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Actual Excipient Test Data on Metal Impurities Submitted to IPEC-Americas from Industry
Priscilla ZawislakChair – 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 ExcipientsExisting Elemental Impurity Data
Item Description Lead Limit Listed on COA Typical Lead Limit Test Method Frequency of Testing
TITANIUM DIOXIDE, USP/FCC/EP/JP Max 10 ppm
1 to 9 ppm based on 2 year history, 2 to 5 ppm
typicallyICP Every Batch
HPMC 3 cP ‐ USP/EP/JP NMT 20 ppm (Heavy Metals) 0.2 to 2 ppm ICP‐MS Once per year
HPMC 6 cP ‐ USP/EP/JP NMT 20 ppm (Heavy Metals) 0.2 to 2 ppm ICP‐MS Once per year
PEG 400 NF/EP/JP < 5 ppm (Heavy Metals) NMT 1 mg/kg * *
SODIUM CITRATE ‐ DIHYD. USP/EP/JP/FCC/JSFA < 2 mg/kg < 1 mg/kg ICP Weekly
POLYSORBATE 80 (VEG.) NF/EP/JP < 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
POLYVINYL ALCOHOL, USP/FCC/EP/JPE NMT 2 ppm * AA Analysis Once per year
PEG 3350 NF/EP/JP < 5 ppm (Heavy Metals) * * *
Common ExcipientsExisting Elemental Impurity Data
Item Description Lead Limit Listed on COA Typical Lead Limit Test Method Frequency of Testing
TALC USP/FCC/EP/JP < 10 ppm < 1 ppm EP 6.6 0438 Talc ICP‐oes acc EN ISO 11885 Once a year
GLYCERIN, 99.7%, USP/EP/JP/FCC/JSFA
USL 1 ppm (Heavy Metals) * * *
FD&C RED NO. 40 DYE, POWDER < 10 ppm < 1 ppm AA Analysis Several Samples a year are tested
FD&C BLUE NO.1 DYE, POWDER < 10 ppm < 1 ppm AA Analysis Several Samples a year are tested
TITANIUM DIOXIDE USP/EP/JP 10 ppmMax.4‐7 ppm based on 2
year history, Average 5 ppm.
THGA‐AAS‐Method Once per week
POLYDEXTROSE FCC < 0.5 mg/kg
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.
AOAC 985.01, 990.08, 975.03
Every 20 lots (across each of the 2 dozen product forms and packaging codes.)
MALTODEXTRIN NF/FCC/EP/JP < 0.500 % * * *MEDIUM CHAIN TRIGLYCERIDES
(NF, EP, JPE)NMT 10 ppm (Heavy
Metals) < 0.3 ppm max (lead) ICP (reference EPA SW 846 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 IRON OXIDE YELLOW (NF,JPE) Supplier A ≤ 2 ≤ 1 ≤ 10 ≤ 1 ≤ 100 ≤ 50 ≤ 200
IC07484 IRON OXIDE RED (NF,JPE) Supplier A ≤ 2 ≤ 1 ≤ 10 ≤ 1 ≤ 100 ≤ 50 ≤ 200
IC07453 IRON OXIDE BLACK JPE 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/A2 0.29 ppm 0.73 ppm 2 ppm N/A N/A N/A N/A3 < 3 ppm 0.19 ppm 2.2 ppm N/A N/A N/A N/A4 < 3 ppm 0.17 ppm 2.4 ppm N/A N/A N/A N/A5 0.42 ppm 0.21 ppm 2.3 ppm N/A N/A N/A N/A6 0.26 ppm 0.5 ppm 2 ppm N/A N/A N/A N/A7 0.21 ppm 0.3 ppm 1.1 ppm N/A N/A N/A N/A8 0.29 ppm 0.5 ppm 4.7 ppm N/A N/A N/A N/A9 0.14 ppm 0.6 ppm 2.5 ppm N/A N/A N/A N/A10 0.35 ppm 0.63 ppm 4.5 ppm N/A N/A N/A N/A11 0.57 ppm 0.44 ppm 2.6 ppm N/A N/A N/A N/A12 0.36 ppm 0.38 ppm 7.1 ppm N/A N/A N/A N/A13 0.16 ppm 0.6 ppm 3 ppm N/A N/A N/A N/A14 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 ICP-MS Origin – US
Source Product Lot Lead, ppm
1 1 1 331 1 2 261 1 3 241 2 1 191 2 2 162 1 1 122 2 2 552 3 3 38
Testing of Aluminum LakesTest 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
low dye%
1 208000 0.946 16.3 1.07 68.0 <0.191 <0.132 <0.0309
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
medium dye%
1 173000 1.10 7.58 0.888 55.0 <0.191 <0.132 0.0315
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
high dye%
1 166000 <0.486 6.00 0.729 39.3 <0.191 <0.132 <0.0309
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 LakesTest 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
low dye%
1 237000 <0.486 8.88 1.05 65.3 <0.191 <0.132 <0.0309
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
medium dye%
1 234000 <0.486 9.89 1.08 66.6 <0.191 <0.132 <0.0309
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
high dye%
1 154000 <0.486 9.94 0.671 51.2 <0.191 <0.132 <0.0309
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 LakesTest 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
low dye%
1 214000 <0.486 10.3 1.04 59.7 <0.191 <0.132 <0.0309
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
medium dye%
1 161000 <0.486 8.85 0.703 49.4 <0.191 <0.132 0.0550
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 LakesTest 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
low dye%
1 230000 <0.486 6.32 1.10 70.4 <0.191 <0.132 <0.0309
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
medium dye%
1 224000 0.972 13.3 1.10 54.3 <0.191 <0.132 <0.0309
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
high dye%
1 185000 <0.486 8.27 0.874 46.8 <0.191 <0.132 0.0380
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 LakesTest 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
low dye%
1 250000 0.688 10.1 1.20 79.1 <0.191 <0.132 <0.0309
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
medium dye%
1 208000 0.876 15.2 1.11 61.7 <0.191 <0.132 <0.0309
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
high dye%
1 161000 <0.486 6.04 0.843 28.3 <0.191 <0.132 <0.0309
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 ZnLOD, ppm 5.00 1.00 1.00 1.00Instrument ICP-AES ICP-AES ICP-AES ICP-AES
Dicalcium PhosphateAnydrous
A 234 4.5 2.66 5.52
B 192 3.2 1.64 5.27C 200 3.4 1.58 5.13
Dicalcium Phosphate Dihydrate
A 186 2.6 1.95 4.40
B 168 2.5 1.67 4.75C 178 2.3 2.26 8.84
Dicalcium Phosphate Anhydrous & Dicalcium Phosphate Dihydrate
Sb As Ba B Cd Cr Co Cu PbLOD, ppm 5.00 0.15 1.00 5.00 1.00 5.00 1.00 1.00 0.50Instrument ICP-
AESICP-MS
ICP-AES
ICP-AES
ICP-MS
ICP-AES
ICP-AES
ICP-AES
ICP-MS
Li Hg Ni Se Ag Ti Sn WLOD, ppm 5.00 0.05 1.00 1.00 1.00 1.00 10.00 5.00Instrument ICP-
AESCV ICP-
AESICP-MS
ICP-AES
ICP-MS
ICP-AES
ICP-AES
None Detected
Tricalcium Phosphate
Product Sample Al As Ba B Cr Hg Mo V ZnLOD, ppm 5.00 0.15 1.00 5.00 5.00 0.05 1.00 1.00 1.00Instrument ICP-
AESICP-MS
ICP-AES
ICP-AES
ICP-AES
CV ICP-AES
ICP-AES
ICP-AES
A 399 0.3 3.4 40 14 ND 3.7 6.04 11.9B 277 0.3 2 13.4 7.5 ND 2.1 3.97 11.5C 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 PbLOD, ppm 5.00 0.15 1.00 5.00 1.00 5.00 1.00 1.00 0.50Instrument ICP-
AESICP-MS
ICP-AES
ICP-AES
ICP-MS
ICP-AES
ICP-AES
ICP-AES
ICP-MS
Li Hg Ni Se Ag Ti Sn WLOD, ppm 5.00 0.05 1.00 1.00 1.00 1.00 10.00 5.00Instrument ICP-
AESCV ICP-
AESICP-MS
ICP-AES
ICP-MS
ICP-AES
ICP-AES
None Detected
Polyvinylpyrrolidone
Batch Cd Pb As Hg Ir Os Pd PtICP - MS
ppm 1 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.12 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.13 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.1
Batch Rh Ru Cr Mo Ni V Cu MnICP - MS
ppm 1 <0.1 <0.1 <1 <1 <1 <1 <1 <12 <0.1 <0.1 <1 <1 <1 <1 <1 <13 <0.1 <0.1 <1 <1 <1 <1 <1 <1
Vinylpyrrolidone - Vinyl Acetate Copolymer
Batch Cd Pb As Hg Ir Os Pd PtLOD, ppm
1 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.12 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.13 <0.05 <0.05 <0.1 <0.1 <0.1 <1 <0.1 <0.1
Product Batch Rh Ru Cr Mo Ni V Cu MnLOD, ppm
1 <0.1 <0.1 <1 <1 <1 <1 <1 <12 <0.1 <0.1 <1 <1 <1 <1 <1 <13 <0.1 <0.1 <1 <1 <1 <1 <1 <1
Sodium Carboxymethylcellulose
ICP # Samples
As Cd Cu Fe Hg Pb Zn
LOD, ppm 0.3 0.2 2 1 0.1 0.1 2Spec, ppm <3 <2 <50 <30 <1 <3 <25
Year 1 10 <0.3 <0.2 <2 <5 <0.1 <0.1 (9)<3 (1)
<2
Year 2 9 <0.3 <0.2 <5 <0.1 <0.1 <2Year 3 9 <0.3 <0.2 <5 <0.1 <0.1 <2Year 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
ICP As Cd Cr Cu Fe Hg Ni Pb ZnLOD, 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 46Avg. ppm 0.2 0.1 0.4 0.2 2.9 0.3 0.5 0.5 0.2Min. ppm 0.1 -- 0.3 0.1 1 0.1 -- 0.2 0.1Max. ppm 0.4 -- 0.9 0.6 8.4 0.5 -- 2.0 0.5
Data 1992 – 2012
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