Current Issues & Challenges in the Development of Pharmacopoeial Monographs:

Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 1

Current Issues & Challenges in the Development of Pharmacopoeial

Monographs:

Some New Challenges in the Impurities Arena

Dr. Susanne KeitelEuropean Directorate for the Quality of

Medicines & HealthCare

Hyderabad, 7 September 2009


StructureStructure

• The European Pharmacopoeia: General Monograph “Substances for Pharmaceutical Use”

• Specific API Monographs

• General chapter “Control of Impurities in Substances for Pharmaceutical Use”

• Residual Solvents

• Genotoxic Impurities

• Mesylates

• Heavy Metals


Contents of the European Pharmacopoeia:more than 2200 monographs

Contents of the European Pharmacopoeia:more than 2200 monographs

Biologicals

Chemicals

Dosage forms Herbals

Fats

Radiopharm.

Human vaccines

Vet. Vaccines

Plastics

Blood deriv.

Antibiotics

Gases

Homeopathy

Biologicals

Chemicals

Dosage forms Herbals

Fats

Radiopharm.

Human vaccines

Vet. Vaccines

Plastics

Blood deriv.

Antibiotics

Gases

Homeopathy


Principles of Impurity Control in the European Principles of Impurity Control in the European PharmacopoeiaPharmacopoeia Reflect regulatory practice in monographsReflect regulatory practice in monographs

Application of ICH guideline Q3A to pharmacopoeial Application of ICH guideline Q3A to pharmacopoeial

substances --> focus on quantitative aspectssubstances --> focus on quantitative aspects

Adaptation to globalisation Adaptation to globalisation constant need for updating constant need for updating Revision of old monographs , in particular progressive Revision of old monographs , in particular progressive

replacement of TLC by LC, GC or CZEreplacement of TLC by LC, GC or CZE


Pharmacopoeial Requirements for

API

Pharmacopoeial Requirements for

API

Requirement for a substance consists of:

– Specific monograph + general

monograph(s)

Whole set of requirements defines quality


General monograph:General monograph:Substances for Pharmaceutical UseSubstances for Pharmaceutical Use

Related substances

Unless otherwise prescribed, organic impurities in Unless otherwise prescribed, organic impurities in

active substances are to be reported, identified active substances are to be reported, identified

wherever possible, and qualified as indicated in wherever possible, and qualified as indicated in

Table 2034.-1.Table 2034.-1.

Specific thresholdsSpecific thresholds may be applied for impurities may be applied for impurities

known to be unusually potent or to produce toxic or known to be unusually potent or to produce toxic or

unexpected pharmacological effects.unexpected pharmacological effects.


Substances for Pharmaceutical Use (2)Substances for Pharmaceutical Use (2)

> 0.5 per cent0.2 per cent> 0.1 per centNot applicableVeterinary only

> 0.05 percent> 0.05 per cent> 0.03 per cent> 2 g/dayHuman or human and veterinary

> 0.15 per cent or daily intake > 1.0 mg (whichever is

the lower)

> 0.10 per cent or daily intake > 1.0 mg (whichever is the lower)

> 0.05 per cent≤ 2 g /dayHuman or human and veterinary

Qualificationthreshold

Identification threshold

Reporting threshold

Maximum daily dose

Use


Thresholds Do not Apply for*Thresholds Do not Apply for*

Biological and biotechnological products PeptidesOligonucleotides RadiopharmaceuticalsProducts of fermentation and semi-synthetic

products derived therefrom Crude products of animal or plant origin or

herbal products*see chapter 5.10 Control of impurities in substances for pharmaceutical use


Tests in Pharmacopoeial MonographsTests in Pharmacopoeial Monographs

• To detect: organic impurities, inorganic impurities, volatiles

• Methods:

– Physical and physico-chemical

– Chemical

– Chromatographic


Basis for MonographsBasis for Monographs

• SAFETY FIRST!

• Products of proven safety

• Products evaluated and approved by competent

authorities of Member States

• Impurity profiles for existing, approved synthetic

routes

• Robust, validated analytical methods based on

collaborative laboratory testing


Impurities Section Impurities Section

• Gives impurities that are known to be detected by

monograph tests

• Usually controlled by related substances test, but

may be other tests

• Not necessarily exhaustive

• Based on information obtained and verified during

elaboration


Monograph Standard RequirementsMonograph Standard Requirements Limits for:

Specified impurities

Unspecified impurities

Total impurities

Disregard limit

Impurities section (transparency list)

Specified impurities

Other detectable impurities

If the impurities section is not divided, all the impurities cited

are specified


Specified ImpuritiesSpecified Impurities

Specified impurities are those in

specifications for approved products

Specifications for approved products and

batch analysis data for approved products

Specified impurities are qualified at or above

the level indicated in the monograph


Other Detectable Impurities (ODIs)Other Detectable Impurities (ODIs)

Specific EP category

Impurities sections in monographs may have a list

of ODIs

Analytical information only: the impurity is detected

by the monograph method

ODIs are limited in the monograph by the limit for

“unspecified impurities” (or Substances for

Pharmaceutical Use )


Transparency List

Bromazepam


General Chapter 5.10General Chapter 5.10

• Control of Impurities in Substances for

Pharmaceutical UseDefines:

Basis for the elaboration of monographs with regards to

the control of impurities

Terminology

Interpretation of related substances tests

Other aspects of impurities control

ESSENTIAL READING!


Control of Impurities in Substances for Pharmaceutical Use

The tests are intended to cover organic and inorganic impurities that are relevant in view of the sources of active substances inauthorised medicinal products.

Control of residual solvents is provided by the general monograph “Substances for pharmaceutical use” and general chapter 5.4“Residual solvents”.

Instructions for the control of impurities may be included in theProduction section of a monograph, for example where the onlyanalytical method appropriate . . . is to be performed by the manuf.since the method is technically too complex for general use . . .


Specified impurities: A, B, C, D, E, F, G, H, I, J

Example: Anhydrous Paroxetine HCl


Interpretation of The Related Substances Test

A specific monograph on a substance for pharmaceutical use isto be read in conjunction with the general monograph on substances for pharmaceutical use.

Where a monograph has no related substances test (or equivalent)but only specific tests, the user of a substance must neverthelessensure that there is suitable control of organic impurities.

Where an impurity other than a specified impurity is found in anactive substance, it is the responsibility of the user of the substance to check whether it has to be identified / qualified


Acceptance criteria for the related substances test presented in different ways in existing monographs.

Decision tree given to be used as an aid in the interpretation of the general acceptance criteria and their relation with the Impurities section of the monograph.

General acceptance criteria for “other” impurities are currently expressed in various ways in the monographs:

“any other impurity”, “other impurities”, “any impurity”, “any spot”, “any band”, etc.

Pending editorial adaptation of already published monographs, the decision tree may be used to determine the acceptance criteria to be applied.

Interpretation of Related Substances Test


Revision NeedsRevision Needs

Replace TLC by LC, GC or CZEAdd a limit for total of impurities Allow unambiguous peak identificationBring general acceptance criterion in line with

“Substances for pharmaceutical use“Introduce impurity section (transparency list)


Directive 2003/63/ECDirective 2003/63/EC

“ However, where a starting material in the European Pharmacopoeia … has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described.”


Monograph RevisionMonograph Revision

• Impurities control has to be updated for newly

authorised products/sources:

• “[Where] a monograph … [may] be insufficient … the

competent authorities shall inform the European

Pharmacopoeia. The marketing authorisation holder shall

provide the European Pharmacopoeia with the details of

the alleged insufficiency and the additional specifications

applied.”(Directive 2003/63/EC)


Residual SolventsResidual Solvents

• Dealt with in Substances for Pharmaceutical

Use and general chapter 5.4 Residual

solvents

• Specific monographs do not include a test for

residual solvents, except:


Residual Solvents: Residual Solvents:

• Class 1 solvents are always named and limited in monographs

• Class 3 solvents are only named and limited in monographs when they exceed 0.5% (impact on assay results)

• Class 2 solvents are NOT named and limited in monographs: chapter 5.4 applies


Genotoxic ImpuritiesGenotoxic Impurities

• CHMP Guideline on the limits of genotoxic impurities in effect 1.1. 2007

• Applicable to1. New active substances2. New applications for existing active substances where

assessment of the route of synthesis, process control and impurity profile does not provide reasonable assurance that no new or higher levels of genotoxic impurities are introduced as compared to products currently authorised in EU containing the same active substance.


Challenges for the PharmacopoeiaChallenges for the Pharmacopoeia

• What about existing substances covered by an EP monographs ?

• Transparency lists may contain structures of potentially genotoxic substances

• Structural alert does not automatically imply genotoxicity

• Sometimes production section to flag up PGIs


PGIs in Transparency Statements (1)PGIs in Transparency Statements (1)

• Classified as « other detectable impurities »• This is analytical information only• This does not necessarily confirm the occurrence of

the impurity at relevant levels• Rarely adequate control of such substances• EP monographs may relate to several routes of

synthesis• The PGI may be irrelevant for certain routes of

synthesis


PGIs in Transparency Statements (2)PGIs in Transparency Statements (2)

• In many cases, introduction of regular testing would not be helpful

• Analytical challenge: sensitivity, specificity• Problem for authors of monograph revisions, new

monographs and users


SolutionSolution

• Policy paper on GTI adopted by European Pharmacopoeia Commission in March 2008

• EMEA QWP and SWP have been consulted• Comments were approved by CHMP and CVMP


Products Authorised Before Issuance of the GuidelineProducts Authorised Before Issuance of the Guideline

• Monograph based on approved specifcations• Structural alert only does not trigger follow-up• Action for monographs only needed when study

data demonstrate genotoxicity of the PGI• New synthetic routes giving rise to new PGIs or

higher levels of previously recognised PGIs => apply Guideline


Products Authorised After Issuance of The GuidelineProducts Authorised After Issuance of The Guideline

Monographs will be based on specifications of the

Marketing Authorisations


ConsequencesConsequences

• Monographs (limit and tests) will be updated if relevant information is submitted from stakeholders (in particular National Competent Authorities)

• The existence/use of a monograph does not release the user from his responsibility to review the synthetic route, the process control and the impurity profile as regards PGIs

• Certification Unit applies the Guideline


Update on MesilatesUpdate on Mesilates

• Working party has been created to work on methanesulfonic and benzenesulfonic acid

• Possible introduction of tests and limits for lower alkylesters

• Work on alkylesters of the mentioned acids in mesilate and besilate monographs

• Currently covered by production sections• Await action by regulatory authorities • Development of general methods may be

considered at a later stage


Heavy Metals – State of PlayHeavy Metals – State of PlayLack of sensitivity of general testPositive results rarely reported

Ph.Eur. Commission recognises the need for a review

Working party will be appointed in 2009

Important factors to be addressed: – Class/ source/ origin of the material

– Focus on metals which are likely to be present

– Focus on priority metals (toxicity, quality)

– Allow flexibility in analytical methods

– Consider general method approach similar to residual solvents

Thank you!Thank you!

Documents

Current Issues & Challenges in the Development of Pharmacopoeial Monographs: