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Complying with Regulatory Guidelines on PGIs

Complying with Regulatory Guidelines on PGIs. The Role and Challenges for Analytical Chemistry Andrew Baker, Analytical Chemistry, Global Process R&D Avlon/Charnwood. Content. Summary of PGIs Analytical Role Strategies and Examples. Introduction. Introduction.

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Complying with Regulatory Guidelines on PGIs

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  1. Complying with Regulatory Guidelines on PGIs The Role and Challenges for Analytical Chemistry Andrew Baker, Analytical Chemistry, GlobalProcess R&D Avlon/Charnwood

  2. Content • Summary of PGIs • Analytical Role • Strategies and Examples

  3. Introduction

  4. Introduction • Regulatory Authorities have over the last few years become increasingly concerned over the presence of impurities present in Drug Substance that are potentially genotoxic • Felt to not be adequately covered by ICH Q3

  5. What is Genotoxicity ? • Toxic to DNA • Interact directly or indirectly • Cause mutations that may lead to cancer

  6. Where do they come from ? • Most (although not all) arise from the synthetic process • Typical compounds that may be genotoxic are alkylating agents, epoxides, nitrosoamines

  7. So why use such substances • Produce APIs with desired properties eg Sulphonic Acid (sulphonate esters) • Good synthetic reagents • High yielding, clean synthetic routes eg Alkyl Halides, Epoxides

  8. FDA Structural Alerts

  9. Guidelines • Little definitive guidance in early days • EMEA Guidance effective Jan 2007 • Introduced concept of ‘Virtually Safe Dose’ • Threshold of Toxicological Concern (TTC) • Already well established eg Drinking Water • Probability/Risk based • Equates to 1.5ug/day (assumes lifetime exposure)

  10. Industry View • Remains some concern • Uncertainty over application • Overestimating risk vs other sources eg Food • But focus on resolving uncertainty

  11. Resolving Uncertainty • Key area of uncertainty relates to development • Higher limits may be permitted if reduced exposure • Recognised in EMEA guidelines • Industry Task Force developed Staged TTC • Relates limits to duration of exposure

  12. Role of Analytical Chemistry

  13. Analytical Chemistry • Managing and Resolving Uncertainty • Staged TTC approach • Fundamentally relies on knowledge of PGI levels present • But also • Hard Facts and Figures vital for Projects • Decision making eg Route Selection

  14. Trace Analysis • Trace analysis well established arm of analytical chemistry • But some differences here: • Diversity of analyte/matrix • Significant chemical similarity between analyte and matrix • Traditional trace techniques limited applicability

  15. Sound Bites • Like looking for needle in a haystack when the needle is made of Straw as well. • Consider the matrix- Which is easier ? • 1ppm Benzene in Toluene • 1ppb Benzene in Water

  16. ‘Old’ Examples and Strategy

  17. Project A • A chloroacetamide • GCMS SIM Chromatograms • 50ppm (wrt to drug) – blue trace • Extracted Sample – black trace

  18. Project A • Triple Quad GCMS • 0.25 ppm equivalent Presented at BMSS by Mark Jackman AZ PR&D

  19. Standard Sample Project B

  20. Project B • Small PGI analyte • Matrix well resolved chromatographically • ‘Variable’ ion ratios • Key confirmatory criteria Presented at BMSS by Mark Jackman AZPR&D

  21. Triple Quad GCMS Standard Sample Project B

  22. Problems • Both required the use of a high(er) end analytical technique • Both Required significant method development • Neither was delivered within timelines required by project

  23. Challenge at AZ • Projects want high quality results • Fast • How do we do this? • Which analytical technique to use? • Which detector to use? • Which cleanup/sample extraction to use? • Provide assurance/have confidence in numbers • Also Get method development balance right • Simple preferred – Complex when required

  24. AZ Approach • How can we meet this challenge?

  25. PGI Analysis Collaboration • AstraZeneca Looked for a collaborative partner • Expert in chromatography and trace analysis • Have an established interest in this area • Have a set up that could deliver results fast • A partner was found and work started Jan 2007

  26. PGI Analysis Collaboration • Aim • Identify best fit analytical method(s) for analysis of any of the FDA structural alert classes of compounds • Hit suitable technique/approach first time • To develop a decision making process • Along with ‘framework’ of analytical methods

  27. Collaboration Scope • Divided into compound classes • Chemical functionality key to solution • Range of test analytes • Range of test matrices (Generic APIs) • Selected to give good representation of chemical and physical properties

  28. Epoxide Test Analytes

  29. Targets for method development • Develop method(s) • 1ppm analyte in matrix • Techniques open – but available • Extraction vital • Mass Spec – Sensitivity and Selectivity • Fully integrated verification of quantification

  30. Currently Available Methods • Highest priorities • Sulphonate Esters (deriv – SHS-GCMS) • Alkyl Halides (SHS and SPME GCMS) • Haloalkenes (SHS and SPME GCMS) • Mustards (deriv – SPME-GCMS) • Aminoaryls (LCMS + switching) • Michael Acceptors, Epoxides and Aldehydes coming soon

  31. Working on • Michael Acceptors • Epoxides • Aldehydes • Aziridines • Nitros • Hydrazine/Azos • ‘Problem Compounds’

  32. Examples of New Approach

  33. Project C • Chloroether and Small Aliphatic Chloroalcohol type substances • Ca 12 weeks • Investigating and developing method • Ca 10 weeks trying things that didn’t work • Project waiting for information • Potential Delays

  34. From Collaboration • Alkyl Halide test analytes included: • Chloroethanol • Bromoethanol • Iodoethanol • 2-(2-Chloroethoxy)ethanol • 4-chloro-butyl ether • A lot of the things tried for Project C were ‘unlikely’ to work

  35. Solutions from Collaboration • Double Aqueous/Organic Extraction • Some Triple Quad GCMS for development • GCMS – SIM analysis • Took about 2-3 weeks • A potential saving of ~10 weeks

  36. Project D • Fluorophenethyl Bromide • ~10 ppm levels in API

  37. Compound already studied • Fluorobenzyl Bromide • Recovery and Linearity data

  38. Alkyl Halides by SHS • Data from collaboration • ppm wrt to 50mg API • 33 varied compounds in total on list

  39. Alkyl Halides by SPME • Data from collaboration

  40. Project E • Sulphonate Ester • Halide • 12 Batches • 3.5 - 4 Days

  41. Confirmation • Need to confirm for our API/matrix combination • But work is more ‘defined’ • Project can therefore plan • Delivering significant time savings

  42. Summary • PGI analysis is a challenge • Requires use of generic methodologies • AZ have established a collaboration • Will provide such methods for all PGI classes • Subjectively is working very well (collating hard data)

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