USP Monograph ModernizationUSP Monograph Modernization

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Topics

RationaleWhat is modernizationExamplesSScope

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USP Commitment

April 24, 2010

Resolutions Supporting Public Health Adopted by ConventionStrengthen USPs Relationship with the U.S. Food and Drug Ad i i t ti USP l t t th it l ti hi ith thAdministration. USP resolves to strengthen its relationship with the Food and Drug Administration (FDA), and work with FDA and other public and private stakeholders to explore mechanisms to enable USP t id d i t i t d t ti l t d d fUSP to provide and maintain up-to-date national standards for legally marketed drugs and excipients in the United States.

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Monograph Modernization

` Primary driver is maintaining up-to-date standards to support USPs commitment to public healthp

` Need for modernization Monographs have been official for several years, decades in some cases

Content does not reflect current expectations for procedures and acceptance criteria

General lack of specificity

` Modernization is a subset of USPs ongoing revision work, started using the term modernization in 2009

` Includes prescription and non prescription drug substances and drug` Includes prescription and non-prescription drug substances and drug products for human and veterinary use

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Monograph Modernization

`BenefitsStrengthens the public standardsStrengthens the public standards

Moves from non-specific to specific proceduresHelps guard against economically motivated adulterationConsiders practical factors

removes unnecessary tests safety/environmental issues such as eliminating use of chlorinated y g

solvents hard to find equipment

Increases consistency across monographsy g p

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Topics

RationaleWhat is modernizationExamplesScope

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Topics

` Monograph Modernizationg p Rationale What is modernization Examples Scope

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Monograph Modernization

` Modernization of monographs achieved by Replacing outdated procedures such asReplacing outdated procedures such as

Packed column GC replaced with capillary GC TLC replaced with HPLC

W t h i t t t ith i l d i t l d ith Wet chemistry test with visual endpoint replaced with instrumental/chromatographic technique

Adding critical tests to the monograph where none exists currently such assuch as Impurities/degradants Enantiomeric purityD l ti t t hDeleting tests such as Odor test Melting point

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Non-carbonizable substances

Topics

RationaleWhat is modernizationExamplesScope

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Monograph Modernization Examples

Monograph PF Citation ModernizationGlycopyrrolate PF 37(1) [Jan-Feb 2011] Replace titration Assay with HPLC; replace

Ordinary Impurities by TLC with HPLC; delete Melting Range or Temperature test;delete Melting Range or Temperature test; add test for Limit of Erythro Isomer by HPLC

Glycopyrrolate Tablets PF 37(1) [Jan-Feb 2011] Replace UV-based Assay and Dissolution procedure with HPLC; add impurities test

C i d l PF 37(3) [M J 2011] R l i i A i h HPLC lCarisoprodol PF 37(3) [May-June 2011] Replace titration Assay with HPLC; replaceLimit of Meprobamate by TLC by TLC with HPLC to monitor more specified impurities; delete Melting Range or Temperature test;

Carisoprodol Tablets PF 37(3) [May-June 2011] Replace UV-based Assay with HPLC; addimpurities test

DiphenhydramineHydrochloride

PF 37(3) [May-June 2011] Replace organic nitrogenous bases ID procedure with IR; add impurities by HPLC; delete melting range test;

Valproic Acid PF 38(3) [May-June 2012] Replace packed column GC Assay with HPLC procedure; replace capillary GC procedure for Organic impurities with HPLC

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p g pprocedure

Example

CarisoprodolCarisoprodol Tablets

Source: manufacturerM ti ti t b t FDA d f t Motivation: agreement between FDA and manufacturer

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Example

Carisoprodol ID by TLC replaced with HPLC Retention time match Titration Assay replaced with a stability indicating HPLC

procedure TLC procedure for Limit of meprobamate replaced with HPLC Residue on Ignition added

Published in PF 37(3) May-June 2011Official in USP 36 Supplement 1Official in USP 36 Supplement 1

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Example

Carisoprodol Tablets Assay with RI replaced with a stability indicating HPLC with UV Introduce an HPLC procedure for Organic Impurities

Published in PF 37(3) May-June 2011Official in USP 36 Supplement 1Official in USP 36 Supplement 1

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Example

Valproic Acid family of monographs Valproic Acid Valproic Acid Capsules Valproic Acid Oral SuspensionValproic Acid Oral Suspension Valproate Sodium Injection

Source: USP LaboratoriesMotivation: Packed column GC and uses Class II solvents

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Example

Valproic Acid Valproic Acid Valproic Acid Capsules Valproic Acid Oral SuspensionValproic Acid Oral Suspension Valproate Sodium Injection

Source: USP LaboratoriesMotivation: Packed column GC and uses Class II solvents

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Example

Valproic Acid Packed column GC Assay procedure replaced with HPLC

Assay procedure Capillary GC procedure for Organic impurities replaced with

HPLC procedureHPLC procedure

Valproic Acid dosage formsValproic Acid dosage forms Packed column GC Assay procedure replaced with HPLC

Assay procedurey p

Proposals in PF38(3) May-Jun 2012 for public commentsPublic comment period ends on July 31 2012

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Public comment period ends on July 31, 2012

Example- Atropine sulfate

Titration Assay procedure replaced with HPLC procedure

Limt of Other Alkaloids test visual turbidimetry replaced with a selective HPLC procedure with specified impurities

M lti T t d l t dMelting range Temperature deleted

Angular rotation replaced with Specific rotation

Proposal in PF38(3)May-Jun 2012 for public comments

Public comment period ends on 31 July 2012.

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FDA Priority Monographs

` Nov 16, 2010 letter to USP from the FDA Monograph Modernization Task Group (MMTG)p ( )

` Small Molecule Drugs Acetaminophen and Diphenhydramine monographs and their associated

d fdosage forms

Primary issue of concern is missing impurity/degradant tests

Need to control p-aminophenol, a nephrotoxin, in Acetaminophen and its dosage forms

` ExcipientsCopovidone Crospovidone Povidone and Talc Copovidone, Crospovidone, Povidone, and Talc

Part of the PDG Harmonization effort

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FDA Priority Monographs

` Aug 22, 2011 Letter from FDA MMTG` From USP Top 200 and Master List` From USP Top 200 and Master List` FDA ranked drug substances by IMS usage data` No prioritization from FDA, list presented alphabeticallyp , p p y` Extends to the corresponding dosage form monographs` More than one salt form in some cases

1. Albuterol (Sulfate)2. Chlorpheniramine (Maleate)3 Cephalexin

6. Metoprolol (Tartrate)7. Phenylephrine (Hydrochloride)8 Promethazine (Hydrochloride)3. Cephalexin

4. Ciprofloxacin (Hydrochloride)5. Dextromethorphan

(Hydrobromide)

8. Promethazine (Hydrochloride)9. Pseudoephedine (Hydrochloride

and Sulfate)10. Warfarin (Sodium)

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Topics

RationaleWhat is modernizationExamplesScope

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Scope of Modernization

` Number of monographs to be modernized About 550 drug substances About 550 drug substances

About 1750 dosage forms- include both prescription and OTC

Total 2300 monographs

` Volume increases when the number of tests are >2/monograph` 50 monographs modernized in 2011` 48 h d i d i Q1 & Q2 f 2012` 48 monographs modernized in Q1 & Q2 of 2012

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Challenges/ConsiderationsUSP Perspective

` Volume and scope of modernization needs`Obtaining validated procedures with supporting data`Obtaining validated procedures with supporting data`New RS (securing a source, receipt of material, collaborative testing)

and re-evaluation for new uses of existing RSExample: adding an impurities test to the monograph which introduces Example: adding an impurities test to the monograph which introduces new RS

Example: replacing a qualitative wet chemistry procedure with a quantitative HPLC procedure resulting in a significant new use of an q p g gexisting RS

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Monograph Modernization

STRATEGIES

B M h

TACTICSCRITERIANon-specific ID Tests

MONOGRAPH TESTS

Identification By Monograph Individual Families Therapeutic

Category Drug Substances

Sources of Data Manufacturers USP Labs FDA CRADA Other

Pharmacopeias

Non specific ID Tests (e.g., ID by HPLC retention time agreement only)

Outdated Technology Packed column GC

Identification

AssayDrug Substances, Dosage Forms

By Test ID Assay

Pharmacopeias

General Chapters Route of

administration Monograph-specific

Packed column GC Titration Wet chemistry Spectrophotometry TLC

Mi iI iti Impurities Specific Test(s) Other

By Technology Platform

Monograph specific procedures

Performance-based procedures

Missing tests (e.g, organic impurities) Outdated technology

Impurities Organic Inorganic Residual Solvents Heavy Metals

Platform Gas chromatography Titrations Spectrophotometry Wet chemistry Other

Other tests(e.g, melting point)Safety/environmental concerns (e.g., odor tests, chlorinated sol ents p ridine

Specific Tests

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Othersolvents, pyridine, mercuric salts, etc)

Moving Forward

` USP EffortsReviewing options for optimizing prioritization and efficiency of work Reviewing options for optimizing prioritization and efficiency of work

Sourcing procedures from manufacturers, other compendia, literature, other

USP will continue to use its lab resources Focus on OTC drug substances as a subset of the larger work needed

Reference procedures are an option in some cases

Exploring options such as monographs-specific general chapters p g p g p p g p

Form Expert Panels, as needed

C ll b ti` Collaboration Explore possible lab support from CRADA with the FDA

Manufacturers, CHPA, FDA and other interested parties

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Contact Information

For additional information visitFor additional information visithttp://www.usp.org/usp-nf/hot-topics/monograph-modernizationor contactKaren Russo, Ph.DVice President, Small Moleculeskar@usp.org@ p g

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