COLD CHAIN
used to perform the digestion. The test samples were supplemented at levels of 1 µg/g and 2 µg/g for all of the targeted elements except Li, B, Al, Fe, Zn, and Sn, which were supplemented at a level of 15 µg/g. Replicates of such supplemented samples were taken through the entire digestion/analysis procedure described previously.
Clinical Use Conditions
The situational analysis performed in this study considers the use of drug products and injection solutions that are intravenously administered to achieve a number of therapeutic outcomes. For the purpose of this manuscript, the dosing regimen that is considered is the administration of the contents of 6 product units of an SVP (small volume parenteral) drug product (50-mL nominal drug product fill volume of each unit) over the course of a 24-hour period. The drug product is contained within a flexible bag consisting of the plasticized PVC that was tested in this study. The amount of plasticized PVC that is present in such a flexible bag is approximately 9.81 grams.
Levels of Aluminum and Zinc in Packaged Drug Products
The levels of zinc in diluent-type solutions (eg, 0.9% Sodium Chloride Injection) stored in PVC containers has been measured during stability studies of those solutions using validated methods (eg, atomic absorption spectrometry). Additionally, levels of Al and Zn in drug solutions stored in PVC containers have been reported in the literature.9-12
Results and Discussion
Analytical Recovery for the Test Method The analytical recovery for the test procedure (digestion plus ICP/ MS analysis of the digest) was in the range of 70% to 150% for all the targeted elements specified previously, except Os. Due to the poorer performance of Os, data for this element are not included in this manuscript. Precision for the replicate analyses performed for the
Table 1. Permissible Daily Exposure (PDE) Thresholds for Elemental Impurities in Parenteral Drug Products. ICH Class Element 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
4f
Mn Be
We Ale
Guidance(s) with most conservative limit
USP (inorganic), ICH USP, ICH ICH
USP (inorganic) USP, ICH ICH ICH ICH ICH ICH ICH
USP, EMA, ICH USP, EMA, ICH EMAd EMAd EMAd EMAd ICH ICH ICH
EMA USP ICH
EMA EMA EMA EMA N/Ae N/Ae N/Ae
Parenteral PDE (µg/day) Most Conservative Highlighted
USPa 15
5.0 2.5 1.5 12 90 - - - -
10 10 10 10 10 10 - - - -
130 -
90 - - - - - -
EMAb
- - - -
25 25 - - - -
10 10
10d 10d 10d 10d - - -
25
250 -
25
1300 1300 250 - - -
ICHc
15 5 2 3
10 20 5
10
100 8
80 10 10 10 10 10 10 90
700 250
1100 300 600
1500 - - - - - -
Most Conservative PDE
µg/day
15 5 2
1.5 10 20 5
10
100 8
80 10 10 10 10 10 10 90
700 250 25
130 600 25
1300 1300 250 - - -
N/A = Not applicable. a) See Reference 2. b) See Reference 3. c) See Reference 1. d) Subclass limit: the total amount of listed metals (Ir, Rh, Ru, Os) should not exceed the individual limit. e) PDEs have not been established for these elemental impurities. f) Class 4 elemental impurities are elemental impurities that have been evaluated but for which a PDE has not been established due to their low inherent toxicity and/or regional regulations.
Pharmaceutical Outsourcing | 30 | March/April 2015
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