janeen a. skutnik-wilkinson ich topic co-creator ewg team ... · please note especially the two...
TRANSCRIPT
Janeen A. Skutnik-Wilkinson
ICH Topic co-creator
EWG Team Member
1 April 2012
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
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
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
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
6
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
Max Concentration in Solid Dosage FormsExisting Specifications for some commonly used grades
mg
H
e
a Lead, ppm
Cadmium,
ppm Arsenic, ppm Mercury, ppm
Aluminum silicate 94
Aluminum stearate 105
Calcium carbonate 550 3 1 3 0.5
Calcium silicate 182.7
Calcium stearate 91.9
Calcium sulfate 443
Colloidal silicon dioxide 170 5
Potassium phosphate, dibasic 30
Sodium phosphate, dibasic, anhydrous 300
Sodium phosphate, dibasic, heptahydrate 500
Anhydrous Dibasic calcium phosphate 850 2 3
Dibasic calcium phosphate, dihydrate 635.5 0.3 1 3 0.1
Dihydroxyaluminum sodium carbonate 1350
Magnesium aluminum silicate hydrate 60
Magnesium carbonate 250
Magnesium hydroxide 450
Magnesium oxide 63
Magnesium stearate 256.4 5 3
Magnesium sulfate 29.8
Magnesium trisilicate 76.89
Talc 220.4
Titanium dioxide 1387 10 1 1 1
Tribasic calcium phosphate 333.3 0.3 1 3 0.1
8
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 = 13.87 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
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
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
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 2012
12
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
Share viewpoints openly and candidly
Take information back to your company, colleagues and contacts
Provide your comments, concerns and suggestions
14
