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© European Compliance Academy (ECA)
Particle Counting
and Strategies for Particle Identification
Scott Aldrich – Ultramikro LLC
March 25-26, 2014 Düsseldorf Germany
2. 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?
© European Compliance Academy (ECA)
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 2
3. 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
4. © European Compliance Academy (ECA)
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
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 4
5. Individual Particle
© European Compliance Academy (ECA)
Particle Complexity
Aggregated by Matrix
Heterogeneous aggregate
Crystalline
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 5
Non-crystalline
Homogeneous aggregate
Nucleated
Phase growth
Layered
Crystalline States
•Hydrate
•Polymorph
Oligomerized
Combination Product growth
6. 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
7. © European Compliance Academy (ECA)
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
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 7
8. 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
© European Compliance Academy (ECA)
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 8
9. 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
© European Compliance Academy (ECA)
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 9
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
10. Visual Inspection System
Inspector Selection
Procedural Selection
and Refinement
© European Compliance Academy (ECA)
Testing
Inspectors
With Standards
Qualified Inspector
Product Inspection & Release
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 10
KKnnaapppp S Stutuddieiess
Procedural Selection
and Refinement
Testing
Inspectors
With Standards
Inspector Familiarization
with Typical Defects
Inspector Training
DDeefefecct tI nInvveesstitgigaatitoionn
11. Ideal Acceptance Characteristics for Automatic Inspection
Knapp and Abramson, J Par Sci Tech 44(2), 1990
1
© European Compliance Academy (ECA)
Accept + Gray Zone 0 – 0.7 Reject Zone 0.7 – 1.0
Reject in Either of Two
Serial Inspections
- Best For Patient
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 11
Acceptance Probability
0.5
Single Manual Inspection
Benchmark
Accept in Any of Three
Serial Inspections
- Best for Producer
12. 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
© European Compliance Academy (ECA)
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 12
13. 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.
© European Compliance Academy (ECA)
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 13
14. 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?
© European Compliance Academy (ECA) ECA Dusseldorf/Compendial Requirements for Particle testing 2014 14
15. 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?
© European Compliance Academy (ECA) ECA Dusseldorf/Compendial Requirements for Particle testing 2014 15
16. 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
© European Compliance Academy (ECA)
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 16
17. 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
© European Compliance Academy (ECA)
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 17
18. Regulatory
•Responses
•Insert changes
•Registration Studies
© European Compliance Academy (ECA)
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
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 18
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
19. Systematic Particle Investigation
Detection
Isolation
Characterization
Identification
Source
Remediation
© European Compliance Academy (ECA)
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 19
20. Forensic Investigation of Particle Identity
© European Compliance Academy (ECA)
SSteterreeoommicicrroossccooppyy E Exxaamm
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 20
Inspection
PPool lL Ligighht tM Micicrroossccooppyy
IRIR/d/d--RRaammaann M Micicrroossppeecctrtroossccooppyy
SSEEMM--EEDDXX
21. 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.
© European Compliance Academy (ECA) ECA Dusseldorf/Compendial Requirements for Particle testing 2014 21
22. © European Compliance Academy (ECA)
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
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 22
23. 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
© European Compliance Academy (ECA)
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 23
24. © European Compliance Academy (ECA)
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
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 24
25. © European Compliance Academy (ECA)
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>
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 25
26. © European Compliance Academy (ECA)
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
ECA Dusseldorf/Compendial Requirements for Particle testing 2014 26
27. © European Compliance Academy (ECA)
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
Notas del editor All sterile injectable and ophthalmic products should be inspected for package integrity and, to the extent possible, for the presence of observable foreign and particulate matter (visible particulates). These unwanted particles arise from two sources, extrinsic, i.e., foreign matter, and intrinsic or product-related matter. Extrinsic matter cannot be associated with product or process. Intrinsic particles are added during assembly of the product or result from change over time. A third category, inherent matter, describes a physical state or particles that are an expected attribute of the product.
100% inspection of injectable products in clear packages is required to remove final packages with visible particles. When 100% inspection of the injectable product in the final package is difficult, such as in opaque containers, alternative methods may be used to determine acceptability. Visible Particulates in Injections &lt;790&gt; provides further guidance for general inspection methods and a definition of “essentially free of visible particles” for batch compliance.
Two general categories apply for product administration to the tissues in the eye. Intraocular administration includes all ophthalmic products which cross (penetrate) boundary tissue, such as cornea and sclera. Extraocular administration of ophthalmic products includes all other ocular components and spaces.
For subvisible particle content, the following USP guidance is followed: Products for intraocular use must comply with Particulate Matter in Ophthalmic Solutions &lt;789&gt;. Products for extraocular use must comply with Particulate Matter in Injections &lt;788&gt;. Considerations for product evaluation and the background for both subvisible methods are found in GC &lt;1788&gt;.