Transcription
Particulate MatterDefinitionsDetection MethodsMeasurement MethodsRegulatory RequirementsCompliance5/6/2022pdamidwest.org1
5/6/2022pdamidwest.org2
There is a ‘Grey Zone’ between Sub-Vis and Visible Compendial MethodSize of the smallest particles detected in visual inspection, depend on the particlecharacteristics and other factors5/6/2022pdamidwest.org3
DefinitionsUSP is a referenced definition:Harmonized in JP, EU, othersExtrinsic: Are completely outside of the Mfr’g process.Hair, rust, wood, insect parts, carbon, paperIntrinsic: Come from within the Process or PkgFibers from Process components, polymers, stainless steel, glass chards, O-ringsInherent: Are part of the formulation or ingredients with the drug product.API particles, degradation products, Protein Aggregates, extractables, product relatedExamples From: Biologics (aggregates), Suspensions, Lyoph Products, Emulsions(where the particles can be the product or related ingredients)5/6/2022pdamidwest.org4
Common Particulates Found in ParenteralsGlass fragmentsStopper & Plunger pieces, lubricants,Fibers from garments, wipers, filters, etc.Dirt, dust, paper, cottonSkin flakes, hairCharred particulatesImmiscible fluids, colorants, surfactants5/6/2022pdamidwest.org5
5/6/2022pdamidwest.org6
5/6/2022pdamidwest.org7
5/6/2022pdamidwest.org8
Methods to Detect Particulate Matter in Injectables Visual Inspection: Manual (human), Semi-Automatic, Fully Automatic Light Obscuration (LO) Microscopic Membrane (MM) Filtration Flow Imaging (FI) Electrozone Sensing (ES) Laser Light Scattering Nano Tracking Analysis (NTA) Methods in Bold are required USP tests. Methods in Italics are suggested ‘Orthogonal’ methods5/6/2022pdamidwest.org9
Test Method Visual Inspection * Light Obscuration (LO) * Microscopic Membrane (MM) * Flow Imaging (FI)USP Chapters Related to Particulates USP 1, 790, 1790 USP 1, 787, 788, 789, 1787, 1788 USP 1, 788, 789, 1787, 1788 USP 1, 1787, 1787, 1788 * Harmonized with EU, JP USP 729 provides 2 methods to verifythat injectable emulsions are safe. Theymust also meet 1 .5/6/2022pdamidwest.org10
VISUAL INSPECTION5/6/2022pdamidwest.org11
5/6/2022pdamidwest.org12
Typical Visual Inspection Booth5/6/2022pdamidwest.org13
It is not a deterministic process Visual inspection of particles is a probabilistic process At least 12 factors influence and affect the probability ofdetection of each particle The choices are: Manual, Semi-Automatic, Fully Automatic5/6/2022pdamidwest.org14
Some VARIABLES FOR PARTICLE DETECTIONVisible particles occur randomlyThe detection process is probabilisticParticles are not sized in the Visual inspection processThere is a different probability of detection for ea. size/typeHumans see particles differentlyThere are different No concrete definition of ‘essentially free’Poor agreement with sub-visible LO & difficult to understandDifficult/impossible to characterize particles inside vialRef Index of particle vs the DP, particle shape & location in vialTraining, Qualification, Rest periods & Breaks for Inspectors5/6/2022pdamidwest.org15
Common Visual Inspection Methods Human inspector @ inspection booth.Human inspector w/ multiple container packs.Human inspector at moving vials.Automated inspection machine using lighttransmission.Automated inspection via Imaging.Cosmetic inspection5/6/2022pdamidwest.org16
Qualification of Inspectors – Visual Inspection Eye tests: vision, color blindness, aquity. Develop a POD for different particle types and sizes (challenge sets). Understanding ‘Cosmetic’ defects and ‘Container Closure’ issues. Handling and manipulating each type of containers for the inspection. When to ‘look’ for particles. Handling distractions (noise, discussion, environment, lighting). When (and how) to report unusual observations or issues.5/6/2022pdamidwest.org17
5/6/2022pdamidwest.org18
QUESTIONS FOR VISUAL INSPECTIONWhat is the smallest particle size our inspectors can see ?How can we best determine that for each inspector ?What are the probabilities for each type of particle for each drug product?How much does this variability affect the outgoing product ?What do we know about visible and sub-visible particles ?What are the critical issues comparing manual & automatic inspec ?5/6/2022pdamidwest.org19
Flowchart for the Visual Inspection Process5/6/2022pdamidwest.org20
USP ChaptersOther Regulatory AgenciesUSP 788 , 789 USP 790 USP 787 USP 1787 , 1788 ,USP 1790 EU 2.9.19, JP 6.07 EU 2.9.20, JP 6.06 EU EU 5.17.2 (Jan 2021) EU, Annex 1 (not released) Section 8 parag 8.29FDA Guidance on Visual Inspectionreleased Dec 2021.5/6/2022pdamidwest.org21
5/6/2022pdamidwest.org22
5/6/2022pdamidwest.org23
5/6/2022pdamidwest.org24
Factors That Affect the Probability of Detection5/6/2022pdamidwest.org25
Factors that effect the Probability of DetectionLighting level and typeTime for inspectionParticle size, shape & R.I.RI of liquidContainer (shape, glass color/type)Time of day (inspector fatigue)Technique for swirling the liquid‘Hawthorne’ Effect5/6/2022pdamidwest.org26
Sub-Visible Particulate Matter TestsUSP 788 , 789 Light ObscurationMicroscopic Membrane5/6/2022pdamidwest.org27
USP 788 (Sub-Visible) vs USP 790 (Visible) Using the LO method leads to confused comparisons The MM method will provide more accurate informationand comparison for large particles and fibers Particles captured should be “characterized” if unknown,added to the reject library and Plan to ID the source. Studies of this type using LO, may produce conflicting datasince the “true size” of the real particles can not be welldefined or identified by human or machine detection.5/6/2022pdamidwest.org28
USP 788 for SVI’s and LVI’sSVI’spercontainerSizes 10umper milliter 25um 10um 25um6,000600253MM 3,000300122LO5/6/2022LVI’spdamidwest.org29
5/6/2022pdamidwest.org30
5/6/2022pdamidwest.org31
5/6/2022pdamidwest.org32
5/6/2022pdamidwest.org33
5/6/2022pdamidwest.org34
5/6/2022pdamidwest.org35
5/6/2022pdamidwest.org36
5/6/2022pdamidwest.org37
5/6/2022pdamidwest.org38
Don’t forget about the USP FREE WEBINARSTHE NEXT ONE IS May 12, 2022Additional Webinar ViewsUSP Websitehttps://www.youtube.com/watch?v mvLK5krEWAMhttps://www.youtube.com/watch?v JR0dTmUecWQhttps://www.youtube.com/watch?v rvwkxuPIO5o5/6/2022pdamidwest.org39
5/6/2022pdamidwest.org40
THANK YOUQUESTIONS ?Comments, suggestions for USP Chapters on Particulate MatterDan Berdovich, Micro Measurement Laboratories, Inc.dberdovich@mmlabs.com5/6/2022pdamidwest.org41
USP 1, 788, 789, 1787, 1788 USP 1, 1787, 1787, 1788 USP 729 provides 2 methods to verify that injectable emulsions are safe. They must also meet 1 . 5/6/2022 pdamidwest.org 10. VISUAL INSPECTION 5/6/2022 pdamidwest.org 11. 5/6/2022 pdamidwest.org 12. Typical Visual Inspection Booth
