pda visual inspection 2009 aldrich
TRANSCRIPT
Particulate Matter - Visual Detection to Identification
Scott Aldrich
PDA Visual Inspection, October 19-20, 2009
Concepts
Visual inspection is the start of the analytical process for particle identification
Inspection-coupled isolation provides the necessary understanding of defect character
Inspection allows connection of package defects to particle content
Rules for Products
Appropriate DesignRobust FormulationNo Changes
Clean Stable
Visual Inspection
Often unappreciated as a diagnostic toolVital process for stability evaluationEssential first step in particle identification
processProvides high-level overview of product
character
Tracking Product Physical Stability
Why? Primary
Verifies Acceptable and Stable Presentation Expedites Development by Revealing Problems Avoids Surprises
Secondary Problem-solving defect incidents
• Investigates all components Why Used How Used Fabrication, Process Stream
Visible Sub-visible Sub-micrometer
Size Domains
1µm25µm 10µm150µm
Increasing Probability of Detection
What size domain matters for the product stability?
Visible Gray zone
Pharma Liquid Products and Presentations – A Complex Array PARENTERAL PRODUCTS, AQUEOUS AND NON-AQUEOUS
Small Molecule; <1000mw Large Molecule; >1000mw Low Concentration High Concentration
Ophthalmic Systems Others
Novel Deliveries Sub-Q Systems Gels, Diffusion substrates
Pharma Liquid Products and Presentations – A Complex Array Package Systems
Glass Vial/closure Ampoule
Plastic Blow-Fill-Seal Formed sheets
Syringes Pre-filled Syringes Devices Delivery (IV) Sets Commercial RTU’s
Formulations Liquid, aseptic/terminal Lyophilized Solids Suspension,
aseptic/terminal Dry-filled sterile powders Emulsions Nano-particle delivery
Development Timeline & Distractions
Small ScaleCrud, ignoredPackage is ChangingSmall Batches, Few Containers UsedFirst of many API Processes
Clinical ScalePackage and Presentation Defined – Set?Customer Use Experience
Full Scale/LaunchProcess “Improvements”
Cost and Time-SavingUnanticipated Insoluble/non-volatile Substances
Vendor Lost or ChangedIngredient Quality/Character different than in Development
Commercial Product Quality
Product Form Well-Described Product Use Well-Understood Product Appearance Consistent to the Level of
Detection Sensitivity Consensus of Defect Definition
Category Identity Effect or Importance
Critical Major Minor
Compendial RequirementsRobust, Safe, Sterile, Pure and Effective
USP Chapter <1> Injections USP Chapter <788> Injections/<789> Ophthalmic
Products USP/EP/JP have Harmonized <788> PM Testing Pharm. Forum re: Chapter <788>:
IM and Sub-Q must meet <788> Pharm. Forum 35[3] May-June 2009, page 628
Radiopharmaceuticals are exempt from <788> limits Parenteral products for which labeling specifies use of a final
filter are exempt from <788>, provided scientific data are available to justify the exemption. (do your homework).
Irrigating solutions are exempt.
PARTICULATE MATTER QUANTITATION
Compendial Methods USP/EP/JP Light Obscuration
Instrument Standardization Tests Calibration
Membrane Microscopy Calibration Setup Calibration day-of-Use
Alternate methods Electrozone (Coulter) Microscopy Image Analysis
Optical Electron
Laser diffraction Nephelometry Flow Microscopy Photon Correlation Spectroscopy
Particle Count by Light Obscuration– First Tier
Groves, 1993
CONSTITUTES KEY FILING DATA
Counting by Membrane Assay – Second Tier
Calibrate Optical Microscope at 100x for 10m, 25m Size Domains
System Suitability Blank Filter Isolation of Particles from
the Liquid Product Oblique and Epi-Illumination
Reveals Particles on the Membrane
Tabulates Particles in Size Categories, Reveals Nature
MOST IMPORTANT IN PRODUCT DEVELOPMENT
The ID Process
ConfirmIsolateCharacterizeIdentifyLocate
What Constitutes a Defect?…Appearance and Evident Changes
ColorHazeSolids/ParticlesContainer to Container Differences Time of Release FailureTrend over Time3 Sigma Failure ?Catastrophic Failure
Just What is Acceptable? “Essentially free”
Just a few per container? Just a few per batch? After defect removal, the batch is essentially free of
foreign and visible particulate matter Inspection result at historical AQL? The Long Range View:
“Essentially free of visible particulate matter means free of particles that are considered indicative of physical instability of the product or of interaction between the formulation and the container/closure system.”…and
The low incidence of containers with observed extrinsic material have been removed.
Identification process should not depend upon definition!
Isolation Methods
Direct removal, liquids Capillary tube (Wiretrol) Poly tube, drawn to fine tip Membrane swipe
Filtration Centrifugation
Direct removal, dry materials Tungsten wire, 1-5µm tip Fine hair Fine scalpel, cleaver
(MicroTool) Facilitate with water, or
weak known adhesive Transfers, Concentrators
Dried KBr Cleaned filter paper Capillary rounds/flats
Capillary Removal and Transfer
Isolate What’s Seen Evaluation of Isolated
Particulate Matter, to Determine: point source environmental formulation/package
Locate and Remove Source(s) Manufacturing Verifies
Improvement RESULT
Design Improvement Manufacturing Improvement
Inspect – Detect – Isolate - Identify
Observation in Context with Event Inspection with observers or in duplication
Categorization of All “Species” Package vs. Free Tiny vs. Obvious
Audit of SpeciesMicroscopy-Spectroscopy Process of
CharacterizationTracking Source from Character/Identity
Inspection at Microscopy BenchTools of the Trade
The Particle Atlas
Microscopy Pathway
Collection of Properties Size, Shape, Color, Hardness, Association Ref. Indices, Birefringence, Crystal System
Simple Experiments Solubility
What extracts, separates? Heating studies Functional Group Tests
Feigl, Stahl, Chamot & Mason, Benedetti-Pichler, McCrone et al
Comparison to Known Materials Public Database Internal Database Careful examination of components, process
Observations via Microscopy
Habit Flake Rod Acicular Equant Tablet/Plate Fiber Lath
Refractive Index (n) Dispersion of n Degree of Transparency Color Resolution is…?
Microscopy Tricks of the Trade
Maintain visual connection as much as possible Withdrawal from fluids
Capillary tubes: Wiretrol• Can you see the isolate• Can you beam it?
Isolation on the package Filtration Sedimentation Location on/in solids
Change views often Transmitted Oblique/darkfield Single pol Crossed pols Filters; ¼ wave, 1 Red Under stress
Pressure Heat Solvent Exposure
Microscopy Tricks of the Trade
Physical Tests Magnetic attraction Hardness via cover slip: Locard’s exchange principle
– put it to work Water exposure – what happens upon humidification?
Visual Stereomicroscopy Compound Pol Electron microscopy IR Microspectroscopy Photographs are great, but can you draw it?
Observations are refined by the need to render accurate drawings.
Membrane Method for ID Isolation
PLM
Spectroscopy
Hotstage
Schemes for Material Ultramicroanalysis
(Light Obscuration)Membrane Isolate
Picking
Direct SEM-EDS
Optical Count
PLM-Spectroscopy
Direct SEM-EDS
ID
Quant
The Nature of Material• Association
Singular• Liquid• Solid• Combinations
• Multiple• Aggregate/Agglomerate
• no distinct boundaries (matrix evident?)
• boundaries?• with similar material,
foreign material?• Groups of groups?• Homogeneous
heterogeneity?• Polycrystalline• Microcrystalline• Cryptocrystalline
• Layered Coated
• Crystallinity• None Evident
• Amorphous• Methods Used?
• Distinct? Or Continuum?• “Liquid”: 2-D order• Solid: 3-D order
• Isometric (1 ri)• Uniaxial (2 ri)
• Tetragonal• Hexagonal
(trigonal)• Biaxial (3 ri)
• Orthorhombic• Monoclinic• Triclinic
• Sub-optimal solid state
PARTICULATE MATTER ORIGINS
ADDITIVE/EXTRINSIC Single event/Unchanging
-environmental -machine -personnel -inadequate prep/cleaning -closure source
INTRINSIC/MULTIPLE EVENT GROWTH/INTRINSIC/CHANGING
Package Change Leaks Ingredient purity/change Active purity/change Product-Package interaction
CHANGE MECHANISMS Coalescence Sedimentation Nucleation Crystallization
Hydrate Formation Solvate Formation Polymorphism Salt Formation
Degradation Chemical Physical Effects
• Temperature• Shear• Light
Oxidation Oligomerization Impurities Drug Concentration Effects/Micelles Leaching/Extraction
Studying the Occurrence
Point Source or General Load? Mfg. Points of ContactBatch CharacterProduct CharacterFacility ImpactProcess Effects
Next Studies/Directions – Analytical Microscopy Partners with Formulation and Manufacturing
Thanks for Your Attention
Questions?
Membrane Microscopic Count is KeyBio: Scott Aldrich is a long-standing member of American Chemical Society, AAPS, State Microscopical Society of Illinois, PDA and Microscopy Society of America. He is a member of the United States Pharmacopeia (USP) Parenteral Products – Industrial Expert Committee for the current (2005-2010) term. He is a 38 year veteran of the pharmaceutical industry, through employment at Upjohn, Pharmacia, and Pfizer. Scott is President of Ultramikro, LLC an independent consulting firm specializing in microscopy training and particulate matter control programs.
Parenteral and Ophthalmic Limits – A Comparison
USP <788> Injectable and <789> Ophthalmic Products Particulate Matter Limits. Particle Size 788 Injectable
LO 788 Injectable
MM 789
Ophthalmic LO
789 Ophthalmic
MM 10m 6000 per
container 3000 per container
50/mL 50/mL
25m 600 per container 300 per container 5/mL 5/mL 50m No specification No specification No
Specification 2/mL
What’s Visible? It Depends…
Brewer & Dunning: about 30m Akers, MJ; Larrimore, DS and Guazzo, DM. Parenteral Quality Control,
Drugs and the Pharmaceutical Sciences, vol 125, 3rd Ed. Marcel Dekker, 2003.
Turco & King: near 50m Turco S and King RE, editors. Sterile Dosage Forms, Chapter 6,
Handling and Administration, Young RE. Lea & Febiger, Philadelphia, PA, 1979, pg. 120.
Delly: 85-100m Delly JG. The Microscope, Diffraction Lines Editorial, The Eyes Have It,
1998, Vol. 37, No. 2, pg 195-211. 70% probability of detecting a single 150m particle
Shabushnig, Melchore, Geiger, Chrai and Gerger, PDA Annual Meeting 1995
FDA Review of Recent PM Data295 Drug Applications (SVP’s, by LO)*
ASEPTIC
PROCESS
TERMINAL STERILE
PROCESS
# Batches 294 112
USP <788>
Limits
6000 ≥10m 600 ≥25m 6000 ≥10m 600 ≥25m
Mean (± 1SD)
Mean + 3SD
245 (438)/pkg
1560/pkg
17 (45)/pkg
153/pkg
154 (289)/pkg
1021/pkg
10 (24)/pkg
82/pkg
ALL – 406 lots
(354 in glass vials)
1983 data (19 LVP products by membrane)
Mean (± 1SD) 219 (415)/pkg 15 (43)/pkg 59 (89)/mL 13 (27)/mL
Mean + 3SD 1504 151 n/a n/a
* Nath, et al. Particulate Contaminants of Intravenous Medication and the Limits set by USP General Chapter <788>, 2005 Pharm. Forum