COLD CHAIN
Table 2. Amounts of Individual Elemental Entities in the Plasticized PVC Test Article.
ICH Class Element Amount in
1
As Pb Cd Hg V
2A Ni
Co Ag Au Tl
2B
Se Pd Pt Ir
Os Rh Ru Sb Ba Li
3 Cr
Cu Sn
Mo Fe Zn
4
Mn Be
We Ale
<0.01 <0.02 <0.01
<0.005 <0.02 0.027 <0.01
N/A (<0.02)d N/A (<0.02)d <0.01 <0.02 <0.01 <0.01 <0.01 N/Af
<0.01 <0.01 <0.02 0.025 <0.01 0.097 0.024 <0.02 <0.02 1.1 56
<0.02 0.79
<0.01 0.42
PVC (µg/g)a
Daily Exposure (µg/day)b
0.6 1.2 0.6
0.29 1.2 1.6 0.6
(1.2) (1.2) 0.6 1.2 0.6 0.6 0.6 ---
0.6 0.6 1.2 1.5 0.6 5.7 1.4 1.2 1.2
64.7 3300 1.2
46.5 1.2
24.7
PDE (µg/ day)
15
5.0 2.0 1.5 10 20
5.0 10
100 8.0 80 10 10 10 10 10 10 90
700 250 25
130 600 25
1300 1300 250 --- ---
5000g
N/A = Not applicable. a) If the result is reported as <X, X is the Reporting Limit.
b) Daily Exposure (µg/day) = amount in PVC (µg/g) × 9.81 grams/bag × 6 bags/day.
c) % Daily Exposure = (Daily exposure/PDE) × 100%.
d) Element not quantified due to unacceptable recovery for a system suitability QC check. However, the calculations in () represent typical results for these analytes.
e) Elements for which no PDE has been established. f) Element not quantified due to low analytical recovery.
g) While neither the ICH nor USP has proposed a PDE for Al, the Agency for Toxic Substances and Disease Registry13
has derived
an intermediate-duration oral minimal risk level of 1 mg/kg/day. Applying an uncertainty factor of 10 for route of administration (oral versus intravenous) and considering a 50-kg person, this corresponds to a PDE of 5000 µg/day.
% Daily Exposure versus PDEc
4.0 24 30 19 12
8.0 12
(12) (1.2) 7.5 1.5 6.0 6.0 6.0 ---
6.0 6.0 1.3 0.2 0.2 23
1.1 0.2 4.8 5.0
250 0.5 --- ---
0.5
supplemented recovery samples was ±20% relative standard deviation (RSD). The reporting level for the analytes in the digests was taken as the analyte’s concentration in the lowest concentration calibration standard.
Permissible Daily Exposure (PDE) Values
PDE values for the targeted elemental entities, as provided in various reference sources, are summarized in Table 1. The PDEs from these various sources were considered, and the lowest, most conservative PDE was taken as the basis of the comparison between PDE and the Daily Exposure.
It is noted that at the time this manuscript was written, neither the ICH Q3D nor USP <232> documents had been fully adopted. Thus the PDEs used in this manuscript, which reflect the documents in place when the manuscript was prepared, may not be the exact PDEs that appear in these documents when they are published as fully adopted.
Composition of the Test Article
The mean levels of the targeted elements in the digests of the test article are summarized in Table 2. Many of the targeted elements were not present in the digest solutions at levels above the reporting level, which was typically 0.01 or 0.02 µg/g. Several elements were present in the digests at levels <1 µg/g including Al, B, Ba, Cr, Cu, and Ni. Only 2 elements, Fe and Zn, were present in the digest at levels greater than 1 µg/g. In the case of Zn, this result is not unanticipated, as the test article is formulated with a Ca/Zn stearate salt. In fact, the theoretical amount of Zn in the test article could be estimated given the composition of the test article (1250 µg Ca/Zn stearate/g of PVC) and the weight percent Zn in the C/Zn salt (4.25%). This theoretical amount, 53 µg Zn/g of PVC, agrees well with the experimentally determined value of 56 µg/g.
As the digests were free from particulate matter, it can be concluded that the test article was fully dissolved in the digests and thus that the levels of the measurable elemental entities in the digests represents the total pool of these elemental entities.
Comparison of Total Pool to PDE Values
Given the clinical use conditions described previously, a product user’s maximum exposure to an elemental entity, should all of the elemental entity leach out of the container, is calculated as follows:
Maximum Daily Exposure (µg/day) =
Level of the entity in the digest (µg/g) × 9.81 grams of PVC /bag × 6 bags/day
For example, the Daily Exposure for Zn becomes: 56 µg/g × 9.81 grams PVC/bag × 6 bags per day = 3296 µg/day.
Figure 1. Comparison of the Daily Exposure to the PDEs for the Elemental Impurities Considered in this Study.
Pharmaceutical Outsourcing | 32 | March/April 2015
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