clean and stable ds aldrich aaps nbc may 2010 low rez
TRANSCRIPT
Clean and Stable: Product Stability and the Investigation of Particle ContentScott AldrichAAPS-NBC May 19, 2010
Outline
Pharma Products and PresentationsCompendial Requirements – Particle LimitsMicroscopy ApplicationsSize DomainsThe Microscopical PathTricks of the TradeAltered States
CleanStable
Pharma Liquid Products and Presentations
PARENTERAL PRODUCTS, AQUEOUS AND NON-AQUEOUS
Small Molecule; <1000mwLarge Molecule; >1000mwLow ConcentrationHigh Concentration
Ophthalmic SystemsOthers
Novel DeliveriesSub-Q SystemsDiffusion substrates
Package SystemsGlass
Vial/closureAmpoule
PlasticBlow-Fill-SealFormed sheets
SyringesPre-filled SyringesDevicesDelivery (IV) SetsCommercial RTU’s
FormulationsLiquid, asepticLiquid, terminalLyophilized LiquidsSuspension, asepticSuspension, terminalDry-filled sterile powdersEmulsionsNano-particles
Compendial RequirementsUSP Chapter <1> InjectionsUSP Chapter <788> Injections/<789> Ophthalmic ProductsUSP/EP/JP have Harmonized <788> PM TestingPharm. Forum re: Chapter <788>:
IM and Sub-Q proposed to meet <788> Pharm. Forum 35[3] May-June 2009, page 628
Radiopharmaceuticals are exempt from <788> limitsParenteral products for which labeling specifies use of a final filter are exempt from <788>, must have scientific data to justify the exemption (do your homework).Irrigating solutions are exempt.
PARTICULATE MATTER QUANTITATION
Compendial Methods USP/EP/JPLight Obscuration (LO)
Instrument Standardization TestsCalibration
Membrane Microscopy (MM)Calibration SetupCalibration day-of-Use
Alternate methodsElectrozone (Coulter) Microscopy Image Analysis
OpticalElectron
Laser diffractionNephelometryFlow MicroscopyPhoton Correlation Spectroscopy
USP Chapter <788> Particulate Matter Limits with EP, JP HarmonizationMethod 1 - LO Method 2 - Microscope
Parenteral Volume
≥
10μm ≥
25μm ≥
10μm ≥
25μm
SVI ≤
100mL6000per
container
600per
container
3000per
container
300per
containerLVI
above 100mL
25per mL
3per mL
12per mL
2per mL
USP Chapter <789> Sub-visible Particle Limits for Ophthalmic Solutions.
Method 1 - LO Method 2 - Microscope
≥
10μm ≥
25μm ≥
10μm ≥
25μm ≥
50μm
50 per mL 5 per mL 50 per mL 5 per mL 2 per mL
Comparison of Injectable & Ophthalmic Solution Product Particulate Load Limits As 5mL Fill Volumes.
Particle Size by M embrane
Assay
USP Limits <788> 5mL Injectable
Volume
USP Limits <789> 5mL Ophthalmic Volume
≥10μm 3000 part./container 250 particles in a 5mL container or 50 particles/mL
≥25μm 300 part./container 25 particles in a 5mL container or 5 particles/mL
≥50μm No specification 10 particles in a 5mL container or 2 particles/mL
Particle Count by Membrane Microscopy –Limits for Liquid Products
What are Particles?Insoluble, mobile solids/semi-solidsSingle entityAggregates
one speciesmultiple specieschemical interactions
Foreign to the Process: ExtrinsicPart of the Process/Product: Intrinsic
Process function failureFormulation/Package origin
Studying the Particle Load aids Refinement of the Final Product
Particulate Matter vs. Foreign Matter“Particulate matter” includes all forms of unwanted solids to immiscible liquidsIntrinsic – of most concern for Development
Debris addition is common and a continual challenge for the assembly process. Minimize and Control…
Processing Equipment, Primary Package
Product contact materials (e.g. stainless steel, aluminum, glass, rubber, silicone oil)
Present or growing - Formulation, PackageActive and other ingredientsPackage design, vendor selection, process
Extrinsic – Truly ForeignEnvironmental Contaminants
Biological matter, hair, fibers, paint, rust, soils, building material +
To Put it Simply….
Parenteral Product Physical QualityClean Stable
Product character and robustness investigations are primary activities in Development
Visible Sub-visible Sub-micrometer
Size Domains
1µm25µm 10µm150µm
Increasing Probability of Detection
What size domain will matter for the product stability?
Visible Gray zone
What size domains are used for product release?
What are Particles?Insoluble, mobile solids/semi-solidsSingle entityAggregates
one speciesmultiple specieschemical interactions
Foreign to the Process: ExtrinsicPart of the Process/Product: IntrinsicStudying the Particle Load aids Refinement of the Final Product
Product Particle Quality Issues
CleanExtrinsic material
Package conditionManufacturing equipment downstreamFilling equipmentPersonnel practicesAssembly arena cleanliness
StableFormulation-related changeProduct-Package interaction
Particle Analysis
Start with visual examinationConfirm in situisolate single particle, orfilter isolate
MicroscopySpectroscopyElemental AnalysisWhat Next?
The Microscopical Path (Using a magnification ladder throughout)
ObservationsAppearance, Context, Nature
First TestsPhysical characteristics
Next TestsChemical Characteristics
Analytical Electron MicroscopySpectroscopy
Microscopical Path
Observations (Use the ladder)ColorLusterTransparencyHomogeneityAssociationHabitSizeNatureInterior and Exterior content
Microscopical PathFirst Tests
Pressing to assess hardness, matrix, componentsHeating to red heat on quartz or Pt:
No change, decrepitation, melting: In/OrgDecomposition, flaming, bubbling, charring, smoking: OrgSublimation: OrgGlowing: carbonAsh: In fillers, Org saltsOxides: metals
Thermal analysis on the microscope stage; microfurnace, general hot-stage methods
Using Kofler, Mettler, LinkamCrystallinity changes, melt, water/solvent loss, degradation
What may be used in subsequent analyses?
Microscopical PathNext Tests
Solubility/Exposure to SolventsHumidification chamber exposureSelected microchemical and functional group tests
ElementalChamot & Mason, Benedetti-Pichler
InorganicWinchell & WinchellFeigl & Anger
OrganicShriner, Fuson, Curtin, MorrillMcCrone et alWinchell & WinchellFeigl & Anger Schneider
Functional Groups, CategoriesStahlMcCrone et al
The Microscopical PathBegin simply
Always simplest first – Occam’s razor!Simple to complex analytical progression
Visual InspectionIsolationLight microscopical Evaluation
Visual-Low-High magnificationStereomicroscopyPolarized Light Microscopy
Determination of PM NatureSingular to Ensemble associationParticle Size, NumberMatrices, UOM’sSize, shape, functional groups, solubilityCrystallinity, particle nature
Electron MicroscopyForm, AssociationElemental analysis
SpectroscopyIRRaman
Mass SpectrometryChoose your modeTOF-SIMS
Chromatography
Observations across all Microscopies
HabitFlakeRodAcicularEquantTablet/PlateFiberLath
Refractive Index (n)Dispersion of nDegree of TransparencyColorResolution is…?
Michel-Levy Chart
Retardation (nm)=1000 x t(μm) x b (ηhigh - ηlow )
ThicknessBirefringence
Interference Colors
Microscopy Tricks of the TradeMaintain visual connection as much as possible
Withdrawal from fluidsCapillary tubes: Wiretrol™
Can you see the isolateCan you beam it?
FiltrationSedimentationLocation on/in solids
Change views oftenTransmittedOblique/darkfieldSingle polCrossed polsFilters; ¼ wave, 1° RedUnder stress
PressureHeatSolvent Exposure
Physical TestsMagnetic attractionHardness via cover slip: Locard’sexchange principle – put it to workWater exposure – what happens upon humidification?
Visual – Stereomicroscopy –Compound Pol – Electron microscopy
Photographs are great, but can you draw it? Observations are refined by the need to render accurate drawings.
Isolation MethodsDirect removal, dry
Tungsten wire, 1-5µm tipCat’s whiskerFine scalpel, cleaver (MicroTool)Facilitate with water, or weak known adhesive
Direct removal, wetCapillary tube (Wiretrol)Poly tube, drawn to fine tipMembrane swipe
FiltrationCentrifugationTransfers, Concentrators
Dried KBrCleaned filter paperCapillaries
Anything by Anna Teetzov
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
• LayeredCoated
• Crystallinity• None Evident
• Amorphous• Methods?
• Evident -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
Microscopy PathwayCollection of Properties
Size, Shape, Color, Hardness, AssociationRef. Indices, Birefringence, Crystal System
Simple ExperimentsSolubility
What extracts, separates?Heating studiesFunctional Group Tests
Feigl, Stahl, Chamot & Mason, Benedetti-Pichler, McCrone et al
Comparison to Known MaterialsPublic DatabaseInternal DatabaseCareful examination of components, process
Normal States
GMP rules and conditionsParenterals – USP chapter <1>
CleanStable
Dry productsOther products’ specific needs
Altered States
ChangesHas the entity been changed?Can the entity be changed?
The Nature (or State) 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
• LayeredCoated
• Crystallinity• None Evident
• Amorphous• Methods?
• Evident -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/EXTRINSICSingle event/Unchanging
-environmental-machine-personnel-inadequate prep/cleaning-closure source
INTRINSIC/MULTIPLE EVENTGROWTH/INTRINSIC/CHANGING
Package ChangeLeaksIngredient purity/changeActive purity/changeProduct-Package interaction
CHANGE MECHANISMSCoalescenceSedimentationNucleationCrystallization
Hydrate FormationSolvate FormationPolymorphismSalt Formation
DegradationChemicalPhysical Effects
TemperatureShearLight
OxidationOligomerizationImpuritiesDrug Concentration Effects/MicellesLeaching/Extraction
PLM
Spectroscopy
Hotstage
Material Ultramicroanalysis Diagram
(Light Obscuration)Membrane Isolate
Picking
Direct SEM-EDS Count
Optical Count
PLM-Spectroscopy
Direct SEM-EDS
ID
Quant
Observations drive next analyses
Studying the Occurrence
Point Source or General Load? Mfg. Points of ContactBatch CharacterProduct CharacterFacility ImpactProcess Effects
Next Studies/Directions
Particulate Matter Remediation
DetectionIsolationCharacterizationIdentificationRemediation/control
Investigation of ChangeProcess ImprovementsSTABILITY PROGRAM
Defined Stability SetsCyclical Analysis
Fundamental Properties of High Quality Commercial Products
Product Form Well-DescribedProduct Use Well-UnderstoodProduct Appearance Consistent to the Level of Detection SensitivityConsensus of Defect Definition
CategoryIdentityEffect or Importance Defined for Ongoing Product Improvement
CriticalMajorMinor
Investigation of Defect Source(s) follow from and Utilize Particle ID
Scott AldrichScott Aldrich is a long-standing member of American Chemical Society, State Microscopical Society of Illinois 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 Pharma industry, through employment at Upjohn, Pharmacia, and Pfizer. He is currently Principal Consultant for Ultramikro, LLC an independent consulting firm specializing in microscopy training and particulate matter control programs.