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Compendial requirements for particle testing 2014

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Particulate Matter - European Compliance academy

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Compendial requirements for particle testing 2014

  1. 1. Compendial Requirements for © European Compliance Academy (ECA) Particle Counting and Strategies for Particle Identification Scott Aldrich – Ultramikro LLC March 25-26, 2014 Düsseldorf Germany
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 19. Systematic Particle Investigation  Detection  Isolation  Characterization  Identification  Source  Remediation © European Compliance Academy (ECA) ECA Dusseldorf/Compendial Requirements for Particle testing 2014 19
  20. 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. 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. 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. 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. 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. 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. 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. 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

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