Marys Medicine

Présentation powerpoint

Control of Impurities in
the European Pharmacopoeia –
Principles and update on new
Dr. Michael Wierer European Pharmacopoeia Department, EDQM, Council of Europe

Principles of Ph.Eur. impurity control Potentially genotoxic impurities in monographs New methods for mesilate salts etc.
New Expression of Acceptance criteria for impurities M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved

1) Principles of Impurity Control in
the European Pharmacopoeia
 Reflect regulatory practice in monographs Application of ICH guideline Q3A R to pharmacopoeial substances  focus on quantitative aspects  Adaptation to globalisation  constant need for  Revision of old monographs , in particular progressive replacement of TLC by LC or GC M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved

Control of Impurities in Substances for
Pharmaceutical Use
Residual solventsControl is provided by the general monograph "Substances for pharmaceutical use" and generalchapter 5.4 "Residual solvents".
Inorganic impurities Specific tests in individual monographs Organic impurities"Related substances test " and/or further tests M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved

Impurities control - key features
• Selective related substances tests• Limits based on ICH Q3A R• Transparency statements • Information column brands• Correct identification of impurities• Meaningful system suitability criteria  Separation  Sensitivity  see chapter 5.10 Control of Impurities M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved

Standard requirements in an
 Specified impurities  Unspecified impurities  Total impurities  Disregard limit  Impurities section (transparency list)  Specified impurities  Other detectable impurities M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved

Transparency list M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved

• Gives impurities that are known to be
detected by monograph tests • Usually controlled by related substances test, but may be other tests • Based on information obtained and verified during elaboration • Not necessarily exhaustive M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Specified Impurities  are those in specifications for approved  limits based on specifications for approved products and batch analysis data  specified impurities are qualified at or above the level indicated in the monograph M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Other Detectable Impurities
• Unique Ph.Eur. category• Impurities sections in monographs may have • 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 M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved General monograph
Substances for Pharmaceutical
Use (2034)
To be read in conjunction with the individual monographs Bridges general requirements to those monographs, which are not yet updated General monograph 2034:
Related substances • Unless otherwise prescribed, organic impurities in active substances are to be reported, identified wherever possible, and qualified as indicated in Table 2034.-1. (general) or in table 2034.-2 (for peptides obtained by chemical synthesis) • Specific thresholds may be applied for impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects Requirements for active substances
except synthetic peptides
M Wierer, 14/09/10 2010 EDQM, Council of Europe, All rights reserved Requirements for peptides
obtained by chemical synthesis
M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Thresholds do not apply for
Biological and biotechnological productsPeptides (not obtained by chem. synthesis)Oligonucleotides RadiopharmaceuticalsProducts of fermentation and semi- synthetic products derived therefrom Crude products of animal or plant origin or Identification of
M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved Is retention time a system suitability requirement ? 250 mm x 4.6 mm, 5µm 250 mm x 4.6 mm, 5µm 250 mm x 4.6 mm, 5µm CEFEPIME FOR SST CRS 1 Essentials for adequate test application LC methods in the Ph. Eur. originally developed and validated by manufacturers, i.e. well-defined equipment and column(s).
Robustness challenged by the fact that only a general description of the column can be given. The chromatographic behaviour with the variety of commercially available "C 18" columns is very often too variable, esp. with gradients.
need to provide CRS and chromatogram
info on the columns used
need to set appropriate criteria (SST)
M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved The identification of a given impurity is needed  when the impurity has an individual limit, and/or when a correction factor must be applied.
 In all the other cases although desirable, the identification is not required.  The method of choice to identify an impurity in a chromatogram is by comparison with an authentic sample.
M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved Example : Torasemide for system suitability CRS Specified impurities: A, B, C, D. M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Ph. Eur. Reference Substances
 Use of the isolated impurity as impurity CRS CONSTRAINT: often impurities are available in scarce quantities only  CRS: a sample containing the impurity of interest (a "bad batch", a spiked batch, a mixture of substance and its impurities). M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved Description of HPLC columns: Example: Amiodarone HClreversed phase LC elution, UV detectionColumn:_ size: l =0.15 m, Ø = 4.6 mm_ stationary phase: octadecylsilyl silica gel for chrom. (5µm)_ temperature: 30 °C What you will find in the monograph: dimensions, type of stationary phase, particle size Not given: brand names of columns M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved EDQM Knowledge database
… contains information on - Reference standards- Column or reagent brand names M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Column ranking/classification
systems available on the internet
System Suitability criteria: Limits to ensure adequate test performance  Resolution of two closely eluting peaks (critical peak pair)  Peak-to-valley ratio (incomplete separation, peaks of very different size)  "Similarity" or "concordance" with a chromatogram supplied  Signal to noise ratio for sensitivity M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved Sumatriptan impurity mixture CRS - resolution imp C / sumatriptan - 5 clearly separated peaks M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved Peak-to-valley ratio M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved Example: Anhydrous paroxetine Signal-to-noise ratio Min. 3 for the peak due impurity H in ref. solution (e). = 0.05% M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved Why are revisions needed?
M. Wierer, 03/12/09 2009 EDQM, Council of Europe, All rights reserved  Replace TLC by LC, GC or CZE Add a limit for total of impurities  Allow unambiguous peak identification Bring general acceptance criterion in line with "Substances for pharmaceutical use"  Introduce impurity section (transparency list) Updates for new active substance sources M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Special revision programme:
Example Norfloxacin
TLC: max. 3 spots, each <= 0.2%, now replaced by LC: M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved 2) Potentially genotoxic
impurities in monographs
• CHMP Guideline on the limits of genotoxic impurities in effect 1.1. 2007 • CPMP/SWP/5199/02, • Applicable to• New active substances• New applications of existing active substances unless there is assurance that no new or higherlevels are introduced as compared to products M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved currently authorised in EU • What about existing substances covered by an • Transparency lists may contain structures of potentially genotoxic substances • Structural alert does not automatically imply • Sometimes production section to flag up PGIs M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved PGIs in transparency statements (1)
• Classified as « other detectable impurities »• This in 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 • The PGI may be irrelevant for certain routes M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved PGIs in transparency statements (2)
• Introduction of regular testing would not be helpful in many cases • Analytical challenge: sensitivity, specificity• Problem for authors of monograph revisions, new monographs and users • Policy paper for European Pharmacopoeia Commission has been adopted after consultation of EMA QWP and SWPwww.edqm.eu/medias/fichiers/NEW_Potentialy_genotoxic_impurities_PhEur_monographs.pdf M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Basic principle of the policy
• For substances uses in human or human and veterinary products: • Folllow the approach of the CHMP guideline • For substances solely used in vet. products: case-by case guidance by comp. authorities M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved • Substance included in a medicinal product authorised after application of the CHMP guideline* ►Monograph should be based on marketing M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved • Substance included in a medicinal product authorised before application of the CHMP guideline*: • no PGI expected from synthetic route.
►No action needed, monograph based on marketing authorization M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved • Substance included in a medicinal product authorised before application of the CHMP guideline*: • PGI expected from synthetic route of first authorised • subsequently authorised products (if any) have no expected PGI or same PGI as the first authorisedproduct at same or lower level and • no data showing genotoxicity. ►No action needed during elaboration of monograph (based on marketing authorization), no revision of existing monographs M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved • Substance included in a medicinal product authorised before application of the CHMP guideline*: • PGI expected from synthetic route of an authorised product and • data showing genotoxicity of an expected ►Monograph should be elaborated or revised based on evaluation by the Competent Authority.
M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved • Substance included in a medicinal product authorised before application of the CHMP guideline*: • PGI expected from synthetic route of first authorised • subsequently authorised products have a new expected PGI or same PGI as innovator product at a higher level and • data showing genotoxicity of an expected PGI.
►Monograph should be elaborated or revised based on evaluation of new PGI or high level of previously known PGI by the Competent Authority M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved • Monographs (limit and tests) will be updated if relevant information is submitted fromstakeholders (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 will apply the Guideline and Regulatory guidance M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved 3) Update on methods concerning Mesilates R= Methyl, Ethyl, Isopropyl
Potentially genotoxic ! Overview of methods developed
• Determination of methansulfonyl chloride in methanesulfonic acid (Pharmeuropa 22.3) • Methyl, ethyl and isopropyl methanesulfonate in methanesulfonic acid (Ph. Eur. 7.1); • Determination of methyl, ethyl and isopropyl methanesulfonate in active substances (adopted, supplement 7.3) M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved 2.5.38. Determination of Methyl-, Ethyl- and Isopropyl- methanesulfonate in active substance mesilates • General method has been validated for the determination of methyl, ethyl and isopropyl esters of methanesulfonic acid ( in concentrations between 0.1 ppm and 5 ppm) for Betahistine mesilate • Method has been examined for 10 further mesilate APIs described in Ph. Eur.
• Solutions need to be adapted to target concentrations and validated by the user M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Method principle: • Dissolution of the mesilate API in H O/ Acetonitrile • Derivatisation of MMS, EMS and IprMS with NaI and Na S O to the respective iodide derivatives • Headspace-GC with MS detection / SIM mode• Internal standard Butylmethanesulphonate 2 EthyI- 3 Isopropyl- M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Limit calculated based
Lower concentration
on maximum daily
tested during method
dose and TTC (ppm)
Betahistine mesilate Bromocriptine mesilate Codergocrine mesilate Deferoxamine mesilate Doxazosin mesilate Pefloxacin mesilate dihydrate Pergolide mesilate Phentolamine mesilate Saquinavir mesilate 4) New Expression of Acceptance
Criteria in the Test for Related
Substances
Acceptance Criteria in the Test for
Related Substances "limit test style"
 So far usually expressed in terms of comparison  "Not more than the area of the principal peak in the chromatogram with the reference solution ." Pass/fail result (limit test)– not a true quantitative (numerical) test result Reasons for the proposed change to
new ("quantitative") style
• Related substances tests were aligned with ICH Q3R and VICH GL 10 requirements • Users have requested a format more adapted to quantitative purposes and to industrial practice of calculating/reporting results M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Proposed change
"Calculate the percentage content of impurity X from the concentration of reference solution ." Numerical result for each impurityTotal of impurities can directly be calculated rather than summing up areas or corrected areas Use of term "reporting threshold" • Numerous (mostly positive) comments received • Agreed by Chairs of Chemical Expert Groups • Due to the large impact o No retrospective application o Use for new and revised texts via Pharmeuropa o General Notices , Chapter 5.10 to be amended to take account of "limit test" style and "quantitative" style o Adoption at Ph.Eur. Commission 3/2011 expected M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved • Impurity control is the key item in Ph.Eur. active substance monographs • Related substances TLC tests are replaced by LC or GC test (spec. revision programme) • Ph.Eur. is updating old monographs whereever possible but ongoing • New challenge: control of genotoxic impurities• New methods for control of mesilates • Style for impurity acceptance criteria now aligned with ICH Q3AR2 and VICH GL 10 M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved Thank you!
M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved

Source: http://www.saq.ch/fileadmin/user_upload/veranstaltungen/referate/459/edqm.pdf