Impact of USP Chapter 232 (Elemental Impurities)

Changes on CaCO3

David BergJanuary 20, 2015

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

Topics

• Terminology

• Background

• Why the Concern?

• USP v. ICH

• Example Calculations

• Impact

• Summary

Terminology

• Calcium Carbonate (CaCO3)

• Natural Ground Calcium Carbonate (GCC)

• Ground Limestone (GLS)

• Precipitated Calcium Carbonate (PCC)

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

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)

• Physical action (texture, mouth-feel, fill-in space, carrier)

• Chemical action (alkaline, raise pH)

• Provide source of calcium

Background - Main Function of CaCO3

Background – End Use Products

USP Monographs – CaCO3U.S. British

Pharmacopeia FCC & Japanese

& FCC Calcium Ground European Excipient

Test Measurement Carbonate Limestone Pharmacopeia Book

Assay Percent 98.0% - 100.5% 94% 98.5% - 100.5% 98.5%

Identification Pass Pass Pass Pass Pass

Barium Pass Pass --- Pass Pass

Loss on Drying Percent 2.0% 2.0% 2.0% 1.0%

Acid Insolubles Percent 0.2% 2.5% 0.2% 0.2%

Fluoride Percent 0.005% 0.005% --- ---

Magnesium & Alkali Salts Percent 1.0% 3.5% 1.5% 0.5%

Iron Percent 0.1% --- 0.02% ---

Sulphates Percent --- --- 0.25% ---

Heavy Metals Percent 0.002% 0.002% 0.002% 0.002%

Arsenic ppm 3 3 4 4

Lead ppm 3 3 --- ---

Mercury ppm 0.5 --- --- ---

Chlorides ppm --- --- 330 ---

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

USP Latest

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

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

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

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 of 1.5 ppm

* 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

Example of Arsenic calculations – Option 2

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

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 of 1.5 ppm

* 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/gOral Permitted Daily Exposure (PDE) = 15 µg/day

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

Summary

• Change is coming

• Global harmonization

• If based on documented health concerns and sound science…Bring it on!

Thank you!