1. Heavy Metals: Regulatory Aspects DIA-SIG RA-CMC working group 15Mar12 Anders Neil Principal Consultant PAREXEL Consulting

2. 2 Disclaimer These views and opinions are the authors own.

3. Contents What is the problem with heavy metals – anyway? The EMEA Guidline of 2008 Ongoing ICH harmonisation Comments and conclusions 3

4. Heavy Metals 4 Picture Transition metals Metalloids Lanthanoids Actinoids Some are toxic

5. EMEA Position in 2008 Heavy metals is a potential quality/impurity issue Metal are used in manufacturing Concern: potential residues from known reagents and catalysts No therapeutic benefit to patients Product risk to be contained Not to offset therapeutic benefit Need for limits and use of validated analytical methods 5

6. EMEA approach Limit metal residues in API Focus on known process related residues Other to be handled by GMP/GDP Divide metals in 3 risk based classes Significant – low - minimal safety concern Set Permitted Daily Exposure (PDE) limits Prescribe analytics and reporting levels Pharmacopoeial procedures – if feasible 6

7. EMEA guidline 2008 7

8. Permitted Daily Exposure (PDE) Method (from ICH Q3C) Based on NOEL or LOEL limits For 3 routes: oral; parenteral; inhalation Assuming human weight adjustment 50 kg F1 species differences F2 individual variability (default 10) F3 duration of study F4 severity of toxicity found F5 limit used 8

9. EU PDE Example – Platinum Oral Toxicity Oral rat NOEL of 13 mg Pt/kg/day for PtCl4 Some soluble platinum salts mutagenic in vitro. Safety factor of 5,000 F1 species differences – rat 5 F2 individual variability - (default) 10 F3 duration of study – 30 d study 10 F4 severity of toxicity found – severe (and genotoxic?) 10 F5 limit used – NOAEL 1 Yields a PDE of 2.6 μg Pt/kg/day, or 130 μg/day @ 50 kg Value rounded to an oral PDE of 100 μg/day.. 9

10. EMEA PDE based grouping Three groups 1.Significant safety concern Known/suspected human carcinogens Other significant toxicity Subdivided A & B platinonoids: Pt, Pd & Ir, Rh, Ru, Os C other Mo, Ni, Cr, V 2.Low safety concerns Cu, Mn 3.Minimal safety concern Fe, Zn 10

11. EMEA guideline: Resulting PDE 11

12. EMEA – PDE Uses Three options 1API ppm limit (assuming dose < 10g/d) Concentration limit for multiple uses 2a Dose adjusted limit for ”pharmaceutical substance” Concentration limit for for each API/constituent 2b Dose adjusted limit for final DP Concentration limit for specific use 12

13. EMEA: Analytical Test for each metal residue Use harmonized procedures ”described in pharmacopoeias” – if feasible Else, most appropriate validated procedure Non-specific methods allowed Class 2 and 3 metals only Note: Pharm Eur metal limits test generally not sufficient 13

14. EMEA guideline: Comments Focus is known residuals (i.e. catalysts) Limited number of metals (14) Some trace elements of low concern (Fe; Zn) Other metal impurities left fo GXP control Environment; process leachables Risks not gauged vs. potential benefits Worst-case scanario for chronic use 14

15. Meanwhile – Back on the Range US Pharmacopeia 2009 New proposal on limits and test changes for heavy metals  Time for harmonisation 15

16. ICH Approach – Drafting ICH Q3D Focus shift: ”residue” => ”impurity” Also API => DP Wider scope equipment water; primary packaging included; excipients addressed Excludes low risk metals – for GMP control Expands metals covered Risk Assessment part of Control Strategy Alignment with Q8/9/10 – risk management/QbD 16

17. ICH Q8 (R2) Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System Q8 Example Risk Assessment Tools 17

18. ICH Q3D Approach 18

19. Draft ICH Q3D: Metal Impurities Scope: safety limits of potentially toxic metal impurities in new drug products Clinical trials material not covered Limits: PDE determined as in Q3C Control Strategy: keep impurities < PDE Risk assessment: all potentially incorporated material Identify metals that really could be present Compare levels vs. PDE – control as needed 19

20. Draft ICH Q3D: Limits Calculated as Q3C (in EMEA guideline) More technical detail provided – also for each metal Most toxic species of a metal assumed Carcinogens Individual assessment from data Also Threshold of Toxicological Concern (TTC) of 1.5 µg/d Other based on WHO/EPA/FDA methods Some may differ from WHO food norms? 20

21. Draft ICH Q3D: Proposed PDEs 21 Typical catalysts Default TTC 1.5 Harmonisation issue!

22. Draft ICH Q3D: Uses 4 options for concentration limit use 1: Limit for daily dose up to 10 g Allow free use of substances or excipients 2a: Dose corrected for each substance 2b: Dose corrected for all substances in DP 3: Determined in final DP 22

23. Draft ICH Q3D: Other Regulatory – CTD Summary of control strategy in 3.P.5.6 Tabular or diagram format Refer to location of control elements Justification of specifications for DS Justification of specifications for DP Justification of specifications for excipients Levels > PDE To be justified on case-by-case basis 23

24. Draft ICH Q3D: Issues Management of potential risk - only No discussion on benefit factoring Chronic toxicity data limits vs. short-term use Applies to new drugs BUT: Earlier Q3C was incorporated into Pharm Eur and became mandatory throughout 24

25. Draft ICH Q3D: Issues Scope not delimited Control from process understanding (Q10)? Proportional to level of risk? Or general 27 metals hunting? Also in supply chain... 25

26. Draft ICH Q3D: Issues Harmonisation gaps Al left to regional demands in draft – acceptable? Analytical methods Pharmacopoeial procedures where feasible Remain to be harmonised Validated methods preferrable 26

27. Conclusions Metals in DP due for harmonisation – new Q3D Scope shift from residues to impurities More metals coverered than in EU guidance Focus on management of potential risk Increases burden of risk exclusion Benefit allowance and short term use not discussed Harmonisation flaws in draft proposal Aluminium Pharmacopoeial procedures for analysis 27

28. Thank you! Any questions? Feedback welcome! anders.neil@parexel.com