Analysis of Genotoxic Impurities：基因毒性杂质的分析.doc

ChairmanDatePageAndrew Teasdale, AstraZeneca23 February 20064/4ChairmanDatePageAndrew Teasdale, AstraZeneca23 February 20061/4ParticipantsSecretaryRichard Dennis (GSK), Gareth Pearce (MSD)Pete Yehl (MSD), Andrew Lipczynski (Pfizer)Karen Taylor-Worth (Pfizer), Paul Ravenscroft (GSK)Chris Hinds (Sanofi-Aventis), Simon Hicks (GSK)Elizabeth Swain (AZ)Meeting dateLocation23 February 2006AstraZeneca, CharnwoodSubjectReferencePASG Sub Group Analysis of Genotoxic ImpuritiesPASG Sub Group Analysis of Genotoxic Impurities1.Role of sub-groupIt was agreed that the group should focus efforts around the following points:o To gain a general consensus on what ALARP (as low as reasonably practicable) means, from both an analytical chemistry and process chemistry perspective. It was also recognised that this would vary technique to technique and be influenced by the analyte/matrix combination.o To share best practice in terms of robust analytical methodology and to consider the appropriate use of generic methodology, especially for specific classes of genotoxic impurities, e.g. alkyl sulphonates.o Understand and agree how Staged TTC concepts are to be applied. (TTC: Threshold of Toxicological Concern) and this will impact upon analytical chemistry in terms of LODs and the techniques applied.o Development of specifications for genotoxic impurities.o Understand regulatory requirements by sharing, where possible, experience gained from clinical submissions. Influence regulatory colleagues internally and define appropriate levels of disclosure during drug development.o Best practice relating to the reduction of levels of genotoxic impurities via process chemistry mechanisms.o To share best practice and influence external bodies via publications (discussed in more detail later in these notes).o To keep a watching brief over emerging toxicological information on this topic.Action: AT to share with the group information relating to the proposed collaboration with PQRI (PQRI Website).It was acknowledged in the meeting that there are several issues regarding the sharing of information on this topic given factors such as proprietary information, competitive advantage, intellectual property etc. However, it was considered possible to share information on broad areas of work being carried out, to prevent duplication. Secondly, it was agreed that this group could work collaboratively in order to have more influence within the industry. This is in line with the work carried out by toxicologist colleagues to produce the draft PhARMA paper. Action: All to consult within own member company to gain buy-in to the proposals above and to determine acceptable levels of disclosure to this sub-group. This action applies to several of the actions given later in these notes.2.Feedback from questionnairesAT presented feedback from questionnaires sent to member companies prior to the meeting. The feedback has been presented to the PASG committee.In addition, Professor David Tweats of the University of Wales conducted a survey of 4 major pharmaceutical companies (see in meeting folders).3.Feedback from DIA Meeting and recent EFPIA documentAT presented and the group discussed the above (see attached slide sets). Points raised:o Terminology, AZ have adopted Potential Genotoxic Impurity (PGI), GSK are using DNA Mutagen.o FDA draft guidance document expected to be published in early 2006.o It is not clear within Europe on how best to approach this issue centrally with the regulatory agencies. Agreed to monitor the EFPIA view both in relation to API related issues and in terms of application of the guidelines to excipients (see attached note highlighting some recent concerns):4.Practical Experiences (focussing on alkyl sulphonates)Published papers (see opposite also):Christopher Lee et al (Sanofi)J. Pharm & Biomed Analysis, 39 (2005) 477-485J. Pharm & Biomed Analysis, 39 (2005) 486-494As confirmed by the feedback received, common issues are:o Matrix effectso Solubility issueso Presence of residual solvents such as DCM or MeOHo It was generally agreed that LC-(MS-MS) was the technique of preference for sulphonate esterso Sensitivity issuesThe group had an initial attempt to create a decision tree, this requires further definition but summarises the key points raised in the debate over appropriate selection of methodology. KTW presented a generic method for the analysis of alkylating agents (due to be published in Analytical Chemistry). The method involves an automated derivatisation procedure followed by analysis using headspace GC-MS (SIM) and incorporates the use of deuterated internal standards. It has been applied to 12 analytes so far including mesylates, besylates, sulfates and tosylates. Stability of analytes under various test conditions was also discussedAction: AT to share stability data.It was agreed that one of the next steps of this group might be to set up a meeting whereby more of the technical specialists involved in the development and validation of methodology for genotoxic impurities could present recent work.Action: AT to consider this as an option.Following the discussion above, the group returned to the question of what does ALARP mean? The initial conclusions were that from an RD perspective an LOQ in the range 1-10 ppm is adequate based on a 1.5 mg/day maximum intake. This would cover most dose ranges and it was not considered necessary to pursue ppb levels. Defining ALARP was considered to be a potential topic for a publication (see later in these notes) 5.Method TransferabilityThe analysis of genotoxic impurities can utilise more specialist equipment and the potential issue of difficulties upon technology transfer was raised. It was agreed to review the available literature and collate information from member companies on current methodology. If, following this information gathering exercise, the group considered that TT is likely to be a major issue then it may be beneficial to conduct an inter-laboratory study.Action: All to share information (as far as possible) and to collate experience with method development; techniques used; levels of validation; analyte stability and tech transfer (or intra-lab variability)Next steps/Future meetingsThe group considered that there would be value in writing a position paper(s) on the analytical chemistry and/or process chemistry of genotoxic impurities as a follow up to the PhARMA paper. A working title of Control and Analysis of Commonly Encountered Sulphonate Ester and Alkyl Halides Low Level Impurities in Active Pharmaceutical Ingredients was proposed.An aim of this paper wo