Dr. Michael Wierer Deputy Head, European Pharmacopoeia Department, EDQM, Council of Europe
Contents
1. Principles of Ph.Eur. impurity control 2. Potentially genotoxic impurities in monographs 3. New methods for mesilate salts etc. 4. New Expression of Acceptance criteria for impurities
M. Wierer, 02/12/10 2009 EDQM, Council of Europe, All rights reserved 2
Unspecified impurities
Total impurities Disregard limit
Transparency list
Bromazepam
Impurities Section
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
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Specified Impurities
are those in specifications for approved products limits based on specifications for approved products and batch analysis data specified impurities are qualified at or above the level indicated in the monograph
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> 2 g/day
Not applicable
Identification of impurities
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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
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Peak identification
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
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Rs
Specified impurities: A, B, C, D.
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What you will find in the monograph: dimensions, type of stationary phase, particle size Not given: brand names of columns
Peak-to-valley ratio
Signal-to-noise ratio
Min. 3 for the peak due impurity H in ref. solution (e). = 0.05%
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Revision Needs
Replace TLC by LC, GC or CZE Add a limit for total of impurities
Problem statement
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
Case 1
Substance included in a medicinal product authorised after application of the CHMP guideline* Monograph should be based on marketing authorization(s)
Case 2
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
Case 3
Substance included in a medicinal product authorised before application of the CHMP guideline*: PGI expected from synthetic route of first authorised product and subsequently authorised products (if any) have no expected PGI or same PGI as the first authorised product 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
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Case 4
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 PGI. Monograph should be elaborated or revised based on evaluation by the Competent Authority.
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Case 5
Substance included in a medicinal product authorised before application of the CHMP guideline*: PGI expected from synthetic route of first authorised product, and 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
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Consquences
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 will apply the Guideline and Regulatory guidance
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Alkylated Agents
Methanesulfonic acid Mesilates (Esters)
O H 3C S O H O
+ R-OH
Potentially genotoxic !
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
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Method principle:
Dissolution of the mesilate API in H2O/ Acetonitrile Derivatisation of MMS, EMS and IprMS with NaI and Na2S2O3 to the respective iodide derivatives Headspace-GC with MS detection / SIM mode Internal standard Butylmethanesulphonate
1 Methyl2 EthyI- 3 Isopropyl4 Butyliodide
Monograph title
Betahistine mesilate
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Bromocriptine mesilate
Codergocrine mesilate Deferoxamine mesilate Dihydroergocristine mesilate Dihydroergotamine mesilate Doxazosin mesilate Pefloxacin mesilate dihydrate Pergolide mesilate Phentolamine mesilate Saquinavir mesilate
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188 0.3 313 150 188 1.9 300 300 0.7
2
20 0.1 30 15 20 0.5 30 30 0.1
Acceptance Criteria in the Test for Related Substances limit test style
So far usually expressed in terms of comparison of peak areas: 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
Current status
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
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Conclusion
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 elaborated Style for impurity acceptance criteria now aligned with ICH Q3AR2 and VICH GL 10
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Thank you!
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