ASTM E2968-23
(Guide)Standard Guide for Application of Continuous Manufacturing (CM) in the Pharmaceutical Industry
Standard Guide for Application of Continuous Manufacturing (CM) in the Pharmaceutical Industry
SIGNIFICANCE AND USE
4.1 Although some CM is used in the pharmaceutical industry (for example, purified water production), and some processes are inherently continuous individual unit operations (such as dry granulation and compression), these operations are generally operated in isolation and do not deliver the potential benefits of an integrated CM operation. The FDA Guidance for Industry PAT document specifically identifies that the introduction of continuous processing (now redefined as CM) may be one of the outcomes from the adoption of a science-based approach to process design.
4.2 This guide does not:
4.2.1 Suggest that CM is suitable for the manufacture of all pharmaceutical products.
4.2.2 Provide guidance on issues related to the safe operation of a CM process or continuous processing equipment. It is the responsibility of the user of this standard to establish appropriate health and safety practices and determine the applicability of regulatory limitations prior to use.
4.2.3 Recommend particular designs or operating regimes for CM.
4.3 Appendix X1 includes a table comparing the characteristics of continuous and discrete or batch processes.
SCOPE
1.1 This guide introduces key concepts and principles to assist in the appropriate selection, development and operation of CM technologies for the manufacture of pharmaceutical products. Athough selected concepts covered here can be applied to biopharmaceutical CM (BioCM), the focus of this guide is on non-biopharmaceutical applications.
1.2 Particular consideration is given to the development and application of the appropriate scientific understanding and engineering principles that differentiate CM from traditional batch manufacturing.
1.3 Most of the underlying concepts and principles (for example, process dynamics and process control) outlined in this guide can be applied to both Drug Substance (DS) and Drug Product (DP) processes. However, it should be recognized that in Drug Substance production the emphasis may be more on chemical behavior and dynamics in a fluid phase whereas for solid drug product manufacture there may be a greater emphasis on the physical behavior and dynamics in a solid/powder format.
1.4 This guide is also intended to apply in both the development of new processes, or the redesign of existing ones.
1.5 All values are stated in SI units. No other units of measurement are included in this standard.
1.6 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.
1.7 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.
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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.
Designation: E2968 − 23
Standard Guide for
Application of Continuous Manufacturing (CM) in the
1
Pharmaceutical Industry
This standard is issued under the fixed designation E2968; 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 2. Referenced Documents
2
1.1 This guide introduces key concepts and principles to 2.1 ASTM Standards:
assist in the appropriate selection, development and operation E2363 Terminology Relating to Manufacturing of Pharma-
of CM technologies for the manufacture of pharmaceutical ceutical and Biopharmaceutical Products in the Pharma-
products. Athough selected concepts covered here can be ceutical and Biopharmaceutical Industry
applied to biopharmaceutical CM (BioCM), the focus of this E2475 Guide for Process Understanding Related to Pharma-
guide is on non-biopharmaceutical applications. ceutical Manufacture and Control
E2537 Guide for Application of Continuous Process Verifi-
1.2 Particular consideration is given to the development and
cation to Pharmaceutical and Biopharmaceutical Manu-
application of the appropriate scientific understanding and
facturing
engineering principles that differentiate CM from traditional
E2629 Guide for Verification of Process Analytical Technol-
batch manufacturing.
ogy (PAT) Enabled Control Systems
1.3 Most of the underlying concepts and principles (for
E2898 Guide for Risk-Based Validation of Analytical Meth-
example, process dynamics and process control) outlined in
ods for PAT Applications
this guide can be applied to both Drug Substance (DS) and
2.2 Regulatory Guidance and Other Documents:
Drug Product (DP) processes. However, it should be recog-
21 CFR 210.3 Current Good Manufacturing Practice in
nized that in Drug Substance production the emphasis may be
Manufacturing, Processing, Packing or Holding of Drugs,
more on chemical behavior and dynamics in a fluid phase
3
General Definitions
whereas for solid drug product manufacture there may be a
EMA Guideline on process validation for finished products
greater emphasis on the physical behavior and dynamics in a
information and data to be provided in regulatory submis-
solid/powder format.
sions
1.4 This guide is also intended to apply in both the devel-
EU Guidelines for Good Manufacturing Practice for Medici-
opment of new processes, or the redesign of existing ones.
nal Products for Human and Veterinary Use, Annex
15: Qualification and Validation
1.5 All values are stated in SI units. No other units of
FDA Guidance for Industry PAT A Framework for Innova-
measurement are included in this standard.
tive Pharmaceutical Development, Manufacturing, and
1.6 This standard does not purport to address all of the
3
Quality Assurance (2004)
safety concerns, if any, associated with its use. It is the
FDA Guidance for Industry Process Validation: General
responsibility of the user of this standard to establish appro-
3
Principles and Practices (2011)
priate safety, health, and environmental practices and deter-
ICH Harmonized Tripartite Guideline, Continuous Manufac-
mine the applicability of regulatory limitations prior to use.
turing of Drug Substances and Drug Products, Q13 (Step
1.7 This international standard was developed in accor-
4
2b version, dated 29 July 2021)
dance with internationally recognized principles on standard-
ICH Harmonized Tripartite Guideline, Pharmaceutical
ization established in the Decision on Principles for the
Development of International Standards, Guides and Recom-
mendations issued by the World Trade Organization Technical
2
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
Barriers to Trade (TBT) Committee.
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
1
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture the ASTM website.
3
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of Available from Food and Drug Administration (FDA), 10903 New Hampshire
Subcommittee E55.11 on Process Design. Ave., Silver Spring, MD 20993-0002, http://www.fda.gov.
4
Current edition approved Jan. 1, 2023. Published February 2023. Originally Available from International Council for Harmonisation of Technical Require-
approved in 2014. Last previous edition approved in 2014 as E2968 – 14. DOI: ments for Pharmaceuticals for Human Use (ICH), ICH Secretariat, Ro
...
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. Because
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: E2968 − 14 E2968 − 23
Standard Guide for
Application of Continuous Processing Manufacturing (CM)
1
in the Pharmaceutical Industry
This standard is issued under the fixed designation E2968; 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 introduces key concepts and principles to assist in the appropriate selection, development and operation of
continuous processing CM technologies for the manufacture of pharmaceutical products. Athough selected concepts covered here
can be applied to biopharmaceutical CM (BioCM), the focus of this guide is on non-biopharmaceutical applications.
1.2 Particular consideration is given to the development and application of the appropriate scientific understanding and
engineering principles that differentiate continuous manufacture CM from traditional batch manufacturing.
1.3 Most of the underlying concepts and principles (for example, process dynamics and process control) outlined in this guide can
be applied into both Drug Substance (DS) and Drug Product (DP) processes. However, it should be recognized that in Drug
Substance production the emphasis may be more on chemical behavior and dynamics in a fluid phase whereas for solid drug
product manufacture there may be a greater emphasis on the physical behavior and dynamics in a solid/powder format.
1.4 This guide is also intended to apply in both the development of a new process,processes, or the improvement/redesignredesign
of an existing one.ones.
1.5 TheAll values are stated in SI units are to be regarded as standard. units. No other units of measurement are included in this
standard.
1.6 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 and healthsafety, health, and environmental 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
2.1 ASTM Standards:
E2363 Terminology Relating to Process Analytical Technology in the Pharmaceutical Industry
E2475 Guide for Process Understanding Related to Pharmaceutical Manufacture and Control
1
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 Dec. 1, 2014Jan. 1, 2023. Published April 2015February 2023. Originally approved in 2014. Last previous edition approved in 2014 as
E2968 – 14. DOI: 10.1520/E2968-14.10.1520/E2968-23.
2
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
1
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E2968 − 23
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
E2898 Guide for Risk-Based Validation of Analytical Methods for PAT Applications
2.2 FDA Regulatory Guidance and Other Documents:
21 CFR 210.3 Current Good Manufacturing Practice in Manufacturing, Processing, Packing or Holding of Drugs, General
3
Definitions
EMA Guideline on process validation for finished products information and data to be provided in regulatory submissions
EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 15: Qualification
and Validation
FDA Guidance for Industry PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality
3
Assurance (2004)
3
FDA Guidance for Industry Process Validatio
...
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