Janeen A. Skutnik-Wilkinson ICH Topic co-creator EWG Team Member

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1 Janeen A. Skutnik-Wilkinson ICH Topic co-creator EWG Team Member April

2 Metal Impurities (aka Heavy Metals) STUCK for at least 10 years No Harmonised guidance in ICH or other regions Establish appropriate controls for those metals with clearly established toxicological concerns. These metal impurities may arise from the drug substances, excipients, or manufacturing processes used for drug products, may include catalysts, reagents, ligands, heavy metals or other residual metals, such as those due to the material source (e.g. Pb, Hg, As, Cd). 2

3 Approved in 2009 by ICH SC EWG created in Spring 2010 Scope restricted to criteria and limits Methodology purview of Compendia Representatives Equal mix of Safety/Toxicologists and Quality Personnel US: FDA & PhRMA EU: EMA & EFPIA Japan: MHLW/PMDA & JPMA Interested Parties IPEC, WSMI, IGPA, KFDA, BIO, WHO 3

4 Limits to be set based on published safety and toxicology data Detailed Safety & Toxicological Assessments have been done on each of the metals of interest Each will have its own report including references to the appropriate studies Build upon EU Metal Catalysts guide Excipients within scope 4

5 Determining how we are impacted? Since it is the finished dosage form that is required to comply BUT.. Testing every dosage form is not feasible Data not yet available for all components Test methods are still unclear How do we get the data we need? Need a layered approach to looking at dosage forms and components 5

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7 Materials which use mined-excipients Since many elemental impurities are naturally present (for example Lead) in mined-excipients and cannot be further processed out, it is important to understand the actual levels present May have finished product which contain multiple mined excipients 7

8 Max Concentration iexisting Specifications for some commonly used grades mg e a Lead, ppm Cadmium, ppm Arsenic, ppm Mercury, ppm Aluminum silicate 94 Aluminum stearate 105 Calcium carbonate Calcium silicate Calcium stearate 91.9 Calcium sulfate 443 Colloidal silicon dioxide Potassium phosphate, dibasic 30 Sodium phosphate, dibasic, anhydrous 300 Sodium phosphate, dibasic, heptahydrate 500 Anhydrous Dibasic calcium phosphate Dibasic calcium phosphate, dihydrate Dihydroxyaluminum sodium carbonate 1350 Magnesium aluminum silicate hydrate 60 Magnesium carbonate 250 Magnesium hydroxide 450 Magnesium oxide 63 Magnesium stearate Magnesium sulfate 29.8 Magnesium trisilicate Talc Titanium dioxide Tribasic calcium phosphate

9 Please note especially the two highlighted per dose levels TiO2 is used in some approved drug products at very high levels and actual typical levels of 1 to 9 ppm for lead have been seen in actual routine commercial batches. This may cause some issues if the lead PDE will be < 5 ug per day. Lead from TiO2 per dose, based on 10 ppm spec 1387 mg x 10 ug/1000 mg = ug <---- One dose could be 2 1/2 times higher than the 5 ug per day PDE. This only takes into consideration Pb from one excipient other excipients in the formulation could also contribute.. What if there are multiple doses prescribed? Even if the lead level in the TiO2 was only 5 ppm which is very typical of actual commercial material, the 5 ug PDE would still be exceeded by one dose. 9

10 Bottom line Finished dosage forms will need to comply New products Eventually will apply to existing Added complication that existing components are not grandfathered 10

11 Some thoughts Analyze products in development / on market focusing on materials with highest risk of having metals Products using mined-excipients (for example) Be prepared to review ICH Step 2 document to provide information, data and concerns Actual data to substantiate concerns will be needed 11

12 Preliminary comments from constituents have been collected and sent back to the ICH EWG EWR still has a goal to reach Step 2 in June

13 An opportunity. Sharing of information / data Addressing challenges Raising awareness Share concerns and brainstorm solutions Outcomes Will be consolidated and shared with ICH EWG 13

14 Share viewpoints openly and candidly Take information back to your company, colleagues and contacts Provide your comments, concerns and suggestions 14

15 Q&A NJPQCA - January