Compendial requirements for particle testing 2014
Click here to load reader
-
Upload
d-scott-aldrich -
Category
Presentations & Public Speaking
-
view
956 -
download
10
description
Transcript of Compendial requirements for particle testing 2014
© European Compliance Academy (ECA)
Compendial Requirements for Particle Counting
and Strategies for Particle Identification
Scott Aldrich – Ultramikro LLC
March 25-26, 2014 Düsseldorf Germany
© European Compliance Academy (ECA)
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?
2 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© European Compliance Academy (ECA) 3 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
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)
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
4 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© European Compliance Academy (ECA)
Particle Complexity
5 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
Individual Particle
Heterogeneous aggregate
Crystalline
Non-crystalline
Homogeneous aggregate
Aggregated by Matrix
Nucleated
Phase growth
Layered
Crystalline States•Hydrate•Polymorph
Oligomerized
Combination Product growth
© European Compliance Academy (ECA) 6
Particulate Matter Size Ranges
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
<1 µm 1- 100 µm >100 µm
Subvisible VisibleSubmicron Aggregates
Narhi, et al. J Pharm Sci, 2012
ECA Dusseldorf/Compendial Requirements for Particle testing 2014
Methods Useful for Probing the Domain
© European Compliance Academy (ECA)
Particle Categories
Extrinsic Intrinsic Inherent
Wild, Outside the System Inside the System Is the System:SolutionMicellesEmulsionColloid
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 StableSame TOR as EOS
Single to Many Particles Various Physical States Defined active ingredient
May be Considered Most Objectionable
Needs Planning & Control Most Acceptable, Known
7 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© European Compliance Academy (ECA)
Visible Particle Content USP <1> Injections
• “…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
8 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
Compendial Guidance
© European Compliance Academy (ECA)
Probability of Detection
Knapp Studies 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
9 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
0
20
40
60
80
100
0 50 100 150 200 250
Particle Size (um)
Dete
ctio
n Pr
obab
ility
(%)
Borchert
Knapp
Ryan
Androver
Borchert
Melchore
One-Pass Simple Manual Inspection, Trained Inspectors, Seeded ProductPDA Annual Meeting 1995: Shabushnig, Melchore, Geiger, Chrai and Gerger
AZ
RZ
Visible Particulate Matter Detection is Probabilistic
© European Compliance Academy (ECA)
Visual Inspection System
10 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
Inspector Selection
Knapp StudiesKnapp Studies
Procedural Selection and Refinement
Procedural Selection and Refinement
Testing InspectorsWith Standards
Testing InspectorsWith Standards
Inspector Familiarizationwith Typical Defects
Inspector Training
Defect InvestigationDefect Investigation
Product Inspection & Release
Qualified Inspector
© European Compliance Academy (ECA)
Ideal Acceptance Characteristics for Automatic InspectionKnapp and Abramson, J Par Sci Tech 44(2), 1990
11 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
Accept + Gray Zone 0 – 0.7 Reject Zone 0.7 – 1.0
Acc
epta
nce
Pro
babi
lity
0.5
1
Single Manual InspectionBenchmark
Reject in Either of TwoSerial Inspections- Best For Patient
Accept in Any of ThreeSerial Inspections- Best for Producer
© European Compliance Academy (ECA)
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
12 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© European Compliance Academy (ECA)
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.
13 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© European Compliance Academy (ECA) 14 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
Harmonized <788> LimitsHarmonized <788> Limits
Two methods = "two-tiered approach”Light Obscuration is the preferred first passMembrane 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
≥ 10µm ≥ 25µm ≥ 10µm ≥ 25µm
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) 15 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
Current USP <789> LimitsCurrent USP <789> Limits
USP Chapter <789>--Particulate Matter in Ophthalmic Solutions• Official for the subvisible particle limits of ophthalmic products
• All limits on a per mL basis.
<789> Methods are essentially <788>
Why only two thresholds for LO?
Method 1 - LO Method 2 - Microscope
≥ 10µm ≥ 25µm ≥ 10µm ≥ 25µm ≥ 50µm
50 per mL 5 per mL 50 per mL 5 per mL 2 per mL
© European Compliance Academy (ECA)
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
16 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© European Compliance Academy (ECA)
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
17 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© European Compliance Academy (ECA)
Particle Lab as Nexus
18 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
Particle Lab Capabilities•Inspection•Microscopical Methods
• Macro – Micro• Particle Manipulation• Microchemical Tests• Photography• PLM• Thermal
•Spectroscopy•Particle Counting•Elemental Analysis
Particle Lab Capabilities•Inspection•Microscopical Methods
• Macro – Micro• Particle Manipulation• Microchemical Tests• Photography• PLM• Thermal
•Spectroscopy•Particle Counting•Elemental Analysis
QC Release788-1, 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 MethodsMaterial Science•Unknowns•Excipient Evaluation•Polymorphism•Material Selection
© European Compliance Academy (ECA)
Systematic Particle Investigation
Detection Isolation Characterization Identification Source Remediation
19 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© European Compliance Academy (ECA)
Forensic Investigation of Particle Identity
20 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
Inspection
Pol Light MicroscopyPol Light MicroscopyIR/d-Raman MicrospectroscopyIR/d-Raman Microspectroscopy
Stereomicroscopy ExamStereomicroscopy Exam
SEM-EDXSEM-EDX
© European Compliance Academy (ECA) 21 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
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)
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
22 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© European Compliance Academy (ECA)
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
23 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© 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
24 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© 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
OphthalmicProducts
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. TestsMethod trainingQualification
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… AlimentaryProducts
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 Method6000 ≥10µm600 ≥25µm
25/mL ≥10µm; NMT 60003/mL ≥25µm; NMT 600
None – discussion of pros and cons
Methods:LO6000 ≥10µm600 ≥25µmMM3000 ≥10µm300 ≥25µm
None - Details for LO and MM methods
Intraocular:<789>Extraocular:<788>
25 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© 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
26 ECA Dusseldorf/Compendial Requirements for Particle testing 2014
© 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.
27 ECA Dusseldorf/Compendial Requirements for Particle Testing 2014