Actual Excipient Test Data on Metal Impurities Submitted to IPEC-Americas from Industry

Transcription

1 Actual Excipient Test Data on Metal Impurities Submitted to IPEC-Americas from Industry Priscilla Zawislak Chair Compendial Review Committee IPEC Americas Global Regulatory Affairs Manager Ashland Inc. April 4, 2012

2 Excipient Data from Industry Existing metal impurity data Data requested from excipient manufacturers and users Blinded data sent to IPEC-Americas counsel Results, test methods, limits of detection - as provided/available

3 Common Excipients Existing Elemental Impurity Data Item Description TITANIUM DIOXIDE, USP/FCC/EP/JP HPMC 3 cp USP/EP/JP HPMC 6 cp USP/EP/JP PEG 400 NF/EP/JP SODIUM CITRATE DIHYD. USP/EP/JP/FCC/JSFA POLYSORBATE 80 (VEG.) NF/EP/JP POLYVINYL ALCOHOL, USP/FCC/EP/JPE PEG 3350 NF/EP/JP Lead Limit Listed on COA Max 10 ppm NMT 20 ppm (Heavy Metals) NMT 20 ppm (Heavy Metals) < 5 ppm (Heavy Metals) Typical Lead Limit Test Method Frequency of Testing 1 to 9 ppm based on 2 year history, 2 to 5 ppm typically ICP Every Batch 0.2 to 2 ppm ICP MS Once per year 0.2 to 2 ppm ICP MS Once per year NMT 1 mg/kg * * < 2 mg/kg < 1 mg/kg ICP Weekly < 10 ppm (Heavy Metals) Max 1 ppm Atomic Absorption Electro thermal Atomization (Furnace Atomization) according to Combined Compendium of Food Additives Specifications, FAO JECFA Monographs, vol 4 (2005). Statistic Basis NMT 2 ppm * AA Analysis Once per year < 5 ppm (Heavy Metals) * * *

4 Common Excipients Existing Elemental Impurity Data Item Description Lead Limit Listed on COA TALC USP/FCC/EP/JP < 10 ppm < 1 ppm GLYCERIN, 99.7%, USP/EP/JP/FCC/JSFA USL 1 ppm (Heavy Metals) Typical Lead Limit Test Method Frequency of Testing EP Talc ICP oes acc EN ISO Once a year * * * FD&C RED NO. 40 DYE, POWDER < 10 ppm < 1 ppm AA Analysis FD&C BLUE NO.1 DYE, POWDER < 10 ppm < 1 ppm AA Analysis TITANIUM DIOXIDE USP/EP/JP POLYDEXTROSE FCC 10 ppm Max. < 0.5 mg/kg 4 7 ppm based on 2 year history, Average 5 ppm. All values from 2010 through 2011 have been < 0.06 ppm with most frequently found values ranging from < 0.01 ppm to < 0.02 ppm. THGA AAS Method AOAC , , Several Samples a year are tested Several Samples a year are tested Once per week Every 20 lots (across each of the 2 dozen product forms and packaging codes.) MALTODEXTRIN NF/FCC/EP/JP < % * * * MEDIUM CHAIN TRIGLYCERIDES NMT 10 ppm (Heavy ICP (reference EPA SW 846 < 0.3 ppm max (lead) (NF, EP, JPE) Metals) Content in Oil Substance) Once per year * = Still Awaiting Suppliers Response

5 Elemental Impurities from Supplier COAs Mineral Based Excipients Item Number Item Description Supplier/Manufacturer As, ppm Cd, ppm Pb, ppm Inorganic Hg, ppm Cr, ppm Cu, ppm Ni, ppm, IC07445 IC07484 IC07453 IRON OXIDE YELLOW (NF,JPE) IRON OXIDE RED (NF,JPE) IRON OXIDE BLACK JPE Supplier A Supplier A Supplier A 3 max 1 max 10 max 1 max 100 max 50 max 200 max The following Elemental Impurities did not have Specifications or Results on the Suppliers COA & Specification: Manganese, Molybdenum, Palladium, Platinum, Vanadium, Osmium, Rhodium, Ruthenium, and Iridium.

6 Iron Oxide Red (NF, JPE) Lot Number Arsenic Cadmium Lead Inorganic Mercury Chromium Copper Nickel 1 < 1 ppm < 1 ppm < 2 ppm < 0.2 ppm 19 ppm 14 ppm 104 ppm 2 < 1 ppm < 1 ppm < 3 ppm < 0.2 ppm 38 ppm 25 ppm 100 ppm 3 < 1 ppm < 1 ppm < 3 ppm < 0.2 ppm 38 ppm 25 ppm 100 ppm 4 < 1 ppm < 1 ppm < 3 ppm < 0.2 ppm 38 ppm 25 ppm 100 ppm 5 < 1 ppm < 1 ppm < 2 ppm < 0.2 ppm 15 ppm 9 ppm 111 ppm 6 < 1 ppm < 1 ppm < 2 ppm < 0.2 ppm 41 ppm 9 ppm 108 ppm 7 < 1 ppm < 1 ppm < 2 ppm < 0.2 ppm 41 ppm 9 ppm 108 ppm 8 < 1 ppm < 1 ppm < 2 ppm < 0.2 ppm 41 ppm 9 ppm 108 ppm 9 < 1 ppm < 1 ppm < 2 ppm < 0.2 ppm 15 ppm 9 ppm 111 ppm 10 < 1 ppm < 1 ppm < 2 ppm < 0.2 ppm 15 ppm 9 ppm 111 ppm 11 < 1 ppm < 1 ppm 1 ppm < 0.2 ppm 16 ppm 16 ppm 111 ppm 12 < 1 ppm < 1 ppm 1 ppm < 0.2 ppm 16 ppm 16 ppm 111 ppm 13 < 1 ppm < 1 ppm 1 ppm < 0.2 ppm 16 ppm 16 ppm 111 ppm 14 < 1 ppm < 1 ppm 1 ppm < 0.2 ppm 16 ppm 16 ppm 111 ppm

7 CALCIUM CARBONATE PhEur Lot Number Arsenic Cadmium Lead Inorganic Mercury Chromium Copper Nickel ppm 0.73 ppm 2 ppm N/A N/A N/A N/A ppm 0.73 ppm 2 ppm N/A N/A N/A N/A 3 < 3 ppm 0.19 ppm 2.2 ppm N/A N/A N/A N/A 4 < 3 ppm 0.17 ppm 2.4 ppm N/A N/A N/A N/A ppm 0.21 ppm 2.3 ppm N/A N/A N/A N/A ppm 0.5 ppm 2 ppm N/A N/A N/A N/A ppm 0.3 ppm 1.1 ppm N/A N/A N/A N/A ppm 0.5 ppm 4.7 ppm N/A N/A N/A N/A ppm 0.6 ppm 2.5 ppm N/A N/A N/A N/A ppm 0.63 ppm 4.5 ppm N/A N/A N/A N/A ppm 0.44 ppm 2.6 ppm N/A N/A N/A N/A ppm 0.38 ppm 7.1 ppm N/A N/A N/A N/A ppm 0.6 ppm 3 ppm N/A N/A N/A N/A ppm < 0.1 ppm 1.4 ppm N/A N/A N/A N/A Excursion

8 Talc USP, PhEur Lot Number Arsenic Cadmium Lead Inorganic Mercury Chromium Copper Nickel ppm N/A 2.21 ppm N/A N/A N/A N/A ppm N/A 2.21 ppm N/A N/A N/A N/A ppm N/A 2.21 ppm N/A N/A N/A N/A ppm N/A 2.21 ppm N/A N/A N/A N/A ppm N/A 2.21 ppm N/A N/A N/A N/A ppm N/A 0.30 ppm N/A N/A N/A N/A ppm N/A 0.30 ppm N/A N/A N/A N/A ppm N/A 0.30 ppm N/A N/A N/A N/A ppm N/A 0.30 ppm N/A N/A N/A N/A ppm N/A 0.30 ppm N/A N/A N/A N/A

9 Kaolin - Lead Content from Different Sources Method MS Origin US Source Product Lot Lead, ppm

10 Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums > Method Reference EPA 6010B EPA 7471B Method Detection Limit Reporting / Quantitation Limit FD&C YELLOW #5/TARTRAZINE ALUMINUM LAKES <0.191 <0.132 < low dye% <0.191 <0.132 < < <0.191 <0.132 < <0.191 < medium dye% < <0.191 <0.132 < <0.191 <0.132 < < <0.191 <0.132 < high dye% < <0.191 <0.132 < < <0.191 <0.132 <0.0309

11 Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums > Method Reference EPA 6010B EPA 7471B Method Detection Limit Reporting / Quantitation Limit FD&C YELLOW #6/SUNSET YELLOW FCF ALUMINUM LAKES < <0.191 <0.132 < low dye% <0.191 <0.132 < <0.191 <0.132 < < <0.191 <0.132 < medium dye% <0.191 <0.132 < <0.191 <0.132 < < <0.191 <0.132 < high dye% < <0.191 <0.132 < <0.191 <0.132 <0.0309

12 Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums > Method Reference EPA 6010B EPA 7471B Method Detection Limit Reporting / Quantitation Limit FD&C RED #40/ALLURA RED AC ALUMINUM LAKES low dye% <0.191 <0.132 < <0.191 <0.132 < < <0.191 <0.132 < low dye% <0.191 <0.132 < <0.191 <0.132 < < <0.191 < medium dye% <0.191 <0.132 < <0.191 <0.132 < medium dye% <0.191 <0.132 < high dye% < <0.191 <0.132 < < <0.191 <0.132 <0.0309

13 Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums > Method Reference EPA 6010B EPA 7471B Method Detection Limit Reporting / Quantitation Limit FD&C BLUE #1/BRILLIANT BLUE FCF ALUMINUM LAKES < <0.191 <0.132 < low dye% <0.191 <0.132 < <0.191 <0.132 < <0.191 <0.132 < medium dye% <0.191 <0.132 < <0.191 <0.132 < < <0.191 < high dye% <0.191 <0.132 < <0.191 <

14 Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums > Method Reference EPA 6010B EPA 7471B Method Detection Limit Reporting / Quantitation Limit FD&C BLUE #2/INDIGO CARMINE ALUMINUM LAKES <0.191 <0.132 < low dye% < <0.191 <0.132 < < <0.191 <0.132 < <0.191 <0.132 < medium dye% <0.191 <0.132 < <0.191 <0.132 < < <0.191 <0.132 < high dye% < <0.191 <0.132 < <0.191 <0.132 <0.0309

15 Phosphate Salts Product Sample Al Mo V Zn LOD, ppm Instrument Dicalcium Phosphate A Anydrous B Dicalcium Phosphate Dihydrate C A B C

16 Dicalcium Phosphate Anhydrous & Dicalcium Phosphate Dihydrate Sb As Ba B Cd Cr Co Cu Pb LOD, ppm Instrument None Detected MS MS MS Li Hg Ni Se Ag Ti Sn W LOD, ppm Instrument CV MS MS

17 Tricalcium Phosphate Product Sample Al As Ba B Cr Hg Mo V Zn LOD, ppm Instrument MS CV A ND B ND C

18 Tricalcium Phosphate Sb As Ba B Cd Cr Co Cu Pb LOD, ppm Instrument None Detected MS MS MS Li Hg Ni Se Ag Ti Sn W LOD, ppm Instrument CV MS MS

19 Polyvinylpyrrolidone Batch Cd Pb As Hg Ir Os Pd Pt ICP - MS ppm 1 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.1 2 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.1 3 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.1 Batch Rh Ru Cr Mo Ni V Cu Mn ICP - MS ppm 1 <0.1 <0.1 <1 <1 <1 <1 <1 <1 2 <0.1 <0.1 <1 <1 <1 <1 <1 <1 3 <0.1 <0.1 <1 <1 <1 <1 <1 <1

20 Vinylpyrrolidone - Vinyl Acetate Copolymer Product Batch Rh Ru Cr Mo Ni V Cu Mn LOD, ppm 1 <0.1 <0.1 <1 <1 <1 <1 <1 <1 2 <0.1 <0.1 <1 <1 <1 <1 <1 <1 3 <0.1 <0.1 <1 <1 <1 <1 <1 <1 LOD, ppm Batch Cd Pb As Hg Ir Os Pd Pt 1 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.1 2 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.1 3 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.1

21 Sodium Carboxymethylcellulose ICP # As Cd Cu Fe Hg Pb Zn Samples LOD, ppm Spec, ppm <3 <2 <50 <30 <1 <3 <25 Year 1 10 <0.3 <0.2 <2 <5 <0.1 <0.1 (9) <2 <3 (1) Year 2 9 <0.3 <0.2 <5 <0.1 <0.1 <2 Year 3 9 <0.3 <0.2 <5 <0.1 <0.1 <2 Year 4 11 <0.3 <0.2 <5 <0.1 <0.1 <2 (10) <25 (1) Year 5 10 <0.3 <0.2 <5 <0.1 <0.1 <2

22 Hydroxyethylcellulose Data ICP As Cd Cr Cu Fe Hg Ni Pb Zn LOD, ppm # Samples < LOD # Samples Avg. ppm Min. ppm Max. ppm

23 Thank You!