Control of Impurities in the European Pharmacopoeia Principles and update on new developments

Control of Impurities in the European Pharmacopoeia Principles and update on new developments 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 2

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 updating Revision of old monographs, in particular progressive replacement of TLC by LC or GC 3

Control of Impurities in Substances for Pharmaceutical Use Residual solvents Control is provided by the general monograph Substances for pharmaceutical use and general chapter 5.4 Residual solvents. Inorganic impurities Specific tests in individual monographs Organic impurities Related substances test and/or further tests 4

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 5

Standard requirements in an Ph.Eur. monograph Limits for: Specified impurities Unspecified impurities Total impurities Disregard limit Impurities section (transparency list) Specified impurities Other detectable impurities 6

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 8

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 9

Other Detectable Impurities Unique Ph.Eur. 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) 10

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 Use Maximum daily dose Reporting threshold Identification threshold Qualification threshold Human or human and veterinary Human or human and veterinary Veterinary only 2 g /day >0.05 per cent > 2 g/day >0.03 per cent Not applicable >0.10 per cent >0.10 per cent or daily intake >1.0 mg (whichever lower) >0.05 per cent >0.15 per cent or daily intake >1.0 mg (whichever lower) > 0.05 percent 0.20 per cent >0.50 per cent M Wierer, 14/09/10 2010 EDQM, Council of Europe, All rights reserved

Requirements for peptides obtained by chemical synthesis Reporting threshold Identification threshold Qualification threshold > 0.1 % > 0.5 % > 1.0 % 14

Thresholds do not apply for Biological and biotechnological products Peptides (not obtained by chem. synthesis) Oligonucleotides Radiopharmaceuticals Products of fermentation and semisynthetic products derived therefrom Crude products of animal or plant origin or herbal products Excipients

Is retention time a system suitability requirement? Inertsil ODS 3 250 mm x 4.6 mm, 5µm Kromasil C18 250 mm x 4.6 mm, 5µm Alltima C18 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 17

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 18

CF CF Example : Torasemide for system suitability CRS Rs Specified impurities: A, B, C, D. 20

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 20

Description of HPLC columns: Example: Amiodarone HCl reversed phase LC elution, UV detection Column: _ 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 22

EDQM Knowledge database contains information on - Reference standards - Column or reagent brand names 23

Column ranking/classification systems available on the internet www.rheodyne.com www.pharm.kuleuven.ac.be/pharmchem/ columnclassification www.acdlabs.com/columnselector

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 24

Revision Needs 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 30

Special revision programme: Example Norfloxacin TLC: max. 3 spots, each <= 0.2%, now replaced by LC: 31

2) Potentially genotoxic impurities in monographs CHMP Guideline on the limits of genotoxic impurities in effect 1.1. 2007 CPMP/SWP/5199/02, EMEA/CHMP/QWP/251344/2006 Applicable to New active substances New applications of existing active substances unless there is assurance that no new or higher levels are introduced as compared to products currently authorised in EU 32

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 33

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 of synthesis The PGI may be irrelevant for certain routes of synthesis 34

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 SWP www.edqm.eu/medias/fichiers/new_potentialy_genotoxic_impuriti es_pheur_monographs.pdf 35

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 36

Case 1 Substance included in a medicinal product authorised after application of the CHMP guideline* Monograph should be based on marketing authorization(s) 37

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 38

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 39

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. 40

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 41

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 42

3) Update on methods concerning Mesilates Methanesulfonic acid C H 3 O S O Sources: O H + R-OH by-product impurities R= Methyl, Ethyl, Isopropyl Alkylated Agents Mesilates (Esters) C H 3 O S O O HR 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) 44

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 45

Method principle: Dissolution of the mesilate API in H 2 O/ Acetonitrile Derivatisation of MMS, EMS and IprMS with NaI and Na 2 S 2 O 3 to the respective iodide derivatives Headspace-GC with MS detection / SIM mode Internal standard Butylmethanesulphonate 1 Methyl- 2 EthyI- 3 Isopropyl- 4 Butyliodide 46

Monograph title Limit calculated based on maximum daily dose and TTC (ppm) Lower concentration tested during method verification (ppm) Betahistine mesilate 42 5 Bromocriptine mesilate 25 2 Codergocrine mesilate 188 20 Deferoxamine mesilate 0.3 0.1 Dihydroergocristine mesilate 313 30 Dihydroergotamine mesilate 150 15 Doxazosin mesilate 188 20 Pefloxacin mesilate dihydrate 1.9 0.5 Pergolide mesilate 300 30 Phentolamine mesilate 300 30 Saquinavir mesilate 0.7 0.1

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 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

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 50

Proposed change ( quantitative style) 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

Current status Numerous (mostly positive) comments received Agreed by Chairs of Chemical Expert Groups Due to the large impact o o o o No retrospective application Use for new and revised texts via Pharmeuropa General Notices, Chapter 5.10 to be amended to take account of limit test style and quantitative style Adoption at Ph.Eur. Commission 3/2011 expected 52

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 53

Thank you! 54