Usp chemical medicines & excipients

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12th USP Science & Standards Symposium - New Delhi

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Usp chemical medicines & excipients

  1. 1. General Session I: Chemical Medicines and Excipients Tuesday, April 16, 2013 (11:00 a.m. to 1:30 p.m.) IPC–USP Science & Standards Symposium Partnering Globally for 21st Century Medicines
  2. 2. Moderator: Dr. Antony Raj Gomes Chair, USP Medicines Compendium Expert Committee
  3. 3. The Medicines Compendia Performance Based Monograph with Reference Procedure Antony Raj Gomas, Ph.D. Chair, USP Medicines Compendium Expert Committee
  4. 4. Introduction  What is Medicines Compendium?  Why is it relevant?  What are the benefits to Industry and regulators?  How the Medicines compendium works? 4
  5. 5. Introduction USP Medicines Compendium –  Public quality standards for medicines (Documentary and reference standards)  Medicines includes chemical and biological drug substances and products; excipients  Approved for marketing by national regulatory authorities outside of the U.S.  Does not include foods, traditional medicines/dietary supplements. 5
  6. 6. Introduction Why is USP publishing the MC?  Part of global public health mission  Availability of public standards - ensure medicines are of good quality.  Check on substandard, spurious, fake, falsified and/or counterfeit medicines.  USP’s global presence  National pharmacopeia of the United States  Work globally—with pharmacopeias  Standards without borders regulators, manufacturers, and other 6
  7. 7. USP MC – Scientifically Unique The MC offers an innovative approach to creating public monographs with reference materials. The process starts with a For Development Monograph that includes a Performance Based Monograph (PBM). This monograph provides tests for critical quality attributes and acceptance criteria, but does not give specific step-by-step procedures. Instead, it gives criteria for an acceptable procedure. The information in the PBM allows manufacturers to consider how they wish to develop their own acceptable procedures. The MC also incorporates Reference Procedures, which are developed by USP laboratories. This Reference Procedure is a procedure that can be used to test articles from multiple sources. An MC Reference Procedure is developed in a manner that identifies impurities associated with a product, regardless of the manufacturer’s process. The Reference Procedure in a MC monograph is developed by USP staff, collaborating with donors of information and materials. 7
  8. 8. USP MC – Scientifically unique Manufacturers also may submit information and materials to support more optimized controls for the medicines and their ingredients. These procedures are called Acceptable Procedures and are incorporated into the MC monograph. MC monographs are accompanied by validation data and reference materials, including Certified Reference Materials for assays and Reference Standards for impurities The MC is produced by a unique online-only process, including online commenting. The online-only approach enables anyone to freely access MC standards, and speeds standards development. 8
  9. 9. Identification and Prioritization of Candidates Identification  Approved by non-US national regulatory authorities Prioritize  Public Health Impact  Exposure to the population  Disease burden  Essential Medicines List 9
  10. 10. Scientific Liaison Process
  11. 11. Scientific Liaison Process (Continued) Scientific Review Identification of Preparation monographs for Development, after prioritization of Monographs for Development Review laboratory results of Reference Procedure development Identify the Reference Materials for development from the monographs Evaluation of laboratory results of Reference Material development Monograph Logistics Draft Reference Procedure in MC format Complete Reference Material data summary (recommend content and uncertainty values) Prepare Reference Procedure development data summary report (validation data) for posting with the Proposed Standard for Comment Prepares for Expert Committee Review Reference Procedure (in MC format) with validation data Reference Material data summary Other Acceptable Procedures with validation data 11
  12. 12. Topics  USP-MC Monographs  What is a Reference Procedure?  Critical characteristics of a Reference Procedure  Reference Procedure Development – Process – Solubility • Dissolution of solid oral drug products – Procedure Development – Forced Degradation Studies – Use of advanced technologies 12
  13. 13.  The MC Monograph MC monograph typically contains…  Tests, Procedures, and Acceptance Criteria  Tests are consistent with USP-NF (Identification, Assay, Impurities, Performance Tests,    Specific Tests) Tests are grouped into one of three separate sections  Performance Based Monograph (Core section)  Reference Procedures (containing monograph specific procedures for Assay and Impurities)  Acceptable Procedures (containing procedures meeting requirements of a criteriabased procedure, but not those of a reference procedure) Procedures differ from USP-NF and include both  Reference Procedures and  Criteria-based Procedures Acceptance Criteria are based upon the ICH Q6A, Q3A, and Q3B limits. 13
  14. 14. Performance Based Monograph  Universal Tests   Identification  Assay   Description Impurities Specific Tests   Content Uniformity   Performance Tests Others Criteria for Acceptance   Any Impurity NMT 0.1% (Includes both known as well as unknown)   Drug Substance, 98% - 102% Drug Product, 95% - 105% Criteria-based Procedures for Assay and Impurities  Procedure Performance Measures (Precision, accuracy, others)  Procedure Criteria of Acceptance (% RSD, Bias, R2, others)  Elemental Impurities 14
  15. 15. Need of a Reference Procedure  Analytical procedures for pharmaceutical products and components are typically derived from an understanding of the manufacturing process, i.e., what’s likely to be present.  These procedures are optimized to be as fast and simple as possible.  Where a party other than the manufacturer wishes to test a component or product, this type of detailed information is not available. 15
  16. 16. Need of a Reference Procedure  To complicate matters further, the global pharmaceutical marketplace includes components and products processed from different starting materials, having different manufacturing processes, and formulated using different excipients and strengths.  This diversity leads to vast array of specific tests and procedures to analysis nearly identical substances.  The goal of establishing a single reference procedure for each test in a pharmacopeia has therefore been a difficult one. 16
  17. 17. MC Approach – Reference Procedure  The MC approach deviates from tradition by developing reference procedures from a different perspective: – Rather than adapting a procedure that has been optimized to be fast and inexpensive by using a single manufacturer’s data; – USP labs develop and implement a procedure that is optimized to find all significant components in a substance through separation and multidimensional detection. – A Reference procedure is developed using a battery of analytical tools that are appropriate for the molecule and matrix. – HPLC / UHPLC + Photodiode Array (PDA) and Mass Spectroscopic (MS) detection in series – Evaporating Light Scattering Detector (ELSD), Corona Detector 17
  18. 18. Reference Procedure  Detailed procedural outline of the experimental details that are to be completed without significant modification.  The amount of modification allowed is included in the General Notices and referenced general Chapters. Reference Procedures can be  Chapter Based    Uniformity of Dosage Units <905>: Meets the requirements Monograph Specific Reference Procedures  Identification  Residual Solvents  Assay and Impurities (As per the requirements) 18
  19. 19. Reference Procedure (Continued) Reference Procedures should  Effectively measure a critical parameter of the monograph article  Adequately describe the solutions, conditions, and calculations necessary to make a meaningful measurement  Provide a validated and verifiable procedure that is source independent.  Validated according to <10>  Verifiable according to <10> for a manufacturers article  Source independence is an approximation, but should, in the best case, provide the ability to quantify the critical parameter measured by the Test regardless of the source of that material. 19
  20. 20. Critical Characteristics of Reference Procedure Target article For Development Monograph prepared using General Chapter <10> Authentic samples of the article Thorough Literature Review Pharmacopeias Procured from at least 2 independent sources More sources are better Published literature Reported synthetic and degradation routes 20
  21. 21. Monograph for development - PBM Monograph for Development PBM Dynamic Document • Prepared by Scientific Liaison • Tests for Identification, Assay, Impurities, etc. • Acceptance Criteria, wherever applicable • Possibilities for changes as we go forward during method development or • If additional information is available 21
  22. 22. “Proposed For Development” Monograph  List of “For Development” Monographs on the MC website 22
  23. 23. A Typical “Proposed For Development” Monograph Reference Procedure 23
  24. 24. Reference Procedure Development Literature Search - Pharmacopeia–USP, EP, BP, JP - Scientific Literature and Online and Paper Journals Procurement - Drug substance, Drug products, Impurities by Standards Acquisition department - Pharmacopeial impurities by Analytical Development department - Method Development by multi-source materials - Specificity studies - LC-MS Analysis for the forced degradation studies - Method finalization - Method validation - Data processing Share the Method validation data with the Scientific Liaison 24
  25. 25. - Method development completed - Transfer to the Scientific Liaison - If MC monograph is common to USP-NF, it provides additional new impurities for USP-NF Method Validation and Data Processing - Forced degradation studies - Acid - Alkali -Thermal - Peroxide - Light - Separation of degradation products (Identification, wherever possible) - Loops back to Method development, if needed Method Finalization - Solubility - Spectroscopic Identification - Assay - Related Substances - Use of multi dimension detectors / orthogonal detectors -LC-PDA-MS -GC-MS Specificity Studies Method Development Reference Procedure Development – In Lab Details Method Validation - Linearity - Accuracy - Precision -Day 1 -Day 2 -Day 3 Data Processing -Review of the validation data -Transfer to Scientific Liaison 25
  26. 26. Method Development Method Development - Solubility - Spectroscopic Identification - Assay - Related Substances - Use of multi dimension detectors / orthogonal detectors -LC-PDA-MS -GC-MS  Solubility – Different pH buffer solutions (1.2, 4.5, 6.8)  Spectroscopic Identification – FT-IR, Specific Optical Rotation, etc.  Assay – Chromatography  Related Substances – Chromatography  Use of multi dimension detectors / orthogonal detectors – LC-PDA-MS, ELSD, Corona, etc. 26
  27. 27. Identification - Clarithromycin 27
  28. 28. Method Development Method Development – Assay and Related Substances - Solubility - Spectroscopic Identification - Assay - Related Substances - Use of multi dimension detectors / orthogonal detectors -LC-PDA-MS -GC-MS  Several criteria – Quantification of important analytes – – – – • Active substances, impurities, other components The most prevalent method is chromatographic separation with spectroscopic or spectrometric detection. The procedure is adjusted to achieve acceptable separation of the primary peak from other peaks. Use a multi-dimensional detector such as LC-PDA with a full scan (200-400 nm or 200-700 nm) Use a mass spectrometric compatible mobile phase 28
  29. 29. Use of MS compatible mobile phases  Routine use of MS detector to evaluate a sample for non-chromophoric species.  Procedure development with mass spec-compatible mobile phases.  The resolving power of these mobile phases may be less than phosphate buffers, but the information obtained from the MS is considered more important that the pure separation.  When Liquid chromatography cannot be used or where adequate separation cannot be accomplished with a mass spec-compatible buffer, then it will be important to consider likely interferences to a procedure and ensure that the procedure can adequately quantify the analyte of interest even in the presence of these interferences. 29
  30. 30. Specificity Studies Specificity (Forced Degradation) Studies - Forced degradation studies - Acid - Alkali -Thermal - Peroxide - Light - Separation of degradation products (Identification, wherever possible) - Loops back to Method development, if needed    Forced degradation studies – Acid – Alkali – Thermal – Peroxide – Light (UV & Fluorescence) • Solution • Solid Separation of degradation products – Identification, wherever possible Loops back to Method development, if needed 30
  31. 31. Method Development, Forced Degradation Studies - I Separation of Clarithromycin & impurities Acid degradation of Clarithromycin drug substance 31
  32. 32. Method Development, Forced Degradation Studies - II Acid degradation of Clarithromycin drug substance Easier quantification and basic identification information with full scan PDA and MS Detection of co-eluting species 32
  33. 33. Method Finalization Final Method - Method development completed - Transfer to the Scientific Liaison - If MC monograph is common to USP-NF, it provides additional new impurities for USP-NF  Forced degradation completed – Non-targeted screening – Unequivocal separation  Method development completed  Internal Review  Method of analysis is transferred to the Scientific Liaison  Types of Reference Standards – Process impurities (Known / Unknown) – Degradation products 33
  34. 34. Method Validation General Chapter <10> 34
  35. 35. Method Validation – Assay - I Assay:  Precision and Accuracy: six independent weighings, two injections per sample  Calculation and Acceptance Criteria: Calculate % RSD and calculated predicted content of the Precision measures using the calibration curve from the Range requirement*  Ruggedness: Precision and Accuracy assessments over 3 day  Range: six independent weighings at 80%, 90%, 100%, 110%, and 120%. The precision and accuracy is determined for each concentration* *the Precision and Accuracy is then compared to defined acceptance criteria of the Test to determine the probability of the procedure returning a passing value if it was 100%. The probability must be greater than 0.95. 35
  36. 36. Method Validation – Impurity Limit Procedure  Precision: six independent weighings spiked at the limit, two injections per sample  Calculation and Acceptance Criteria: Calculate % RSD: NMT an amount calculated in <10> (for a 0.1% impurity, NMT 5.7%; for an 0.05% impurity, NMT 6%; etc)  Limit of Detection: five injections each of; one sample spiked at the limit; and one sample spiked at (limit - %RSD above)  Acceptance criteria: the mean value of the second standard must pass the limit test  Specificity: each impurity must be quantifiable to within the LOD 36
  37. 37. Method Validation – Quantitative Impurities Procedure - I  Precision: six independent weighings spiked at the limit, two injections per sample  Calculation and Acceptance Criteria: Calculate % RSD: NMT an amount calculated in <10> (for a 0.1% impurity, NMT 2.8%; for an 0.05% impurity, NMT 3%; etc)  Ruggedness: Precision and Accuracy assessments over 3 day  Calculation and Acceptance Criteria: Calculate % RSD: NMT an amount calculated in <10> (for a 0.1% impurity, NMT 5.7%; for an 0.05% impurity, NMT 6%; etc) 37
  38. 38. Method Validation – Quantitative Impurities Procedure - II  Accuracy: six independent solutions spiked at 50%, 75%, 100%, 125% and 150% of the limit for each specified impurity  Calculation and Acceptance Criteria: Calculate Spike Recovery and each concentration: between 100-%RSD to 100+%RSD (for a 0.1% impurity; 97%-103%;this is under consideration for a change to 94%-106%)  Specificity: Resolution of NLT 1.5 between all impurities (where unattainable, meeting Accuracy is sufficient) 38
  39. 39. Method Validation – Assay - II  Specificity: Resolution of NLT 1.5 between main and all impurities  Process Impurities: evaluation of candidate material at 120% to 200% of the analytical concentration identification (of presence) of impurity peaks at 0.01% or greater  Degradation Products: Target 30% reduction in active content using Acid, Base, Heat, Light (UV and ambient), Peroxide, others as appropriate: identification (of presence) of impurity peaks at 0.10% or greater  Un-retained and non-eluted Impurities: HPTLC with attention to the Origin and Solvent front  Ancillary Data  FT-IR Spectrum, Water Determination, Enantiomeric purity, Solubility in pH 1.2 and 6.8 buffers 39
  40. 40. Data Processing and Transfer  Review of the validation data  Transfer to the Scientific Liaison 40
  41. 41. Acceptable Procedures Acceptable Procedures Provided by any manufacturer with validation package  Not a direct comparison to a Reference Procedure but to the PBM requirements / pre-established criteria appropriate to the Test Any procedure that meets the performance requirements of PBM is considered “equivalent” and published as `acceptable procedure’ There can be multiple acceptable procedure for one monograph 41
  42. 42. Acceptable Procedures (Continued) 42
  43. 43. Industry Use of Medicines Compendium Approaches Nicholas Cappuccino, Ph.D. Member, USP Small Molecules Expert Committee
  44. 44. Monograph Modernization Todd L. Cecil, Ph.D. Vice President, Chemical Medicines Development, USP
  45. 45. Modernization Scope  Monographs in USP: ~6000  Monographs needing Modernization: ~2700  Procedures to be replaced: ~2/ monograph 55
  46. 46. Monograph Modernization Initiative MONOGRAPH TESTS Identification CRITERIA Non-specific ID Tests (e.g., ID by HPLC retention time agreement only) Assay Outdated Technology • • • • • Packed column GC Titration Wet chemistry Spectrophotometry TLC Impurities • Organic • Inorganic • Residual Solvents • Heavy Metals Missing tests (e.g, Specific Tests Other tests organic impurities) Outdated technology (e.g, melting point) Safety/environmental concerns (e.g., odor tests, chlorinated solvents, pyridine, mercuric salts, etc) STRATEGIES By Monograph • Individual • Families • Therapeutic Category • Drug Substances, Dosage Forms By Test • ID • Assay • Impurities • Specific Test(s) • Other By Technology Platform • Gas chromatography • Titrations • Spectrophotometry • Wet chemistry • Other TACTICS Sources of Data • Manufacturers • USP Labs • FDA CRADA • Other Pharmacopeias General Chapters • Route of administration • Monograph-specific procedures • Performance-based procedures PRIORITIZATION • USP model (default) • OTC drug substances a priority in FY13 • Input from FDA Task Group (high priority items) and FDA CRADA labs
  47. 47. Status Update Status Monographs In USP-NF compendium 90 Awaiting bulk RS Release Modernization Underway 6 4 In development 335 In production In Forum 78 Total Yet to begin 29 542 ~2000 To accelerate from current rate of 150/year to over 300/year, USP has been adding internal laboratory capacity to develop needed procedures from scratch.
  48. 48. Reference Procedure  USP’s Reference Procedure approach deviates from ‘tradition’ developing a monograph’s specification from a different perspective: – Rather than adapting a procedure that has been optimized to be fast and inexpensive – Our labs develop and implement a procedure that is optimized to find all significant components in a substance through separation and multidimensional detection – A Reference Procedure is developed using a battery of analytical tools that are appropriate for the molecule (ingredient) and matrix (drug product). – HPLC / UHPLC + Photodiode Array (PDA) and Mass Spectroscopic (MS) detection in series – Evaporating Light Scattering Detector (ELSD), Corona Detector – The approach includes forced degradation studies and validation, which is publicly available 58
  49. 49. Critical Characteristics of Reference Procedure Target article For Development Monograph prepared using General Chapter <10> Authentic samples of the article Thorough Literature Review Procured from at least 2 independent sources Pharmacopeias More sources are better Reported synthetic and degradation routes Published literature 59
  50. 50. Reference Procedure Development Pre Lab Literature Search - Pharmacopeia–USP, EP, BP, JP - Scientific Literature and Online and Paper Journals Procurement - Drug substance, Drug products, Impurities by Standards Acquisition department - Pharmacopeial impurities by Analytical Development department In Lab - Method Development by multi-source materials - Specificity studies - LC-MS Analysis for the forced degradation studies - Method finalization - Method validation - Data processing Post Lab Share the Method validation data with the Scientific Liaison 60
  51. 51. - Acid - Alkali -Thermal - Peroxide - Light - Separation of degradation products (Identification, wherever possible) - Loops back to Method development, if needed - Method development completed - Transfer to the Scientific Liaison - If MC monograph is common to USP-NF, it provides additional new impurities for USP-NF Method Validation and Data Processing -LC-PDA-MS -GC-MS - Forced degradation studies Method Finalization - Solubility - Spectroscopic Identification - Assay - Related Substances - Use of multi dimension detectors / orthogonal detectors Specificity Studies Method Development Reference Procedure Development – In Lab Details Method Validation - Linearity - Accuracy - Precision -Day 1 -Day 2 -Day 3 Data Processing -Review of the validation data -Transfer to Scientific Liaison 61
  52. 52. Components of the Approach  1. Not Less Than 2 sources  2. 5 Modules across 4 Regions  3. Family approach  4. Target of 200 – 300 monographs/yr  5. Reach beyond standard technology  6. Respect industry resources 62
  53. 53. Drug Product Performance and Optimal Bioavailable Products (OBA) Roger Williams, M.D. Chief Executive Officer and Chair, Council of Experts, USP
  54. 54. Topics  Overall Goal  Reference Procedure Approach  Drug Products—The Challenge  BCS and Determination of OBA—A Solution for Many Medicines  Summary 65
  55. 55. Overall Goal  Manufacturers – – – –  Strong discovery and development Good registration processes Well manufactured, safe and effective drug products Interchangeable in global commerce Pharmacopeias – Fully harmonized ingredient and product monographs – Modern, relevant, timely and free with validation 66
  56. 56. Topics  Overall Goal  Reference Procedure Approach  Drug Products—The Challenge  BCS and Determination of OBA—A Solution for Many Medicines  Summary 67
  57. 57. USP’s Medicine Compendium: Reference Procedures  Begins with PBM  Non-optimized Reference-Procedures, and Acceptable Procedures  Suitable for All Ingredients and Products in Global Markets  Requires a ‘Module’—about six staff and highly sophisticated analytical equipment  Each Module produces about 60 monographs with 2-3 reference materials a year  Working Together: A Full Cohort of Monographs (Timely, Relevant, Free, Fully Harmonized) for All Medicine Ingredient and Products
  58. 58. Topics  Overall Goal  Reference Procedure Approach  Drug Products—The Challenge  BCS and Determination of OBA—A Solution for Many Medicines  Summary 69
  59. 59. Drug Product Monographs: The Challenge  Global Sources Make Product Performance Measures difficult – Different regulatory expectations – Different reference producs (US: Reference Listed Drugs – Different patient expectations  Many countries have no bioavailability or bioequivalence (BA/BE) requirements  USP’s Medicine Compendium attempts to address through general application in monographs and General Chapter <12> 70
  60. 60. Topics  Overall Goal  Reference Procedure Approach  Drug Products—The Challenge  BCS and Determination of OBA—A Solution for Many Medicines  Summary 71
  61. 61. BCS Concept  Published by Amidon and co-workers 1995  Biopharmaceutics Classification System is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability  The aim is to optimize the development of oral dosage forms relying only on rate limiting factors for absorption
  62. 62. Drug Release – The Rate Limiting Step Modern Biopharmaceutics, G.L. Amidon, M. Bermejo 2003
  63. 63. Biopharmaceutics Classification System Human Permeability 10 I Gastric emptying determines on-set of absorption II Dissolution likely to be “rate limiting” 1.0 III IV Absorption might be: - incomplete - sensitive to certain excipients 0.1 Generally “problem” molecules 0.01 1 10 100 1000 10000 Volume of water (ml) required to dissolve the highest dose strength at pH 1.2 - 8 100000
  64. 64. Medicines Compendium, General Chapter <12>  Drug Product Performance  Non-solution orally administered immediate release drug products  A partial solution for “well-behaved” IR drug products  Creates a default characterization for most IR drug products  Linked to the BCS classification of the drug substance
  65. 65. Chapter Details  Determine the Solubility of the Drug Substance  Aqueous media at pH 1.2 and pH 6.8  Maximum unit dose in 250 mL media  Room temperature, gentle stirring  High or low solubility  Determine Dissolution Conditions  4 cases possible  Conduct dissolution tests
  66. 66. Dissolution Cases  High solubility in both pH 1.2 and 6.8 – Conduct dissolution according to USP-NF <711> in each pH 1.2 and 6.8 – App. 1@100 rpm or App. 2@50 rpm in 900 mL – Q=85% in 30 minutes  High solubility in pH 1.2 only – Conduct dissolution according to USP-NF <711> in pH 1.2 – App. 1@100 rpm or App. 2@50 rpm in 900 mL – Q=85% in 15 minutes  High solubility in pH 6.8 only – Conduct dissolution according to USP-NF <711> in pH 6.8 – App. 1@100 rpm or App. 2@50 rpm in 900 mL – Q=85% in 15 minutes  Low solubility in both pH values – Product specific development needed – Suggestions on surfactant usage could be included
  67. 67. MC Drug Product Performance Test PERFORMANCE TESTS • Dissolution <711> Medium, Apparatus, Time, and Acceptance criteria: See MC general chapter Assessing Drug Product Performance <12>. Standard solution: USP Metamizole Sodium CRM in an appropriate diluent Sample solution: Pass a portion of the solution under test through a suitable filter, and dilute with an appropriate diluent to obtain a concentration approximately the same as that of the Standard solution. Instrumental conditions: Proceed as directed in the Assay or in an alternatively validated procedure. • Uniformity of Dosage Units <905>: Meets the requirements 78
  68. 68. What Would This ‘Further’ Look Like?  Pharmaceutically equivalence  Highly soluble drug substance (API)  Then optimally bioavailable (OBA) – All O-BA are also BE – No comparator product; no comparison studies – Registration only – No regulatory review – Only pharmacopoeial monographs – Periodic inspection to assure conformity – Label OBA  All others: in vivo studies and Comparator Pharmaceutical Product (CPP—also US Reference Listed Drug)
  69. 69. Topics  Overall Goal  Reference Procedure Approach  Drug Products—The Challenge  BCS and Determination of OBA—A Solution for Many Medicines  Summary 80
  70. 70. The Revolution  Up to 70% Ingredients  No Comparative BE Studies—Ever  A Label that Says OBA (and USP and MC)  OBA Medicines Fully Interchangeable Globally  Part of Fully Harmonized Monograph – PBM and Reference Procedures in Monograph – Good for all pharmacopeias—USP and MC and others  Achieves Stated Goals (see First PPT) 81
  71. 71. Pioneers and Harmonization
  72. 72. New Pharmacopeial Approaches to Excipient Monographs Sameer Navalgund, Ph.D. President, Analytical Research and Development USP
  73. 73. Today’s Topics for Discussion  Typical Excipient Monographs  Challenges involved for Excipient Monographs  USP-MC Monographs  What is a Reference Procedure? – Critical characteristics of a Reference Procedure – Reference Procedure Development • • • •  Process Solubility Procedure Development Use of advanced technologies Some examples 85
  74. 74. Excipient – One of the Definitions  “An excipient is an inactive substance used as a carrier for the active ingredients of a medication.”  In addition excipients can be used to aid the process by which a product is manufactured.  In general, the active substances may not be easily administered and absorbed by the human body; they need to be put in some appropriate form. In such cases, the active substance is dissolved or mixed with an excipient.  Excipients are also sometimes used to bulk up formulations with very potent active ingredients, to allow for convenient and accurate dosage” 86
  75. 75. Typical Excipient Monographs  Definition  Identification  Assay    Other information available Nonproprietary Names  Synonyms Impurities  Empirical Formula and Molecular Weight and structural Formula Specific Tests  Functional Category – Methods of analysis – Acceptance Criteria    Applications in Pharmaceutical Formulation or Technology  Stability and Storage Conditions  Incompatibilities  Safety  Regulatory Status Additional requirements 87
  76. 76. Challenges Involved for Excipient Monographs  Multiples – Different Starting Materials – Different Sources of Starting Materials – Use of natural products • Inherent variability – Manufacturing Processes – Polymeric products • Nature and extent of polymerization • Degree of polymerization • Use of higher temperatures for polymerization – Isolation – Characterization 88
  77. 77. USP-MC Monograph  MC    monograph typically contains… Tests, Procedures, and Acceptance Criteria Tests are consistent with USP-NF (Identification, Assay, Impurities, Performance Tests, Specific Tests) Tests are grouped into one of three separate sections • Performance Based Monograph (Core section) • Reference Procedures (containing monograph specific procedures for Assay and Impurities) • Acceptable Procedures (containing procedures meeting requirements of a criteria-based procedure, but not those of a reference procedure)  Procedures differ from USP-NF  Includes both • Reference Procedures and • Criteria-based Procedures 89
  78. 78. What is a Reference Procedure?  The MC approach deviates from tradition by developing reference procedures from a different perspective: – Rather than adapting a procedure that has been optimized to be fast and inexpensive by using a single manufacturer’s data – Our labs develop and implement a procedure that is optimized to find all significant components in a substance through separation and multidimensional detection – A Reference procedure is developed using a battery of analytical tools that are appropriate for the molecule and matrix – HPLC / UHPLC / IC + Photodiode Array (PDA) and Mass Spectroscopic (MS) detection in series, Evaporating Light Scattering Detector (ELSD), Corona Detector 90
  79. 79. Need of a Reference Procedure - I  Analytical procedures for excipients are typically derived from an understanding of the manufacturing process, i.e., what’s likely to be present  These procedures are optimized to be as fast and simple as possible  Where a party other than the manufacturer wishes to test a component or product, this type of detailed information is not available 91
  80. 80. Need of a Reference Procedure - II  To complicate matters further, the global pharmaceutical marketplace includes components and products processed from different starting materials and having different manufacturing processes – Many excipients are polymeric in nature, adding additional complexity  This diversity leads to vast array of specific tests and procedures to analysis nearly identical substances  The goal of establishing a single reference procedure for each test in a pharmacopeia has therefore been a difficult one 92
  81. 81. Critical Characteristics of Reference Procedure Target article “For Development Monograph” prepared using General Chapter <10> Authentic samples of the article Thorough Literature Review Pharmacopeias Procured from at least 2 independent sources Published literature More sources are better Reported synthetic and degradation routes 93
  82. 82. For Development Monograph - PBM For Development Monograph PBM • Prepared by Scientific Liaison • Tests for Identification, Assay, Impurities, etc. • Acceptance Criteria, wherever applicable • Possibilities for changes as we go forward during method development or Dynamic Document • If additional information is available 94
  83. 83. “Proposed For Development” Monograph  List of “For Development” Monographs on the MC website 95
  84. 84. Performance Based Monograph (Aluminum Stearate) 96
  85. 85. Performance Based Monograph (Aluminum Stearate) Reference Procedure 97
  86. 86. Reference Procedure Development Pre Lab In Lab Post Lab Literature Search - Pharmacopeia - Scientific Literature and Online and Paper Journals Procurement - Drug substance, Drug products, Impurities by Standards Acquisition department - Pharmacopeial impurities by Analytical Development department - Method Development by multi-source materials - Method finalization - Method validation - Data processing Share the Method validation data with the Scientific Liaison 98
  87. 87. - Method development completed - Transfer to the Scientific Liaison - If MC monograph is common to USP-NF, it provides additional new impurities for USP-NF Method Validation and Data Processing -LC-PDA-MS -GC-MS - IC Method Finalization - Solubility - Spectroscopic Identification - Assay - Related Substances - Use of multi dimension detectors / orthogonal detectors Specificity Studies Method Development Reference Procedure Development – In Lab Details Data Processing -Review of the validation data -Transfer to Scientific Liaison 99
  88. 88. Method Development Method Development - Solubility - Spectroscopic Identification - Assay - Related Substances - Use of multi dimension detectors / orthogonal detectors -LC-PDA-MS -GC-MS - IC  Solubility – Different solvents and solutions  Spectroscopic Identification – FT-IR, NIR, Specific Optical Rotation, etc.  Assay – Chromatography  Related Substances – Chromatography  Use of multi dimension detectors / orthogonal detectors – LC-PDA-MS, ELSD, Corona, etc. 100
  89. 89. Method Development Method Development – Assay and Related Substances - Solubility - Spectroscopic Identification - Assay - Related Substances - Use of multi dimension detectors / orthogonal detectors  Several criteria – Quantification of important analytes – – -LC-PDA-MS -GC-MS -IC – – • Main substances, impurities, other components The most prevalent method is chromatographic separation with spectroscopic or spectrometric detection. The procedure is adjusted to achieve acceptable separation of the primary peak from other peaks. Use a multi-dimensional detector such as LCPDA with a full scan (200-400 nm or 200-700 nm), LC-MS/MS, IC, Corona Detector Use a mass spectrometric compatible mobile 101 phase wherever possible
  90. 90. Method Finalization Final Method - Method development completed - Transfer to the Scientific Liaison - If MC monograph is common to USP-NF, it provides additional new impurities for USP-NF  Non-targeted screening  Unequivocal separation  Method development completed  Internal Review  Method of analysis is transferred to the Scientific Liaison  Types of Reference Standards – Process impurities (Known / Unknown) – Degradation products 102
  91. 91. Data Processing and Transfer  Review of the validation data  Transfer to the Scientific Liaison  Science Review  Review by the Expert Committee  Presented on the website for 90 day comment period  Ballot by the Expert Committee 103
  92. 92. Sodium Bisulfite An Example 104
  93. 93. Sodium Bisulfite  Sodium Bisulfite consists predominantly of the sodium salts of Bisulfite.  The molecular formula is NaHSO3  The molecular weight is 104.6.  A common reducing agent  Readily reacts with dissolved oxygen  The related compound  Sodium metabisulfite  is used in almost all commercial wines to prevent oxidation and preserve flavor.  Sodium bisulfite is sold by some home winemaking suppliers for the same purpose. In fruit canning, sodium bisulfite is used to prevent browning (caused by oxidation) and as an antimicrobial agent. 105
  94. 94. Bisulfite Identification / Assay / Impurity Bisulfite Identification/Assay/Impurity Ion Chromatograph + Electrical Conductivity Detector Chromatographic conditions: Column: IonPac AS17-C RFIC 4.0 X 250 mm Guard column: IonPac AG17-C 4.0 X 50 mm Detector Cell Temperature: 35º Column temperature: 30º Flow rate: 1.0 mL/min Suppressor Current: 109 mA Injection volume: 10 µL Mobile phase: Gradient of Potassium hydroxide (KOH) by IC Eluent generator 106
  95. 95. Bisulfite Identification / Assay / Impurity Ion Chromatograph with Mass Spectrometry Chromatographic conditions: Parameters: Column: IonPac CS16 RFIC 5 X 250 mm Guard column: IonPac CG16 5 X 50 mm Detector Cell Temperature: 35º Column temperature: 40º Flow rate: 1.0 mL/min Suppressor Current: 88 mA Injection volume: 25 µL Run time: 30 min Mobile Phase: 30 mM of Methanesulfonic acid 107
  96. 96. Challenges & trouble -shooting HPLC-UV or HPLC-CAD The HPLC method is not appropriate with CN-column, Ion pair reagent and UV detector. Attempted the CAD detector, but since the very big background noises brought about by the CN-column bleeding and the Ion pair reagent, so the CAD detector didn’t work for the sulfite Titration: The commercial Sodium Bisulfite usually contains the Sodium metabisulfite. Attempted to use non-aqueous potentiometric titration to differentiate the bisulfite from metabisulfite, but can’t find a suitable organic solvent. Ion chromatography: An IC method was developed to evaluate the Sodium Identification / Assay / Purities with Cation mode An IC method was developed to evaluate the Bisulfite Identification / Assay / Purities with Anion mode Unique Innovation: IC-Inhibitor combined with LCMS to Identify Anions. 108
  97. 97. Resolution solution: Mixed impurities at 5 μg/mL at 1% level 109
  98. 98. Reference Procedure Characterization (Sodium) Resolution Solution 110
  99. 99. Aluminum Stearate Potassium Stearate Other Examples 111
  100. 100. Resolution – Al- and K- Stearate  S/N Peak Name Ret. Time Area Height Width (50%) Asymmetry (USP) Resolution (USP) Plates (USP) LA 6.307 0.7219 4.8 0.138 1.03 7.85 11490 648.2 MA 8.367 10.6437 60.29 0.171 1.04 6.58 13223 8173.3 PA 10.507 23.2015 108.35 0.212 1.04 1.7 13560 14663.7 OA 11.123 23.4109 105.14 0.216 1.09 3.74 14638 14227.6 SA 12.473 21.8556 102.54 0.209 1.07 n.a. 19659 13872.5 Fig. Lauric acid, Myristic acid, Palmitic acid, Stearic acid, Oleate acid 0.5mg/ml in methanol 112
  101. 101. Assay Method Development Conc. mg/ml 0.01 0.02 0.03 0.04 PA Resp. 0.6825 1.7723 2.9063 SA Resp. 0.05 0.5742 1.4165 2.1816 3.0349 4.056 0.06 0.07 0.08 0.09 0.10 0.20 0.30 5.2793 6.3445 7.3218 8.3028 9.1541 9.9864 16.733 22.148 3.808 4.6371 5.4261 6.2224 6.9682 7.6548 13.142 17.763 Linear Range Selection: Sample solution 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300 μg/ml of Potassium Stearate in methanol. Diluent: Acetonitrile : Tetrahydrofuran : 60 mM Acetic Acid= 60: 5: 35) Fig. The relationship between area responses and the concentrations 113 Comments: The sample concentration will be set at between 0.1~0.3mg/mL.
  102. 102. USP-MC Excipients Monographs • Monographs completed so far… 1. 4. Aluminum Stearate Potassium Stearate Sodium Bisulfite Sodium Oleate • Work in progress … 1. Lauryl alcohol Nutmeg oil Sodium Caseinate Turpentine oil 2. 3. 2. 3. 4. 114
  103. 103. Development of Standards for Indian Pharmacopoeia Dr. Raman Mohan Singh Principal Scientific Officer & Quality Manager, Indian Pharmacopoeia Laboratory Indian Pharmacopoeia Commission Sector-23, Raj Nagar, Ghaziabad-201002 email : ipclab@vsnl.net web: www.ipc.gov.in
  104. 104. INDIAN PHARMACOPOEIA COMMISSION • Government of India has formed Indian Pharmacopoeia Commission (IPC) as an Autonomous Institution under the Ministry of Health and Family Welfare.
  105. 105. It has become fully operational w.e.f. 1st January, 2009
  106. 106. Vision To promote the highest standards of drugs for use in humans and animals within practical limits of the technologies available for manufacture and analysis
  107. 107. Mission To promote public health in India by bringing out authoritative and officially accepted standards for quality of drugs including APIs, excipients, dosage forms and medical devices for use by health professionals, patients and consumers
  108. 108. MANDATES OF THE COMMISSION • Publication of Indian Pharmacopoeia at regular and shorter intervals. • Publication of National Formulary of India. • Providing Reference Substances to the stakeholders. • National Coordination Centre (NCC) for running of the Pharmacovigilance Programme of India (PvPI). • Providing training to the Stakeholders.
  109. 109. Legal requirement of Indian Pharmacopoeia As per the Drugs and Cosmetics Act 1940, the Indian Pharmacopoeia is the legally recognized book of Standards for the quality of drug substances and preparations included therein.
  110. 110. GLP REQUIREMENTS  As per Schedule - L1 of Drugs and Cosmetics Act 1940 and Rules 1945 (Rules 74, 78 and 150E). In the said rules, after Schedule L, the following shall be inserted, namely:- SCHEDULE L-I  These rules may be called the Drugs and Cosmetics (Third Amendment) Rules, 2008.  Effective from 1st November, 2010.
  111. 111.  Provisions in Schedule L1 are legal requirement and are to be complied with strictly therefore clarifications may be sought from Indian Pharmacopoeia for the provisions which are relevant.  IP is a official compendia of the drugs statutory recognized by the Govt. of India plays an important role to control spurious, counterfeit and substandard drugs in India and also contribute for implementation of the Good Laboratory Practices.
  112. 112. Publication of Indian Pharmacopoeia Edition I II III IV Addenda V Addenda VI Addenda VII Edition Year 1955 1966 1985 1996 2000 2000 (Vet. Suppl) 2002 2005 2007 2008 2010 (Last Edition) 2012 (Last Publication) 2014 (Coming Edition)
  113. 113. IP Addendum 2012  This Addendum has the same authority as the Indian Pharmacopoeia 2010. The General Notices, Monographs, Appendices and other portions of the Indian Pharmacopoeia that are amended by this Addendum supersede the original matter to that extent.  This Addendum amends as well as adds new materials to the Indian Pharmacopoeia 2010. The General Notices and Appendices included in the Indian Pharmacopoeia 2010 apply to the contents of this Addendum as well unless specifically stated otherwise.
  114. 114. How it Produces  Letters or e-mails related to IP 2010 amendments, corrections received from various manufacturers and users.  Most of the queries are sorted out at Secretariat level. Typographical mistakes Printing mistakes Based on other related pharmacopoeia/ literature.  Queries related to technical debate sent to Subject Experts or concerned committees for their opinion.
  115. 115. How it Produces  Incorporation of suggestions after reviewing by Subject Experts.  Harmonization of different views of various companies on a specific query.  Working group of 03 Experts:  Mr. J L Sipahimalani  Mr. R. Raghunandanan  Mr. R. Sridharan
  116. 116. Features: Addendum 2012  Total No. of New Monographs  No. of API Monographs  No. of Dosage Forms : 52 : 10 : 30 : 08 : 04 : MT 250 Monographs  Blood and Blood-related Product Monographs  No. of Herbs and Herbal Products Monographs  No. of Monographs Upgraded
  117. 117. Features: Addendum 2012  Added API monographs whose formulation monographs was already in IP-2010 and formulation monographs whose API monographs was given in IP 2010.  Added 6 New Appendices related to Blood Products.  Added New General Chapter on Analytical Method Validation.  Added 11 new HPLC Chromatogram of Herbal Products.  Added 4 new IR Spectra in IR Spectra bank.  Extensively worked on the harmonization of existing IP Monographs in IP-2010 as per other International Pharmacopoeias.
  118. 118. Presentation of Indian Pharmacopoeia-2010 Introduction The Indian Pharmacopoeia is presented in three volumes.  Volume I contains the Notices, Preface, the Structure of the IPC, Acknowledgements, Introduction, and the General Chapters.  Volume II contains the General Notice, General Monographs on Dosage Forms, Monographs on drug substances, dosage forms and pharmaceutical aids (A to M).  Volume III contains Monographs on drug substances, dosage forms and pharmaceutical aids (N to Z) followed by Monographs on Vaccines and Immunosera for Human use, Herbs and Herbal products, Blood and blood-related products, Biotechnology products and Veterinary products.
  119. 119. Introduction  General chemical tests for identification of an article have been almost eliminated and the more specific infrared and ultraviolet spectrophotometric tests have been given emphasis. The concept of relying on published infrared spectra as a basis for identification has been continued.
  120. 120. Introduction  The use of chromatographic methods has been greatly extended to cope with the need for more specificity in assays and in particular, in assessing the nature and extent of impurities in drug substances and drug products. Most of the existing Assays and Related substances tests are upgraded by liquid chromatography method in view to have more specificity and to harmonise with other International Pharmacopoeias.  The test for pyrogens involving the use of animals has been virtually eliminated. The test for bacterial endotoxins introduced in the previous edition is now applicable to more items. The test for abnormal toxicity is now confined to certain vaccines.
  121. 121. General Notices  General Notices mentioned in all three volumes of IP- 2010 with blue pages to make it user friendly which have common terms & definitions used in the monograph/ appendices.  The General Notices provide the basic guidelines for the interpretation and application of the standards, tests, assays, and other specifications of the Indian Pharmacopoeia (IP), as well as to the statements made in the monographs and other texts of the Pharmacopoeia.
  122. 122. General Notices  The active pharmaceutical ingredients (drug substances), excipients (pharmaceutical aids), pharmaceutical preparations (dosage forms) and other articles described in the monographs are intended for human and veterinary use (unless explicitly restricted to one of these uses).  The requirements given in the monographs are not framed to provide against all possible impurities, contaminants or adulterants; they provide appropriate limitation of potential impurities only.
  123. 123. General Notices 136 Alternative Methods. The tests and assays described are the official methods upon which the standards of the Pharmacopoeia are based. Alternative methods of analysis may be used for control purposes, provided that the methods used are shown to give results of equivalent accuracy and enable an unequivocal decision to be made as to whether compliance with the standards of the monographs would be achieved if the official methods were used. Automated procedures utilizing the same basic chemistry as the test procedures given in the monograph may also be used to determine compliance. Such alternative or automated procedures must be validated. In the event of doubt or dispute, the methods of analysis of the Pharmacopoeia are alone authoritative and only the result obtained by the procedure given in this Pharmacopoeia is conclusive.
  124. 124. Monographs General monographs General monographs on dosage forms include requirements of general application and apply to all preparations within the scope of the Introduction section of the general monograph, except where a preamble limits the application. The requirements are not necessarily comprehensive for a given specific preparation; additional requirements may sometimes be given in the individual monograph for it.
  125. 125. Monographs  Individual Monographs: The terms used in the individual monograph are defined in General Notices.  Reagent , Solutions & indicators given in the individual monographs are italicized which are available in Appendices.  Storage & Labelling: The conditions given in the individual monographs are well defined in the General Notices.
  126. 126. Presentation of IP 2014 IP 2014 would be presented in four volumes: Volume 1 Volume 2 Volume 3 Volume 4
  127. 127. Content of Volume 1 • • • • • • Notices Preface Indian Pharmacopoeia Commission Acknowledgements Introduction General Chapters
  128. 128. Content of Volume 2 • General Notices • General Monographs on Dosage Forms • Monographs on Drug substances, Dosage forms and Pharmaceutical Aids Monographs A to M
  129. 129. Content of Volume 3 • General Notices • Monographs on Drug substances, Dosage forms and Pharmaceutical aids Monographs N to Z • Monographs on Vaccines and Immunosera for Human Use • Monographs on Herbs and Herbal Products • Monographs on Blood and Blood-related Products • Monographs on Biotechnology Products • Index
  130. 130. Content of Volume 4 • Monographs on Veterinary Products  Non-Biological  Biological  Diagnostics
  131. 131. Features of NEW EDITION Monographs on Drug substances, Dosage forms & Pharmaceutical aids (A to Z) • New API’s Formulations : 204 : 169 Vaccine & immunosera for human use : 05 Monographs on Herbs & Herbal products : 30 Biotechnology Products : 06 Monographs on Veterinary products : Chemical : 39 Vet Vaccines : 16 Diagnostics : 01
  132. 132. NEW EDITION Vet. Appendices : 06 Vet. General Chapter : 10 Vet. Surgical materials monograph : 07 Radiopharmaceutical Monographs : first time being introduced in this edition. General Monograph : 01 Monographs : 19
  133. 133. Specific features Adding: (i) 480 new monographs. (ii) 32 new General Chapters. (iii) About 200 new IR spectra’s. (iv) Introducing first time 19 Radiopharmaceutical Monographs & 1 General Chapter. (v) Separate Veterinary Volume for easy access . (vi) 11 New Anticancer monographs (vii) 06 New Antiviral Monographs
  134. 134. List of Anticancer monographs: 1. Bortezomib 2. Carboplatin 3. Docetaxel Anhydrous 4. Gemicitabine Hydrochloride 5. Lapatinib Ditosylate 6. Mitomycin 7. Sorafenib Tosylate 8. Premetrexed Disodium 9. Erlotinib Hydrochloride 10. Fludarabine Phophate 11. Bicalutamide
  135. 135. List of Antiviral monographs: 1. Famciclovir 2. Famciclovir Tablet 3. Aciclovir Cream 4. Aciclovir Eye Ointment 5. Aciclovir Dispersible Tablets 6. Aciclovir Oral Suspension
  136. 136.  The scope of the Pharmacopoeia has been extended to include products of biotechnology, indigenous herbs and herbal products, Veterinary vaccines and additional antiretroviral drugs and formulations, inclusive of commonly used fixeddose combinations.  Standards for new drugs and drugs used under National Health Programmes are added in this edition and drugs as well as their formulations not in use now a days are ommited from this edition.
  137. 137. Format  In an effort to make the pharmacopoeia more user-friendly, design of the texts of the monographs and of the test methods are kept same however they are upgraded.  Cross-referencing has been avoided to make each monograph complete in itself thus making it convenient to the analyst performing the tests and to the ones checking the results of analysis.
  138. 138. Basis of Pharmacopoeial requirement  As in the past, this compendium provides a publicly available statement concerning the quality of a product that can be expected and demonstrated at any time throughout the accepted shelf-life of the article.  The standards laid down represent the minimum with which the article must comply and it is incumbent on the manufacturer to ensure that the article is manufactured in accordance with Good Manufacturing Practices (GMPs).  It is essential that sufficiently stringent limits are applied at the time of release of a batch of a material or product so that the pharmacopoeial standards are met until its expiry date under the storage conditions specified.
  139. 139.  It must be noted that a valid interpretation of any requirement of the Pharmacopoeia should be done in the context of the monograph as a whole, the relevant general monograph, where appropriate, the specified tests and methods of analysis including any reference to the relevant General Notices.  Familiarity with the General Notices will facilitate the correct application of the requirements.
  140. 140. Changes  Keeping in view the essential requirement under the Drugs and Cosmetics Act, 1940 and Rules there in the information on category of a drug, dosage and usual available strengths of dosage forms has been re-kept in this edition.  General chemical tests for identification of an article have been almost eliminated and the more specific infrared and ultraviolet spectrophotometric tests have been given emphasis. The concept of relying on published infrared spectra as a basis for identification has been continued.
  141. 141.  The use of chromatographic methods has been greatly extended to cope with the need for more specificity in assays and in particular, in assessing the nature and extent of impurities in ingredients and products.  Most of existing Assays and Related substances tests are upgraded by liquid chromatographic method in view to harmonize with other international Pharmacopoeias.
  142. 142.  The test for pyrogens involving the use of animals has been virtually eliminated.  The test for bacterial endotoxins introduced in the previous editions is now applicable to more items.  The test for abnormal toxicity is now confined to certain vaccines.
  143. 143. General Chapters  Volume I is devoted mainly to test methods that are applicable to all the articles of the pharmacopoeia and general information pertaining to the quality requirements of medicinal substances.  It also includes reference data such as reference spectra, typical chromatograms etc.  The test methods reflect the sophistication of analytical methodology and instrumentation.
  144. 144.  Analytical methods are in general in harmony with those adopted internationally monitoring the quality of drugs. for  The steps taken for harmonization have been initiated by the need to cope with the increasing demand for drugs manufactured in the country to globally accepted standards.
  145. 145.  The trend towards controlling the microbial quality of all medicinal products has been recognized and the requirement regarding limits of bacterial contamination even of products for oral administration and topical application so that adequate controls are exercised by manufacturers by the adoption of GMPs has been continued.
  146. 146. General Monographs  The General Monographs for dosage forms of active pharmaceutical ingredients (APIs) are grouped together at the beginning of Volume II.  They are followed by the monographs for the APIs, pharmaceutical aids and individual dosage forms, all in alphabetical order. Monographs for other articles of a special nature such as vaccines and immunosera for human use, herbs and herbal products, blood and blood related products & biotechnology products are given in separate sections in Volume III.  Veterinary Monographs are given in Volume IV.
  147. 147. Purchase of Indian Pharmacopoeia IP-2014 & Addendum-2012 can be procured from the office of the Secretary-cum-Scientific Director,IP Commission at IPC Campus, Rajnagar, Sector 23, Ghaziabad – 201 002 (UP),India or from our distribution network (see website:www.ipc.gov.in). Other Distribution Centres: (1) M/s Educational BookCentre 133, Gala Complex, Din Dayal Upadhyay Road, Mulund (W), Mumbai-400080. Phone :- + 91-22-2560 3324 Fax:- 91-22- 25685341 E-mail: ebc@vsnl.net
  148. 148. (2) M/s Educational Book Agency (India), 5-D , Kamla Nagar , New Delhi-110 007. Phone : 23844216, 41530228 Fax: 011-23842077, Mobile:- 9811672690 E-Mail : eba@airtelmail.in, ebaindia200@yahoo.co.in Web: indianpharmacopoeia.in (3) M/s Pharma Book Syndicate, 4-3-375, Ansuya Bhawan Opp.Lane to Central Bank, Bank Street, Hyderabad-500095. Phone:- 23445666, 23445622, 23445644, Fax:- 040- 23445611 E-mail : info@ pharmabooksyndicate.com
  149. 149. Your Participation in the work of IP Interested parties can participate in the following ways:  Submit draft monographs along with supporting documents. The Indian Pharmacopoeia encourages you to submit draft monographs. Your draft may be the starting point for an official public standard.  Propose Revisions to Existing General Chapters and Monographs You can propose revisions to the general chapters and monographs in the current official edition of the Indian Pharmacopoeia.
  150. 150. IP Chemical Reference Substance Current Status  Total candidate materials received till date = 400 Nos.  Total IPRS available for distribution = 253 Nos.  IPRS under process of filling and Labeling = 25 Nos.  IPRS under characterization = 25 Nos.  Candidate materials under review = 71 Nos.  IPRS available for distribution till Mar. 2013= 253 Nos.
  151. 151. IPRS Distribution • No. of IPRS vials Supplied to Govt. Labs = 1934 • No. of IPRS Vials Supplied to Pvt. Labs = 265
  152. 152. IP Reference Substances  IPC has proposed to provide IPRS as complementary to all regulatory / pharmacopoeial bodies for harmonization among SAARC, SEARO & ASEAN Countries as presented by the Scientific Director, IPC during his visit at FIP Conference Amsterdam, Netherland.  IPC is also going to include 50 New drug monographs in IP-2014 which are not available in any other Pharmacopoeia like EP/BP/USP with validated protocol and IPRS.
  153. 153. Challenges  To prepare Impurity Reference Substances  To maintain continuous Supply of IPRS  To achieve the target of 900 IPRS
  154. 154. How to contact IPC By email: IPC Secretariat at ipclab@vsnl.net By post: Indian Pharmacopoeia Commission Ministry of Health & Family Welfare Government of India Sector-23, Raj Nagar, Ghaziabad (U.P.)-201002, India Fax: 0120-2783311

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