Abstract
One source of elemental impurities in drug products is substances leached from the product’s packaging system. The maximum amount of elemental entities that can be leached into a packaged drug product is the total pool of the elemental entity in the packaging system; the actual amount that is leached is established by testing the packaged drug product over the course of its clinical shelf life. Either the actual or maximum leachable levels of the elemental impurities can be compared to documented permissible daily exposures (PDEs) to establish the packaging system’s overall impact on the packaged product’s ability to meet elemental impurity requirements. In this study, the total pool of relevant elemental entities in a plasticized poly-vinyl chloride (PVC) material used in aqueous parenteral drug product packaging was established by digesting the material in strong mineral acids (microwave assisted) and analyzing the digesting solution via inductively coupled plasma/mass spectrometry (ICP/MS). The resultant total pools were used to assess a therapeutic situation where six 50-mL PVC packages of a drug solution product would be administered daily. In such a circumstance, zinc is the only elemental entity whose total pool is larger than the associated PDE. However, zinc levels that are measured in packaged drug products are much lower than the total pool and well below the PDE.
Key words
elemental impurities, drug product packaging, plasticized poly-vinyl chloride, permissible daily exposure, total pool
Introduction
Extraneous impurities in a drug product do not provide a therapeutic benefit to the product’s user and could adversely impact the safety and/or efficacy of the drug product. An important set of impurities (known as elemental impurities) are those entities, organic or inorganic, whose chemical formulae include elements from the following series in the periodic table: transition metals, metalloids, other metals, and lanthanides and actinides. As is the case with all impurities, elemental impurities should be managed so that their levels in drug products are known and low. To this end, standards-setting organizations such as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the United States Pharmacopeia (USP), and others have developed—or are developing—guidelines and recommendations that address the management of elemental impurities in drug products.1-6
Elemental impurities in drug products can arise from a number of different sources including the active pharmaceutical ingredient, excipients, the vehicle, and the packaging system. Considering the packaging system specifically, it is well known that materials used in packaging contain certain elemental entities and that these entities can leach into drug products (or simulating solvents) under conditions that reflect clinical storage and use.7,8 Despite this circumstance, there are relatively few published studies that examine the issue of elemental impurities derived from packaging materials in the context of the developed drug product standards for such impurities and which contrast the total pool of elemental entities in packaging materials versus the amount that is readily leached from such materials under clinical conditions of storage and use.
In this manuscript, we report the elemental entities profile of a plasticized poly-vinyl chloride (PVC) material which has historically been used in packaging systems for aqueous drug products. This profile, which establishes the total amount of elemental entities present in the PVC material, is used to determine the maximum daily dose of elemental impurities associated with a typical therapeutic situation. Such daily doses can be compared to relevant drug product Permissible Daily Exposures (PDEs) for elemental impurities to establish how much of the PDE is “used up” by packaging-related impurities. In the case of 2 of the predominant elemental entities, aluminum and zinc, the total pools of the elements in the material are compared to the amount that has been measured in solution products stored in PVC packaging.
Experimental
Test Article
The test article consisted of sheets of plasticized PVC material. In addition to the PVC resin, primary and secondary plasticizers, and other additives, the PVC material was formulated to contain approximately 1250 ppm (mg/kg) of a mixed calcium/zinc stearate, used as an acid scavenger. Otherwise, the test article was not formulated to intentionally contain any other elemental entity.
Reagents
Acids used for digestion and standard preparation were J.T. Baker Ultrex II Ultrapure grade (J.T.Baker, Center Valley, PA). The water used in this study was obtained from a Milli-Q Purified Water generator (Millipore Corp., Billerica, MA).
Digestion (Total Pool)
Triplicate 0.5-g portions of the test article were digested using closed-vessel microwave-assisted strong acid digestion. This portion of the test article, along with 3 mL concentrated nitric acid and 1 mL water, was placed into quartz microwave digestion vessels (15-mL capacity). The quartz vessels were initially cleaned and were cleaned between uses by taking the vessels through the vendor’s recommended cleaning process. Digestion was performed with a Milestone (Shelton, CT) UltraWave Single reaction chamber microwave digestion system. The instrument was operated with a 3-step operating ramp: step 1 = 15-minute operating ramp (Temperature T1 = 120°C, Temperature T2 = 60°C), power = 800 watts, pressure = 160 bar; step 2 = 15-minute operating ramp (Temperature T1 = 220°C, Temperature T2 = 60°C), power = 1500 watts, pressure = 160 bar; step 3 = 5-minute operating ramp (Temperature T1 = 240°C, Temperature T2 = 60°C), power = 1500 watts, pressure = 160 bar. The digestion was performed at a pressure of approximately 50 bar. After the digestion was complete and the samples were cooled to ambient temperature, the contents of the digestion vessel (termed the digest) were transferred, with associated rinsing of the vessel, to a 100-mL volumetric flask, to which 2 mL of concentrated hydrochloric acid was added and which was subsequently diluted to the mark with water.
Digest Analysis
The digests were analyzed for 30 elements (Al, Sb, As, Ba, B, Cd, Co, Cr, Cu, Au, Ir, Fe, Pb, Li, Mn, Hg, Mo, Ni, Os, Pd, Pt, Rh, Ru, Se, Ag, Sn, Tl, W, V, and Zn) by inductively coupled plasma/mass spectrometry (ICP/MS) using 2 instrumental systems: Thermo (Waltham, MA) ThermoElemental X-Series 2 ICP/MS and Agilent (Santa Clara, CA) 7700x ICP/MS. The ThermoElemental X-Series 2 ICP/MS included an axial quartz torch (Catalog # 1281360), a Conikal glass expansion nebulizer (Catalog # AR-350-1-FC1E), and a quartz cyclonic spray chamber with a baffle and auxiliary gas port (Catalog # ES-3160-1111-23). The Agilent 770x ICP/MS included an axial quartz torch (Catalog # G3280-80053), a Micromist glass expansion nebulizer (catalog # ARG-1- UM04X), and a quartz spray chamber (Catalog # G3280-80008). In general, digests were analyzed using optimized conditions for both instruments. To optimize analytical performance for certain elements, Li and B were analyzed in the Standard Mode on the ThermoElemental instrument or the No Gas Mode on the Agilent instrument. The other elements were analyzed via the CCT Mode (7 % H2, 93% He) on the ThermoElemental instrument and the He Gas Mode (100% He) on the Agilent instrument. While multiple masses were monitored (when available) for each of the targeted elements, the data reported in this manuscript were obtained from the primary masses, thereby producing the greatest specificity and sensitivity.
Standards used to calibrate the ICP/MS systems were prepared by dilution of multielement stock solutions obtained from High Purity Standards (Charleston, SC). The diluent was a mixture of 5% (v/v) nitric acid and 2% (v/v) hydrochloric acid. Multiple calibration standards were prepared at approximate concentrations of 0.1, 0.5, 1, 25, and 50 ng/mL (0.05, 0.1, 0.5, and 1 ng/mL for Hg).
In addition to the calibration standards, analytical performance throughout the analytical runs performed in this study was assessed, primarily with regard to response drift, via the sporadic analysis of quality control (QC) standards throughout the runs. These QC standards were prepared at concentrations comparable to the calibration standards but from stock solutions from an alternate vendor (Inorganic Ventures, Christiansburg, VA).
Analytical Recovery
The recovery of the digestion/analysis process was established by supplementing portions of the test sample with known amounts of the target elements prior to microwave digestion. Specifically, aliquots of standard mixtures were added to the acid and water solutions 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 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.
Table 1. Permissible Daily Exposure (PDE) Thresholds for Elemental Impurities in Parenteral Drug Products.
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.
Table 2. Amounts of Individual Elemental Entities in the Plasticized PVC Test Article.
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.
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.
Figure 1. Comparison of the Daily Exposure to the PDEs for the Elemental Impurities Considered in this Study.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 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 and 0.05 μg/mL reported in continuous ambulatory peritoneal dialysis fluids10 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
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:
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 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). Hayes et al12 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
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
- 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.
- 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.
- EMA/CHMP/SWP/4446/2000, Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents, 21 February 2008.
- International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Pharmaceutical Development. Q8(R2). Current Step 4 Version, August, 2009.
- tInternational Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Quality Risk Management. Q9. Current Step 4 Version, November 9, 2005.
- International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline. Pharmaceutical Development. Q10. Current Step 4 Version, June 4, 2008.
- Jenke D, Rivera C, Mortensen T, et al. A compilation of metals and trace elements extracted from materials relevant to pharmaceutical applications such as packaging systems and devices. PDA J Pharm Sci Technol. 2013;67(4):354-375.
- Jenke DR, Stults CLM, Paskiet DM, Ball DJ., Nagao LM. Materials in manufacturing and packaging systems as sources of elemental impurities in packaged drug products: a literature review. PDA J Pharm Sci Technol. 2015;69(1):1-48.
- Desai NR, Shah SM, Koczone J, Vencyl-Joncic M, Sisto C, Ludwig SA. Zinc content of commercial diluents used in drug admixtures prepared for intravenous infusion. Int J Pharm Compounding. 2007;11(5):426-432.
- Padovese P, Gallieni M, Brancaccio D, et al. Trace elements in dialysis fluids and assessment of the exposure on patients on regular hemodialysis, hemofiltration and continuous ambulatory peritioneal dialysis. Nephron. 1992;61:442-448.
- McHalsky ML, Rabinow BE, Ericson SP, Weltzer JA, Ayd SW. Reduction of aluminum levels in dialysis fluids through the development and use of accurate and sensitive analytical a methodology. J Parenteral Sci Technol. 1987;41(2):67-75.
- Hayes P, Martin TP, Pybus J. Aluminum content of intravenous solutions, additives and equipment used to prepare parenteral nutrition mixtures. Aust J Hosp Pharm. 1992;22(5):353-357.
- Toxicological Profile for Aluminum. U.S. Department of Health and Human Services; Agency for Toxic Substances and Disease Registry. Atlanta, GA; September, 2008.
Dr. Dennis Jenke is a Baxter Distinguished Scientist at Baxter Healthcare Corporation, where he works to establish the suitability for use of packaging systems, manufacturing systems, and administration devices for pharmaceutical products (for example, leachables/extractables and drug binding). He has published extensively in analytical chemistry, environmental science, and material/solution compatibility and serves as an expert reviewer for numerous pharmaceutical and analytical journals. He is the author of Compatibility of Pharmaceutical Solutions and Contact Materials; Safety Considerations Associated with Extractables and Leachables and is a contributing author to the Leachables and Extractables Handbook. Dr. Jenke is a member of several professional organizations that establish best demonstrated practices in the area of material/solution compatibility and is a frequently invited speaker on that subject.
Dr. Barrett E. Rabinow is Baxter Distinguished Scientist at Baxter Healthcare Corporation. Dr. Rabinow received his PhD in Chemistry from the University of Chicago and joined Baxter in 1977 where he headed chemistry and related functions, supporting the parenterals solutions business. He has engaged in collaborative studies with PDA, AdvaMed, AAMI, ISO, USP, FDA, and NIH. Dr. Rabinow holds numerous patents and authored 4 book chapters and over 40 articles in physical-organic chemistry, clinical and analytical chemistry, biomaterials, packaging, pharmaceutical science, drug delivery, pharmacokinetics, pharmacology, and drug targeting.
Molly Chacko is a Research Scientist in the Analytical Center of Excellence at Baxter Healthcare Corporation. Molly is an expert in trace element analysis, including Inductively Coupled Plasma Mass Spectrometry (ICP-MS), Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES), and Flame and Graphite Furnace Atomic Absorption Spectrometry. She was a member of the USP <231> Heavy Metals (GC) Ad hoc Advisory Panel from 2006 to 2009 and has co-authored several publications in her field of expertise.