Actual Excipient Test Data on Metal Impurities Submitted ...Actual Excipient Test Data on Metal...

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 [email protected]

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










11 < 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










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







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







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







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







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

Thank You !

Actual Excipient Test Data on Metal Impurities Submitted ...Actual Excipient Test Data on Metal...

Documents

Transcript of Actual Excipient Test Data on Metal Impurities Submitted ...Actual Excipient Test Data on Metal...