Status <191> Identification Tests General: Tests that are frequently referred to in the Pharmacopeia for identification of official articles Referenced hundreds of times in USP, NF, FCC and DSC Monographs Wet chemistr or flame tests Wet chemistry or flame tests Using of potentially hazardous substances Most tests have several reactions for the same ion Some tests need adjustments of amounts and concentrations concentrations 2 <191> Identification Tests - General Flame Tests: A chemical is introduced to a flame and K + Na + introduced to a flame and the color imparted on the flame is used to identify the presence of the chemical Color based Precipitation Cu + Li + (Sully, 2009) Color based Precipitation Reactions: A designated procedure is followed and a positive result is denoted by the formation of a specific color solid or precipitate color solid or precipitate 1:20 Decanted Ammonium Sulfate 3 Disadvantages of Current Methods Wet Chemistry Methods can be subjective and unclear: Dependent on telling the difference between colors Dependent on determining the presence or absence of precipitates Water Penicillin G Blank Potassium 4 Background Since last cycle 2005-2010, the former GC EC decided to update (modernize) IDtests in <191> containing: update (modernize) ID tests in <191> containing: Out-of-date technology Personal safety risks Personal safety risks Environmental concerns Two ID tests were updated after their verification in USP labs (official in USP 32-NF 27, S1): Acetate Ammonium 5 Background 6 Background Other six additional ID tests were evaluated: Potassium Sodium Calcium Calcium Zinc Hypophosphite Chlorate Four projects were conducted in USP labs based Four projects were conducted in USP labs based on EP procedures (cations) 7 Background 8 Background In October 2010, during the first CA EC face-to-face meeting, it was concluded that further analysis should be done by the it was concluded that further analysis should be done by the Subcommittee F (Wet Chemistry) with inclusion of Experts from FCC and DSC: Nancy Lewen (Chair) CA EC Anthony Bevilacqua CA EC Geoff Carr CA EC J onathan DeVries FCC Pei Chen DSC Pei Chen DSC 9 Main Points for Revision Rationale for replacement of current wet chemistry methods Convenience of having two wet chemistry tests A single default ID test, when applicable Suitability for dosage forms A way to identify different tests for the same molecule/ion/functional group molecule/ion/functional group Standardization of the wording, and a new style to be aligned with the monograph redesign process A plan on how USP will update monographs referencing these tests, as well as how USP will incorporate the tests into new monographs monographs 10 Overview of the Process of Modernization 44 ID tests in GC <191> 19 h d Analysis of GC <191> tests Analysis of monographs Analysis of literature 19 use hazardous reagents 5 flame tests monographs literature Leading World Pharmacopeias Another approaches 8 ions were chosen Sodium Potassium C l i Chloride S lf f pp Calcium Magnesium Aluminum Sulfate Phosphate Proposals for modernization Survey for manufacturers What manufactures Covered about 80 % monographs Analysis of lab reports Potassium really do with ID? Approval by EC Sodium Calcium Zinc Approval by EC Stimuli article 11 Analysis of GC <191> Tests 44 ID tests in GC <191> 19 h d Analysis of GC <191> tests Analysis of monographs Analysis of literature 19 use hazardous reagents 5 flame tests monographs literature Leading World Pharmacopeias Another approaches 8 ions were chosen Sodium Potassium C l i Chloride S lf 2 Chlorine evolved f pp Calcium Magnesium Aluminum Sulfate Phosphate 35 40 45 Lanthanum nitrate TS Ammonium sulfide TS Chlorine TS Proposals for modernization Survey for manufacturers What manufactures Covered about 80 % monographs 20 25 30 2 Mercuric chloride TS Mercurous nitrate TS Formaldehyde TS Lead acetate TS Analysis of lab reports Potassium really do with ID? Approve by EC 10 15 20 2 Potassium permanganate TS Potassium chromate Hydrogen sulfide Sodium Calcium Zinc Approve by EC Stimuli article 0 5 44 19 5 y g Phosphine Chloroform 12 IDtests for Na+ion Analysis of Literature 44 ID tests in GC <191> 19 h d Analysis of GH <191> tests Analysis of monographs Analysis of literature 80 90 100 ID tests for Na+ ion 19 use hazardous reagents 5 flame tests monographs literature Leading World Pharmacopeias Another approaches 8 ions were chosen Sodium Potassium C l i Chloride S lf 30 40 50 60 70 f pp Calcium Magnesium Aluminum Sulfate Phosphate 0 10 20 1 2 substances Dosage forms Proposals for modernization Survey for manufacturers What manufactures Covered about 80 % monographs - monographs containing ID tests according GC <191> - monographs containing f l h fl ID tests for K+ ion 25 30 Analysis of lab reports Potassium really do with ID? Approve by EC reference only to the flame test - monographs containing no ID tests for target ion - monographs which do 10 15 20 25 Sodium Calcium Zinc Approve by EC Stimuli article have wet chemistry ID test for target ion but do not have rference to the GC <191> Dosage forms 0 5 10 substances 13 f Proposals for modernization Survey for manufacturers What manufactures really do with ID? Approve by EC Approve by EC Stimuli article 14 Identification Testing Methods Survey Some Findings Approximately 400 responses: 92% use wet chemistry for ID testing 64% also use additional testing methods 35% Atomic Absorption 30% Spectrophotometric methods 22% Ion Chromatography 19% Inductively Coupled Plasma 68% provided suggestions to improve or modernize the chapter (e g addition of modern techniques or clarifying chapter (e.g. addition of modern techniques or clarifying procedures) 15 Identification Testing Methods Survey Some Findings Top reason for favoring wet chemistry replacement was Top reason for favoring wet chemistry replacement was that alternative methods are more quantitative and less subjective Top reason for being opposed was instrument cost Nearly 20% indicated that other methods should be alternative or optional 16 Proposals for Modernization Exclude flame tests fromIDmethods for cations Analysis of literature Exclude flame tests from ID methods for cations Replace procedures using potentially hazardous reagents When appropriate, harmonize wet chemistry methods for ions literature pp p , y When appropriate, include instrumental approaches Evaluate the inclusion of alternative ID tests f Clarify the current techniques and standardize the text Make a decision about Proposals for modernization necessity ID tests for counter ions in DF C d t l b t di t k Analysis of lab reports Approved by EC Conduct lab studies to make sure that proposed methods will work properly Approved by EC Stimuli article will work properly 17 Alternative Approaches Evaluate ID Testing Methods Survey results auate est g et ods Su ey esuts Perform individual revisions Harmonize with other major pharmacopeias Harmonize with other major pharmacopeias Evaluate instrumental approaches (Ion Chromatography, Capillary Electrophoresis, ICPMS, Atomic Absorption, p y p , , p , etc.) Publish a Stimuli Article Others? 18 USP Expert Panel USP has established an Expert Panel (EP) to work on Modernization of Identification Tests Charter The purpose of this EP will be to perform a comprehensive and holistic analysis of the current identification tests for ions and functional groups comprised in general chapter <191> Identification g p p g p Tests General, especially to the already identified points in need of revision, in order to make recommendations of a suitable process of modernization to the CA EC Proposals of modernization could include alternative approaches including, but not limited to: performing individual revisions of ID tests, harmonization with other pharmacopeias, and evaluation of tests, harmonization with other pharmacopeias, and evaluation of instrumental approaches (such as atomic absorption, spectrophotometric methods, ion chromatography, induced coupled plasma, etc.) p ) SM Experts and staff will work closely because of the high impact in monographs 19 Panel Members Nancy Lewen CA EC (Chair) Anthony Bevilacqua CA EC G ff P R C CAEC Geoffrey P.R. Carr CA EC J onathan DeVries FCC Pei Chen DSC Pei Chen DSC Bernard Olsen SM3 MichelleAdamson Michelle Adamson Maryna Dmitriieva Michael Hornig J eff Rohrer SM1 Anne Warner FDA Liaisons (TBD) 20 Current Status Expert Panel reports to Chemical Analysis Expert Committee Timothy J. Wozniak, Chair Antonio Hernandez-Cardoso, Senior Scientific Liaison General Chapters Elena Gonikberg, Principal Scientific Liaison Small Molecules Leonel Santos, Senior Scientific Liaison Small Molecules Kristie Laurvick, Scientific Liaison Food Chemical Codex Huy Dinh, Scientific Liaison Dietary Supplements Compendium Good mix of members representing key stakeholders First face-to-face meeting scheduled by mid-J uly, 2012 21