ASTM E3060-23
(Guide)Standard Guide for Subvisible Particle Measurement in Biopharmaceutical Manufacturing Using Dynamic (Flow) Imaging Microscopy
Standard Guide for Subvisible Particle Measurement in Biopharmaceutical Manufacturing Using Dynamic (Flow) Imaging Microscopy
SIGNIFICANCE AND USE
4.1 This guide will encompass considerations for manufacturers regarding sources and potential causes of subvisible particles in biomanufacturing operations and the use of dynamic imaging particle analyzers as a suggested common method to monitor them. The guide will address the following components of particle analysis using dynamic imaging microscopy: fundamental principles, operation, image analysis methods, sample handling, instrument calibration, and data reporting.
SCOPE
1.1 Biotherapeutic drugs and vaccines are susceptible to inherent protein aggregate formation which may change over the product shelf life. Intrinsic particles, including excipients, silicone oil, and other particles from the process, container/closures, equipment or delivery devices, and extrinsic particles which originate from sources outside of the contained process, may also be present. Monitoring and identifying the source of the subvisible particles throughout the product life cycle (from initial characterization and formulation through finished product expiry) can optimize product development, process design, improve process control, improve the manufacturing process, and ensure lot-to-lot consistency.
1.2 Understanding the nature of particles and their source is a key to the ability to take actions to adjust the manufacturing process to ensure final product quality. Dynamic imaging microscopy (also known as flow imaging or flow microscopy) is a useful technique for particle analysis and characterization (proteinaceous and other types) during product development, in-process and commercial release with a sensitive detection and characterization of subvisible particles at ≥2 µm and ≤100 µm (although smaller and larger particles may also be reported if data are available). In this technique brightfield illumination is used to capture images either directly in a process stream, or as a continuous sample stream passes through a flow cell positioned in the field of view of an imaging system. An algorithm performs a particle detection routine. This process is a key step during dynamic imaging. The digital particle images in the sample are processed by image morphology analysis software that quantifies the particles in size, count, image intensity, and morphological parameters. Dynamic imaging particle analyzers can produce direct determinations of the particle count per unit volume (that is, particle concentration), as a function of particle size by dividing the particle count by the volume of imaged fluid (see Appendix X1).
1.3 This guide will describe best practices and considerations in applying dynamic imaging to identification of potential sources and causes of particles during biomanufacturing. These results can be used to monitor these particles and where possible, to adjust the manufacturing process to avoid their formation. This guide will also address the fundamental principles of dynamic imaging analysis including image analysis methods, sample preparation, instrument calibration and verification and data reporting.
1.4 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.
1.5 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.
1.6 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: E3060 − 23
Standard Guide for
Subvisible Particle Measurement in Biopharmaceutical
1
Manufacturing Using Dynamic (Flow) Imaging Microscopy
This standard is issued under the fixed designation E3060; 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 1.3 This guide will describe best practices and consider-
ations in applying dynamic imaging to identification of poten-
1.1 Biotherapeutic drugs and vaccines are susceptible to
tial sources and causes of particles during biomanufacturing.
inherent protein aggregate formation which may change over
These results can be used to monitor these particles and where
the product shelf life. Intrinsic particles, including excipients,
possible, to adjust the manufacturing process to avoid their
silicone oil, and other particles from the process, container/
formation. This guide will also address the fundamental
closures, equipment or delivery devices, and extrinsic particles
principles of dynamic imaging analysis including image analy-
which originate from sources outside of the contained process,
sis methods, sample preparation, instrument calibration and
may also be present. Monitoring and identifying the source of
verification and data reporting.
the subvisible particles throughout the product life cycle (from
initial characterization and formulation through finished prod- 1.4 The values stated in SI units are to be regarded as
uct expiry) can optimize product development, process design, standard. No other units of measurement are included in this
improve process control, improve the manufacturing process, standard.
and ensure lot-to-lot consistency.
1.5 This standard does not purport to address all of the
safety concerns, if any, associated with its use. It is the
1.2 Understanding the nature of particles and their source is
responsibility of the user of this standard to establish appro-
a key to the ability to take actions to adjust the manufacturing
priate safety, health, and environmental practices and deter-
process to ensure final product quality. Dynamic imaging
mine the applicability of regulatory limitations prior to use.
microscopy (also known as flow imaging or flow microscopy)
1.6 This international standard was developed in accor-
is a useful technique for particle analysis and characterization
dance with internationally recognized principles on standard-
(proteinaceous and other types) during product development,
ization established in the Decision on Principles for the
in-process and commercial release with a sensitive detection
Development of International Standards, Guides and Recom-
and characterization of subvisible particles at ≥2 μm and
mendations issued by the World Trade Organization Technical
≤100 μm (although smaller and larger particles may also be
Barriers to Trade (TBT) Committee.
reported if data are available). In this technique brightfield
illumination is used to capture images either directly in a
2. Referenced Documents
process stream, or as a continuous sample stream passes
2
2.1 ASTM Standards:
through a flow cell positioned in the field of view of an imaging
system. An algorithm performs a particle detection routine. E2589 Terminology Relating to Nonsieving Methods of
Powder Characterization
This process is a key step during dynamic imaging. The digital
3
particle images in the sample are processed by image morphol- 2.2 ISO Standards:
ISO 3951-1 Sampling Procedures for Inspection by Vari-
ogy analysis software that quantifies the particles in size, count,
image intensity, and morphological parameters. Dynamic im- ables
ISO 8871 Elastomeric Parts for Parenterals and for Devices
aging particle analyzers can produce direct determinations of
the particle count per unit volume (that is, particle for Pharmaceutical Use
ISO 9276-6 Representation of Results of Particle Size
concentration), as a function of particle size by dividing the
particle count by the volume of imaged fluid (see Appendix Analysis Part 6: Descriptive and Quantitative Representa-
tion of Particle Shape and Morphology
X1).
1 2
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture For referenced ASTM standards, visit the ASTM website, www.astm.org, or
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
Subcommittee E55.03 on General Pharmaceutical Standards. Standards volume i
...
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: E3060 − 16 E3060 − 23
Standard Guide for
Subvisible Particle Measurement in Biopharmaceutical
1
Manufacturing Using Dynamic (Flow) Imaging Microscopy
This standard is issued under the fixed designation E3060; 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 Biotherapeutic drugs and vaccines are susceptible to inherent protein aggregate formation which may change over the product
shelf life. Intrinsic particles, including excipients, silicone oil, and other particles from the process, container/closures, equipment
or delivery devices, and extrinsic particles which originate from sources outside of the contained process, may also be present.
Monitoring and identifying the source of the subvisible particles throughout the product life cycle (from initial characterization and
formulation through finished product expiry) can optimize product development, process design, improve process control, improve
the manufacturing process, and ensure lot-to-lot consistency.
1.2 Understanding the nature of particles and their source is a key to the ability to take actions to adjust the manufacturing process
to ensure final product quality. Dynamic imaging microscopy (also known as flow imaging or flow microscopy) is a useful
technique for particle analysis and characterization (proteinaceous and other types) during product development, in-process and
commercial release with a sensitive detection and characterization of subvisible particles at ≥2 and ≤100 micrometers ≥2 μm and
≤100 μm (although smaller and larger particles may also be reported if data are available). In this technique brightfield illumination
is used to capture images either directly in a process stream, or as a continuous sample stream passes through a flow cell positioned
in the field of view of an imaging system. An algorithm performs a particle detection routine. This process is a key step during
dynamic imaging. The digital particle images in the sample are processed by image morphology analysis software that quantifies
the particles in size, count, image intensity, and other morphological parameters. Dynamic imaging particle analyzers can produce
direct determinations of the particle count per unit volume (that is, particle concentration), as a function of particle size by dividing
the particle count by the volume of imaged fluid (see Appendix X1).
1.3 This guide will describe best practices and considerations in applying dynamic imaging to identification of potential sources
and causes of particles during biomanufacturing. These results can be used to monitor these particles and where possible, to adjust
the manufacturing process to avoid their formation. This guide will also address the fundamental principles of dynamic imaging
analysis including image analysis methods, sample preparation, instrument calibration and verification and data reporting.
1.4 The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.
1.5 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.
1.6 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.
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 E55.14E55.03 on Measurement Systems and AnalysisGeneral Pharmaceutical Standards.
Current edition approved June 1, 2016Oct. 1, 2023. Published June 2016October 2023. Originally approved in 2016. Last previous edition approved in 2016 as E3060 – 16.
DOI: 10.1520/E3060-16.10.1520/E3060-23.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
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E3060 − 23
2. Referenced
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