A Commentary on Several Study Design Considerations Pertaining to the Screening of Substances Extracted and/or Leached from Pharmaceutical Contact Materials.

The assessment of substances that can be extracted (extractables) or leached (leachables) from the materials that come in contact with pharmaceutical products often starts with a general screening of these substances in relevant samples. Although such screening studies may be of a qualitative and semi-quantitative nature, the data they generate are critical in ensuring the suitability of the system(s) used to manufacture, store, and/or administer the product. As such, it is important they are designed using appropriate analytical techniques and methodologies so that representative and reproducible data are obtained. The goal of this commentary is to provide insight into several, but by no means all, good practices for the preparation and analysis of samples in extractable and/or leachable screening studies in order to help ensure representative and reproducible results are ultimately obtained. The specific topics covered are extraction stoichiometry, the importance of verifying method performance, assessing the need for incorporating derivatization in gas chromatography-based analyses, and properly accounting for analytical uncertainty when calculating the analytical evaluation threshold.

Comparison of the Levels of Rubber Stopper-Related Organic Leachables in Commercially Available Vialed Liquid and Lyophilized Drug Products.

PURPOSE: Rubber stoppers that seal the primary packaging systems of parenteral pharmaceutical products have the potential to introduce impurities into the drug during storage. While this interaction has been well characterized for products stored as an aqueous liquid, it is not well understood how the interaction is affected when the product is stored as a lyophilized solid. Accordingly, the goal of this study was to determine how lyophilization affects the propensity for impurity migration (leaching) into the product. METHODS: The concentration of substances in the stopper and the concentration of these substances that had leached into the product at equilibrium were measured and used to calculate equilibrium constants, which quantifies the degree of partitioning of each compound between each unique stopper and drug matrix, for twelve lyophilized and twelve liquid commercial drug products. RESULTS: Lyophilized products were shown to have a significantly increased propensity to contain substances that migrated from their stopper as compared to liquid products, as supported both by the general qualitative/quantitative leachable profile and the equilibrium constants obtained. CONCLUSIONS: The conversion of a liquid drug formulation to a lyophilized solid during storage will increase the number and concentration of impurities leached from the stopper.

Comparison of the Extraction Properties of Binary Polysorbate 80/Water and Isopropanol/Water Solutions for Organic Substances Originating from a Parenteral Infusion Pump.

Pharmaceutical products come into contact with a diverse range of materials during their manufacture, storage, and administration. As a consequence of this contact, substances can leach from these materials and into the product, which may negatively affect its quality. It has been shown that leaching is increased for drug products that contain the nonionic surfactant polysorbate 80. However, the specific extraction properties of this surfactant are not well characterized. To address this deficiency in the knowledge base, the goal of this study was to determine the quantitative profile of 10 compounds extracted from a parenteral infusion pump by aqueous polysorbate 80 solutions. For comparison purposes, the extractable profiles of isopropanol/water solutions, which were utilized as a representative nonsurfactant solvent system, were also determined. The results obtained in this study have shown that relatively low (≤0.1%) concentrations of polysorbate 80 were capable of facilitating leaching, consistent with previous reports. More importantly, it was found that the full quantitative extractable profiles obtained for the polysorbate 80 solutions were not comparable to those obtained for isopropanol/water. However, when considering extractables as subsets based on their polarity, it was found that 10% and 45% isopropanol solutions could be used to simulate the quantitative profile of polysorbate 80 for polar and non-polar substances, respectively.LAY ABSTRACT: When a pharmaceutical product comes into contact with a material during its manufacturing, packaging, or delivery, the substances present in that material may migrate (leach) into the product. Because these substances are not an intended constituent of the product, they have the potential to negatively impact its quality and ultimately patient safety. In general, the surfactant polysorbate 80 has been shown to facilitate the leaching of these substances when present in a product's formulation; however, its specific extraction properties are not well understood. Thus, the goal of this study was to better characterize these properties by determining what compounds, and in what quantities, can be solubilized by polysorbate 80 solutions from a representative pharmaceutical packaging system. Additionally, a range of isopropanol/water solutions were also assessed as a comparative nonsurfactant solvent. The results obtained illustrate the differences between the extraction properties of polysorbate 80 and isopropanol/water, including the concentration of each required to extract substances and the overall quantitative profiles obtained. However, it was shown that isopropanol/water solutions could be used to simulate the extractable profiles obtained for a solution containing polysorbate 80 when evaluating compounds as subsets based on their physical properties, namely their solubility in an aqueous medium.

Assessment of Patient Exposure to Leachables From Lyophilized Drug Formulations Following Reconstitution, Storage, and Administration via Polymeric Packaging/Delivery Systems.

It has been demonstrated that lyophilized drug formulations have an increased propensity to leach substances from the rubber stoppers comprising their primary packaging system when compared to aqueous liquid formulations stored in the same manner. Unfortunately, patient exposure to leachables originating in lyophilized drug products is not known. To that end, the goal of this study was to assess patient exposure to these leachables after reconstitution, storage, and administration of the lyophilized drug. To achieve this goal, several leachables present in 2 commercial lyophilized drug products were quantified after contact with polyvinyl chloride and non-polyvinyl chloride medication bags as well as an infusion set for durations of 15 min to 7 days at refrigerated and ambient temperature. The results obtained from this study showed that the bag's material of construction and the drugs formulation did not impact the mass of the leachables administered. Conversely, the mass of each leachable administered to the patient was reduced or eliminated as the contact duration with the intravenous bag and the temperature increased. However, for shorter contact durations, refrigerated storage, and higher molecular weight compounds, the patient would be exposed to a majority of the leachables originating from the vial.

Establishment of a reference standard database for use in the qualitative and semi-quantitative analysis of pharmaceutical contact materials within an extractables survey by GC-MS.

The analysis of reference standards may be performed to enhance the qualitative and quantitative data generated by non-specific screening methods utilized in extractables studies performed on pharmaceutical contact materials. However, the establishment of a database containing relative response factor and retention index values obtained from these standards has not been published. In this study, the establishment of such a database for GC-MS, a methodology commonly included in extractables studies, on an intra-lab basis was investigated. A set of 154 organic compounds representing a diverse range of chemical functionalities and properties was analyzed at eight time points on four GC-MS instruments that represent the diversity of age and model at our laboratory. The results of this study have shown that any variance in relative response factor between instruments was not significant from a practical perspective as supported by the coefficient of variation values (n = 32), which were ≤15% and ≤10% for 75% and 45% of the compounds tested, respectively. Furthermore, the retention index of the compounds, as expressed by retention time and relative retention time, did not have more than a 2% coefficient of variation between instruments or columns in most cases. It was concluded that a database of these values could be established for future use in extractables studies on an intra-laboratory basis.

Comparison of a Lyophilized Drug Product to Other Solid and Liquid Media for the Extraction of Elastomeric Oligomers from a Butyl Rubber Stopper.

Lyophilization is commonly used to extend the shelf life of pharmaceutical products that are otherwise unstable when stored as a liquid formulation. However, the ability of a lyophilized drug, or other solid medium, to leach or extract substances from a pharmaceutical packaging material is not well characterized. To provide insight into this area of uncertainty, the extraction properties of a lyophilized drug product, the lyophilized drug product reconstituted in water, and several other solid and liquid media of varying polarity were determined using a glass vial with a butyl rubber stopper as a representative pharmaceutical packaging system. The results obtained in this study show that the extracting power of a medium, whether solid or liquid, was primarily a function of polarity. Thus, the amount of each extractable observed for the lyophilized and reconstituted drug product were in trend with the other solid and liquid media, respectively. Nevertheless, it was notable that the lyophilized drug product was able to leach substances from the stopper in quantifiable amounts, whereas the reconstituted drug product contained no detectable leachables. Using a mathematical relationship, it was determined that the extraction power of the lyophilized drug product was equivalent to a 50/50 isopropanol/water solution.LAY ABSTRACT: Freeze drying is commonly used to extend the shelf life of pharmaceutical products that are otherwise unstable when stored as a liquid formulation. However, the propensity for substances to migrate from a pharmaceutical packaging material and into a solid drug formulation is not well characterized. To provide insight into this area of uncertainty, the migration of substances from a glass vial with a butyl rubber stopper and into a lyophilized drug product, the drug product reconstituted with water, as well as several solid and liquid media of varying polarity were assessed. The results obtained in this study show that the extracting power of a medium, whether solid or liquid, was primarily a function of polarity and thus could be related to one another. Furthermore, the results for the freeze-dried and reconstituted drug products were in trend with the other solid and liquid media tested, respectively, and showed that the freeze-dried drug was able to leach substances from the stopper in measureable amounts, whereas the reconstituted drug product contained no substances that had originated from the stopper.

Comparison of the Solubilization Properties of Polysorbate 80 and Isopropanol/Water Solvent Systems for Organic Compounds Extracted from Three Pharmaceutical Packaging Configurations.

It has been reported that the presence of polysorbate 80 in a pharmaceutical product's formulation may increase the number and/or amount of impurities leached from materials used during its manufacture, storage, and/or administration. However, it is uncertain if/how the solubilization properties of this surfactant compare to non-surfactant solvent systems. The goal of this study is to provide insight into this area of uncertainty by comparing the solubilization properties of polysorbate 80 to those of isopropanol/water solutions while in contact with a plasticized polyvinylchloride parenteral delivery bag, a single-use type manufacturing bag, and a polypropylene bottle. These properties were determined via a binding experiment, in which a set of model compounds was introduced into the solutions, and via an extraction experiment, in which compounds were extracted from the packaging material by the solutions. In both experiments, the amount of each compound present at equilibrium was assayed to determine the extent they were solubilized by the solution from the packaging material. Results from these experiments illustrate differences in the magnitude of solubilization obtained from solutions containing polysorbate 80 as compared to those composed of isopropanol/water. However, it was also demonstrated that their solubilization properties can be linked via a mathematical model.

Solid phase extraction in tandem with GC/MS for the determination of semi-volatile organic substances extracted from pharmaceutical packaging/delivery systems via aqueous solvent systems.

An extractable survey is one of several studies performed on a pharmaceutical storage/delivery system as part of the process of demonstrating that the system is suitable for its intended use. In this paper, a solid phase extraction method for the preparation of aqueous extracts generated during an extractable survey is presented. The method offers a convenient means to isolate semi-volatile organic extractable compounds from aqueous extraction solvents for analysis by gas chromatography/mass spectrometry. Following the solid phase extraction procedure, derivatization is performed to convert problematic functionalities (such as amines and acids) into appropriate chromatographically friendly derivatives. Demonstration of method performance is achieved in three ways using a set of 31 commonly observed extractable substances as model compounds. First, a breakthrough experiment was performed with a 2 solvent system consisting of water and 10/90 isopropanol/water over a range of 6 mL to 100 mL. Results from this experiment show only caprolactam possessed a significant level of breakthrough in either solvent over the range of volumes evaluated. Second, a formal accuracy/precision study was conducted using a three solvent system consisting of water, 10/90 isopropanol/water and 1% polysorbate 80. This experiment demonstrates the quantitative ability of the method at levels ranging from 20 ng/mL to 50 µg/mL. Recovery values of 70% to 130% of the theoretical concentration, with relative standard deviation values of less than 15% for replicate preparations, are obtained for a majority of the compounds evaluated. Finally, a case study involving the extraction of an intravenous drug delivery bag with multiple aqueous solvent systems further demonstrates the viability of solid phase extraction for use in an extractables survey.

A Method Utilizing Ultra-High Performance Liquid Chromatography with Ultraviolet and Mass Spectrometric Detection for the Analysis of Material Extracts Produced during a Controlled Extraction Study.

Pharmaceutical packaging/delivery systems and medical devices are characterized via a controlled extraction study as part of the development process for new pharmaceutical products. The purpose of this study is to determine compounds that may be extracted from the packaging using various solvents and exposure conditions. Results generated from a controlled extraction study serve to evaluate the suitability of the materials in the package configuration as well as provide an assessment of compounds that may potentially leach into the drug product. Analysis of extract samples generated during a controlled extraction study is performed utilizing multiple analytical methodologies to help establish a complete extractable profile regardless of the polarity, volatility, or other unique physical properties of each compound that may be present. The work presented in this article describes a method for the analysis of non-volatile as well as thermally labile, or otherwise not suited for analysis by gas chromatography, semi-volatile compounds from extraction samples. An ultra-high performance liquid chromatographic system with both atmospheric chemical ionization mass spectrometric and ultra violet detectors is used as the platform for the method. Adequate separation and retention is achieved for a mix of model compounds representing a wide range of common extractables within a 22 min analysis time. Ionization of this diverse range of compounds is also achieved with acceptable responses in the total ion chromatography data. Finally, analysis of extraction samples directly, even those comprised of non-compatible organic solvents, is demonstrated with no significant impact on the chromatography. Three case studies are presented to further illustrate method performance and its use for controlled extraction samples. LAY ABSTRACT: Pharmaceutical packaging/delivery systems and medical devices are characterized via a controlled extraction study as part of the development process for new pharmaceutical products. The purpose of this study is to determine compounds that may be extracted from the packaging using various solvents and exposure conditions. Results of this work serve to evaluate the suitability of the material for use in the package as well as provide an assessment of compounds that may potentially contaminate the drug product. Analysis of extract samples generated during a controlled extraction study is performed utilizing multiple analytical methodologies to help establish a complete extractable profile regardless of the unique physical properties of each compound that may be present. The work presented in this article describes a method for the analysis of non-volatile as well as semi-volatile compounds from extraction samples. Separation and detection of a diverse range of extractables were demonstrated in a 22 min analysis time. Three case studies are presented to further illustrate method performance and its use for controlled extraction samples.