ASTM E2537-08
(Guide)Standard Guide for Application of Continuous Quality Verification to Pharmaceutical and Biopharmaceutical Manufacturing
Standard Guide for Application of Continuous Quality Verification to Pharmaceutical and Biopharmaceutical Manufacturing
SIGNIFICANCE AND USE
Application of the approach described within this standard guide applies science-based concepts and principles introduced in the FDA initiative Pharmaceutical cGMPs for the 21st Century.
This guide supports, and is consistent with, elements from ICH Q8 and ICH Q9.
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 strategy will enable control of the CQAs, should provide the confidence needed to show validation with each batch. This is as opposed to a conventional discrete process validation approach.
SCOPE
1.1 This guide describes Continuous Quality Verification (CQV) as an 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 is similarly described as Continuous Quality Assurance (U.S. FDA) and Continuous Process Verification (ICH Q8).
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, 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 improvement will be established where the following may be possible: (1) risk mitigated, (2) process variability reduced, (3) process capability enhanced, (4) process design space defined or enhanced, and ultimately (5) 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 Water and Water for Injection 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 of an existing process.
1.6 Continuous quality verification may be applied to manufacturing processes that use monitoring systems that provide frequent and objective measurement of process data. 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.
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Designation:E2537 −08
Standard Guide for
Application of Continuous Quality 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 1.5 The principles in this guide may be applied during the
developmentandmanufacturingofanewprocessorproductor
1.1 This guide describes Continuous Quality Verification
for the improvement and/or redesign of an existing process.
(CQV) as an approach to process validation where manufac-
turing process (or supporting utility system) performance is 1.6 Continuousqualityverificationmaybeappliedtomanu-
continuously monitored, evaluated and adjusted (as necessary). facturing processes that use monitoring systems that provide
Itisascience-basedapproachtoverifythataprocessiscapable frequent and objective measurement of process data. These
and will consistently produce product meeting its predeter- processes may or may not employ in-, on-, or at-line analyzers/
mined critical quality attributes. CQV is similarly described as controllers that monitor, measure, analyze, and control the
Continuous Quality Assurance (U.S. FDA) and Continuous processperformance.Theassociatedprocessesmayormaynot
Process Verification (ICH Q8). have a design space.
1.2 Pharmaceutical and biopharmaceutical product manu- 1.7 This guide may be used independently or in conjunction
facturing companies are required to provide assurance that the with other proposed E55 standards to be published by ASTM
processes used to manufacture regulated products result in International.
productswiththespecifiedcriticalqualityattributesofstrength
2. Referenced Documents
identity and purity associated with the product safety, and
efficacy. Process validation is a way in which companies
2.1 ASTM Standards:
provide that assurance.
E2363 Terminology Relating to ProcessAnalytical Technol-
ogy in the Pharmaceutical Industry
1.3 With the knowledge obtained during the product
lifecycle, a framework for continuous quality improvement 2.2 Other Publications:
will be established where the following may be possible: (1) ICH Q8 Pharmaceutical Development (Step 4 version), 10
risk mitigated, (2) process variability reduced, (3) process November 2005
capability enhanced, (4) process design space defined or ICH Q9 Quality Risk Management (Step 4 version), 9
enhanced, and ultimately (5) product quality improved. This November 2005
can enable a number of benefits that address both compliance Pharmaceutical cGMPs for the 21st Century —A Risk-
and operational goals (for example, real time release, continu- Based Approach
ous process improvement). Guidance for Industry, PAT —A Framework for Innovative
Pharmaceutical Development, Manufacturing and Quality
1.4 The principles in this guide may be applied to drug
Assurance
product or active pharmaceutical ingredient/drug substance
pharmaceutical and biopharmaceutical batch or continuous
manufacturing processes or supporting utility systems (for
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
example, TOC for Purified Water and Water for Injection
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
systems, and so forth). Standards volume information, refer to the standard’s Document Summary page on
the ASTM website.
Available from International Conference on Harmonisation of Technical
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH
ofPharmaceuticalandBiopharmaceuticalProductsandisthedirectresponsibilityof Secretariat, c/o IFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20,
Subcommittee E55.03 on General Pharmaceutical Standards. Switzerland, http://www.ich.org.
Current edition approved Jan. 1, 2008. Published February 2008. DOI: 10.1520/ Available from Food and Drug Administration (FDA), 5600 Fishers Ln.,
E2537-08. Rockville, MD 20857, http://www.fda.gov.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E2537−08
3. Terminology into actionable elements for process monitoring and control as
part of the quality systems framework.
3.1 For definitions of terms used in this guide, refer to
Terminology E2363. 5.4 Product and Process Understanding:
5.4.1 Product and Process understanding accumulates dur-
4. Significance and Use
ing the development phase and continues throughout the
commercialization phase of the product lifecycle. In the
4.1 Application of the approach described within this stan-
desired state, “A process will be considered well understood
dard guide applies science-based concepts and principles
when (1)…critical sources of variability are identified and
introducedintheFDAinitiativePharmaceuticalcGMPsforthe
explained; (2) variability is managed by the process; and (3)
21st Century.
product quality attributes can be accurately and reliably pre-
4.2 This guide supports, and is consistent with, elements
dicted over the design space established for materials, process
from ICH Q8 and ICH Q9.
parameters, manufacturing, environmental, and other condi-
4.3 According to FDA Guidance for Industry, PAT, “With tions.” (FDA Guidance for Industry, PAT)
real time quality assurance, the desired quality attributes are
5.4.2 A focus on product and process understanding can
ensured through continuous assessment during manufacture. reduce the burden for validating systems by providing more
Data from production batches can serve to validate the process
options for justifying and verifying systems intended to moni-
and reflect the total system design concept, essentially support- tor and control biological, physical, and/or chemical attributes
ing validation with each manufacturing batch.” In other words,
of materials and processes.
the accumulated product and process understanding used to
5.5 Quality Risk Management:
identify the Critical Quality Attributes (CQAs), together with
5.5.1 Quality risk management approaches should be used
the knowledge that the risk-based monitoring and control
as a proactive means to identify potential quality issues during
strategy will enable control of the CQAs, should provide the
product development and manufacturing to further ensure the
confidence needed to show validation with each batch. This is
high quality of the drug product to the patient.
as opposed to a conventional discrete process validation
5.5.2 Quality risk management can, for example, help guide
approach.
the setting of specifications and process parameters for drug
manufacturing, assess and mitigate the risk of changing a
5. Key Concepts
process or specification.
5.1 This guide applies the following key concepts: (1)
5.5.3 Risk management should be an ongoing part of the
science-based approach, (2) quality by design, (3) product and
quality management process and the output/results of the risk
process understanding, (4) quality risk management, and (5)
management process should be reviewed to take into account
continuous improvement.
new knowledge and experience.
5.2 Science-based Approach:
5.6 Continuous Improvement:
5.2.1 Product and process information, as it relates to
5.6.1 Improved process understanding provides opportuni-
product quality and public health, should be used as the basis
ties for further risk mitigation by optimizing process design
for making science- and risk-based decisions that ensure that a
and control.
product consistently attains a predefined quality at the end of
5.6.2 Comprehensive statistical process data analysis may
the manufacturing process.
be used to provide the rationale for justifying changes to
5.2.2 Examples of product and process information to
measurement, control, and testing requirements along with
consider include: Critical Quality Attributes (CQAs), Critical
associated specifications for each product.
Process Parameters (CPPs), control strategy information, and
prior production experience.
6. Continuous Quality Verification Process
5.3 Quality by Design:
6.1 Overview:
5.3.1 Quality by design concepts may be applied in the
6.1.1 Continuous learning and quality verification occurs
design and development of a product and associated manufac-
overthelifecycleofaproductandshouldincludethefollowing
turing processes to ensure critical quality attributes can be
aspects:
accurately and reliably predicted (for example, for materials
6.1.1.1 Product understanding and process understanding,
used, process parameters, manufacturing, environmental and
6.1.1.2 Continuous quality monitoring and control,
other conditions).
6.1.1.3 Process performance evaluation,
5.3.2 Quality by design, when built into an organization’s
6.1.1.4 Acceptance and release, and
quality system, provides a framework for the transfer of
6.1.1.5 Continuous process improvement.
product and process knowledge from drug development to the
6.1.2 Manufacturers should have a comprehensive and
commercial manufacturing processes for launch, post-
modern quality systems in place. Robust quality systems will
development changes, and continuous improvement. It is this
promote process consistency by integrating effective
knowledge which enables the organizational understanding
knowledge-building mechanisms into routine operations.
that is required for effective risk management and decision
excellence. Continuous quality verification can only be 6.1.3 Science-based approaches should be applied at each
achieved if systems exist to capture and codify this knowledge stage of the process.
E2537−08
6.1.4 Quality risk management should be applied at each 6.3.3.1 The steps/unit operations included in the scope of
stage of the process. the control strategy document.
6.3.3.2 The critical quality attributes, critical quality
6.2 Product and Process Understanding:
parameters, intended operating ranges that need to be moni-
6.2.1 In a modern quality systems manufacturing
tored and controlled, and acceptance criteria as determined
environment, the significant characteristics of the product
through the quality by design approach.
being manufactured should be defined from design through the
6.3.3.3 The facility environment and equipment operating
full lifecycle to retiremen
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