Current Issues & Challenges in the Development of Pharmacopoeial Monographs: Some New Challenges in the Impurities Arena. Dr. Susanne Keitel European Directorate for the Quality of Medicines & HealthCare Hyderabad, 7 September 2009. Structure. - PowerPoint PPT Presentation
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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
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 . . .
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.
“ 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.”
• 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.
• 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