COLD CHAIN


Considering Zn further, it is noted that given the clinical use conditions noted previously (six 50-mL bags used per day), the maximum allowable level of Zn in the aqueous drug product would be:


Testing of a plasticized PVC material representative of materials used in packaging for aqueous drug solutions has established that it generally contains amounts of elemental entities that are lower than permissible daily exposure levels of these substances.


The percentage of the PDE that would be “used up” by the contribution from the packaging, were the packaging’s total available pool to be leached into a drug product, is reported in Table 2 and was calculated as:


% of PDE accounted for by Packaging Leachables = (Daily Exposure [µg/g]/PDE [µg/g]) × 100%.


Such percentages are contained in Table 2 and are pictorially summarized in Figure 1. In most cases, the PVC used in the packaging would at most account for (or “use up”) <10% of the total pools of the individual elemental entities. In several cases, such as Pb, Cd, Co, Cr, Hg, and Pb, the PVC film would account for as much as 25% of the PDE. Most significantly, the maximum Daily Exposure for Zn is approximately 2.5 times this elemental impurity’s PDE. Thus were all of the available Zn to leach from the packaging and into the packaged drug solution, the Daily Exposure would exceed the PDE by a factor of roughly 2.5.


Levels of Zinc and Aluminum in Packaged Ready-to-Use Drug Products and Solutions


Although the previous discussion established the maximum exposure to elemental impurities from a drug product’s packaging, it is reasonable to note that it is unlikely that the total pool of elemental entities in packaging would leach out of the packaging and into aqueous solution drug products under their typical conditions of manufacturing, distribution/storage, and clinical use.8


Maximum allowable level of Zn (µg/mL) = (1300 µg/day)/(300 mL/day) = 4.3 µg/mL.


The actual measured levels of leached Zn are roughly 10% or less of this maximum allowable level.


A similar analysis can be performed for Al. Considering the PDE for Al, the maximum allowable level of Al would be 16 µg/mL. Were the total pool of Al measured in the test article to leach into 50-mL of an aqueous drug product, the concentration of Al in such a drug product would be 0.08 µg/mL, which is <1% of the maximum allowable level. Moreover, typical reported levels of Al present in aqueous drug products packaged in PVC containers (from all sources including packaging, ingredients, water vehicle, and manufacturing) are generally less than the total pool levels (0.002 µg/mL10


and 0.001 to 0.030 µg/mL11 ). Hayes et al12 in


continuous ambulatory peritoneal dialysis fluids and 0.004 to 0.034 µg/ mL in intravenous injections such as Water for Injection and Glucose for Injection12


considered the various sources of the Al


in the dialysis fluids and concluded that the container was only a minor contributor to the fluid’s Al levels.


Conclusions This circumstance is illustrated in


data pertaining to the levels of measured levels of Al and Zn in aqueous solution-based drug products stored in PVC containers. Considering Zn specifically, Zn has been measured in aqueous solution drug products stored in PVC containers as part of the registration stability testing of such drug products. Typical measured levels of Zn present in such drug products (from all sources including packaging, ingredients, water vehicle, and manufacturing) range from 0.2 to 0.4 µg/mL. This concentration is somewhat larger than the reported values of 0.01 to 0.24 µg/mL measured in commercial diluents9 in continuous ambulatory peritoneal dialysis fluids10


and 0.05 µg/mL reported packaged in PVC


containers. Even so, the measured levels of Zn reported herein represent a small portion (roughly 4% or less) of the total available amount of Zn (10.5 µg/mL), calculated as follows:


Total available Zn (µg/mL) =


(0.0425 g Zn/g Ca/Zn salt) × (0.2 g Ca/Zn salt/159.1 g PVC) × (9.81 g PVC/50 mL bag volume) × 106


µg/g = 10.5 µg/mL


Elemental impurities in packaged drug products can be derived from their packaging systems if elemental entities leach from the packaging under the product’s conditions of manufacturing, distribution/storage, and clinical use. The maximum amount of elemental impurities that packaging can contribute to a packaged drug product is the total amount of elemental entities in the packaging. Testing of a plasticized PVC material representative of materials used in packaging for aqueous drug solutions has established that it generally contains amounts of elemental entities that are lower than permissible daily exposure levels of these substances. In the specific case of an elemental entity that is intentionally added to the PVC material (Zn as a stearate salt), the material contains quantities of this substance that would exceed the PDE should it all leach into the drug product. However, analysis of authentic packaged drug products has established that the actual levels of leached Zn are much less than the total pool and are corresponding lower than the PDE. In another case, Al, which is not intentionally added to the PVC, is present in the both the material and in packaged drug products at levels well below the PDE. Furthermore, the available literature suggests that the actual leaching of Al into aqueous drug products packaged in PVC containers is well below aluminum’s total pool in the PVC.


This analysis suggests that this particular material will not contribute to unsafe levels of elemental impurities in aqueous drug products stored in packaging systems constructed from this material.


References 1.


International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Draft Consensus Guideline. Guideline for Elemental Impurities. Q3D. Current Step 4 Version, December 16, 2014.


2. PF 40(2), official in First Supplement to USP 38-NF 33, <232> Elemental Impurities—Limits (August 1, 2015). General Notices 5.60.30 Elemental Impurities in USP Drug Products and Dietary Supplements, Updated December 27, 2013, official date December 1, 2015.


3. EMA/CHMP/SWP/4446/2000, Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents, 21 February 2008.


Pharmaceutical Outsourcing | 34 | March/April 2015


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