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There are many factors to consider when selecting a container closure system for parenteral drug products to maintain their quality, efficacy, and safety. One aspect to consider for products stored in glass vials is the glass type. Although the glass vials in which most parenteral products are stored are classified as Type I by the United States Pharmacopoeia, Chapter <660>, not all glass vials that meet the glass performance characteristics of Type I are equivalent. In the study presented here, Type I glass vials from three suppliers of three different Type I glass vials (standard, delamination control, and coated) were investigated to evaluate the impact that each Type I glass vial had on the stability of a drug product under development. To evaluate this impact, a three-phase study was conducted in which the compatibility between the drug product and each vial was assessed through the measurement of the critical quality attributes of the product, extractable and leachable inorganic elements were analyzed for each vial, and finally a stability study under accelerated conditions was conducted for the drug product in the most compatible vial based on the aforementioned experiments. Results from this study demonstrated that there are, in fact, significant differences in glass vials regardless of their classification as Type I. In the study conducted here, delamination control Type I glass vials were found to be superior to both Standard Type I and coated Type I vials for the drug product under investigation. [ABSTRACT FROM AUTHOR]

The thermodynamic and kinetic contributions to the over-extraction of extractables by nonpolar organic solvents relative to biological lipids in exhaustive and exaggerated extractions of medical devices are studied based on the Abraham solvation model and solvent–material interactions, using low-density polyethylene (LDPE) as an exemplary material. The thermodynamic effect is evaluated by the partition constant of extractables between LDPE and extraction solvents, hexane and lipids, defined as the concentration in the polymer phase divided by the concentration in the solvent phase. The Abraham solvation model is used to correlate the measured LDPE-lipid partition constant (log10Pldpe/lipid) to construct the predictive model. Similar models are also derived from the thermodynamic cycle conversion, using the system constants of LDPE-water and Lipid-water partition systems. These constructed models, together with the predictive LDPE-hexane (log10Pldpe/hexane) model established from a previous study, are used to predict and compare the ranges and values of Pldpe/s (s = lipids and hexane) for the observed LDPE extractables over a wide hydrophobicity range in log10Po/w from zero to 30. The solvent-LDPE interactions are examined by the degree of swelling of LDPE by hexane (or other nonpolar solvents) and lipids, including the solvent diffusion rates into the material. These parameters allow the evaluation of kinetic effect on the over-extraction. The extent of over-extraction is compiled directly by experimental “overall” or “specific” migration data or indirectly calculated by the diffusion coefficient of extractables when extracted by hexane or lipids. It is concluded from this study that the extractables distribution between LDPE and lipids highly favors the lipid phase thermodynamically (Pldpe/lipid<1), and the values of Pldpe/lipid are always lower than those of Pldpe/hexane, thereby indicating that the thermodynamic effect is not the cause of over-extraction. It is the kinetic effect that dominantly contributes to the over-extraction, as supported by the material swelling and solvent diffusion rates. Finally, the extent of over-extraction has been established from a few folds to over a hundred-fold, and the median value is 7. Furthermore, the methods adopted and developed in this study can be invaluable tools in other disciplines such as the reliable prediction of extractables from other device materials and environmental sampling.

The Abraham's solvation parameter model is an important tool to model and predict distribution properties of compounds in numerous partitioning systems in chemistry, environmental chemistry, medicine, and biology. The evaluation of the distribution properties in extractables and leachables (E&L) studies in pharmaceutical and medical device industries is another major application of this model. This tutorial is aimed at illustrating the applications of the model in E&L studies. Specific examples of the application illustrated in this tutorial include: (a) establishment of equivalent or similar solvents; (b) determination of polarity of solvents, biological tissues, and materials; (c) development of drug product simulating solvents; (d) understanding solvent extraction power for a material; (e) selection of solvent and standards in pretreatment of extraction samples; and (f) chromatography retention prediction for E&L.

This study aimed to investigate the impact of including teak wood in recycled high-density polyethylene wood plastic composites (WPC) with pine wood on their resistance to degradation caused by termite attack and accelerated weathering. A 23 factorial experimental design was conducted with three repetitions in the center to analyze the weight loss and termite mortality during the experiments. The factors studied were the days of exposure to accelerated weathering, days of exposure to termite attack, and the concentration of teak wood in the composite. Surface characterizations (SEM and FTIR) were carried out to analyze the exposed surfaces and determine the chemical modification of the composite components. The results showed that the WPC manufacturing process promotes a heterogeneous distribution of the wood particles, being greater within the center of the samples than on the surface. Specimens exposed to both accelerated weathering and termite attack resulted in a certain weight loss and termite mortality, depending on the material, conditions of exposure, and the content of teak wood in the WPC. When those compounds were subjected to accelerated weathering followed by termite attack they exhibited a higher termite attack. The presence of teak wood in the WPC produced a reduction in the effects of termite attack and accelerated weathering on weight loss and an increase in termite mortality compared to the WPC with only pine wood, as teak wood contains extractables with termiticidal action. The lowest value of weight loss (0.06%) was observed for the WPC with the highest amount of teak wood with termite attack, resulting in a termite mortality rate of 100% after 17 days of exposure. [ABSTRACT FROM AUTHOR]

Over the past decade, Cell and Gene Therapies (C&GT) have been an emerging therapeutic area with more than twenty C&GT drug products approved and over 1000 registered trials. The remarkable progress in these modalities brings new challenges for scientists who evaluate manufacturing and storage materials, including risk assessments for extractables and leachables (E&L). Establishing a business process to qualify materials for these applications is an important risk mitigation strategy in support of these assessments. Process validation verifying process performance and product quality requirements using qualified materials also ensures that leachables from the materials do not result in an impact to process and product. The authors provide an overview of available guidelines and publications relevant to E&L risk assessments that can be used to support ex vivo C&GT products, highlighting gaps and standardization needs in the areas of biocompatibility and extractables conditions. Finally, the authors present leachable testing strategies, relevant to the specific manufacturing and storage conditions of C&GT products, and safety assessment considerations for organic and inorganic chemical entities. [ABSTRACT FROM AUTHOR]

The thermodynamic and kinetic contributions to the over-extraction of extractables by nonpolar organic solvents relative to biological lipids in exhaustive and exaggerated extractions of medical devices are studied based on the Abraham solvation model and solvent–material interactions, using low-density polyethylene (LDPE) as an exemplary material. The thermodynamic effect is evaluated by the partition constant of extractables between LDPE and extraction solvents, hexane and lipids, defined as the concentration in the polymer phase divided by the concentration in the solvent phase. The Abraham solvation model is used to correlate the measured LDPE-lipid partition constant ( l o g 10 P l d p e / l i p i d ) to construct the predictive model. Similar models are also derived from the thermodynamic cycle conversion, using the system constants of LDPE-water and Lipid-water partition systems. These constructed models, together with the predictive LDPE-hexane ( l o g 10 P l d p e / h e x a n e ) model established from a previous study, are used to predict and compare the ranges and values of P l d p e / s (s = lipids and hexane) for the observed LDPE extractables over a wide hydrophobicity range in l o g 10 P o / w from zero to 30. The solvent-LDPE interactions are examined by the degree of swelling of LDPE by hexane (or other nonpolar solvents) and lipids, including the solvent diffusion rates into the material. These parameters allow the evaluation of kinetic effect on the over-extraction. The extent of over-extraction is compiled directly by experimental "overall" or "specific" migration data or indirectly calculated by the diffusion coefficient of extractables when extracted by hexane or lipids. It is concluded from this study that the extractables distribution between LDPE and lipids highly favors the lipid phase thermodynamically ( P l d p e / l i p i d < 1 ), and the values of P l d p e / l i p i d are always lower than those of P l d p e / h e x a n e , thereby indicating that the thermodynamic effect is not the cause of over-extraction. It is the kinetic effect that dominantly contributes to the over-extraction, as supported by the material swelling and solvent diffusion rates. Finally, the extent of over-extraction has been established from a few folds to over a hundred-fold, and the median value is 7. Furthermore, the methods adopted and developed in this study can be invaluable tools in other disciplines such as the reliable prediction of extractables from other device materials and environmental sampling. [ABSTRACT FROM AUTHOR]

This study utilized ultra‐high‐performance liquid chromatography combined with quadrupole time‐of‐flight mass spectrometry and gas chromatography–mass spectrometry techniques to analyze multiple batches of non‐polyvinyl chloride (PVC) soft bags exposed to three extractants. Based on an established library of relative response factors for more than 30 different polymer additives, analytical evaluation thresholds for large volume injectables were determined, and 30 extractables were screened and (semi‐)quantitatively analyzed. To identify variations in extractables between batches, multivariate statistical methods such as principal component analysis, heat map analysis, and hierarchical cluster analysis were employed. Additionally, a comprehensive risk assessment of extractables and a biosafety assessment of leachables were conducted. The results of the study revealed that the concentrations of two extractables exceeded the established safety threshold. Moreover, one of these extractables was deemed to pose a mutagenic risk based on the consistent findings of two (Q)SAR software tools. Notably, certain extractables exhibited discrepancies in their content between batches, with particular emphasis on 1,3‐bis(3,5‐di‐tert‐butyl‐4‐hydroxybenzyl)‐1,3,5‐triazinane‐2,4,6‐trione. This discrepancy led to inconsistencies in risk levels across batches. However, the levels of leachables detected in the non‐PVC soft bags were found to be within the safety threshold, and cytotoxicity assessments consistently yielded negative results for leachables. Consequently, this study provides valuable data for conducting batch stability investigations concerning extractables in large volume parenteral drug delivery containers and other forms of pharmaceutical packaging. [ABSTRACT FROM AUTHOR]

In the production of biological therapeutics such as monoclonal antibodies (mAbs), ultrafiltration and diafiltration (UF/DF) are widely regarded as effective downstream processing steps capable of removing process equipment related leachables (PERLs) introduced upstream of the UF/DF step. However, clearance data available in the literature are limited to species with low partition coefficients (log P) such as buffer ions, hydrophilic organic compounds, and some metal ions. Additional data for a wide range of PERLs including hydrophobic compounds and elemental impurities are needed to establish meaningful, comprehensive safety risk assessments. Herein, we report the results from studies investigating the clearance of seven different organic PERLs representing a wide range of characteristics (i.e., log P (−0.3 to 18)), and four model elements with different chemical properties spiked into a mAb formulation at 10 ppm and analyzed during clearance using gas chromatography–mass spectrometry (GC–MS), liquid chromatography‐photodiode‐array‐mass spectrometry (LC‐PDA‐MS), and inductively coupled plasma mass spectrometry (ICP‐MS). The clearance data showed ideal clearance and sieving of spiked organic PERLs with log P < 4, partial clearance of PERLs with 4 < log P < 9, and poor clearance of highly hydrophobic PERLs (log P > 9) after nine diafiltration volumes (DVs). Supplemental clearance studies on seven additional PERLs present at much lower concentration levels (0.1–1.5 ppm) in the mAb formulation upstream of UF/DF and three PERLs associated with the tangential flow filtration (TFF) equipment also demonstrated the similar correlations between log P and % clearance. For model elements, the findings suggest that UF/DF in general provides ideal clearance for elements. Evidence showed that the UF/DF process does not only help mitigate leachables risk from PERLs introduced upstream of UF/DF, but also from the TFF operation itself as all three TFF‐related PERLs were effectively cleared. Overall, the UF/DF clearance presented in this work demonstrated whereas highly hydrophobic PERLs and elements that exist as charged species, particularly transition metal ions, may not be as effectively cleared and thus warrant further risk assessment; hydrophilic and some hydrophobic PERLs (log P < 4) are indeed well‐cleared and thus present a lower overall safety risk. [ABSTRACT FROM AUTHOR]

The thermodynamic and kinetic contributions to an exhaustive extraction of medical devices are studied using the Abraham solvation parameter model and a systematic analysis of the material–solvent interactions, using low-density polyethylene (LDPE) as an example material and extraction solvents of varying polarities. The thermodynamic distribution of extractables compounds between LDPE and solvents of different polarities (water as polar, methanol/ethanol as semipolar, and hexane as nonpolar), used in the exhaustive extraction of medical devices, are first correlated by Abraham solvation parameter model using experimental data. The constructed models are used to derive the partition coefficient between LDPE and various solvents for the representative extractables entities over a wide hydrophobicity range in log 10 P o/w (the octanol–water partition coefficient) from − 1 to 18. The derived partition coefficients are then used to compute the extraction efficiency by a repeated extraction with five extraction cycles. The ranges of partition coefficient and extraction efficiency by each solvent or three combined solvents allow the assessment of the exhaustive extraction coverage over the hydrophobicity range. In addition to the thermodynamic analysis, the kinetic contribution to the exhaustive extraction by each solvent is also analyzed systematically, starting from the LDPE–solvent interaction, as indicated by a material swelling, to a consequential change in diffusion coefficient, and to a solvent-dependent release rate. The ratios of experimental diffusion coefficients of extractables by hexane extraction to that by alcohol extraction are collected to demonstrate the impact of solvent swelling on the diffusion and release of extractables. The ratios of amounts of extractables released by 24-h and 72-h extraction cycles, recommended by ISO 10993-12 (2021), are also collected to show the influence of cycle time on extraction efficiency. It is concluded from the study that the three solvents of varying polarities are very adequate to extract LDPE to exhaustion over the hydrophobicity range ( log 10 P o/w from − 1 to 18) or beyond. The extraction by water and methanol/ethanol is a slower "diffusion-controlled" process, compared to a faster "relaxation-controlled" process by hexane. It is also demonstrated that the use of 72-h extraction cycle time has no realistic advantage. The 24-h extraction cycle time is a better choice in achieving an exhaustive extraction efficiently, particularly for extractables with a very slow migration kinetics. [ABSTRACT FROM AUTHOR]

Microplastics and their associated plastic additives are contaminants of emerging environmental concern. The extent and rate of additive leaching affects the behaviour and fate of these contaminants, and therefore the risk they present to organisms. However, most studies examining the leaching of additives from microplastics use methods that are not environmentally relevant. We evaluated additive leaching from a range of common plastics using an environmentally relevant dynamic leaching method with additives and non-intentionally added substances quantified by liquid chromatography-mass spectrometry. The leaching method was validated to ensure sink conditions were maintained over the duration of the test. Release was not solubility limited indicating that the test conditions were representative of those occurring in the environment. Leaching profiles showed significantly different kinetics across the different types of plastic, with cumulative additive release over 64 days spanning more than five orders of magnitude. This study highlights the wide variation in additive leaching behaviour between different plastics and the importance of understanding leaching kinetics to assess the chemical impacts of microplastic pollution. Furthermore, we identify the need for environmentally relevant leaching methods and suggest the creation of standardised methods to enable robust risk assessments and regulation.

Summary: Background: Ensuring menstrual cup safety is paramount, yet a menstrual cup safety assessment scheme is lacking. This paper presents a quadripartite scheme, showing how it can be applied. Methods: The Tampax Menstrual Cup was evaluated in the safety assessment scheme: (1) Biocompatibility and chemical safety of cup constituents. Extractables were obtained under different use condition; exposure-based risk assessments (EBRA) were conducted for extractables exceeding thresholds of toxicological concern. (2) Physical impact to vaginal mucosa. After physical evaluations, the Tampax Cup and another cup were assessed in a randomised double-blinded, two-product, two-period cross-over clinical trial (65 women, mean age 34.2 years). (3) Impact to vaginal microbiota (in vitro mixed microflora assay and evaluation of vaginal swabs). (4) In vitro growth of Staphylococcus aureus and toxic shock syndrome toxin-1 (TSST-1) production. Findings: Biocompatibility assessments and EBRA of cup constituents showed no safety concerns. In the randomised clinical trial, all potentially product-related adverse effects were mild, vaginal exams were unremarkable, no clinically relevant pH changes occurred, post-void residual urine volume with and without cup were similar, and self-reported measures of comfort along with reports of burning, itching and stinging between cups were comparable. Cup use had no effect on microbial growth in vitro or in the 62 subjects who completed the trial or on in vitro TSST-1 production. Interpretation: The quadripartite safety assessment scheme allows evaluation of menstrual cup safety. The Tampax Cup is safe and well-tolerated upon intended use. As with all feminine hygiene products, post-market safety surveillance confirmed this conclusion. Funding: By Procter & Gamble.

Chromatographic considerations and requirements in developing general RPLC profiling analytical methods for eluting complex medical device extracts are investigated using linear gradient conditions, based on Abraham general solvation model. The focus of the study is not on the development of a specific RPLC method for a particular extract, but on the general considerations and requirements in retention and peak capacity optimization in the separation of complex unknown extracts, possibly with a high number of components and a wide-ranging diversity in hydrophobicity, volatility, and molecular weight (MW). The published representative RPLC gradient conditions, together with nearly 2000 selected compounds as a representation of potential extractables, are used to correlate the gradient retention time and hydrophobicity ( Log P o / w ) of extractables, both calculated by Abraham solvation model. The hydrophobicity range that each gradient separation condition of defined run time can cover is determined, and the Log P o / w values, at which late-eluting and early-eluting issues occur, are computed as well. It is concluded that the complex medical device extraction samples should be separated by RPLC linear gradient elution, and retention time and peak capacity should be optimized to retain and resolve all extractables components for the discovery of extractables components in the sample. [ABSTRACT FROM AUTHOR]

Organic solvents of different polarities (polar, semipolar, and nonpolar) are typically used in extraction studies on medical devices for chemical characterization of their constituents (called extractables or leachables, E/L) potentially exposed to patients during clinical uses per ISO 10993-18 (2020). This study evaluates the difference in solubility of semipolar solvents relative to ethanol for a wide range of E/L in hydrophobicity to help the selection of semipolar solvents for extraction studies. The solvents studied include methanol, ethanol, 1-propanol, 2-propanol (IPA), acetonitrile (ACN), acetone, dioxane, dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and ethylene glycol. A quantitative analysis of solubility difference (relative to ethanol) among these commonly used semipolar organic solvents over a wide hydrophobicity range based on Abraham general solvation model is presented. These semipolar solvents are also classified according to their solvation properties. The results of the calculation include a slope parameter with respect to hydrophobicity ( log 10 P O / W to describe the solubility ratio changes with an increase in E/L hydrophobicity, and an intercept parameter to describe the relative solubility for more polar E/L compounds. The calculation results are also corroborated by other solvent strength parameters. A recommendation on the rational selection of semipolar solvents in extraction studies is finally provided based on the two parameters, extraction type, and instrumental analysis. [ABSTRACT FROM AUTHOR]

Quality by design is the foundation of the risk management framework for extractables and leachables (E&Ls) recommended by the Extractables and Leachables Safety Information Exchange (ELSIE). Following these principles during the selection of materials for pharmaceutical product development minimizes the presence of highly toxic substances and decreases the health risk of potential leachables in the drug product. Therefore, in the context of the broad arena of chemicals, it is important to distinguish E&Ls as a subset of chemicals and evaluate this relevant chemical space to derive appropriate analytical and safety thresholds. When considering the health hazards posed by E&Ls, one area presenting a challenge is understanding the sensitization potential and whether it poses a risk to patients. A dataset of E&Ls compiled by ELSIE (n = 466) was analyzed to determine the prevalence and potency of skin sensitizers in this chemical subset and explore a scientifically justified approach to the sensitization assessment of potential leachables in parenteral drug products. Approximately half of the compounds (56%, 259/466) had sensitization data recorded in the ELSIE database and of these, 20% (52/259) are potential skin sensitizers. Only 3% (8/259) of the E&L dataset with sensitization data were considered potent (strong or extreme) sensitizers following in silico analysis and expert review, illustrating that potent sensitizers are not routinely observed as leachables in pharmaceutical products. Our analysis highlights that in silico potency prediction and expert review are key tools during the sensitization assessment process for E&Ls. The results confirm where material selection is anticipated to mitigate the risk of presence of strong and/or extreme sensitizers (e.g., extractable testing via ISO 10993-10), and that implementing thresholds per ICH M7 and/or Masuda-Herrera et al. provides a reasonably conservative approach for establishing the analytical testing and safety thresholds., (© PDA, Inc. 2024.)

As a popular format of primary container closure systems, rubber stoppered glass vials are often used in storing and delivering lyophilized and liquid formulated therapeutic protein products. Assessing extractables and leachables from rubber stoppered glass vial systems is required to ensure drug product quality and patient safety. Lyophilized biopharmaceutical drug products are generally considered as less impacted by leachables during storage and transportation than the liquid formulated drug products. Single time point leachables testing for lyophilized biopharmaceutic drug products is recommended. The recommendation is based on our published comprehensive leachable data collected at multiple time points for five lyophilized drug products stored in different rubber stoppered glass vial systems with additional supporting comprehensive leachable data collected for nineteen liquid formulated drug products stored in different syringe and vial systems, which is statistically and scientifically sound. The leachable data evaluated herein were generated based on a holistic approach which ensured successful qualification of different vial systems as primary containers and delivery systems for various biotherapeutic products. The organic and elemental impurities of the leachable profiles of all the twenty-four drug product samples were below the limit of detection at all the time points. For lyophilized drug products, product surface interaction during storage time and shipping is unlikely. Timing of single time point leachables testing can be flexible. Performing leachables testing at one-year time point is recommended as it allows for enough time for chemicals to leach out from product contact surfaces into drug products and thus provides the earliest opportunity for mitigation of unpredicted leachables of concern, if any. However, testing at other stability time points can also be considered depending on the development strategy of the sponsor. Therefore, recommendation of single time point leachables testing for lyophilized drug products stored in rubber stopped glass vials at an appropriate time point is a scientifically sound approach. [ABSTRACT FROM AUTHOR]

During the toxicological assessment of extractables and leachables in drug products, localized hazards such as irritation or sensitization may be identified. Typically, because of the low concentration at which leachables occur in pharmaceuticals, irritation is of minimal concern; therefore, this manuscript focuses on sensitization potential. The primary objective of performing a leachable sensitization assessment is protection against Type IV induction of sensitization, rather than prevention of an elicitation response, as it is not possible to account for the immunological state of every individual. Sensitizers have a wide range of potencies and those which induce sensitization upon exposure at a low concentration (i.e. strong, or extreme sensitizers) pose the highest risk to patients and should be the focus of the risk assessment. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium has reviewed the status of dermal, respiratory, and systemic risk assessment in cosmetic and pharmaceutical industries, and proposes a framework to evaluate the safety of known or potential dermal sensitizers in pharmaceuticals. Due to the lack of specific regulatory guidance on this topic, the science-driven risk-based approach proposed by ELSIE encourages consistency in the toxicological assessment of extractables and leachables to maintain high product quality and ensure patient safety. [ABSTRACT FROM AUTHOR]

Battery-powered drug delivery devices are widely used as primary containers for storing and delivering therapeutic protein products to improve patient compliance and quality of life. Compared to conventional delivery approaches such as pre-filled syringes, battery-powered devices are more complex in design requiring new materials/components for proper functionality, which could cause potential product safety and quality concerns from the extractable and leachables (E&L) of the new materials/components. In this study, E&L assessments were performed on a battery-powered delivery device during the development and qualification of the device, where novel compound 2‑hydroxy-2-methylpropiophenone (HMPP) and related compounds were observed in both E&L. The source of the HMPP and related compounds was identified to be the nonproduct contact device batteries, in which HMPP photo-initiator was used as a curing agent in the battery sealant to prevent leakage of the battery electrolytes. Toxicology assessment was performed, which showed the levels of HMPP observed in the device lots were acceptable relative to the permitted daily exposure. A drug product HMPP spike study was also performed, where no product impact was observed. Based on these assessments, an action threshold and specification limits could be established as a control strategy, if needed, to mitigate the potential risks associate with the observed leachables. As a full resolution, seven battery candidates from different suppliers were screened and one new battery was successfully qualified for the delivery devices. Overall, the holistic E&L approach was fully successful in the development and qualification of the battery-powered devices for biotherapeutic products delivery ensuring product quality and patient safety. Non-product contact materials are commonly rated as low or no risk and typically considered as out of scope of E&L activities for delivery systems following industry benchmark and regulatory agency guidance. This case study is novel as it brings into attention the materials that might not normally be in consideration during the development process. It is highly recommended to understand materials in the context of intended use on a case-by-case basis and not to generalize to ensure successful development and qualification. [ABSTRACT FROM AUTHOR]

Rubber stoppered glass vial systems are widely used as primary containers for storing and delivering therapeutic protein products to patients. Addressing concerns and regulatory expectations related to the risk to biologic drug product quality and patient safety from rubber stoppered glass vial systems requires implementation of an extractable and leachable evaluation program based on material understanding, risk assessment, literature review, and a comprehensive scientifically sound analytical testing methodology. The extractable and leachable study design consisted of twelve drug products filled in twelve different size glass vials capped with laminated and nonlaminated rubber stoppers made from three different rubber formulations. Design of the model solvents was successful as they had little to no analytical interference and mimicked the formulation conditions and generated representative extractables capable of predicting leachables. The extraction conditions of time and temperature were appropriate as not to degrade the test materials or the extractable compounds, and yet generated significant quantities for identification of the extractable compounds with confidence. The extractables testing results were capable of predicting the leachable profiles of the twelve drug products. In each case, the leachable profile was a subset of the extractable profile. The organic and elemental impurities of the leachable profiles of drug products were the end-to-end verification of the quality of the glass vials, rubber stoppers and drug product lifecycles. Overall, the holistic approach was fully successful in the qualification of different vial systems as primary containers and delivery systems for different biotherapeutic products to ensure product quality and patient safety. [ABSTRACT FROM AUTHOR]

Leachables in pharmaceutical products may react with biomolecule active pharmaceutical ingredients (APIs), for example, monoclonal antibodies (mAb), peptides, and ribonucleic acids (RNA), potentially compromising product safety and efficacy or impacting quality attributes. This investigation explored a series of in silico models to screen extractables and leachables to assess their possible reactivity with biomolecules. These in silico models were applied to collections of known leachables to identify functional and structural chemical classes likely to be flagged by these in silico approaches. Flagged leachable functional classes included antimicrobials, colorants, and film-forming agents, whereas specific chemical classes included epoxides, acrylates, and quinones. In addition, a dataset of 22 leachables with experimental data indicating their interaction with insulin glargine was used to evaluate whether one or more in silico methods are fit-for-purpose as a preliminary screen for assessing this biomolecule reactivity. Analysis of the data showed that the sensitivity of an in silico screen using multiple methodologies was 80%-90% and the specificity was 58%-92%. A workflow supporting the use of in silico methods in this field is proposed based on both the results from this assessment and best practices in the field of computational modeling and quality risk management., (© PDA, Inc. 2024.)

Leachables are quantified and identified to enable their quantitative toxicological safety risk assessment (qTSRA). The leachable's reported concentration and identity must meet certain quality expectations to be suitable for qTSRA. In this Correspondence, the author considers accuracy and protectiveness as competing key quality attributes and suggests that protectiveness is the proper quality attribute for qTSRA, as qTSRA is based on the foundation that a leachable's potential adverse effect on patient health and safety must not be underestimated. Considering this conclusion, means of making concentration estimates and proposed identities protective are discussed., (© PDA, Inc. 2024.)

The production of hospital-compounded medicines with a longer shelf life raises questions about drug-packaging interactions, especially desorption events involving extractables and leachables (E/L). A meta-synthesis of the literature was performed to describe which mass spectrometer is suitable for identifying and quantifying E/L.

Biological activity and pharmacological efficacy of protein drugs may be affected by the compatibility between drug and packaging materials. The compatibility of rubber closures seal cap has become the focus of many studies due to its complicated formulation. Despite of the significance of the issue, currently, there is little available data about organic leachables in drugs which is also not comprehensive. Since the concentration of migrants in drug is usually low and the matrix is complicated, the establishment of overall profile of extractables is crucial for the characterization of leachables. Herein, the supercritical fluid extraction (SFE) method was used because of its great extraction capacity and efficiency for low to medium polar extractables in rubber stoppers. The SFE conditions were optimized by response surface methodology (RSM). Experimental results of the extract yield were close to the predicted values (R2 = 0.95). Then the extractables were qualitatively and quantitatively analyzed with ultrahigh performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Finally, risk assessment was made by comparing predicted exposure with injection permitted daily exposure (pPDE) limit or threshold recommended by threshold of toxicological concern (TTC). The results showed that there are many extractables such as glyceride, fatty acids and derivatives, antioxidants, and degradation products. Among them degradation products were in the majority and content of 17 substances exceeded corresponding limits. Considering their unknown toxicology, more experiments are therefore needed to provide information on their toxicology and risk assessment. The study provides a reference for the compatibility of drugs, and quality supervision of pharmaceuticals packaging. [ABSTRACT FROM AUTHOR]

Biological safety assessments for drug-device combination products involve evaluation of the drug container closure and the device constituent part. When the device constituent part is the drug delivery system as well as the drug container closure system, both device and drug-based packaging standards have been deemed applicable. Approaches used for the biological safety assessment of medical devices differ from those used for pharmaceutical packaging/delivery systems. One area of difference is the extent to which chemical characterization with toxicological assessment is used either in addition to, or in place of, biological in vivo or in vitro tests. Differences also exist in the way nonclinical studies are used to evaluate the safety of medical devices or drug delivery systems. The lack of alignment in standards and guidance has resulted in confusion over what combination of tests and methods of evaluation constitute a biological safety assessment that will meet regulatory expectations for a drug-device combination product. The intent of this article is to discuss the challenges created when the packaging or delivery system is also a device constituent part of a drug-device combination product. Suggestions are offered regarding approaches that may be useful for conducting suitable biological safety assessments for drug-device combination products., (© PDA, Inc. 2024.)

The present study analyzes the composition of pine wood cultivated on artificial plantations in the Leningrad Oblast (Region). Comparing to pine wood from natural stands, a smaller heartwood zone along the height of the pine trunk and a lower content of resinous substances are noted. The content of cellulose and lignin in the heartwood and sapwood of pine is distributed differently along the trunk. The distribution of pentosans and water-soluble substances in the heartwood and sapwood along the trunk is associated with the lignin complex. The component composition of the studied pine wood from planted stands is quite uniform in its indicators if compared to the wood of older natural stands. Sulphate pulping of planted pine wood showed a higher yield of technical cellulose than the average yield from wood obtained at natural stands of the studied region. [ABSTRACT FROM AUTHOR]

Semifluorinated alkanes (SFAs) are aprotic solvents, which may be used as drug solvents for topical ocular applications, for instance, in dry eye syndrome. Their physical properties suggest that they might be prone to interaction with plastic materials, such as, polyethylene (PE) and polypropylene (PP), which are commonly used as packaging materials for pharmaceutical products. In this study, we investigate interactions of PE and PP with a liquid SFA perfluorohexyloctane (PFHO) using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and cross-polarized light microscopy. Binary phase diagrams of PFHO–PE and PFHO–PP systems demonstrating interactions of PFHO with the polymeric materials were constructed based on DSC data. According to this data, PFHO tends to lower the melting temperatures of PE and PP. The equilibrium values of solubilities of the polymers in PFHO and PFHO in the polymers were obtained by extrapolation of melting enthalpy data. Absorption of PFHO by PE and PP materials at ambient conditions after 4 weeks of equilibration was also studied by TGA. From the presented results, it may be concluded that thorough studies of interactions of PE or PP with SFAs are required when these materials are used as packaging components in SFA-based formulations. [ABSTRACT FROM AUTHOR]

In addition to degradation products, impurities, and exogenous contaminants, industries such as pharmaceutical, food, and others must concern themselves with leachables. These chemicals can derive from containers and closures or migrate from labels or secondary containers and packaging to make their way into products. Identification and quantification of extractables (potential leachables) and leachables, typically trace level analytes, is a regulatory expectation intended to ensure consumer safety and product fidelity. Mass spectrometry and related techniques have played a significant role in the analysis of extractables and leachables (E&L). This review provides an overview of how mass spectrometry is used for E&L studies, primarily in the context of the pharmaceutical industry. This review includes work flows, examples of how identification and quantification is done, and the importance of orthogonal data from several different detectors. E&L analyses are driven by the need for consumer safety. These studies are expected to expand in existing areas (e.g., food, textiles, toys, etc.) and into new, currently unregulated product areas. Thus, this topic is of interest to audiences beyond just the pharmaceutical and health care industries. Finally, the potential of universal detector approaches used in other areas is suggested as an opportunity to drive E&L research progress in this arguably understudied, under‐published realm. [ABSTRACT FROM AUTHOR]

Impurity investigations are important in pharmaceutical development to ensure drug purity and safety for the patient. The impurities typically found in drug products are degradants or reaction products of the active pharmaceutical ingredient (API) or leachable compounds from the container closure system. However, secondary reactions may also occur between API degradants, excipient impurities, residual solvents, and leachables to form adduct impurities. We hereby report an adduct-forming interaction of API (moxifloxacin) with a leachable compound (ethylene glycol monoformate) in moxifloxacin ophthalmic solution. The leachable compound originated from a low-density polyethylene bottle used in the packaging of drug products. The adduct impurity was tentatively identified as 1-cyclopropyl-6-fluoro-7-(1-(2-(formyloxy)ethyl) octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (C 24 H 28 FN 3 O 6 , MW = 473.19621) using accurate mass LC-QTOF analysis. The mass accuracy error between the theoretical mass and the experimental mass of an impurity was found to be 0.2 ppm. An MS/MS analysis was utilized to provide mass spectrometry fragments to support verification of the proposed structure. [ABSTRACT FROM AUTHOR]

Health-based exposure limits (HBELs) are derived for leachables from polymeric components that interact with the drug substance which exceed a safety concern threshold (SCT). However, given the nature of leachables, there is not always chemical-specific toxicology data. Read-across methodology specific to extractables and leachables (E&Ls) was developed based on survey data collected from 11 pharmaceutical companies and methodology used in other industries. One additional challenge for E&L read-across is most toxicology data is from the oral route of administration, whereas the parenteral route is very common for the leachable HBEL derivation. A conservative framework was developed to estimate oral bioavailability and the corresponding oral to parenteral extrapolation factor using physical chemical data. When this conservative framework was tested against 73 compounds with oral bioavailability data, it was found that the predicted bioavailability based on physico-chemical properties was conservatively greater than or equal to the experimental bioavailability 79% of the time. In conclusion, an E&L read-across methodology has been developed to provide a consistent, health protective framework for deriving HBELs when toxicology data is limited. • E&L read-across methodology developed to derive HBELs. • Pharmaceutical companies surveyed on current E&L practices and read-across approach. • Read-across literature from other industries reviewed. • Oral to parenteral bioavailability factors predicted based on phys-chem properties. [ABSTRACT FROM AUTHOR]

The effectiveness of an elevated temperature on the thermodynamic and kinetic properties of the solvent extraction of medical devices is evaluated in this study. The main objective of the current work is to specifically address the question of how effective a temperature of 50 °C, relative to 37 °C, is in improving the extractability and rate of the exaggerated and exhaustive extractions of medical devices. The extractability at equilibrium is related to the extraction partition coefficient, while the extraction rate is related to the corresponding diffusion coefficient. The partition and diffusion coefficients (or the enthalpies of extraction and diffusional activation energies) of solid-liquid extractions for different polymeric materials, solvents, and types of extractables entities at different temperatures are compiled comprehensively from extensive publications in the literature. The collected partition and diffusion coefficients at different temperatures are used to derive the partition enthalpies and diffusional activation energies in this study. The combined 209 partition enthalpies and 262 diffusional activation energies are then used to calculate the ratios of the partition and diffusion coefficients, when the extraction temperature increases from 37 °C to 50 °C. It is concluded from the study that the maximum improvement in extracted chemical amount with this specific temperature increase is about 3-fold, but the median improvement is only 16%. The most probable improvement is 25%. The maximum improvement (or decrease) in extraction time is 3.2-fold by the change in the diffusional coefficient, but the median value is 1.9-fold. The most probable decrease in extraction time is 2.4-fold. The collected data also allow the calculation of the ratio of the diffusion coefficient for a 10 °C increase, and the results are compared with the "factor 10 rule" in the literature on the relationship between the diffusion coefficient and temperature. The explicit conclusions of the study certainly provide evidences (not assumptions) in designing practical and cost-effective exaggerated and exhaustive extractions in the chemical characterization of medical devices, taking into considerations of extraction cycle time, temperature-dependent chemical stability, and the number of repeated extractions. • The effect of temperature from 37° to 50°C on medical device extractions evaluated. • The maximum increase in extractability is 3-fold with a median increase by 16%. • The maximum decrease in extraction time is 3-fold with a median value by 1.9-fold. • The "factor 10 rule" is found to correspond to the median value in this study. [ABSTRACT FROM AUTHOR]

The purpose of the study was to investigate the migration of oleamide, a polymer lubricant, and a bioactive compound, from various plastic, marketed containers for food/beverages and medicines into polymer contact liquid. Methanol, food/medicine simulants or real samples were used to extract polymer leachables and extractables. Migrated oleamide into polymer contact liquids was determined by ultra-high performance liquid chromatography coupled to mass spectrometry (UHPLC-MS). The concentration of oleamide in the extracts of medicinal and insulin syringes was 7351 ng mL−1 and 21,984 ng mL−1, respectively. The leachates of intravenous (i.v.) infusion bottle, medicinal and insulin syringes contained 17 ng mL−1, 12 ng mL−1 and 152 ng mL−1, respectively. Oleamide in the extracts of dummies ranged from 30 to 39 ng mL−1, while in the leachates of baby bottles, from 12 to 23 ng mL−1. Leachates of soft drink bottles contained from 6 to 15 ng mL−1 oleamide, milk bottles from 3 to 9 ng mL−1, liquid yogurt bottles 17 ng mL−1 and water bottles from 11 to 18 ng mL−1. Bottled real matrices of oil and milk contained oleamide in the range from 217 to 293 ng mL−1. Moreover, the source of migrated oleamide (e.g., containers, caps, other parts) was identified. Oleamide is listed in the current EU regulations without a specific migration limit. Accordingly, these values are considered of no concern, unless future toxicological studies prove the opposite.

Drug products and medical devices can contain leachable impurities that could adversely affect patient health during their clinical use. To establish patient exposure to leachables, drug products and packaging, manufacturing system, or medical device extracts are analytically screened for leachables or extractables. For organic extractables/leachables, the screening process typically involves a chromatographic separation coupled with an information-rich detection method. Information contained in the detector response (e.g., the chromatographic peak) is processed to establish quantities and to elucidate identities for the detected compounds. Organic extractables and leachables screening methods and procedures have proliferated with little, if any, attempt at standardization, creating the situation in which virtually every testing laboratory has their own analytical testing and data processing methodology. This raises the possibility that two different labs screening the same extract or drug product would report extractables or leachables profiles that differ in the number of compounds reported, the identities of the reported compounds, and the extracted (or leached) amounts of the identified compounds. Although standardization of the screening methods and procedures themselves would reduce lab-to-lab variation, such an approach would be difficult to implement. Thus, standardization of the screening outputs by setting quality standards for the outputs is considered. For example, the method's ability to detect a broad cross-section of potential extractables/leachables is established by testing a test mixture of representative compounds. Additionally, this author proposes that reported compound identities should be confident to be used in safety risk assessment; use of lower quality identities requires that the lower quality be accounted for in the assessment, perhaps by use of an uncertainty factor. Similarly, it is proposed that reported concentrations should be semi-quantitative to be used in safety risk assessment; use of lower quality concentrations requires that the lower quality be accounted for in the safety risk assessment, perhaps by use of an uncertainty factor., (© PDA, Inc. 2023.)

Commercially available, uncoated elastomeric closures were examined in regard to a potential contribution of extracted compounds from the rubber stoppers to protein aggregation under worst-case conditions. All rubber stoppers were confirmed to comply with Ph. Eur. quality requirements. Extraction with 2-propanol under reflux-conditions for 3 h led to closure-specific extraction profiles of the tested samples. One type of rubber stopper exhibited a considerably greater number and higher content of extractables. Four extracted compounds were identified as trialkyl benzene-1, 2, 4–tricarboxylates (trivial name: trimellitates), a substance class which is increasingly established as an alternative to phthalates. A highly concentrated aqueous solution of total extractables from this rubber stopper facilitated the formation of soluble and non-soluble high-molecular aggregates when incubated with model biopharmaceuticals (recombinant human immunoglobulin G (IgG) and recombinant erythropoietin (EPO)) under stress conditions (IgG: 60–64 °C for 130 min, EPO: 55 °C for 8 days). Furthermore, it was shown that the surfactant concentration (polysorbate 20, 0.1 m/v% vs. 1.0 m/v%) decisively influenced the formation of high-molecular aggregates. In case of EPO, the 10 fold increased concentration of surfactant was sufficient to prevent the aggregate formation completely. This study suggests the necessity of revisiting the current test system of Ph. Eur. monograph 3.2.9 for appropriate rubber stopper quality evaluation. [ABSTRACT FROM AUTHOR]

Pharmaceutical drug products (DP) can contain foreign impurities due to contact with manufacturing, storage, distribution and administration systems. These foreign impurities (leachables) are leached from these systems by the drug product and can be linked to extractables measured in the systems during laboratory investigations. Assessing the impact of leachables on the suitability of the DP requires that it be screened to discover, identify and quantify leachables. Given the large number and great chemical diversity of potential leachables, an analytical strategy involving multiple, orthogonal analytical methods is necessary to generate a complete leachables profile. Once the profile has been delineated, the effect of leachables on the DP's suitability can be established. The potential adverse effect of leachables on patient safety can be established via chemical safety risk assessment, which involves comparing a DP user's (patient) exposure to individual leachables with exposure thresholds which are toxicologically established for the individual leachables. [ABSTRACT FROM AUTHOR]