Module 7 General Chapter 191 Update

Modernization of chapter:p Identification Tests - General

Status

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 testsWet chemistry or flame testsUsing of potentially hazardous substances Most tests have several reactions for the same ion Some tests need adjustments of amounts and

concentrationsconcentrations

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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 precipitatecolor solid or precipitate

1:20 Decanted Ammonium Sulfate

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Disadvantages of Current Methods

Wet Chemistry Methods can be subjective and unclear:

Dependent on telling the difference between colorsDependent on determining the presence or absence

of precipitates

Water Penicillin G Blank Potassium

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Background

Since last cycle 2005-2010, the former GC EC decided to update (modernize) ID tests in containing:update (modernize) ID tests in containing:

Out-of-date technologyPersonal safety risksPersonal safety risksEnvironmental concerns

Two ID tests were updated after their verification in USP labs (official in USP 32-NF 27, S1):

Acetate Ammonium

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Background

6

Background

Other six additional ID tests were evaluated:

PotassiumSodiumCalciumCalciumZincHypophosphiteChlorate

Four projects were conducted in USP labs basedFour projects were conducted in USP labs basedon EP procedures (cations)

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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 theit 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 ECAnthony Bevilacqua CA ECGeoff Carr CA ECJonathan DeVries FCCPei Chen DSCPei Chen DSC

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Main Points for Revision

Rationale for replacement of current wet chemistry methodsConvenience of having two wet chemistry testsA single default ID test, when applicableSuitability for dosage formsA way to identify different tests for the same

molecule/ion/functional groupmolecule/ion/functional groupStandardization of the wording, and a new style to be aligned

with the monograph redesign processA plan on how USP will update monographs referencing these

tests, as well as how USP will incorporate the tests into new monographsmonographs

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Overview of the Process of Modernization

` 44 ID tests in GC ` 19 h d

Analysis of GC 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 article11

Analysis of GC Tests


Analysis of GC tests


Analysis of literature` 19 use hazardous

reagents` 5 flame tests




`Chloride `S lf 2 Chlorine evolved

f


`Sulfate`Phosphate

35

40

45

Lanthanum nitrate TS Ammonium sulfide TS Chlorine TS



What manufactures


20

25

30

2

Mercuric chloride TS Mercurous nitrate TS Formaldehyde TS Lead acetate TS


really do with ID?

Approve by EC1015

20 2 Potassium

permanganate TS Potassium chromate Hydrogen sulfide

` Sodium` Calcium` Zinc

Approve by EC

Stimuli article05

44 19 5

y g Phosphine Chloroform

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ID tests for Na+ ion

Analysis of Literature


Analysis of GH tests


Analysis of literature80

90

100

ID tests for Na+ ion

` 19 use hazardous reagents` 5 flame tests




`Chloride `S lf

30

40

50

60

70

f


`Sulfate`Phosphate

0

10

20

1 2substances Dosage forms



What manufactures


- monographs containing ID tests according GC

- monographs containing f l h fl

ID tests for K+ ion

25

30


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 articlehave wet chemistry ID test for target ion but do not have rference to the GC Dosage forms0

5

10

substances 13

fProposals for modernization


What manufactures really do with ID?

Approve by ECApprove by EC

Stimuli article14

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 clarifyingchapter (e.g. addition of modern techniques or clarifying procedures)

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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

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Proposals for Modernization

Exclude flame tests from ID methods for cations

Analysis of literature

Exclude flame tests from ID methods for cationsReplace procedures using potentially hazardous reagentsWhen appropriate, harmonize wet chemistry methods for ionsliterature pp p , yWhen appropriate, include instrumental approachesEvaluate 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 DFC d t l b t di t kAnalysis 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

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Alternative Approaches

Evaluate ID Testing Methods Survey resultsa uate est g et ods Su ey esu tsPerform individual revisionsHarmonize with other major pharmacopeiasHarmonize with other major pharmacopeiasEvaluate instrumental approaches (Ion Chromatography,

Capillary Electrophoresis, ICPMS, Atomic Absorption, p y p , , p ,etc.)

Publish a Stimuli ArticleOthers?

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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 Identification g p p g pTests 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 oftests, 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 CA EC` Geoffrey P.R. Carr CA EC` Jonathan DeVries FCC` Pei Chen DSC` Pei Chen DSC` Bernard Olsen SM3 ` Michelle Adamson` Michelle Adamson` Maryna Dmitriieva` Michael Hornig` Jeff Rohrer SM1` Anne Warner` FDA Liaisons (TBD)

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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-July, 201221

Module 7 General Chapter 191 Update

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Transcript of Module 7 General Chapter 191 Update