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Pda Visual Inspection 2009 Aldrich

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  • 1. Particulate Matter - Visual Detection to Identification Scott Aldrich PDA Visual Inspection, October 19-20, 2009
  • 2. 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
  • 3. Rules for Products
    • Appropriate Design
    • Robust Formulation
    • No Changes
      • Clean
      • Stable
  • 4. Visual Inspection
    • Often unappreciated as a diagnostic tool
    • Vital process for stability evaluation
    • Essential first step in particle identification process
    • Provides high-level overview of product character
  • 5. 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
  • 6. Visible Sub-visible Sub-micrometer Size Domains 1µm 25µm 10µm 150µm Increasing Probability of Detection What size domain matters for the product stability? Visible Gray zone
  • 7. 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
  • 8. 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
  • 9. Development Timeline & Distractions Small Scale Crud, ignored Package is Changing Small Batches, Few Containers Used First of many API Processes Clinical Scale Package and Presentation Defined – Set? Customer Use Experience
    • Full Scale/Launch
      • Process “Improvements”
        • Cost and Time-Saving
        • Unanticipated Insoluble/non-volatile
        • Substances
      • Vendor Lost or Changed
      • Ingredient Quality/Character different
      • than in Development
  • 10. 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
  • 11. Compendial Requirements Robust, 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.
  • 12. 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
  • 13. Particle Count by Light Obscuration – First Tier Groves, 1993 CONSTITUTES KEY FILING DATA
  • 14. Counting by Membrane Assay – Second Tier
    • Calibrate Optical Microscope at 100x for 10  m, 25  m 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
  • 15. The ID Process
    • Confirm
    • Isolate
    • Characterize
    • Identify
    • Locate
  • 16. What Constitutes a Defect? … Appearance and Evident Changes
      • Color
      • Haze
      • Solids/Particles
      • Container to Container Differences
      • Time of Release Failure
      • Trend over Time
      • 3 Sigma Failure ?
      • Catastrophic Failure
  • 17. 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!
  • 18. 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
  • 19. Capillary Removal and Transfer
  • 20. 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
  • 21. 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 Species
    • Microscopy-Spectroscopy Process of Characterization
    • Tracking Source from Character/Identity
  • 22. Inspection at Microscopy Bench Tools of the Trade The Particle Atlas
  • 23. 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
  • 24. Observations via Microscopy
    • Habit
      • Flake
      • Rod
      • Acicular
      • Equant
      • Tablet/Plate
      • Fiber
      • Lath
    • Refractive Index (n)
    • Dispersion of n
    • Degree of Transparency
    • Color
    • Resolution is…?
  • 25. 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
  • 26. 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 .
  • 27. Membrane Method for ID Isolation
  • 28. PLM Spectroscopy Hotstage Schemes for Material Ultramicroanalysis (Light Obscuration) Membrane Isolate Picking Direct SEM-EDS Optical Count PLM-Spectroscopy Direct SEM-EDS ID Quant
  • 29. 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
  • 30. 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
  • 31. Studying the Occurrence
    • Point Source or General Load?
      • Mfg. Points of Contact
      • Batch Character
      • Product Character
      • Facility Impact
      • Process Effects
    • Next Studies/Directions – Analytical Microscopy Partners with Formulation and Manufacturing
  • 32. Thanks for Your Attention Questions?
  • 33. Membrane Microscopic Count is Key Bio: 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.
  • 34. Parenteral and Ophthalmic Limits – A Comparison
  • 35. What’s Visible? It Depends…
    • Brewer & Dunning: about 30  m
      • Akers, MJ; Larrimore, DS and Guazzo, DM. Parenteral Quality Control, Drugs and the Pharmaceutical Sciences, vol 125, 3 rd Ed. Marcel Dekker, 2003.
    • Turco & King: near 50  m
      • Turco S and King RE, editors. Sterile Dosage Forms, Chapter 6, Handling and Administration, Young RE. Lea & Febiger, Philadelphia, PA, 1979, pg. 120.
    • Delly: 85-100  m
      • 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 150  m particle
      • Shabushnig, Melchore, Geiger, Chrai and Gerger, PDA Annual Meeting 1995
  • 36. FDA Review of Recent PM Data 295 Drug Applications (SVP’s, by LO)* * Nath, et al. Particulate Contaminants of Intravenous Medication and the Limits set by USP General Chapter <788>, 2005 Pharm. Forum n/a n/a 151 1504 Mean + 3SD 13 (27)/mL 59 (89)/mL 15 (43)/pkg 219 (415)/pkg Mean (± 1SD) 1983 data (19 LVP products by membrane) ALL – 406 lots (354 in glass vials) 10 (24)/pkg 82/pkg 154 (289)/pkg 1021/pkg 17 (45)/pkg 153/pkg 245 (438)/pkg 1560/pkg Mean (± 1SD) Mean + 3SD 600 ≥25  m 6000 ≥10  m 600 ≥25  m 6000 ≥10  m USP <788> Limits 112 294 # Batches TERMINAL STERILE PROCESS ASEPTIC PROCESS