1、Designation: E3060 16Standard Guide forSubvisible Particle Measurement in BiopharmaceuticalManufacturing Using Dynamic (Flow) Imaging Microscopy1This standard is issued under the fixed designation E3060; the number immediately following the designation indicates the year oforiginal adoption or, in t
2、he case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.1. Scope1.1 Biotherapeutic drugs and vaccines are susceptible toinherent protein aggregate format
3、ion which may change overthe product shelf life. Intrinsic particles, including excipients,silicone oil, and other particles from the process, container/closures, equipment or delivery devices, and extrinsic particleswhich originate from sources outside of the contained process,may also be present.
4、Monitoring and identifying the source ofthe subvisible particles throughout the product life cycle (frominitial characterization and formulation through finished prod-uct expiry) can optimize product development, process design,improve process control, improve the manufacturing process,and ensure lo
5、t-to-lot consistency.1.2 Understanding the nature of particles and their source isa key to the ability to take actions to adjust the manufacturingprocess to ensure final product quality. Dynamic imagingmicroscopy is a useful technique for particle analysis andcharacterization (proteinaceous and othe
6、r types) during productdevelopment, in-process and commercial release with a sensi-tive detection and characterization of subvisible particles at 2and 100 micrometers (although smaller and larger particlesmay also be reported if data are available). In this techniquebrightfield illumination is used
7、to capture images either directlyin a process stream, or as a continuous sample stream passesthrough a flow cell positioned in the field of view of an imagingsystem. An algorithm performs a particle detection routine.This process is a key step during dynamic imaging. The digitalparticle images in th
8、e sample are processed by image morphol-ogy analysis software that quantifies the particles in size, count,and other morphological parameters. Dynamic imaging par-ticle analyzers can produce direct determinations of the particlecount per unit volume (that is, particle concentration), as afunction of
9、 particle size by dividing the particle count by thevolume of imaged fluid (see Appendix X1).1.3 This guide will describe best practices and consider-ations in applying dynamic imaging to identification of poten-tial sources and causes of particles during biomanufacturing.These results can be used t
10、o monitor these particles and wherepossible, to adjust the manufacturing process to avoid theirformation. This guide will also address the fundamentalprinciples of dynamic imaging analysis including image analy-sis methods, sample preparation, instrument calibration andverification and data reportin
11、g.1.4 The values stated in SI units are to be regarded asstandard. No other units of measurement are included in thisstandard.1.5 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsibility of the user of this standard to establish ap
12、pro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use.2. Referenced Documents2.1 ASTM Standards:2E2589 Terminology Relating to Nonsieving Methods ofPowder Characterization2.2 ISO Standards:3ISO 2859 Sampling Procedures for Inspection by Attrib
13、utesISO 8871 Elastomeric Parts for Parenterals and for Devicesfor Pharmaceutical UseISO 9276-6 Representation of Results of Particle SizeAnalysis Part 6: Descriptive and Quantitative Representa-tion of Particle Shape and Morphology2.3 Other Standards:ANSI/ASQ Z1.4-2003 Sampling Procedures and Tables
14、 forInspection by Attributes3ASME BPE-2014 Bioprocessing Equipment41This guide is under the jurisdiction of ASTM Committee E55 on Manufactureof Pharmaceutical and Biopharmaceutical Products and is the direct responsibility ofSubcommittee E55.03 on General Pharmaceutical Standards.Current edition app
15、roved June 1, 2016. Published June 2016. DOI: 10.1520/E3060-16.2For referenced ASTM standards, visit the ASTM website, www.astm.org, orcontact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM websit
16、e.3Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, New York, NY 10036, http:/www.ansi.org.4Available from American Society of Mechanical Engineers (ASME), ASMEInternational Headquarters, Two Park Ave., New York, NY 10016-5990, http:/www.asme.org.Copyright ASTM
17、International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States1BS 6001-1:1999+A1:2011 Sampling procedures for inspec-tion by attributes. Sampling schemes indexed by accep-tance quality limit (AQL) for lot-by-lot inspection5USP Subvisible Particulate Matter in Ther
18、apeuticProtein Injections6USP Particulate Matter in Injections6USP Assessment of Extractables Associated withPharmaceutical Packaging/Delivery Systems6USP Assessment of Drug Product Leachables Asso-ciated with Pharmaceutical Packaging Delivery Systems6USP Subvisible Particulate Matter in Therapeutic
19、Protein Injections63. Terminology3.1 Definitions:3.1.1 For definitions of terms used in this standard, refer toTerminology E2589.3.2 Definitions of Terms Specific to This Standard:3.2.1 brightfield illumination, na method of providinglight into a measurement space whereby the illuminated objectsare
20、located between the light source and the viewing receiver.3.2.2 circularity, ndegree to which a particle (or itsprojection area) is similar to a circle.3.2.3 cumulative particle size distribution, narepresentation, as a table, graph, or mathematical function, thatgives the total fraction or concentr
21、ation of particles greater thanor less than a set of specified size values.3.2.3.1 DiscussionCumulative particle size distributionsmay be expressed as either mass, volume, area, number, orconcentration values.3.2.4 depth of field, ndepth of field is the distance betweenthe nearest and farthest objec
22、ts that are in acceptably sharpfocus in an image.3.2.5 dynamic imaging, nparticle size and shape analysisusing computer image analysis techniques on instantaneouslycaptured still frame projected images of particles in motion(also referred to as flow imaging, flow microscopy, directimaging).3.2.6 equ
23、ivalent diameter, nthe diameter of a sphere orcircle that is equal to the measured diameter obtained by aparticle sizing instrument.3.2.6.1 DiscussionFor dynamic imaging, the reported di-ameter is based on the projected area of a measured particle.3.2.7 extrinsic particle, na particle introduced fro
24、msources that are foreign or external to the manufacturingprocess.3.2.8 Feret diameter, F, napparent diameter of an objectdetermined from the distance between two parallel tangents onopposite sides of a binary object.3.2.8.1 DiscussionThere are an infinite number of Feretsdiameters; the maximum and
25、the minimum Ferets find mostuse within imaging.3.2.9 field of view, nthe two dimensional, lateral extent ofthe imaged area.3.2.10 frequency distribution, na representation, as atable, graph, or mathematical function, that gives the frequencyor count of values within a set of specified intervals.3.2.
26、11 inherent particle, na particle made entirely ofcomponents of the formulated drug product or its manufactur-ing intermediate, arising from the product itself.3.2.12 intrinsic particle, na particle composed of materi-als that the product or intermediate contacts or is mixed withduring the manufactu
27、ring process or during storage in primarypackaging components.3.2.13 particle size distribution (PSD), na frequency orvolume distribution of the concentration of particles versusparticle size.3.2.13.1 DiscussionDynamic imaging particle analyzersof use to the biopharmaceutical industry report the PSD
28、 as theconcentration of particles per unit volume within specified sizeranges, where the size is most commonly the equivalentdiameter but may be another morphological size attribute. SeeAppendix X1.3.2.14 subvisible particle, na particle with a measuredequivalent diameter within the approximate rang
29、e 1 m to 100m.NOTE 1When it is necessary to specify an exact size range, the rangeshould be defined explicitly rather than by such adjectives as subvisible.3.2.14.1 DiscussionThe term particle may be used todesignate any self-contained object that is optically distin-guishable from the background im
30、age, including liquid drop-lets and gas-phase bubbles.3.2.14.2 DiscussionThe 100 m upper limit is based onthe historical definition of subvisible particle as used in thefield of drug inspection. Particles of 20 m or smaller ofsufficient optical contrast are readily visible under brightillumination,
31、especially when present in numerous quantity.3.2.15 threshold, nthe minimum quantitative change inintensity (of either positive or negative sign) from the back-ground pixel value for a pixel to be identified as a possibleparticle.3.2.16 volume distribution, na frequency distribution thatgives the di
32、stribution of particle volume as a function ofparticle size.4. Significance and Use4.1 This guide will encompass considerations for manufac-turers regarding sources and potential causes of subvisibleparticles in biomanufacturing operations and the use of dy-namic imaging particle analyzers as a sugg
33、ested commonmethod to monitor them. The guide will address the followingcomponents of particle analysis using dynamic imaging mi-croscopy: fundamental principles, operation, image analysismethods, sample handling, instrument calibration, and datareporting.5Available from British Standards Institutio
34、n (BSI), 389 Chiswick High Rd.,London W4 4AL, U.K., http:/.6Available from U.S. Pharmacopeial Convention (USP), 12601 TwinbrookPkwy., Rockville, MD 20852-1790, http:/www.usp.org.E3060 1625. Types of Particles5.1 USP defines three subcategories of particlesrelated to their source or nature. When comb
35、ined with appro-priate strategies for characterizing particle types, this catego-rization scheme provides a framework for assessing the rootcause and acceptable concentrations of different types ofparticles.5.1.1 Inherent particles are related to the product formula-tion (for example, chemical and p
36、hysical properties and con-centration of the Active Pharmaceutical Ingredient (API)proteins, excipients, API solid suspensions, emulsions, adju-vant aluminum salts added to vaccines). Packaging of theproduct and external stresses (including temperature, mechani-cal shock or movement, light exposure,
37、 and interaction withliquid/solid and liquid/air interfaces) can all have substantialimpact on the concentration and characteristics of proteinaggregates. Protein aggregates may change over time, in bothconcentration and characteristics, and some levels of proteindegradation or related aggregation,
38、or both, may be expected.Inherent particles must be well characterized and monitoredover the product shelf-life.5.1.2 Intrinsic particles include product contact materialsfrom the manufacturing process or primary packaging compo-nents (that is, silicone oil, glass, stainless steel, rubber closure,po
39、lymer tubing, semi-solid silicone lubricant, process relatedfibers, etc.). This category also includes stability-indicatingparticles found predominantly during development or stabilitystudies (formulation degradation, container closure-related,glass delamination, stopper degradation, etc.). The pres
40、ence ofintrinsic particle types must be minimized, and if they arestability-indicating, they should be eliminated whenever pos-sible.5.1.3 Extrinsic particles comprise any particles not sourcedfrom the manufacturing process or product contact materialsincluding particles of a biological source (that
41、 is, externalenvironmental fibers, hair, airborne particles, etc.). Extrinsicparticle types should be a rare occurrence and eliminated.6. Sources of Particles6.1 Subvisible particles may be generated by a number ofsources during the manufacturing process. In analyzing the riskof particle generation
42、introduced by various process steps, it isuseful to understand the sensitivity of the drug product orsubstance to a variety of stresses known to promote particleformation.6.2 Sources of Inherent Particles:6.2.1 Stresses which may cause inherent particle changesmay include:6.2.1.1 Interaction with in
43、terfaces or other particles.(1) Increased interfacial transport resulting from agitation,stirring, etc.(2) Interfacial adsorption: both liquid/vapor and liquid/solid(3) Nucleation on other particles(4) Trace metals and other molecules promoting oxidationand aggregation6.2.1.2 Chemical environment.(1
44、) Formulation, which may promote or hinder particlegeneration(2) Excipients(3) Impurities6.2.1.3 Physical environment.(1) Vibration(2) Mechanical shock(3) Cavitation(4) Temperature and humidity(5) Environmentcontamination(6) Intense light exposure6.2.2 The count and characteristics of the particles
45、formedas a result of these stresses will vary in general with theduration of the stress and subsequent storage time and condi-tions.6.3 Sources of Intrinsic Particles:6.3.1 Intrinsic particles may be formed when materials incontact with drug substance or product are stressed, such as theshedding of
46、particles by pumps used in fill and finish opera-tions. In other cases, the stresses may be minimal, but thematerials are not verified to be sufficiently particle free; anexample would be the shedding of particles from a filter. Aswith inherent particles, the creation of particles depends bothon the
47、 duration of particular stresses and the time of storage.6.4 Combinations of particular stresses may arise in differ-ent process steps during manufacturing operations, including:6.4.1 Formulation,6.4.2 Sterilization,6.4.3 Storage: conditions, time of storage, and choice ofcontainer,6.4.4 Transport,6
48、.4.5 pH adjustments,6.4.6 Viral Inactivation Steps,6.4.7 UF/DF,6.4.8 Container or closure siliconization, which may pro-mote aggregation of proteins,6.4.9 Freeze-thaw,6.4.10 Mixing, and6.4.11 Fill/Finish.6.5 Components in the manufacturing process may contrib-ute particles directly (for example, pol
49、ymer particles shed by asingle use system component or other flexible systemcomponents), or may contribute to increased particle loadindirectly (for example, protein adsorption and subsequentdesorption as a particle from a hydrophobic polymer surface).The use of components and filters requires the development ofcompatibility profiles with the product and solutions to assureleachable substances are not a concern as discussed in USPand USP . The therapeutically active drugsubstance (small or large molecule) would have to be shownnot to
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