Table XVI

Elemental Impurities Reported in Packaged Drug Products, Pharmaceutical Materials, or in Extracts Generated with Drug Products or Their Simulants

Sample MaterialExtraction ConditionsMeasured Levels, ng/mL (ppb)Ref.
AlCaCdFeMnPbSiSZn
Glass bottleExtracted with large volume parenteral (LVP) products3500NR1175NRNRNRNRNRNR13, 14
Glass bottleWater, 121 °C for 30 min70NRNRNRNRNRNRNRNR13, 14
Glass bottleDilute NaOH, 121 °C for 30 min, stoppered glass bottles4500NRNRNRNRNRNRNRNR13, 14
Glass, Type 1 vialsAqueous solutions, autoclave10001000NRNRNRNR15,000NRNR13, 14
Glass bottlesWater, 121 °C for 1 h, stoppered glass bottles336NRNRNRNRNRNRNRNR13, 14
Glass vial5% human serum albumin, 20 °C for 700 h in stoppered glass vials140NRNRNRNRNRNRNRNR13, 14
Glass bottles (stoppered)3Various commercial product diluentsNRNRNRNRNRNRNRNR10–21017
Glass bottle40.1% Polysorbate 80, room temperature for 21 days<1NR<11<1<1NRNR<119
Glass bottle with rubber closure3,13Amino acids, 10%11615NRNRNRNRNRNRNRNR45
Albumin 20%64417NRNRNRNRNRNRNRNR45
Glass bottles with rubber closuresCommercial LVPs, 0.9% NaCl; results listed are for elements contributed by the container640–346020NR5–200NRNR<10NRNRNR46
Glass bottles with rubber closuresCommercial LVPs, 5–33% dextrose; results listed are for elements contributed by the container2–33NR5–240NRNR<10NRNRNR46
Glass ampoule3,13Potassium phosphate, 2 meq/mL132514NRNRNRNRNRNRNRNR45
25% glucose37016NRNRNRNRNRNRNRNR45
Heparin, 5000 UI/mL73818NRNRNRNRNRNRNRNR45
Glass ampoulesWater for injection<10NRNRNRNRNRNRNRNR50
50% glucose injection17NRNRNRNRNRNRNRNR50
Plastic ampoulesWater for injection0–3NRNRNRNRNRNRNRNR50
Rubber stopper for glass bottleExtracted with LVP solution products34NR4NRNR3NRNRNR13, 14
Rubber stopper for glass bottleWater, 121 °C for 30 min in stoppered glass bottles50NRNRNRNRNRNRNRNR13, 14
Rubber stopperEDTA solution, 121 °C for 30 min in stoppered glass bottles5000NRNRNRNRNRNRNRNR13, 14
Rubber stopperDrug products, 80 °C for 51 weeks in stoppered glass vials13,000NRNRNRNRNRNRNRNR13, 14
Rubber stopper5% human serum albumin, 20 °C for 700 h in stoppered glass vial50NRNRNRNRNRNRNRNR13, 14
Rubber stopperProducts stored in stoppered glass vialsNR11,000NRNR9NRNRNR15013, 14
Rubber gloves4% acetic acid, 105 °C for 2 h20024,000NRNRNRNR300800640013, 14
Rubber gloves4% acetic acid, 105 °C for 2 h30015,000NRNRNRNR16,00031,00013,00013, 14
Rubber stopperProduct stored in stoppered glass vial13,0002NRNRNRNRNRNRNRNR15
Sample MaterialExtraction ConditionsExtracted Levels, ng/mL (ppb)Ref.
AlCaCdFeMnPbSiSZn
Plasticized PVC sheetspH 8.5 bicarbonate, 121 °C for 30 minNR4800NRNRNRNRNRNR160013, 14
Plasticized PVC bagsDrug product, up to 24 months ambient temperatureNR330300NRNR<1NRNR26013, 14
Plasticized PVC sheets4% acetic acid, 105 °C for 2 h200200NRNRNRNRNR80040013, 14
Plasticized PVC blood transfusion bagsVarious solvents, 60 °C for 10 daysNRNRNRNRNR1600NRNR290013, 14
Plasticized PVC3 bagsVarious commercial product diluentsNRNRNRNRNRNRNRNR5–24017
PVC bag9Final dialysate83.2NR0.151062.65.1NRNR5534
PVC bag10Substitution solution for hemofiltration811NR<0.10267.512NRNR7534
PVC bag11Continuous ambulatory peritoneal dialysis dialysate82.0NR0.2336.58NRNR4834
PVC bagGlucose 5% to 70%8–34NRNRNRNRNRNRNRNR50
Polyethylene sheets4% acetic acid, 105 °C for 2 h400200NRNRNRNR300NRNR13, 14
Polyethylene sheetsHydrofluoric acid, 4 months, ambient temperature500NRNR200NRNRNRNRNR13, 14
Polyethylene-based bags3Various commercial product diluentsNRNRNRNRNRNRNRNR10–2617
Polyethyelene3 vialsCommercial products1719NRNRNRNRNRNRNRNR45
Polyolefin7 bagsFilled with total parenteral nutrition, 30 °C for 30 days86NRNRNRNRNRNRNRNR22
Silicone sheets (used in devices)1% Trition X-100, 37 °C for 18 daysNRNRNRNRNRNR34,000NRNR13, 14
Stainless steel5 tanks0.1% Polysorbate 80, room temperature for 21 days<1NR<153063<1NRNR<119
Stainless steel6 tanks0.1% Polysorbate 80, room temperature for 21 days<1NR<113030<1NRNR<119
Stainless steel12 couponsOrganic buffers, pH 5–9, 25 °C for 34 weeksNRNRNR70NRNRNRNRNR39

  • Notes:

  • ↵1 NR = not reported.

  • ↵2 This is the highest amount reported in this study (50 °C for 51 weeks). The total pool of Al in the rubber stopper was as high as 25,000 mg/kg.

  • ↵3 Testing of commercial product within its stated expiry.

  • ↵4 Results for Cr, Cu, Co, Ni, and V were also reported as <1 ng/mL.

  • ↵5 Unpassivated. Results also reported for Cr (<1 ng/mL), Cu (<1 ng/mL), Co (<1 ng/mL), Ni (140 ng/mL), and V (<1 ng/mL).

  • ↵6 Passivated. Results also reported for Cr (<1 ng/mL), Cu (<1 ng/mL), Co (<1 ng/mL), Ni (80 ng/mL), and V (<1 ng/mL).

  • ↵7 Although these elements were identified as contaminants in the total parenteral nutrition solutions, the study did not establish that they were related to the bag. Other elements that were listed as contaminants included Ba (50 ng/mL), Co (1 ng/mL), Sr (11 ng/mL), Ti (60 ng/mL), and V (7 ng/mL).

  • ↵8 Solutions prepared by dilution of packaged concentrates that were within their labeled expiry. Although these elements were identified as contaminants in the solutions, the study did not establish that they were related to the bag.

  • ↵9 Other targeted elements and their measured levels (in ng/mL) included Ag (0.006), As (0.032), Au (0.003), B (84), Ba (48), Br (198), Ce (0.6), Co (0.45), Cr (1.4), Cs (0.05), Cu (9.8), Eu (0.15), Ga (0.25), Hf (0.005), Hg (0.11), In (<0.02), Ir (<0.001), La (0.025), Lu (0.001), Mo (0.2), Nd (0.04), Ni (11), Rb (8.6), Sb (0.07), Sc (0.003), Se (0.42), Sm (0.002), Sn (0.7), Sr (21), Ta (0.07), Tb (0.011), Th (0.013), Tl (0.04), U (0.06), W (0.035), V (0.31), and Zr (2.4).

  • ↵10 Other targeted elements and their measured levels (in ng/mL) included Ag (<0.005), As (<1), Au (<0.001), B (68), Ba (2), Br (120), Ce (0.08), Co (0.1), Cr (1.1), Cs (0.02), Cu (5.7), Eu (<0.02), Ga (0.5), Hf (0.002), Hg (0.15), In (<0.01), Ir (<0.001), La (0.005), Lu (<0.001), Mo (0.3), Nd (0.07), Ni (2.5), Rb (2.5), Sb (1.9), Sc (0.001), Se (0.75), Sm (<0.001), Sn (1.8), Sr (8), Ta (0.005), Tb (0.002), Th (0.007), Tl (0.11), U (0.07), W (0.002), V (0.95), and Zr (7).

  • ↵11 Other targeted elements and their measured levels (in ng/mL) included Ag (<0.01), As (1.2), Au (0.02), B (113), Ba (1.5), Br (81), Ce (0.08), Co (0.17), Cr (2.8), Cs (0.15), Cu (5.5), Eu (<0.01), Ga (<0.5), Hf (0.002), Hg (0.15), In (<0.02), Ir (<0.001), La (<0.002), Lu (<0.001), Mo (1.2), Nd (0.002), Ni (2.8), Rb (5), Sb (0.95), Sc (0.005), Se (0.5), Sm (<0.001), Sn (1.2), Sr (<10), Ta (0.003), Tb (<0.001), Th (<0.002), Tl (0.08), U (0.08), W (0.003), V (0.4), and Zr (3).

  • ↵12 Other targeted elements and their measured levels (in ng/mL) included Cr (8) and Ni (4).

  • ↵13 These results are representative of a larger reported dataset. Generally, the largest extracted amount is reported for a group of extraction solvents (e.g., salt solutions, amino acids solutions, glucose solutions albumin and heparin).

  • ↵14 The studied container had 2.45% Al by weight.

  • ↵15 The studied container consisted of a glass bottle that had 0.76% Al by weight and a rubber closure that had 4.23% Al by weight.

  • ↵16 The studied container had 1.87% Al by weight.

  • ↵17 The studied container consisted of a glass bottle that had 0.67% Al by weight and a rubber closure that had 4.06% Al by weight.

  • ↵18 The studied container had 3.03% Al by weight.

  • ↵19 The studied materials generally contained Al at levels of less than 0.1% by weight. This result is for a product that contained sodium acetate, 2 meq/mL. Lesser amounts of Al were reported in other solutions including NaCl 20%, KCl 10%, and glucose 50%.

  • ↵20 The highest levels of Al leaching were exhibited with Type II versus Type 1 glass.