ASTM E3060-16
(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 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 (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, 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 health practices and determine the applicability of regulatory limitations prior to use.
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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 − 16
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 tial sources and causes of particles during biomanufacturing.
These results can be used to monitor these particles and where
1.1 Biotherapeutic drugs and vaccines are susceptible to
possible, to adjust the manufacturing process to avoid their
inherent protein aggregate formation which may change over
formation. This guide will also address the fundamental
the product shelf life. Intrinsic particles, including excipients,
principles of dynamic imaging analysis including image analy-
silicone oil, and other particles from the process, container/
sis methods, sample preparation, instrument calibration and
closures, equipment or delivery devices, and extrinsic particles
verification and data reporting.
which originate from sources outside of the contained process,
may also be present. Monitoring and identifying the source of
1.4 The values stated in SI units are to be regarded as
the subvisible particles throughout the product life cycle (from
standard. No other units of measurement are included in this
initial characterization and formulation through finished prod-
standard.
uct expiry) can optimize product development, process design,
1.5 This standard does not purport to address all of the
improve process control, improve the manufacturing process,
safety concerns, if any, associated with its use. It is the
and ensure lot-to-lot consistency.
responsibility of the user of this standard to establish appro-
1.2 Understanding the nature of particles and their source is
priate safety and health practices and determine the applica-
a key to the ability to take actions to adjust the manufacturing
bility of regulatory limitations prior to use.
process to ensure final product quality. Dynamic imaging
microscopy is a useful technique for particle analysis and
2. Referenced Documents
characterization (proteinaceous and other types) during product
2
2.1 ASTM Standards:
development, in-process and commercial release with a sensi-
E2589 Terminology Relating to Nonsieving Methods of
tive detection and characterization of subvisible particles at ≥2
Powder Characterization
and ≤100 micrometers (although smaller and larger particles
3
may also be reported if data are available). In this technique
2.2 ISO Standards:
brightfield illumination is used to capture images either directly
ISO 2859 Sampling Procedures for Inspection by Attributes
in a process stream, or as a continuous sample stream passes
ISO 8871 Elastomeric Parts for Parenterals and for Devices
through a flow cell positioned in the field of view of an imaging
for Pharmaceutical Use
system. An algorithm performs a particle detection routine.
ISO 9276-6 Representation of Results of Particle Size
This process is a key step during dynamic imaging. The digital
Analysis Part 6: Descriptive and Quantitative Representa-
particle images in the sample are processed by image morphol-
tion of Particle Shape and Morphology
ogy analysis software that quantifies the particles in size, count,
2.3 Other Standards:
and other morphological parameters. Dynamic imaging par-
ANSI/ASQ Z1.4-2003 Sampling Procedures and Tables for
ticle analyzers can produce direct determinations of the particle
3
Inspection by Attributes
count per unit volume (that is, particle concentration), as a
4
ASME BPE-2014 Bioprocessing Equipment
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 consider-
2
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
ations in applying dynamic imaging to identification of poten-
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.
1 3
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture Available from American National Standards Institute (ANSI), 25 W. 43rd St.,
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of 4th Floor, New York, NY 10036, http://www.ansi.org.
4
Subcommittee E55.14 on Measurement Systems and Analysis. Available from American Society of Mechanic
...
NOTICE: This standard has either been superseded and replaced by a new version or withdrawn.
Contact ASTM International (www.astm.org) for the latest information
Designation: E3060 − 16
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 tial sources and causes of particles during biomanufacturing.
These results can be used to monitor these particles and where
1.1 Biotherapeutic drugs and vaccines are susceptible to
possible, to adjust the manufacturing process to avoid their
inherent protein aggregate formation which may change over
formation. This guide will also address the fundamental
the product shelf life. Intrinsic particles, including excipients,
principles of dynamic imaging analysis including image analy-
silicone oil, and other particles from the process, container/
sis methods, sample preparation, instrument calibration and
closures, equipment or delivery devices, and extrinsic particles
verification and data reporting.
which originate from sources outside of the contained process,
may also be present. Monitoring and identifying the source of
1.4 The values stated in SI units are to be regarded as
the subvisible particles throughout the product life cycle (from
standard. No other units of measurement are included in this
initial characterization and formulation through finished prod-
standard.
uct expiry) can optimize product development, process design,
1.5 This standard does not purport to address all of the
improve process control, improve the manufacturing process,
safety concerns, if any, associated with its use. It is the
and ensure lot-to-lot consistency.
responsibility of the user of this standard to establish appro-
1.2 Understanding the nature of particles and their source is
priate safety and health practices and determine the applica-
a key to the ability to take actions to adjust the manufacturing
bility of regulatory limitations prior to use.
process to ensure final product quality. Dynamic imaging
microscopy is a useful technique for particle analysis and
2. Referenced Documents
characterization (proteinaceous and other types) during product
2
2.1 ASTM Standards:
development, in-process and commercial release with a sensi-
E2589 Terminology Relating to Nonsieving Methods of
tive detection and characterization of subvisible particles at ≥2
Powder Characterization
and ≤100 micrometers (although smaller and larger particles
3
may also be reported if data are available). In this technique
2.2 ISO Standards:
brightfield illumination is used to capture images either directly
ISO 2859 Sampling Procedures for Inspection by Attributes
in a process stream, or as a continuous sample stream passes
ISO 8871 Elastomeric Parts for Parenterals and for Devices
through a flow cell positioned in the field of view of an imaging
for Pharmaceutical Use
system. An algorithm performs a particle detection routine.
ISO 9276-6 Representation of Results of Particle Size
This process is a key step during dynamic imaging. The digital
Analysis Part 6: Descriptive and Quantitative Representa-
particle images in the sample are processed by image morphol-
tion of Particle Shape and Morphology
ogy analysis software that quantifies the particles in size, count,
2.3 Other Standards:
and other morphological parameters. Dynamic imaging par-
ANSI/ASQ Z1.4-2003 Sampling Procedures and Tables for
ticle analyzers can produce direct determinations of the particle
3
Inspection by Attributes
count per unit volume (that is, particle concentration), as a
4
ASME BPE-2014 Bioprocessing Equipment
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 consider-
2
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
ations in applying dynamic imaging to identification of poten-
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.
1 3
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture Available from American National Standards Institute (ANSI), 25 W. 43rd St.,
of Pharmaceutical and Biopharmaceutical Products and is the direct responsibility of 4th Floor, New York, NY 10036, http://www.ansi.org.
4
Subcommittee E55.14 on Measurement Systems and Analysis. Available from American Society of Mechanical Engineers (ASME), ASME
Current edition approved June 1, 2016. Published June 2016. DOI: 10.1520/ International Headquarters, Two Park Ave., New
...
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