1. Impact of USP Chapter 232
(Elemental Impurities)
Changes on CaCO3
David Berg
January 20, 2015

2. Caveat on Global Harmonization
• Ensure that <232> limits are based on documented health-based concerns
• Global harmonization is laudable, yet all USP limits must be based on sound
science
• USP should be open to meet with individual producers of drug substances
and excipients, especially those derived from natural mineral sources, to
better understand how naturally-occurring trace metals levels compare with
current, and future <232> elemental impurities limits
International Conference on Harmonization

3. Topics
• Terminology
• Background
• Why the Concern?
• USP v. ICH
• Example Calculations
• Impact
• Summary

4. Terminology
• Calcium Carbonate (CaCO3)
• Natural Ground Calcium Carbonate (GCC)
• Ground Limestone (GLS)
• Precipitated Calcium Carbonate (PCC)

5. Background – CaCO3
• CaCO3 commonly used in food/pharma
• Quarried from ground, washed?, ground/milled
• Precipitated from lime… Ca(OH)2 + CO2  CaCO3 + H2O
• High purity

6. Background - CaCO3
CaCO3 is used in:
• Finished drugs as an excipient…a pharmacological inactive
substance used as a carrier for the active ingredient
• As an Active Pharmaceutical Ingredient (API) in antacids
– Antacids (USP)
– Granulators…tablet making (USP)
– Dietary supplement ie., calcium supplement (FCC)

7. • Physical action (texture, mouth-feel, fill-in space, carrier)
• Chemical action (alkaline, raise pH)
• Provide source of calcium
Background - Main Function of CaCO3

8. Background – End Use Products

9. USP Monographs – CaCO3
U.S. B
Pharmacopeia FCC
& FCC Calcium Ground Eur
Test Measurement Carbonate Limestone Pharm
Assay Percent 98.0% - 100.5% 94% 98.5%
Identification Pass Pass Pass P
Barium Pass Pass --- P
Loss on Drying Percent 2.0% 2.0% 2
Acid Insolubles Percent 0.2% 2.5% 0
Fluoride Percent 0.005% 0.005%
Magnesium & Alkali Salts Percent 1.0% 3.5% 1
Iron Percent 0.1% --- 0
Sulphates Percent --- --- 0
Heavy Metals Percent 0.002% 0.002% 0.
Arsenic ppm 3 3
Lead ppm 3 3
Mercury ppm 0.5 ---
Chlorides ppm --- ---

10. Why the Concern?
• Chapter <232> essentially replaces trace heavy metal limits
on individual CaCO3 monographs
• Although limits established by <232> will apply to finished
drugs, the finished drug manufacturers indirectly will impose
comparable limits on their ingredient suppliers
• Some finished drugs contain as much as 90% CaCO3, as an
API or excipient, and thus can have high daily dosage rates
• As many CaCO3 suppliers produce their product via grinding
natural ore, it is not possible to alter the trace metal content

11. USP Latest

12. ICH latest - Q3D Step 4 (12/16/14)

13. ICH Q3D Step 4 – Arsenic (As)
Option 1: Permitted common concentration limits across drug product component
materials for products with daily intakes of not more than 10 grams
Table A.2.2
Option 2: Permitted concentration limits in individual components of a product with
specified daily intake

14. Example of Arsenic calculations – Option 1
Amount in
Formulation
Example 1 Arsenic Actual Calculated
Actual Element Daily
Daily Arsenic dose
dose Content PDE
Component g µg/g (ppm) µg/day
Drug Substance (a.i.) 0.3 1 0.3
Excipient 1 4.7 1 4.7
Excipient 2 (CaCO3) 5 1 5
Overall Drug Product 10 10
All components under Individual Component Limits for Arsenic
so Drug Product MEETS Arsenic requirement
Example 2 Arsenic Actual Calculated
Maximum permitted concentration = 1.5 µg/g

15. Example of Arsenic calculations – Option 2
Excipient 2 (CaCO3) 5 1 5
Overall Drug Product 10 10
All components under Individual Component Limits for Arsenic
so Drug Product MEETS Arsenic requirement
Example 2 Arsenic Actual Calculated
Actual Element Daily
Daily Arsenic dose
dose Content PDE
Component g/day µg/g (ppm) µg/day
Drug Substance (a.i.) 0.3 1 0.3
Excipient 1 4.7 1 4.7
Excipient 2 (CaCO3) 5 2*** 10
Overall Drug Product 10** 15*
***Arsenic level in Excipient 2 (CaCO3) does not meet Individual Component Limit
* However Arsenic calculated daily exposure of 15 = proposed PDE of 15
** Drug Product Daily Intake of 10 g/day = max. daily intake of 10 g/day
so Drug Product MEETS Arsenic requirement
Maximum permitted concentration = 1.5 µg/g
Oral Permitted Daily Exposure (PDE) = 15 µg/day

16. Impact
• Increased scrutiny of CaCO3 purity
• Customers now set purity limits for CaCO3
• Reduction of domestic natural CaCO3 sources
• Increased costs (testing, alternatives, manpower, etc)
• Opportunity

17. Summary
• Change is coming
• Global harmonization
• If based on documented health concerns and
sound science…Bring it on!
Thank you!