administration.
4.3 According to FDA Guidance for Industry, PAT, “With real time quality assurance, the desired quality attributes are ensured
through continuous assessment during manufacture. Data from production batches can serve to validate the process and reflect the
total system design concept, essentially supporting validation with each manufacturing batch.” In other words, the accumulated
product and process understanding used to identify the Critical Quality Attributes (CQAs), together with the knowledge that the
risk-based monitoring and control strategycontrol strategy, will enable control of the CQAs, should provide providing the
confidence needed to show validation with each batch. This is as opposed to a conventionaltraditional discrete process validation
approach.
5. Key Concepts
5.1 This guide applies the following key concepts: (1) science-based approach, (2) quality by design, (3) product and process
understanding, (4) quality risk management, and (5) continuous improvement.
5.2 Science-based Approach:
5.2.1 Product and process information, as it relates to product quality and public health, should be used as the basis for making
science- and risk-based decisions that ensure that a product consistently attains a predefined quality at the end of the manufacturing
process.quality.
5.2.2 Examples of product and process information to consider include: Critical Quality Attributes (CQAs), Critical Process
Parameters (CPPs), control strategy information, and prior production and development experience.
5.3 Quality by Design:
5.3.1 Quality by design concepts may be applied in the design and development of a product and associated manufacturing
processes to ensure critical quality attributes can be accurately and reliably predicted (for example, for materials used, process
parameters, manufacturing, environmental and other conditions).
5.3.2 Quality by design, when built into an organization’s quality system, provides a framework for the transfer of product and
process knowledge from drug development to the commercial manufacturing processes for launch, post-development changes, and
continuous improvement. It is this knowledge which enables the organizational understanding that is required for effective risk
management and decision excellence. Continuous quality Successful continuous process verification can only be achieved if
systems exist to capture and codify this knowledge into actionable elements for process monitoring and control as part of the
quality systems and production framework.
5.3.3 Continuous process verification can be an alternate to traditional process validation.
5.4 Product and Process Understanding:
Available from Food and Drug Administration (FDA), 5600 Fishers Ln., Rockville, MD 20857, http://www.fda.gov.
Available from European Medicines Agency (EMA), 30 Churchill Place, Canary Warf, London E14 5EU United Kingdom, http://www.ema.europa.eu/ema.
Available from European Commission (EC), 1049 Brussels, Belgium, http://ec.europa.eu.
Available from Pharmaceutical Inspection Co-operation Scheme (PIC/S), 14 Rue du Roveray, 1207 Geneva, Switzerland, http://www.picscheme.org.
Available from China Food and Drug Administration, Building #2, 26 Xuanwumen West Street, Xicheng District, Beijing, 100053, P.R. China, http://eng.sfda.gov.cn.
E2537 − 16
5.4.1 Product and Process understanding accumulates during the development phase and continues throughout the commer-
cialization phase of the product lifecycle. In the desired state, “A process will be considered well understood when (1)
…criticalcritical sources of variability are identified and explained; (2) variability is managed by the process; and (3) product
quality attributes can be accurately and reliably predicted over the design space established for materials, process parameters,
manufacturing, environmental, and other conditions.” (FDA Guidance for Industry, PAT)
5.4.2 A focus on product Product and process understanding can reduce the burden for validating systems by providing more
options for justifying and verifying systems focusing on aspects that are critical to product quality. Systems are verified that are
intended to monitor and control biological, physical, and/or chemical attributes or chemical attributes, or combinations thereof, of
materials and processes.
5.5 Quality Risk Management:
5.5.1 Quality risk management approaches should be used as a proactive means to identify potential quality issues during
product development and manufacturing to further ensure the high quality of the drug product to the patient.
5.5.2 Quality risk management can, for example, help guide the setting of specifications and process parameters for drug
manufacturing, assess and mitigate the risk of changing a process or specification.
5.5.3 Risk management should be an ongoing part of the quality management process and the output/results of the risk
management process should be reviewed to take into account new knowledge and experience.
5.6 Continuous Improvement:
5.6.1 Improved process understanding provides opportunities for further risk mitigation by optimizing process design and
control.
5.6.2 Comprehensive statistical process data analysis may analysis, where applicable, should be used to provide the rationale
for justifying changes to measurement, control, and testing requirements along with associated specifications for each product.
6. Continuous QualityProcess Verification Process
6.1 Overview:
6.1.1 Continuous learning and quality verification occurs over the lifecycle of a product and should include the following
aspects:
6.1.1.1 Product understanding and process understanding,
6.1.1.2 Continuous process and quality monitoring and control,
6.1.1.3 Process performance evaluation,
6.1.1.4 Acceptance and release, and
6.1.1.5 Continuous process improvement.
6.1.2 Manufacturers should have a comprehensive and moderncurrent quality systemssystem in place. Robust process
development and quality systems will promote process consistency by integrating effective knowledg
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