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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 2
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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 3
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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 4
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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 5
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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 6
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.
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 7
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
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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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 9
Tests in Pharmacopoeial MonographsTests in Pharmacopoeial Monographs
• To detect: organic impurities, inorganic impurities, volatiles
• Methods:
– Physical and physico-chemical
– Chemical
– Chromatographic
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 10
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
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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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 12
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
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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
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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 )
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 15
Transparency List
Bromazepam
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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!
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 17
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 . . .
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 18
Specified impurities: A, B, C, D, E, F, G, H, I, J
Example: Anhydrous Paroxetine HCl
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 19
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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 20
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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 21
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)
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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.”
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 23
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)
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 24
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:
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 25
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
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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.
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 27
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
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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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 29
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
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 30
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
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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
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Products Authorised After Issuance of The GuidelineProducts Authorised After Issuance of The Guideline
Monographs will be based on specifications of the
Marketing Authorisations
Dr. Susanne Keitel, 09/2009 ©2009 EDQM, Council of Europe, All rights reserved 33
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
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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
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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!