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


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


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



Particle Complexity


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


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



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


Compendial Guidance


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


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


Visual Inspection System


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


Ideal Acceptance Characteristics for Automatic InspectionKnapp and Abramson, J Par Sci Tech 44(2), 1990


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


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.



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?


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


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



Particle Lab as Nexus


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


Systematic Particle Investigation

Detection Isolation Characterization Identification Source Remediation



Forensic Investigation of Particle Identity


Inspection

Pol Light MicroscopyPol Light MicroscopyIR/d-Raman MicrospectroscopyIR/d-Raman Microspectroscopy

Stereomicroscopy ExamStereomicroscopy Exam

SEM-EDXSEM-EDX


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

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>



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.

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Compendial requirements for particle testing 2014

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