Particulate matter evaluation and control for all Pharma products

1. Clean and Stable:
Product Stability and
the Investigation of
Particle Content
Scott Aldrich
AAPS-NBC May 19, 2010

2. Outline
Pharma Products and Presentations
Compendial Requirements – Particle Limits
Microscopy Applications
Size Domains
The Microscopical Path
Tricks of the Trade
Altered States
Clean
Stable

3. Pharma Liquid Products and
Presentations
PARENTERAL Package Systems
PRODUCTS, AQUEOUS Glass
Vial/closure
AND NON-AQUEOUS Ampoule
Small Molecule; <1000mw Plastic
Large Molecule; >1000mw Blow-Fill-Seal
Formed sheets
Low Concentration Syringes
High Concentration Pre-filled Syringes
Ophthalmic Systems Devices
Delivery (IV) Sets
Others Commercial RTU’s
Novel Deliveries Formulations
Sub-Q Systems Liquid, aseptic
Liquid, terminal
Diffusion substrates Lyophilized Liquids
Suspension, aseptic
Suspension, terminal
Dry-filled sterile powders
Emulsions
Nano-particles

4. Compendial Requirements
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 proposed to 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>, must have scientific data to
justify the exemption (do your homework).
Irrigating solutions are exempt.

5. PARTICULATE MATTER QUANTITATION
Compendial Methods USP/EP/JP
Light Obscuration (LO)
Instrument Standardization Tests
Calibration
Membrane Microscopy (MM)
Calibration Setup
Calibration day-of-Use
Alternate methods
Electrozone (Coulter)
Microscopy Image Analysis
Optical
Electron
Laser diffraction
Nephelometry
Flow Microscopy
Photon Correlation Spectroscopy

6. USP Chapter <788> Particulate Matter Limits with
EP, JP Harmonization
Method 1 - LO Method 2 - Microscope
Parenteral ≥ 10μm ≥ 25μm ≥ 10μm ≥ 25μm
Volume
SVI 6000 600 3000 300
≤ 100mL per per per per
container container container container
LVI 25 3 12 2
above per mL per mL per mL per mL
100mL

7. 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

8. Particle Count by Membrane Microscopy –
Limits for Liquid Products
C omparison of Injectable & O phthalmic Solution
Product Particulate L oad L imits A s 5mL Fill V olumes.
Particle Size U SP Lim its <788> U SP Lim its <789>
by M em brane 5m L Injectable 5m L O phthalm ic V olum e
A ssay V olum e
≥ 10 μ m 3000 part./container 250 particles in a 5mL
container or 50 particles/mL
≥ 25 μ m 300 part./container 25 particles in a 5mL
container o r 5 particles/mL
≥ 50 μ m N o specification 10 particles in a 5mL
container o r 2 particles/mL

9. What are Particles?
Insoluble, mobile solids/semi-solids
Single entity
Aggregates
one species
multiple species
chemical interactions
Foreign to the Process: Extrinsic
Part of the Process/Product: Intrinsic
Process function failure
Formulation/Package origin
Studying the Particle Load aids Refinement of
the Final Product

10. Particulate Matter vs. Foreign Matter
“Particulate matter” includes all forms of unwanted solids to immiscible
liquids
Intrinsic – 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, Package
Active and other ingredients
Package design, vendor selection, process
Extrinsic – Truly Foreign
Environmental Contaminants
Biological matter, hair, fibers, paint, rust, soils, building material +

11. To Put it Simply….
Parenteral Product Physical Quality
Clean
Stable
Product character and robustness
investigations are primary activities in
Development

12. Size Domains
What size domains are used for product release?
Visible Sub-visible Sub-micrometer
Visible
150µm 25µm 10µm 1µm
Gray zone
Increasing Probability of Detection
What size domain will matter for the product stability?

13. What are Particles?
Insoluble, mobile solids/semi-solids
Single entity
Aggregates
one species
multiple species
chemical interactions
Foreign to the Process: Extrinsic
Part of the Process/Product: Intrinsic
Studying the Particle Load aids Refinement of
the Final Product

14. Product Particle Quality Issues
Clean
Extrinsic material
Package condition
Manufacturing equipment downstream
Filling equipment
Personnel practices
Assembly arena cleanliness
Stable
Formulation-related change
Product-Package interaction

15. Particle Analysis
Start with visual examination
Confirm in situ
isolate single particle, or
filter isolate
Microscopy
Spectroscopy
Elemental Analysis
What Next?

16. The Microscopical Path
(Using a magnification ladder throughout)
Observations
Appearance, Context, Nature
First Tests
Physical characteristics
Next Tests
Chemical Characteristics
Analytical Electron Microscopy
Spectroscopy

17. Microscopical Path
Observations (Use the ladder)
Color
Luster
Transparency
Homogeneity
Association
Habit
Size
Nature
Interior and Exterior content

18. Microscopical Path
First Tests
Pressing to assess hardness, matrix, components
Heating to red heat on quartz or Pt:
No change, decrepitation, melting: In/Org
Decomposition, flaming, bubbling, charring, smoking: Org
Sublimation: Org
Glowing: carbon
Ash: In fillers, Org salts
Oxides: metals
Thermal analysis on the microscope stage; microfurnace,
general hot-stage methods
Using Kofler, Mettler, Linkam
Crystallinity changes, melt, water/solvent loss, degradation
What may be used in subsequent analyses?

19. Microscopical Path
Next Tests
Solubility/Exposure to Solvents
Humidification chamber exposure
Selected microchemical and functional group tests
Elemental
Chamot & Mason, Benedetti-Pichler
Inorganic
Winchell & Winchell
Feigl & Anger
Organic
Shriner, Fuson, Curtin, Morrill
McCrone et al
Winchell & Winchell
Feigl & Anger
Schneider
Functional Groups, Categories
Stahl
McCrone et al

20. The Microscopical Path
Begin simply Electron Microscopy
Always simplest first – Occam’s Form, Association
razor! Elemental analysis
Simple to complex analytical
progression Spectroscopy
Visual Inspection IR
Isolation Raman
Light microscopical Evaluation Mass Spectrometry
Visual-Low-High magnification Choose your mode
Stereomicroscopy
TOF-SIMS
Polarized Light Microscopy
Determination of PM Nature Chromatography
Singular to Ensemble
association
Particle Size, Number
Matrices, UOM’s
Size, shape, functional groups,
solubility
Crystallinity, particle nature

21. Observations across all
Microscopies
Habit
Flake
Rod
Acicular
Equant
Tablet/Plate
Fiber
Lath
Refractive Index (n)
Dispersion of n
Degree of Transparency
Color
Resolution is…?

22. Thickness
Michel-Levy Chart Birefringence
Interference Colors
Retardation (nm)=1000 x t(μm) x b (ηhigh - ηlow)

23. Microscopy Tricks of the Trade
Maintain visual connection as
much as possible Physical Tests
Withdrawal from fluids Magnetic attraction
Capillary tubes: Wiretrol™ Hardness via cover slip: Locard’s
Can you see the isolate exchange principle – put it to work
Can you beam it? Water exposure – what happens
Filtration upon humidification?
Sedimentation Visual – Stereomicroscopy –
Location on/in solids Compound Pol – Electron
Change views often microscopy
Transmitted Photographs are great, but can
you draw it? Observations are
Oblique/darkfield refined by the need to render
Single pol accurate drawings.
Crossed pols
Filters; ¼ wave, 1° Red
Under stress
Pressure
Heat
Solvent Exposure

24. Isolation Methods
Direct removal, dry
Tungsten wire, 1-5µm tip
Cat’s whisker
Fine scalpel, cleaver (MicroTool)
Facilitate with water, or weak known adhesive
Direct removal, wet
Capillary tube (Wiretrol)
Poly tube, drawn to fine tip
Membrane swipe
Filtration
Centrifugation
Transfers, Concentrators
Dried KBr
Cleaned filter paper
Capillaries
Anything by Anna Teetzov

25. The Nature of Material
• Association • Crystallinity
Singular • None Evident
• Liquid
• Amorphous
• Solid
• Combinations • Methods?
• Multiple • Evident -or- Continuum
• Aggregate/Agglomerate • “Liquid”: 2-D order
• no distinct boundaries • Solid: 3-D order
(matrix evident?) • Isometric (1 ri)
• boundaries?
• Uniaxial (2 ri)
• with similar material,
foreign material? • Tetragonal
• Groups of groups? • Hexagonal
• Homogeneous (trigonal)
heterogeneity? • Biaxial (3 ri)
• Polycrystalline • Orthorhombic
• Microcrystalline • Monoclinic
• Cryptocrystalline • Triclinic
• Layered • Sub-optimal solid state
Coated

26. 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

27. Normal States
GMP rules and conditions
Parenterals – USP chapter <1>
Clean
Stable
Dry products
Other products’ specific needs

28. Altered States
Changes
Has the entity been changed?
Can the entity be changed?

29. The Nature (or State) of Material
• Association • Crystallinity
Singular • None Evident
• Liquid
• Amorphous
• Solid
• Combinations • Methods?
• Multiple • Evident -or- Continuum
• Aggregate/Agglomerate • “Liquid”: 2-D order
• no distinct boundaries • Solid: 3-D order
(matrix evident?) • Isometric (1 ri)
• boundaries?
• Uniaxial (2 ri)
• with similar material,
foreign material? • Tetragonal
• Groups of groups? • Hexagonal
• Homogeneous (trigonal)
heterogeneity? • Biaxial (3 ri)
• Polycrystalline • Orthorhombic
• Microcrystalline • Monoclinic
• Cryptocrystalline • Triclinic
• Layered • Sub-optimal solid state
Coated

30. PARTICULATE MATTER
ORIGINS CHANGE MECHANISMS
Coalescence
ADDITIVE/EXTRINSIC Sedimentation
Nucleation
Single event/Unchanging
Crystallization
-environmental
Hydrate Formation
-machine
Solvate Formation
-personnel Polymorphism
-inadequate prep/cleaning Salt Formation
-closure source Degradation
INTRINSIC/MULTIPLE EVENT Chemical
GROWTH/INTRINSIC/CHANGIN Physical Effects
G Temperature
Package Change Shear
Leaks Light
Ingredient purity/change Oxidation
Active purity/change Oligomerization
Product-Package Impurities
interaction Drug Concentration
Effects/Micelles
Leaching/Extraction

31. Material Ultramicroanalysis Diagram
ID
Hotstage Quant
PLM
PLM-Spectroscopy
Spectroscopy
(Light Obscuration)
Direct SEM-EDS Membrane Isolate
Picking
Optical Count
Observations drive next analyses Direct SEM-EDS Count

32. Studying the Occurrence
Point Source or General Load?
Mfg. Points of Contact
Batch Character
Product Character
Facility Impact
Process Effects
Next Studies/Directions

33. Particulate Matter Remediation
Detection
Isolation
Characterization
Identification
Remediation/control
Investigation of Change
Process Improvements
STABILITY PROGRAM
Defined Stability Sets
Cyclical Analysis

34. Fundamental Properties of High
Quality Commercial Products
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 Defined for Ongoing Product Improvement
Critical
Major
Minor
Investigation of Defect Source(s) follow from and Utilize
Particle ID

35. Thanks for your
attention!
Questions?
info@ultramikro.com

36. Scott Aldrich
Scott 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.