2015 PDA Visual Inspection Forum DS Aldrich Presentation

2015 PDA Visual Inspection Forum | October 26-27, 2015 | Bethesda North Marriott Hotel and Conference Center | Bethesda, MD

The Parenteral Drug Association presents the…

2015 PDA Visual Inspection Forum October 26-27, 2015 | Bethesda, MD Bethesda North Marriott Hotel and Conference Center Exhibition: October 26-27 | Course: October 28-29

The leading meeting and exhibition dedicated to quality assurance of injectable products


Forensic Microscopy – The Process of Particle Identification

Scott Aldrich Ultramikro LLC

[email protected]


Outline • Introduction

– Integrated systems – Process of identification

• Level 1 Detection • Level 2 Separation and Description • Level 3 Identification Methods • Forensic Capability as Part of the Product Life Cycle

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Introduction • Analytical Resources Supporting the Visual

Inspection System are Essential • Forensic Microscopy Anchors the Process • Resources are Ideally Internal

– Engineering Support of Production – Visual Inspection Training – Laboratory Investigations

• When External, must be directed – Documentation of Defect – Direction of Analyses

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Visual Inspection Program

Inspector Selection

Knapp Studies

Procedural Selection and Refinement

Testing Inspectors With Standards

Inspector Familiarization with Typical Defects

Inspector Training

Defect Investigation

Product Inspection & Release

Qualified Inspector

Microscopy Lab


Process

• Level 1: Locate, Verify • Level 2: Isolate and Characterize

– Triage Process

• Level 3: Identify • Life Cycle promotes remediation

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Level 1 Detection • Duplicate original conditions

– Verify – Observe in Situ

• Initiate critical evaluation – Illumination – Dwell – Agitation

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Level 1 Detection and Observations • Is photography/videography in situ possible? • By…eye, low magnification, microscopy • What observations are possible?

– Size ( given lensing of container) – Color – Shape – Buoyancy – ??

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Level 2 - Separation, Description and Triage • The PM must be removed • All PM must be categorized • Categories must be explored

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Level 2 Separation and Description • Removal by Capillary

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Isolation and Manipulation Methods

• Direct removal, dry – Tungsten wire, 1-5µm tip – Cat’s whisker – Fine scalpel, cleaver (MicroTool™) – Facilitate with water or adhesive

• Direct removal, wet – Capillary tube (Wiretrol) – Poly tube, drawn to fine tip – Swipe of a Membrane wedge

• Filtration – Membrane selection/prep

• Centrifugation • Transfers, Concentration

– Dried KBr – Cleaned filter paper – Capillary tube

Teetsov 1977


Level 2 Separation and Description • Removal by Filtration

– 788 style method – Selection of media

• Modified cellulose esters • PVDF • Silver • Polycarbonate/Polyester • Gold-coated media

• Physical Removal – Mechanical separation

with MicroTool or wires – Dry Powder, Lyo cake, Packaging

– Panning: allowing foreign material to separate by gravity in a clean Petri dish - Suspensions

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Level 2 – Membrane Capture <788> 2

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Thin Flake (Poor Color Dispersal)

Long Fiber + Flake (Mottled Background)

100µm in 10µm divisions


Triage

• PM located by eye, verified at highest magnification

• PM moved to work area, examined dry, examined wet (water mount) – Aha?? – Next steps directed by observations

• Fundamental Testing

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Microchemical • Chemical tests are ideal when attempting a general

categorization of the unknown. General reference texts containing a wide variety of elemental spot tests, functional group, chemical categorization and complex material identification may be found in the following references: – Feigl: organic and inorganic spot tests – Chamot & Mason: fundamental methods and elemental tests – Stahl: practical spot tests for a variety of common materials

• Further, there are selections of tests for more common types of material that may end up in the sample, especially raw materials, commodities (starches, grains, brans, etc.), oils, fibers, excreta, etc.

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Wet Elemental Analysis

• Microchemical testing for suspect components – Elements – Functional groups – Complex materials (Stahl, 1973)

• Cellulose • Lipids/fats • Starch • Proteins

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Level 2 Process • A stepwise process

– Observations and tests • By Eye • By Magnifier • By Stereomicroscope • By Compound Microscope, ideally binocular PLM

– Microscopy Provides Context, Association, Direct ID

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Generally, we use the following sequence as a progression of analysis: visual → hand lens → stereomicroscopy → polarized light microscopy →

SEM-EDX → spectroscopy


Level 2 - Diagnosis

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• Morphology • Refractive Index • Birefringence (Michel-Levy) • Extinction • Elongation • Pleochroism

Bloss 1961


Microscopy Unit Operations • Applied polarized light microscopy

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McCrone 6-digit Binary code Opaque Colored Birefringent High Index (> n1.66) Flat Elongated-Needles or Rods 1 1 1 1 1 1 Value: 32 16 8 4 2 1: 0 to 63 score possible 0 0 0 0 0 0 Flat or Equant Not Flat Low Index (< n1.66) Isotropic Colorless Transparent McCrone WC, Delly JG. (1973). The Particle Atlas, Ann Arbor Science Publishers, Ann Arbor MI.


Particle Identity May Be Obvious

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…Or Not! Mixtures and Masses

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Level 3 Identification • Solid State Elemental

– SEM-EDX (WDX) and X-ray fluorescence – LIBS

• Micro-spectroscopy – Infrared – dispersive-Raman

• X-ray diffraction • Mass Analyses

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Solid State Elemental Analysis - SEM-EDX • Scanning Electron Microscopy – Energy-Dispersive

X-ray Spectrometry – Robust and Non-destructive – Periodic Table coverage > Z5 (boron)

– Lightest elements most difficult – Infinite thickness above 3-5 micrometers – Not Quantitative – See USP <1811>

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Solid State Elemental Analysis - LIBS

• Laser-Induced Breakdown Spectroscopy – Rapid analysis of the elemental constitution of

the unknown. – Laser excitation produces atomic emission

spectra from the (ultimately) destroyed particle. – LIBS can analyze all elements, limited by the laser

power and detector efficiency (as for almost all spectroscopical techniques)

– Provides relative, not highly quantitative, elemental abundance.

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Microspectroscopy

– Infrared • Functional groups strong in IR: C-F, Si-O, O-H, N-H, C-H;

C≡N, C=O, C-Cl, NO2

– dispersive-Raman • Functional groups strong in Raman: C≡C, C=C, N=N, S-

H, C=S, C-S, S-S, CH2, C≡N, C=O, C-Cl, NO2

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Spectroscopy Unit Operations

• Spectrometer is an Extension of the Microscope

• Location of Zones/Separation by Solvents • Spatial Resolution according to Technique • Specimen Prepared by Microscopical

Operations • Zone of Analysis Defined by Prior

Characterization 26


USP 1787 - Information Chapter for Particle Analysis • Methods

– Light Microscopy • Staining methods

– Light Obscuration – Dynamic Image Analysis (Flow Imaging) – Electrozone-Coulter – Laser Diffraction – Infrared and Raman Microspectroscopy – Electron Microscopy – EDX, EELS – ToF-SIMS

• Silicones discussed as particulate matter 27


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Particle Lab as Nexus Particle Lab Capabilities • Inspection • Microscopical Methods

• Macro – Micro • Particle Manipulation • Microchemical Tests • Photography • PLM • Thermal

• Spectroscopy • Particle Counting • Elemental Analysis

QC Release 788-1, 788-2

Production Support • Process Capability

• Component Prep • Consumables Integrity • Fixtures Wear

• Vendor Evaluation

Regulatory • Responses • Insert changes • Registration Studies

Inspection Standards • Generation • Verification

QA Support • AQL Rejects • Complaints • Recalls

R&D Support • CCC studies • Product Use Trials

• Inserts • Labelling

• Alternate Methods Material Science • Unknowns • Excipient Evaluation • Polymorphism • Material Selection


Thank You

Questions?

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References • Aldrich, D.S. and Smith, M.A. (1995). Chapter 9 - Pharmaceutical Applications of Infrared Microspectroscopy, in Practical

Guide to Infrared Microspectroscopy, Howard Humecki, Editor, Marcel Dekker 1995; New York, NY, 323-375. • Aldrich, D.S. (2010). Chapter 5 - Particulate Matter: Subvisible, in Pharmaceutical Dosage Forms: Parenteral Medications,

Nema S and Ludwig JD, eds. Third ed. Volume 2, Informa Healthcare, New York, pps. 114-145. • Barber, T.A. (1993). Pharmaceutical Particulate Matter - Analysis and Control, InterPharm Press, Buffalo Grove, IL. • Bloss, F.D. (1961). An Introduction to the Methods of Optical Crystallography, New York: Holt, Rinehart and Winston. • Chamot, E.M. and Mason, C.W. (1958). Handbook of Chemical Microscopy, Volume I, J. Wiley and Sons, Inc., New York, NY. • Chamot, E.M. and Mason, C.W. (1960). Handbook of Chemical Microscopy, Volume II, J. Wiley and Sons, New York, NY. • Feigl, F. and Anger, V. (1966). Spot Tests in Organic Analysis, Elsevier, New York, NY. • Feigl, F. and Anger, V. (1972). Spot Tests in Inorganic Analysis, Elsevier, New York, NY • McCrone, W.C. and Delly, J.G. (1973). The Particle Atlas, Volumes I-IV, Ann Arbor: Ann Arbor Science Publishers. • McCrone, W.C. (1982). Particle Characterization by PLM, Part I - No Polars. Microscope 30, 3, 185-196. • McCrone, W.C. (1982). Particle Characterization by PLM, Part II - Single Polars. Microscope 30, 4, 315-331. • McCrone, W.C. (1983). Particle Characterization by PLM, Part III - Crossed Polars. Microscope 31, 2, 187-206. • Stahl, E.; Ed. (1973). Drug Analysis by Chromatography and Microscopy, A Practical Supplement to Pharmacopoeias, Ann

Arbor Science Publishers, Ann Arbor, MI. • Teetsov, A. S. (1977). Techniques of Small Particle Manipulation, Microscope, 25: 103.

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2015 PDA Visual Inspection Forum DS Aldrich Presentation

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