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