Evaluating Drug Delivery Systems in Line with USP General Chapters <232> Elemental Impurities Limits

This article presents the test results for samples described as:

1. H2O Extraction of Bag
2. H2O Extraction of Filter
3. H2O Extraction of Tube
4. Saline (5 M) Extractions of Bag
5. Saline (5 M) Extractions of Filter
6. Saline (5 M) Extractions of Tube
7. Saline (5 M) Extractions of Assembled Bag-Filter-Tubing Device
8. H2O Blank
9. Saline (5 M) Blank

The following test was conducted:

  1. Inductively Coupled Plasma-Mass Spectrometry (ICP-MS)

Objective

Nine samples including four saline extractions, three H2O extractions and two blanks (H2O and saline) were submitted for analyzes by ICP-MS. The goal of this research was to establish the levels of elements identified as elemental impurities by USP General Chapters <232> Elemental Impurities-Limits in these extractions.

Summary of Results

The levels of twenty-four elements identified as elemental impurities by USP General Chapters <232> Elemental Impurities were successfully determined by ICP-MS for both the saline (5 M) extractions and the water extractions. Twenty-one elements were detected in either H2O extraction samples or saline (5 M) extraction samples. A low level Detection Limit (DL) of 0.01 ng/mL (ppb) was accomplished in the analyzes.

Individual Test Results

A summary of the individual test results is given below. All related data, including spectra, have been added in the data section of this report.

ICP-MS

Nine samples including seven extraction samples and two blank samples were tested using an Agilent 7900 ICP-MS. The samples comprised of H2O extractions of filters, a bag and a tube; Saline (5 M) extractions of filters, a bag and a tube and an assembled bag-filter-tubing device; an H2O blank and a saline blank. The instrument was calibrated with Agilent multi-element prepared standards using 5.0% HNO3. The samples were diluted 1:10 with matrix matched 5.0% HNO3 in one analysis.

Table 1 shows the results for all elements identified as elemental impurities for the risk assessment in compliance with USP General Chapters <232> Elemental Impurities-Limits.

Table 2 shows elements detected in samples which are identified as elemental impurities for the risk assessment in compliance with USP General Chapters <232> Elemental Impurities-Limits.

Table 1. ICP-MS Results for Elements to be Considered in the Risk Assessment.1 (ng/mL [ppb])

Element Tested Saline Extractions (10 x concentrated) Water Extractions (10 x concentrated)
Filter Tube Bag Device Blank Filter Tube Bag Blank
Li <DL2 <DL <DL <DL <DL <DL <DL <DL <DL
V 0.048 0.012 0.021 0.026 0.015 0.007 <DL <DL <DL
Cr 0.076 0.049 0.043 <DL 0.039 0.029 <DL <DL <DL
Co <DL 0.190 <DL 0.082 <DL <DL 0.323 <DL <DL
Ni <DL <DL <DL <DL <DL <DL 0.169 <DL <DL
Cu <DL <DL <DL 4.981 <DL <DL <DL <DL <DL
As 0.063 0.033 0.035 0.048 0.033 0.074 0.004 0.004 0.003
Se 0.014 <DL <DL <DL <DL <DL <DL <DL <DL
Mo 0.243 0.184 0.173 0.227 0.201 0.009 0.011 <DL 0.007
Ru 0.000 0.000 0.000 0.001 0.001 0.000 0.000 0.000 0.000
Rh 0.003 <DL 0.001 0.001 <DL 0.001 <DL <DL <DL
Pd 0.002 0.002 0.002 0.002 0.001 0.002 0.001 0.001 <DL
Ag 2.431 2.742 1.637 0.261 0.063 0.260 0.047 0.144 0.028
Cd <DL 0.009 0.005 <DL <DL <DL 0.017 0.011 <DL
Sn 0.019 0.024 0.022 <DL <DL <DL <DL <DL <DL
Sb 105.496 0.042 1.052 0.260 0.013 20.267 0.007 <DL <DL
Ba 0.307 0.311 0.588 0.016 0.302 0.199 0.057 0.102 <DL
Os <DL <DL <DL <DL <DL <DL <DL <DL <DL
Ir 0.168 0.005 0.004 0.006 <DL 0.099 0.003 <DL <DL
Pt <DL 0.005 <DL <DL <DL <DL 0.003 <DL <DL
Au 0.028 0.022 0.020 0.035 0.011 0.015 0.022 0.011 0.012
Hg 0.024 0.017 0.012 0.023 0.004 0.012 0.012 0.012 0.007
Tl <DL <DL <DL <DL <DL <DL <DL <DL <DL
Pb 0.010 0.022 0.024 0.085 0.015 <DL 0.013 0.027 <DL

1 In accordance with USP General Chapters <232> Elemental Impurities-Limits
2 <DL= Below Detection Limit (0.01 ng/mL)

Table 2. ICP-MS Results Summary for Detected Elements.
(Levels < Detection Limit are shown in Blank)

Sample Extraction Solvent V Cr Co Ni Cu As Se Mo Ru Rh Pd
Filter Saline X X X X X X X
Water X X X X X X
Tube Saline X X X X X X
Water X X X X X
Bag Saline X X X X X X
Water X X
Device Saline X X X X X X X X

Sample Extraction Solvent Ag Cd Sn Sb Ba Ir Pt Au Hg Pb
Filter Saline X X X X X X X X
Water X X X X X X
Tube Saline X X X X X X X X X X
Water X X X X X X X X X
Bag Saline X X X X X X X X X
Water X X X X X X
Device Saline X X X X X X X

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Analysis Conditions

ICP-MS

Instrument: Agilent 7900 ICP-MS equipped with an Agilent SPS4 auto sampler.

ICP-MS Conditions

Instrument Agilent 7900 ICP-MS
Spray chamber Scott-type at 2 °C
Nebulizer Micromist
Forward power 1550 W
Carrier gas flow rate 1.03 L/minute
Cell gas flow rate 5.0 mL/minute (He) 6.0 mL/minute (H2)
Sampling depth 10 mm
Sampling mode He collision
KED voltage 5.0 V (He) 3.0 V (H2)

Calculated Detection Limits (ppb)

Mass Name MH DL Calc DL Mass Name MH DL Calc DL Mass Name MH DL Calc DL
7 Li 0.22215 0.08388 60 Ni 0.00486 0.00199 137 Ba 0.00046 0.00039
9 Be 0.00000 0.00691 62 Ni 0.00365 0.00203 139 La 0.00005 0.00004
10 B 0.22760 0.39643 63 Cu 0.00235 0.00048 140 Ce 0.00008 0.00003
11 B 0.10713 0.19462 65 Cu 0.00133 0.00043 141 Pr 0.00003 0.00001
23 Na 0.08938 1.04746 66 Zn 0.02553 0.00515 146 Nd 0.00005 0.00007
24 Mg 0.00655 0.01127 69 Ga 0.00078 0.00017 147 Sm 0.00006 0.00002
26 Mg 0.02588 0.03600 71 Ga 0.00000 0.00017 157 Gd 0.00003 0.00002
27 Al 0.03023 0.02122 75 As 0.00007 0.00026 163 Dy 0.00002 0.00002
28 Si 4.58972 4.21094 77 Se 0.00000 0.01553 165 Ho 0.00001 0.00001
29 Si 6.22431 6.40883 77 Se 0.01290 0.00662 166 Er 0.00002 0.00003
31 P 1.53589 0.86923 78 Se 0.02619 0.02057 169 Tm 0.00002 0.00001
34 S 59.68298 205.81999 78 Se 0.00045 0.00014 172 Yb 0.00009 0.00007
39 K 0.05847 0.16713 80 Se 0.11203 0.21388 175 Lu 0.00130 0.00047
40 Ca 0.13407 0.00718 82 Se 0.12317 0.05629 178 Hf 0.00002 0.00006
42 Ca 0.21698 0.04237 82 Se 0.00285 0.00650 181 Ta 0.00001 0.00197
43 Ca 0.14149 0.05350 85 Rb 0.00023 0.00018 182 W 0.00007 0.00140
43 Ca 0.20596 0.02442 88 Sr 0.00112 0.00028 185 Re 0.00001 0.00001
44 Ca 0.03851 0.01518 90 Zr 0.00032 0.00025 191 Ir 0.00010 0.00055
44 Ca 0.12146 0.01032 93 Nb 0.00000 0.00023 193 Ir 0.00015 0.00058
47 Ti 0.01468 0.00440 95 Mo 0.00023 0.00069 194 Pt 0.00016 0.00006
48 Ti 0.00558 0.00163 97 Mo 0.00014 0.00104 195 Pt 0.00010 0.00009
51 V 0.00022 0.00014 101 Ru 0.00000 0.00005 197 Au 0.00001 0.00181
52 Cr 0.00043 0.00075 103 Rh 0.00002 0.00003 200 Hg 0.00001 0.00028
53 Cr 0.00116 0.00173 105 Pd 0.00002 0.00023 201 Hg 0.00003 0.00027
54 Fe 0.02520 0.00467 107 Ag 0.00017 0.00060 202 Hg 0.00003 0.00028
55 Mn 0.00208 0.00115 111 Cd 0.00004 0.00005 205 Tl 0.00019 0.00008
55 Mn 0.00131 0.00020 114 Cd 0.00012 0.00003 206 Pb 0.00010 0.00010
56 Fe 0.00409 0.00336 118 Sn 0.00045 0.00036 207 Pb 0.00027 0.00016
56 Fe 0.02245 0.00186 119 Sn 0.00059 0.00048 208 Pb 0.00026 0.00005
57 Fe 0.00762 0.01973 121 Sb 0.00016 0.00011 232 Th 0.00002 0.00002
57 Fe 0.02100 0.00300 123 Sb 0.00020 0.00015 238 U 0.00001 0.00001
59 Co 0.00027 0.00006 133 Cs 0.00004 0.00006

This information has been sourced, reviewed and adapted from materials provided by Jordi Labs.

For more information on this source, please visit Jordi Labs.

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