Compendial requirements for particle testing 2014

Compendial Requirements for
© European Compliance Academy (ECA)
Particle Counting
and Strategies for Particle Identification
Scott Aldrich – Ultramikro LLC
March 25-26, 2014 Düsseldorf Germany

Outline
 Particle Definition & Discussion
• Size Ranges
• Categories
• Nature
 Visibility
 Compendial Guidance
• U.S. – EU - Japan
 Specific USP Chapters
 Particle Investigation and Control
 What’s Next?
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 2

What is Particulate Matter?
 “Particulate matter in injections and parenteral infusions consists of
mobile undissolved particles, other than gas bubbles,
unintentionally present in the solutions.” (USP <788>) (EP 2.9.20)
 We monitor the Visible and Subvisible Size Domains
 What is Being Seen?
• Substances detected by unaided human vision within a small time
window
 What is being counted?
• Not just single, hard particles
 any immiscible to semi-solid to solid material, soft to hard, transparent to opaque may
be counted as a particle
 singular solids, aggregates, drug solids, salts, polymorphs, gels, lubricants, plasticizers
© European Compliance Academy (ECA) ECA Dusseldorf/Compendial Requirements for Particle testing 2014 3

Particle Definition and Categorization
 For All Particles:
• Mobile (not attached?)
• Undissolved (Lyo recon? Recrystallization? Immiscibles?)
• Not air bubbles (not oil?)
 Particles may be many things
• Single
• Aggregated
 Matrix?
 Heterogeneous?
• Non-crystalline vs. crystalline
• Complex
 Layered
 Nucleated

Individual Particle
Particle Complexity
Aggregated by Matrix
Heterogeneous aggregate
Crystalline
Non-crystalline
Homogeneous aggregate
Nucleated
Phase growth
Layered
Crystalline States
•Hydrate
•Polymorph
Oligomerized
Combination Product growth

Particulate Matter Size Ranges
Narhi, et al. J Pharm Sci, 2012
<1 μm 1- 100 μm >100 μm
Submicron Subvisible Visible
Aggregates
Methods Useful for Probing the Domain
 SEC (Size Exclusion
Chromatography)
 FFF (Field Flow
Fractionation)
 SDS-Page Gels
 AUC (Analytical Ultra-
Centrifugation)
 Light Obscuration
 Microscopy
 Flow Microscopy
 Coulter Counter
 Image Analysis
 Microscopy
 Inspection
 Manual
(Human)
 Semi –
Automated
 Automated
© European Compliance Academy (ECA) ECA Dusseldorf/Compendial Requirements for Particle testing 2014
6

Particle Categories
Extrinsic Intrinsic Inherent
Wild, Outside the System Inside the System Is the System:
Solution
Micelles
Emulsion
Colloid
Protein Assembly
Extremes are “Filth” Product-contact n/a
Microbial Vector May have Microbial Content Formulation-Relevant
Uncontrolled Unplanned Controlled, Expected
Additive Additive or Changing Stable
Same TOR as EOS
Single to Many Particles Various Physical States Defined active ingredient
May be Considered Most
Objectionable
Needs Planning & Control Most Acceptable, Known

Visible Particle Content
 USP <1> Injections
Compendial Guidance
• “…presence of observable foreign and particulate matter…”
• “…every lot of all parenteral preparations is essentially free from visible
particulates.”
 EP <6.0> Parenteral Preparations, Injections
• “…clear and practically free from particles.”
 JP <6.06> Foreign Insoluble Matter Test for Injections
• “…must be free and clear from readily detectable foreign insoluble
matter.”
 World Health Organisation
 British Pharmacopeia
 Korea, China, India

Probability 100
of Detection
80
60
40
20
 Knapp Studies
RZ
Visible Particulate Matter
Detection is Probabilistic
 Accept Zone 0 to 0.30 p < Gray Zone 0.3 to 0.70 p < Reject Zone 0.70 p
 “Essentially Free” meaning
 “Visible particle quality is the last holdout of philosophical vs. scientific quality
requirements”…JZ Knapp
 New USP GC <790> offers acceptance criterion for samples
 PM is Major = 0.65% AQL per ANSI/ASQ Z1.4 - 2003
0
0 50 100 150 200 250
Particle Size (um)
Detection Probability (%)
Borchert
Knapp
Ryan
Androver
Borchert
Melchore
One-Pass Simple Manual Inspection,
Trained Inspectors, Seeded Product
PDA Annual Meeting 1995:
Shabushnig, Melchore, Geiger, Chrai and Gerger AZ

Visual Inspection System
Inspector Selection
Procedural Selection
and Refinement
Testing
Inspectors
With Standards
Qualified Inspector
Product Inspection & Release
KKnnaapppp S Stutuddieiess
Procedural Selection
and Refinement
Testing
Inspectors
With Standards
Inspector Familiarization
with Typical Defects
Inspector Training
DDeefefecct tI nInvveesstitgigaatitoionn

Ideal Acceptance Characteristics for Automatic Inspection
Knapp and Abramson, J Par Sci Tech 44(2), 1990
1
Accept + Gray Zone 0 – 0.7 Reject Zone 0.7 – 1.0
Reject in Either of Two
Serial Inspections
- Best For Patient
Acceptance Probability
0.5
Single Manual Inspection
Benchmark
Accept in Any of Three
Serial Inspections
- Best for Producer

Subvisible Content and Determination
 Two Methods with 10μm and 25μm size thresholds for counting
 Primary method is an optical particle counter - Light Obscuration
(LO) - for moving fluid
• What is being measured electronically?
 Size is Equivalent Circular Diameter of suspended substance
 Optical particle counter will register air and immiscible liquids as “particles”
 Secondary method - Membrane Microscopy (MM) - fluid filtration
and membrane capture, with light microscopy count
• What is being measured microscopically?
 Particles retained on a membrane may appear different than in their “wet”
state
 Size is Longest Chord

Compendial Guidance for Subvisible Content
 Harmonization of the Major Compendial Chapters
 Pharmacopeial Discussion Group through ICH
 European Pharmacopoeia (Ph. Eur.): 5th Edition (official on January 2005), Particulate
Contamination: Sub-visible Particles (reference 01/2005:20919).
 Japanese Pharmacopoeia (JP): 6.07 Insoluble Particulate Matter Test for Injections as
it appears in the JP Fifteenth Edition (March 31, 2006, The Ministry of Health, Labour
and Welfare Ministerial Notification No. 285).
 United States Pharmacopeia (USP): <788> Particulate Matter in Injections, Revision
Bulletin, April 4, 2007.

HHaarrmmoonniizzeedd <<778888>> LLiimmiittss
Two methods = "two-tiered approach”
Light Obscuration is the preferred first pass
Membrane Microscopic method is run if LO results are
suspicious, or fail limits, or alone when LO cannot be run
(emulsions)
Method 1 – LO Method 2 - Microscope
Parenteral
Volume
³ 10mm ³ 25mm ³ 10mm ³ 25mm
SVI
100 mL and lower
6000 per
container
600 per
container
3000 per
container
300 per
container
LVI
above 100 mL
25 per mL 3 per mL 12 per mL 2 per mL
Should there be a Total Load limit for LVI’s?

CCuurrrreenntt UUSSPP <<778899>> LLiimmiittss
 USP Chapter <789>--Particulate Matter in Ophthalmic Solutions
• Official for the subvisible particle limits of ophthalmic products
• All limits on a per mL basis.
Method 1 - LO Method 2 - Microscope
³ 10mm ³ 25mm ³ 10mm ³ 25mm ³ 50mm
50 per mL 5 per mL 50 per mL 5 per mL 2 per mL
<789> Methods are essentially <788>
Why only two thresholds for LO?

Official, Scheduled and Planned
USP Chapters
 General Chapters
• <1> Injections
• <771> Ophthalmic Products
• <787> Subvisible Particulate Matter in Therapeutic Protein Injections
• <788> Particulate Matter in Injections
• <789> Particulate Matter in Ophthalmic Solutions
• <790> Visible Particulates in Injections
 Informational Chapters
• <1788> Methods for Determination of Particulate Matter in Injections and
Ophthalmic Solutions
• <1787> Measurement of Subvisible Particulate Matter in Therapeutic
Protein Injections
• <1790> Visual Inspection of Injectable Products for Particulates

Particle Investigation and Control
 Product and Process Knowledge is Imperative
 A Holistic Approach is Necessary
• No single count method, no single number can comprehensively monitor product
particle content and stability
• No single particle size or shape standard can represent the natural particle
population
 Particle Categories Matter
 Particle Complexity – Nature is a Key Identification Clue
 Compendial Limits are Configured for Broad Application – But Are Minimal
 Regulatory Expectations
• Meeting public standards
• Avoiding Failure
 High numbers
 High variability
 Point source
 Objectionable Particle Types
• Response to Incidents, Failure

Regulatory
•Responses
•Insert changes
•Registration Studies
Particle Lab as Nexus
Particle Lab Capabilities
•Inspection
•Microscopical Methods
Particle Lab Capabilities
•Inspection
•Microscopical Methods
• Macro – Micro
• Particle Manipulation
• Microchemical Tests
• Photography
• PLM
• Thermal
• Macro – Micro
• Particle Manipulation
• Microchemical Tests
• Photography
• PLM
• Thermal
•Spectroscopy
•Particle Counting
•Elemental Analysis
•Spectroscopy
•Particle Counting
•Elemental Analysis
QC Release
788-1, 788-2
Production Support
•Process Capability
• Component Prep
• Consumables Integrity
• Fixtures Wear
•Vendor Evaluation
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

Systematic Particle Investigation
 Detection
 Isolation
 Characterization
 Identification
 Source
 Remediation

Forensic Investigation of Particle Identity
SSteterreeoommicicrroossccooppyy E Exxaamm
Inspection
PPool lL Ligighht tM Micicrroossccooppyy
IRIR/d/d--RRaammaann M Micicrroossppeecctrtroossccooppyy
SSEEMM--EEDDXX

Forensic Investigation
 Categorical Description
 Level 1: Verify visible defect
 Provide Sample
 Evaluate physical state
 Level 2 – morphology, condition, size, any
immediate ID?
 Evaluate
 Microscopy – physical state
 Any AHAS ! ?
 Level 3
 Crystallinity
 Composition – elemental and molecular state
 elemental composition, spectroscopies, etc.

Examples of Particle Sources
 Extrinsic
• Hairs
• Biologicals
• Celluloses
• Fibers
• Insect parts
• Metals
• Glass
• Incoming Package
Cleanliness
 Intrinsic
• Glass Delamination
 High pH
 Aggressive formulation
• Metal
 Vial washer metal
 Valve wear
 Cannula strike
• Container Finishing
 Tungsten in staked-in syringes
 Rubber closure fragments
 Lehring debris
• Polymers
 Plasticizer extracts
 Whole plastic bits from wear
• Char from dry heat processing
• Haze and Precipitation Upon Use
 Dilution
 Chilling
 Blooms

Summary
 Compendial guidance provides the minimum benchmarks for
visible and subvisible particle content
 Visual inspection is not just manual, semiautomatic or automatic
processing – it consists of a comprehensive system of detection
 Subvisible determination methods are part of a system of particle
content monitoring and investigation

Expectations for Particle Methods…
 Performance of the method has been evaluated, and complies with
• cGMPs
• Regional expectations for calibration and particle count accuracy (e.g. ICH)
 Methods may have to be altered to fit the product.
 You and/or your contract labs are adept at the compendial methods and
can investigate further as necessary with orthogonal methods.
 While LO is excellent for routine release and trending a controlled
production process, it is not diagnostic for particle type.
 Comprehensive studies during Development have revealed process flaws
and typical particle types, sources have been investigated and have yielded
improvements.
 Control charting for particle load and variation with correlation to particle
types, sources and remediation efforts is an ongoing quality improvement
effort.
 Particle identity and sourcing is a systematic approach in your company

Summary of USP Guidance
<1> <790> <787> <1787> <788> <1788> <771>
Scope Injections Liquid
Products
Bio Products Bio Products Particle
Methods
Particle
Methods
Background
Ophthalmic
Products
Guidance Product Quality
and
Performance
Tests
Methods and
Acceptance
criteria for Visual
Inspection
Determining
Load for all
Particles
Probing the
inherent protein
character
Determining
Load for all
Particles
Inst. Std. Tests
Method training
Qualification
Product
Quality and
Tests
For… Liquids, Solids,
Emulsions,
Suspensions
Injections
Fluid Products Biotherapeutic
Products
Interrogation
of protein
formulations,
especially for
sub-10
Parenteral
Products
Particle
Determination
support
All current
Ophthalmic
Product forms
outside of
Monograph
direction
Not For… Alimentary
Products
Solids Protein
suspensions,
emulsions,
vaccines
Limits Veterinary,
irrigation,
radiopharma-ceuticals
and
filter-specified
Limits Non-Ocular
applications
Methods Many Manual Visual
Inspection
LO, qualitative
MM
Methods for 1-
100μm:
LO, LM, FM,
Nephelometry,
EC, LD, FTIR,
FTRS, SEM-EDX,
EELS
Quantitative
LO, MM
Visual
Inspection:
100%
for intra-
As-needed
for extra-
Limits Foreign and
Particulate
Matter
-Visual
inspection
<790>
-<788>
AQL criterion
for Major
defects:
0.65%
LO Method
6000 ≥10μm
600 ≥25μm
25/mL ≥10μm;
NMT 6000
3/mL ≥25μm;
NMT 600
None –
discussion of
pros and cons
Methods:
LO
6000 ≥10μm
600 ≥25μm
MM
3000 ≥10μm
300 ≥25μm
None -
Details for LO
and MM
methods
Intraocular:
<789>
Extraocular:
<788>

USP: What’s Next? Several revisions…
 <1> will include Implants and will reference <790>
 <790> and <787> will be Published May 1, Official August 1
 <1790> Completion and Review of Draft
 <1787> USP-EC vote in 2014
 <788>
 Revision planned to include Total particle load NMT 6000 ≥10μm/600 ≥25μm
 Will evaluate adding Flow Microscopy as 788-3 method
 Guideline method needed
 Limits?
 <1788>
 Adding considerations for method validation
 <789> to add third tier limit for LO
 <771>
• Broadly covers all ophthalmic dose forms
• Removed <751> Metal Particles in Ophthalmic Ointments
• PF publication July-August 2014

Bibliography
 Aldrich, D.S. and Smith, M.A. 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. 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, (2010).
 Barber, T.A. (1993). Pharmaceutical Particulate Matter - Analysis and Control, InterPharm Press, Buffalo Grove, IL.
 Borchert, S.J., Maxwell, R.J. Davison, R.L. and Aldrich, D.S. Standard Particulate Sets for Visual Inspection Systems:
Their Preparation, Evaluation and Applications. Pharm Sci and Tech., 1986, 265-276.
 Groves, M.J. Parenteral Products, the preparation and quality control of products for injection, Wm. Heinemann Medical
Books, Ltd., London 1973.
 Knapp, J.Z., Kushner, H.K. and Abramson, L.R. Particulate Inspection of Parenteral Products: an Assessment. J. Parent.
Sci. Tech. 1981; 35, 176.
 Knapp, J. Z., “Absolute” Sterility and “Absolute” Freedom from Particle Contamination, PDA J. Pharm Sci. Technol. 1997,
52, 4, 173-181.
 Langille, S.E. Particulate Matter in Injectable Drug Products. PDA J Pharm Sci and Tech 2013, 67, 186-200.
 McCrone, W.C. and Delly, J.G. (1973). The Particle Atlas, Volumes I-IV, Ann Arbor Science Publ., Ann Arbor, MI.
 Madsen R.E, Cherris R.T., Shabushnig J.G. and Hunt D.G. Visible Particulates in Injections – A History and a Proposal to
Revise USP General Chapter Injections <1>, Phar. Forum 35(5), pg 1383-1387, 2009.
 Melchore, J.A. and Berdovich, D. Considerations for Design and Use of Container Challenge Sets for Qualification and
Validation of Visible Particulate Inspection, PDA J Pharm Sci and Tech 2012, 66, 273-284.
 Nath N, McNeal E, Obenhuber D, et al. Particulate contaminants of intravenous medication and the limits set by USP
General Chapter <788>. Pharm. Forum 30(6), 2004.
 Stahl, E. (Editor) (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.
ECA Dusseldorf/Compendial Requirements for Particle Testing 2014 27

Compendial requirements for particle testing 2014

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