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. pszawislak@ashland.com April 4, 2012
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
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) * * *
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 6.6 0438 Talc ICP oes acc EN ISO 11885 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 985.01, 990.08, 975.03 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 < 0.500 % * * * 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
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 2 1 10 1 100 50 200 Supplier A 2 1 10 1 100 50 200 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.
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
CALCIUM CARBONATE PhEur Lot Number Arsenic Cadmium Lead Inorganic Mercury Chromium Copper Nickel 1 0.29 ppm 0.73 ppm 2 ppm N/A N/A N/A N/A 2 0.29 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 5 0.42 ppm 0.21 ppm 2.3 ppm N/A N/A N/A N/A 6 0.26 ppm 0.5 ppm 2 ppm N/A N/A N/A N/A 7 0.21 ppm 0.3 ppm 1.1 ppm N/A N/A N/A N/A 8 0.29 ppm 0.5 ppm 4.7 ppm N/A N/A N/A N/A 9 0.14 ppm 0.6 ppm 2.5 ppm N/A N/A N/A N/A 10 0.35 ppm 0.63 ppm 4.5 ppm N/A N/A N/A N/A 11 0.57 ppm 0.44 ppm 2.6 ppm N/A N/A N/A N/A 12 0.36 ppm 0.38 ppm 7.1 ppm N/A N/A N/A N/A 13 0.16 ppm 0.6 ppm 3 ppm N/A N/A N/A N/A 14 0.43 ppm < 0.1 ppm 1.4 ppm N/A N/A N/A N/A Excursion
Talc USP, PhEur Lot Number Arsenic Cadmium Lead Inorganic Mercury Chromium Copper Nickel 1 0.087 ppm N/A 2.21 ppm N/A N/A N/A N/A 2 0.048 ppm N/A 2.21 ppm N/A N/A N/A N/A 3 0.048 ppm N/A 2.21 ppm N/A N/A N/A N/A 4 0.048 ppm N/A 2.21 ppm N/A N/A N/A N/A 5 0.048 ppm N/A 2.21 ppm N/A N/A N/A N/A 6 0.087 ppm N/A 0.30 ppm N/A N/A N/A N/A 7 0.087 ppm N/A 0.30 ppm N/A N/A N/A N/A 8 0.087 ppm N/A 0.30 ppm N/A N/A N/A N/A 9 0.087 ppm N/A 0.30 ppm N/A N/A N/A N/A 10 0.087 ppm N/A 0.30 ppm N/A N/A N/A N/A
Kaolin - Lead Content from Different Sources Method MS Origin US Source Product Lot Lead, ppm 1 1 1 33 1 1 2 26 1 1 3 24 1 2 1 19 1 2 2 16 2 1 1 12 2 2 2 55 2 3 3 38
Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums >100000 1 500 1 500 1 500 1 Method Reference EPA 6010B EPA 7471B Method Detection Limit 389 0.486 0.245 0.0225 2.08 0.191 0.132 0.0309 Reporting / Quantitation Limit 10 1 1 0.4 5 2 1 0.1 FD&C YELLOW #5/TARTRAZINE ALUMINUM LAKES 1 208000 0.946 16.3 1.07 68.0 <0.191 <0.132 <0.0309 low dye% 2 172000 0.676 9.17 0.893 50.7 <0.191 <0.132 <0.0309 3 198000 <0.486 15.7 1.01 63.8 <0.191 <0.132 <0.0309 1 173000 1.10 7.58 0.888 55.0 <0.191 <0.132 0.0315 medium dye% 2 178000 <0.486 7.94 0.926 56.4 <0.191 <0.132 <0.0309 3 204000 0.802 13.9 1.07 66.3 <0.191 <0.132 <0.0309 1 166000 <0.486 6.00 0.729 39.3 <0.191 <0.132 <0.0309 high dye% 2 170000 <0.486 6.27 0.771 39.4 <0.191 <0.132 <0.0309 3 171000 <0.486 9.34 0.760 37.8 <0.191 <0.132 <0.0309
Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums >100000 1 500 1 500 1 500 1 Method Reference EPA 6010B EPA 7471B Method Detection Limit 389 0.486 0.245 0.0225 2.08 0.191 0.132 0.0309 Reporting / Quantitation Limit 10 1 1 0.4 5 2 1 0.1 FD&C YELLOW #6/SUNSET YELLOW FCF ALUMINUM LAKES 1 237000 <0.486 8.88 1.05 65.3 <0.191 <0.132 <0.0309 low dye% 2 226000 0.725 15.3 1.03 55.8 <0.191 <0.132 <0.0309 3 265000 1.22 14.5 1.21 75.1 <0.191 <0.132 <0.0309 1 234000 <0.486 9.89 1.08 66.6 <0.191 <0.132 <0.0309 medium dye% 2 212000 0.821 8.60 0.964 70.4 <0.191 <0.132 <0.0309 3 221000 1.32 13.3 0.978 65.4 <0.191 <0.132 <0.0309 1 154000 <0.486 9.94 0.671 51.2 <0.191 <0.132 <0.0309 high dye% 2 151000 <0.486 3.70 0.682 34.4 <0.191 <0.132 <0.0309 3 157000 0.575 5.20 0.692 9.77 <0.191 <0.132 <0.0309
Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums >100000 1 500 1 500 1 500 1 Method Reference EPA 6010B EPA 7471B Method Detection Limit 389 0.486 0.245 0.0225 2.08 0.191 0.132 0.0309 Reporting / Quantitation Limit 10 1 1 0.4 5 2 1 0.1 FD&C RED #40/ALLURA RED AC ALUMINUM LAKES low dye% 1 226000 0.724 8.60 1.00 57.1 <0.191 <0.132 <0.0309 2 235000 0.492 16.6 1.08 74.2 <0.191 <0.132 <0.0309 1 214000 <0.486 10.3 1.04 59.7 <0.191 <0.132 <0.0309 low dye% 2 225000 1.70 14.2 1.03 66.3 <0.191 <0.132 <0.0309 3 233000 0.740 8.44 1.14 65.8 <0.191 <0.132 <0.0309 1 161000 <0.486 8.85 0.703 49.4 <0.191 <0.132 0.0550 medium dye% 2 155000 0.978 5.71 0.674 58.8 <0.191 <0.132 <0.0309 3 154000 0.731 6.07 0.677 63.7 <0.191 <0.132 <0.0309 medium dye% 1 169000 0.755 8.00 0.761 57.4 <0.191 <0.132 <0.0309 high dye% 1 153000 <0.486 5.59 0.681 18.0 <0.191 <0.132 <0.0309 2 158000 <0.486 5.31 0.699 18.0 <0.191 <0.132 <0.0309
Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums >100000 1 500 1 500 1 500 1 Method Reference EPA 6010B EPA 7471B Method Detection Limit 389 0.486 0.245 0.0225 2.08 0.191 0.132 0.0309 Reporting / Quantitation Limit 10 1 1 0.4 5 2 1 0.1 FD&C BLUE #1/BRILLIANT BLUE FCF ALUMINUM LAKES 1 230000 <0.486 6.32 1.10 70.4 <0.191 <0.132 <0.0309 low dye% 2 225000 0.490 7.99 1.07 63.8 <0.191 <0.132 <0.0309 3 238000 0.920 5.61 1.13 73.2 <0.191 <0.132 <0.0309 1 224000 0.972 13.3 1.10 54.3 <0.191 <0.132 <0.0309 medium dye% 2 221000 0.799 14.1 1.07 58.1 <0.191 <0.132 <0.0309 3 218000 1.13 10.5 1.05 76.3 <0.191 <0.132 <0.0309 1 185000 <0.486 8.27 0.874 46.8 <0.191 <0.132 0.0380 high dye% 2 175000 0.820 4.88 0.801 34.4 <0.191 <0.132 <0.0309 3 180000 0.682 6.18 0.807 39.6 <0.191 <0.132 0.0435
Testing of Aluminum Lakes Test Results Target Maximum Limits (ppm) Product Batch No Aluminum Arsenic Barium Cadmium Iron Lead Zinc Mercury Expected Target Maximums >100000 1 500 1 500 1 500 1 Method Reference EPA 6010B EPA 7471B Method Detection Limit 389 0.486 0.245 0.0225 2.08 0.191 0.132 0.0309 Reporting / Quantitation Limit 10 1 1 0.4 5 2 1 0.1 FD&C BLUE #2/INDIGO CARMINE ALUMINUM LAKES 1 250000 0.688 10.1 1.20 79.1 <0.191 <0.132 <0.0309 low dye% 2 241000 <0.486 16.2 1.18 45.5 <0.191 <0.132 <0.0309 3 231000 <0.486 15.0 1.40 51.3 <0.191 <0.132 <0.0309 1 208000 0.876 15.2 1.11 61.7 <0.191 <0.132 <0.0309 medium dye% 2 210000 2.44 14.6 1.17 55.0 <0.191 <0.132 <0.0309 3 213000 0.572 14.4 1.20 57.2 <0.191 <0.132 <0.0309 1 161000 <0.486 6.04 0.843 28.3 <0.191 <0.132 <0.0309 high dye% 2 169000 <0.486 4.92 0.872 38.6 <0.191 <0.132 <0.0309 3 178000 0.713 9.81 0.904 39.1 <0.191 <0.132 <0.0309
Phosphate Salts Product Sample Al Mo V Zn LOD, ppm 5.00 1.00 1.00 1.00 Instrument Dicalcium Phosphate A 234 4.5 2.66 5.52 Anydrous B 192 3.2 1.64 5.27 Dicalcium Phosphate Dihydrate C 200 3.4 1.58 5.13 A 186 2.6 1.95 4.40 B 168 2.5 1.67 4.75 C 178 2.3 2.26 8.84
Dicalcium Phosphate Anhydrous & Dicalcium Phosphate Dihydrate Sb As Ba B Cd Cr Co Cu Pb LOD, ppm 5.00 0.15 1.00 5.00 1.00 5.00 1.00 1.00 0.50 Instrument None Detected MS MS MS Li Hg Ni Se Ag Ti Sn W LOD, ppm 5.00 0.05 1.00 1.00 1.00 1.00 10.00 5.00 Instrument CV MS MS
Tricalcium Phosphate Product Sample Al As Ba B Cr Hg Mo V Zn LOD, ppm 5.00 0.15 1.00 5.00 5.00 0.05 1.00 1.00 1.00 Instrument MS CV A 399 0.3 3.4 40 14 ND 3.7 6.04 11.9 B 277 0.3 2 13.4 7.5 ND 2.1 3.97 11.5 C 267 0.46 2.3 73.2 12 1.5 1.5 4.16 11.7
Tricalcium Phosphate Sb As Ba B Cd Cr Co Cu Pb LOD, ppm 5.00 0.15 1.00 5.00 1.00 5.00 1.00 1.00 0.50 Instrument None Detected MS MS MS Li Hg Ni Se Ag Ti Sn W LOD, ppm 5.00 0.05 1.00 1.00 1.00 1.00 10.00 5.00 Instrument CV MS MS
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
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
Sodium Carboxymethylcellulose ICP # As Cd Cu Fe Hg Pb Zn Samples LOD, ppm 0.3 0.2 2 1 0.1 0.1 2 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
Hydroxyethylcellulose Data 1992 2012 ICP As Cd Cr Cu Fe Hg Ni Pb Zn LOD, ppm 0.1 0.1 0.3 0.1 1 0.2 0.4 0.2 0.1 # Samples < LOD 66 57 51 33 10 24 55 72 6 # Samples 9 5 16 30 53 7 1 12 46 Avg. ppm 0.2 0.1 0.4 0.2 2.9 0.3 0.5 0.5 0.2 Min. ppm 0.1 -- 0.3 0.1 1 0.1 -- 0.2 0.1 Max. ppm 0.4 -- 0.9 0.6 8.4 0.5 -- 2.0 0.5
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