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

Thanks for your attention!

Questions?

info@ultramikro.com

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.