Search

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., Competing Interests: Conflict of Interest The authors declare that they have no competing interests., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

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.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

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.)

The three-dimensional (3D) global space of organic extractables and leachables (E&L) in volatility, hydrophobicity, and molecular weight (MW), covering the pharmaceutical container-closure system, biopharmaceutical single use equipment, and tissue-contacting medical devices, has been quantitatively explored by an extensive collection of E&L compounds from the publicly available sources. The total number of compounds collected is 776, including name, CAS number, MW, and boiling point (BP). The hydrophobicity of these compounds in logP o/w are computed by Abraham solvation parameter model, using compounds' descriptors generated by an online computational program "RMG: Solvation Tools". A "global" 3D space is built to represent the physicochemical property limits of E&L quantitatively, envisioned to cover a variety of materials extracted by different solvents. This 3D space also represents the scope and capability requirements of general-purpose chromatography-based methods to profile unknown material samples, if a limited number of analytical methods are used in a routine laboratory analysis. It is concluded from the study that the 3D space corresponding to MW of 1000 Da are: BP up to 857 °C and hydrophobicity in logP o/w between - 2.3-19. Additionally, the roles of temperature programmed GC (TPGC) and reversed-phase liquid chromatographic (RPLC) methods are quantitively and critically examined in the comprehensive analysis of the 3D space, particularly for RPLC methods in retention and resolution requirements, and it is also concluded that the current concept of analytical E&L testing strategies based on volatility needs to be challenged. Finally, this study proposes a semi-empirical method in correlation and prediction of the retention time of TPGC using Abraham solvation parameter model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Assessment of extractables and leachables (E&L) released from the pharmaceutical container closure systems (CCS), single-use polymeric processing materials (PPM), and medical devices is one of regulatory requirements in the submission and approval of pharmaceutical products and medical devices. The analytical activities involved in E&L studies are the solvent extraction of test articles, followed by instrumental analysis to determine both concentration and identities. Most E&L publications today are centered around the latter part, and the effect of extraction solvents on the chemical composition of extracts in the number, concentration and molecular weight (M W ) has not been systematically delineated and conceptualized to the best of our knowledge. The focus of this study is on a systematic review and analysis of the effect of solvents on the composition of extracts based on an extensive collection and study of relevant publications. The details of the discussions include: (1) the solvent extraction processes; (2) the degree of solvent-material interactions; (3) the material swelling and diffusion rate of material constituents; (4) the M W impact from swelling; and (5) finally, the conclusion of the dependency of chemical compositions in final extracts on solvent. Experimental data have also been collected and presented to support the conclusions of the study. The implications of the solvent-dependent chemical composition on analytical measurements of E&L by using both chromatography-based and gravimetric methods are briefly and critically discussed at the end., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Extractables and leachables from pharmaceutical packaging material can potentially be detrimental, which may affect the safety of the drug products. In this study, two compounds were found to be the possible extractables from the secondary packaging material. A strategy combining high performance liquid chromatography (HPLC), fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and nuclear magnetic resonance (NMR) spectroscopy was utilized for identification of the two compounds. Afterwards, a simple and sensitive HPLC method was developed and validated for the simultaneous quantification of both. The results indicated that this method was suitable for quantificating the two extractables in the pharmaceutical packaging material., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Leachables can potentially and adversely affect patient safety. Thus, drug products and medical devices are chromatographically screened for organic leachables (and extractables), establishing these compounds' identity and quantity. Accurate quantitation of extractables and leachables is challenging given compound-to-compound variation in response factors. One proposed means for managing variation and improving quantitation accuracy is the use of retention time (RT) and structure to match analytes with their most relevant quantitation surrogate. Although the scientific basis for relationships between RT and structure versus response is unclear, the use of matching was investigated using databases of response factors (RFs) or relative response factors (RRFs), RTs, and structures for extractables/leachables. Gas chromatography with mass spectrometry (MS) detection was investigated as response variation in this technique is less than with other screening methods such as liquid chromatography with MS detection. The overall RF variation across RT and structure makes it difficult to establish whether RT and response or structure and response can be correlated. Rigorous statistical analysis of the data concludes that there are no discernible relationships between these quantities; however, casual visual examination suggests that subtle relationships might exist. The effect that RT or structure matching could have on quantitation accuracy was considered, presuming that the visual trends were real. Under this presumption, it was estimated that RT matching could at most improve quantitation accuracy by 25%, and that structure matching could improve accuracy by at most 50%. However, these improvements do not address the response variation that is independent of RT or structure, and thus it is concluded that RT or structure matching are not viable solutions to RF variation. Rather, it is recommended that databases of authentic RRFs be aggressively populated to provide accurate quantitation. Compounds for which authentic RRFs cannot be secured are most effectively quantified using the median RRF., (© PDA, Inc. 2022.)

Ophthalmic solutions and suspensions have long been classified into a high-risk category with respect to concerns over extractables and leachables (E&L), though specific guidance on the management of leachables in these products is generally absent from regulatory authorities or the scientific literature. As a result, ophthalmic drug products (ODPs) were originally included in the scope of the Product Quality Research Institute Leachables and Extractables Working Group for Parenteral and Ophthalmic Drug Products (PQRI-PODP). Relative to other high concern dosage forms such as metered-dose inhalers or injectables, ODPs possess unique challenges with respect to the nature of impactful E&L as well as the safety assessment of leachables. For example, extensive use of semipermeable low-density polyethylene primary packaging for ODPs necessitates a strong focus on E&L from secondary packaging sources. For safety assessment, a key challenge is the lack of a sufficient database developed on all relevant ophthalmic toxicity endpoints. As result, the working group is unable to recommend a safety concern threshold (SCT) for ODPs at this time. Nevertheless, the ophthalmic industry has developed a number of time-tested practices to manage E&L for ODPs. This article describes those science-based practices and key considerations in the analysis, management, and safety assessment of E&L in ODPs., (© PDA, Inc. 2022.)

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.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

To address patient safety, a drug product is chromatographically screened for organic leachables. Similarly, medical device and packaging system extracts are chromatographically screened for organic extractables as probable leachables. To protect patient health, the screening methods must respond to all potentially unsafe substances. To be efficient, analytes determined to be below the toxicologically relevant threshold are removed from consideration before the subsequent analytical tasks of identification and quantitation are performed. The analytical evaluation threshold (AET) was established for use as a toxicologically relevant threshold to differentiate between chromatographic peaks that are unlikely to be unsafe (and thus do not need safety assessment) and those that are possibly unsafe (and thus require safety assessment). In practice, the instrumental response associated with the AET is determined using surrogate standards. It is then assumed that the response strength for an unknown extractable is equivalent to that for the surrogate standard at the AET concentration (i.e., relative response factor = 1). It is an unfortunate reality that response factors vary for different compounds on nearly all detector systems. This complicates the application of the AET and can result in a failure to include potentially toxicologically relevant compounds in the identification phase of the analysis. To ensure protection, an uncertainty factor was built into the AET equation that adjusts the AET downward to address response variation. Although this mechanism does increase the protectiveness of the AET, it assumes that the available methodology and instrumentation is sufficiently sensitive to reach the new lowered AET value. However, in some cases, the response variation is so great and the resulting uncertainty factor so large that the revised AET is below the achievable sensitivity specifications of even state-of-the art, expertly operated instrumental technologies. The only option then remaining is to concentrate the samples, which can result in adverse effects on analysis quality-counteracting the perceived benefit of lowering the AET. This article demonstrates how an analytical strategy based on methods with multiple complementary and orthogonal detection techniques (a multidetector approach) mitigates the problem of response factor variation and thus eliminates the need for large uncertainty factors and the resulting lower AET values. The primary concept is that all analytes only need to be effectively detected by at least one of the combination of detectors applied, and it is this effective technique (combination of all detectors and chromatographic methods utilized) that is used to perform the AET assessment., (© PDA, Inc. 2021.)

Prefilled dual chamber devices (DCDs) are combination products containing freeze-dried drug and diluent in two separate chambers of the device. DCDs provide high stability and convenience to patients and doctors, thus significantly improving product quality, patient compliance and market competitiveness. DCDs should also provide seal integrity, sterility and compatibility with biopharmaceuticals and avoid leachability and needle stick injuries. DCDs are promising alternatives to traditional containers or devices for biopharmaceuticals. The regulatory and medical practice to choose plastic DCDs as better alternatives over well-established glass syringes will be addressed here. The impact and major issues during processing, manufacturing, and storage of DCDs are also highlighted. Further discussion clears its business potential, composition, stability testing, and quality standard requirements to deal with market competition. It also covers major role of extractables and leachables in storage stability of the product., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 (R 2  = 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.

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The current study was undertaken to evaluate clinical-grade disposable syringes of various brands based on the identification of an extraneous impurity leaching out from the rubber gasket of the syringe during sample preparation for liquid chromatography method development. The syringes were evaluated using aqueous and organic solvents and their mixtures to understand susceptibility towards extractables. It was observed that the extraction propensity of different brands of syringes was varying in terms of number and levels of extractables. A total of eight extractables (including the extraneous impurity observed during method development) were identified from the syringe gaskets with the help of liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS), nuclear magnetic resonance (NMR) and/or infrared (IR) spectroscopy. To the best of authors' knowledge, four out of eight proposed extractables are not reported in the literature. A tentative pathway for the formation of the extractables was also proposed., Competing Interests: Declaration of Competing Interest There are no financial or non-financial competing interests to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

It is generally acknowledged that quantitation in extractables and leachables (E&L) can be variably reproducible and accurate, depending on the quantitation approach taken. This is especially true for "simple" quantitation, which is the practice of estimating an analyte's concentration based on its response relative to that of an internal standard that has been added to the sample in a known amount. Simple quantitation is prone to error and variation as it is based on the largely false premise that the response factors for all extractables, leachables, and internal standard candidates are the same. It has been proposed that this uncertainty (inaccuracy and variation) be accounted for by adjusting two key parameters in E&L assessment, the reported concentrations themselves and the analytical evaluation threshold (AET) via an uncertainty factor (UF). This paper examines quantitation variation and discusses the means of establishing and utilizing the UF to adjust the AET to lower values and to adjust reported concentrations to higher values, enabling an impact assessment performed with this data to be more protective of patient safety. Although adjustment of the AET lower with the UF is supported, flaws in the concept of using the UF to adjust reported concentrations upward are considered, and it is recommended that the UF not be used in this manner. Rather, E&L quantitation should be based on compound-specific relative response factors, collected and collated in an E&L database., (© PDA, Inc. 2020.)

Elemental impurities in drug products arise from different sources and via a number of different means, including leaching of elemental entities (including the elements themselves or element-containing compounds) from the drug product's manufacturing or packaging systems. Thus, knowledge about the presence, level, and likelihood of leaching of elements in manufacturing and packaging systems is relevant to understanding how these systems contribute to a drug product's total elemental impurity burden. To that end, this manuscript updates a previous review of available literature on elemental entities in pharmaceutically relevant polymers and the presence of these elemental entities in material extracts and/or drug products. This updated review contains the information that has been published subsequent to the publication of the initial review and considers two questions: (1) What elemental entities are present in the relevant polymers and materials and at what levels are they present? (2) To what extent are these elemental entities leached from these materials under conditions relevant to the manufacturing and storage/distribution of solution drug products? The compiled recent data reaffirms the conclusions drawn from the original review: (1) Elemental entities are present in the materials used to construct packaging and manufacturing systems as these materials either contain these elemental entities as additives or are exposed to the elemental entities during their production. (2) Unless the elemental entities were parts of the materials themselves (e.g., SiO 2 in glass) or intentionally added to the materials (e.g., metal stearates in polymers), their incidental amounts in the materials were generally low. (3) If elemental entities were present in materials and systems, generally only a very small fraction of the total available amount of the entity could be leached under conditions that were relevant to the packaged drug products. Thus, although sources of certain elemental impurities may be ubiquitous in the natural environment, they were not ubiquitous in materials used in pharmaceutical packaging and manufacturing systems and when they were present, they were not extensively leached under relevant conditions of use for those systems. This conclusion, supported by an ever-increasing body of literature, suggests that in general the manufacturing and packaging systems, by themselves, do not contribute sufficiently large quantities of elemental impurities that the impurities pose a meaningful threat to patient safety. Furthermore, this conclusion should be considered when standards are developed for the characterization and qualification of manufacturing systems, packaging systems, and their associated materials and components of construction., (© PDA, Inc. 2020.)

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., (© 2019 Wiley Periodicals, Inc.)

Extractables and leachables (E&L) are identified and quantified so that their impact on patient safety can be established and assessed. The uncertainty in the impact assessment is affected by the uncertainty in the substance's experimentally determined identity and concentration. Thus, these experimentally determined quantities must be reported not only in terms of their absolute result but also in terms of the uncertainty in the result, which is based on the amount and rigor of the information on which the result is based. In this way, the impact assessment can be tempered to account for the uncertainty in its input data. To facilitate the assignment and reporting of uncertainty, classification hierarchies are proposed and discussed for both identification and quantitation. Both hierarchies establish levels or degrees of identification and quantitation based on the uncertainty of the result and contain descriptions of the quality and quantity of information required to achieve a certain level within the hierarchy. The minimal levels that must be achieved to support impact assessment are also established., (© PDA, Inc. 2020.)

Pharmaceutical containers for parenterals have been predominantly manufactured using glass as a packaging material of choice, especially Type-I glass, since it has been regarded as a chemically inert and an effective container closure system (CCS). Nevertheless, there have been reports and recalls related to glass quality issues, such as breakage, flakes, and particles observed in marketed products. The novelty of this research is based on the knowledge gathered from our previously conducted risk assessments and establishing a comprehensive testing platform focused on risk factors for glass container failure modes and applicability to other types of pharmaceutical containers. The evaluation of container quality attributes was performed for three model glass vials using a mechanical and chemical durability testing platform: freeze-thaw, lyophilization, compression, scratch tests; visual inspection, pH, particle size analyses, extractable, leachable and imaging studies that were conducted under normal (4 and 25 °C), and stress condition (60 °C), respectively. The performance between the glass containers tested under certain stress conditions (failure modes) were variable and differentiated. The systematic platform testing approach shows the importance of lab-based risk evaluation in assessing common failure modes of pharmaceutical containers, since the quality attributes for injectable products are complex and can impact final product quality., (Published by Elsevier B.V.)

Pharmaceutical drug products are packaged in containers so that they can be manufactured, distributed, and stored. During these events in a drug product's life cycle, the drug product and its packaging could interact, resulting in substances leaching from the plastic and accumulating in the drug product. As the leached substances could adversely impact a key quality attribute of the drug product, drug products must be tested to establish which leachables are present and in what quantities.Because a drug product's lifetime can be long, it is common practice to accelerate leaching by using temperatures higher than clinical use conditions. While use of accelerated conditions is a well-accepted practice, there are questions with respect to the means by which the degree of acceleration can be calculated and justified. In this manuscript, experimental data from 10 case studies are used to evaluate commonly utilized, Arrhenius-based approaches to acceleration, and recommendations are made in terms of the proper approaches to be used for concentration and duration extrapolations. Specifically, when accumulation levels are projected from a clinical to an elevated temperature, the Arrhenius model formulated by ASTM for the accelerated aging of medical devices using a Q10 value of 1.5 most frequently provides the best fit to experimental leaching data. Alternatively, when contact durations are projected from a clinical to an elevated temperature, the Arrhenius model reflected in the empirically derived "factor 10 rule," developed for and applied to food contact packaging, most frequently provides the best fit to experimental leaching data. LAY ABSTRACT: Pharmaceutical drug products are packaged in containers so that they can be manufactured, distributed, and stored. During these events in a drug product's life cycle, the drug product and the plastic systems may interact, resulting in substances leaching from the plastic and accumulating in the drug product. As the leached substances could adversely impact a key quality attribute of the drug product, drug products must be tested to establish what leachables are present and in what quantities.Because a drug product's lifetime can be long, it is common practice to accelerate leaching by using temperatures higher than clinical use conditions. While use of accelerated conditions is a well-accepted practice, there are questions with respect to the means by which the degree of acceleration can be calculated and justified. In this manuscript, experimental data from 10 case studies are used to evaluate commonly utilized approaches to acceleration, and recommendations are made in terms of the proper approaches to be used for concentration and duration extrapolations., (© PDA, Inc. 2019.)

Purpose: The proper understanding of glass delamination is important to glass manufacturers, pharmaceutical companies, and health authorities to mitigate the occurrence of glass flakes from the vial when in contact with specific drug product solutions. The surface of glass vials is altered during glass cane- and vial forming processes and is exposed to different stress conditions during drug product processing before coming in contact with the drug product solution. In this study, the impact of vial washing and depyrogenation including an evaluation of various residual water volumes on surface properties of glass vials was investigated for a defined set of vials., Methods: 3D laser scanning microscopy was established as a new method for topographic analysis of curved surfaces of glass vials operating in high-throughput mode. A subset of vials was subsequently exposed to delamination stress testing and both the stressed solution and inner vial surface were analyzed by a panel of conventional and advanced analytical techniques including 3D laser scanning microscopy., Results: The data showed that vial washing and depyrogenation strongly influenced surface properties, in particular those of uncoated vials. Surface characteristics such as pits increased depending on the process conditions, which especially applies to Expansion 33 vials. Even low residual water volumes of 50 μL after vial washing were sufficient to change the surface properties of the glass and weaken the surface in those positions prone to glass delamination. An increase in pits was related to a greater risk for glass delamination., Conclusions: Vial processing conditions need to be assessed when aiming at minimizing the glass delamination risk during parenteral product storage.

A non-target analysis was developed for the analysis of extractables from multi-layer coextrusion bags exposed to 4% benzyl alcohol solution and 0.1 M sodium acetate at pH = 5 for defined periods (15 day, 45 day and 90 day) according to manufacturer instructions based on the ultra-performance liquid chromatography (UPLC) quadrupole-time of flight mass spectrometry (Q-TOF MS). In order to confirm the extractables, principal component analysis (PCA) was used to indicate the differences among samples of different periods. Then, the extractables were identified based on searching the self-built library or online searching. The total content of extractables of 90 day samples was 589.78 μg/L, and the content was in the range of acceptable levels for pharmaceutical manufacturers. The risk assessment of the extractables were evaluated by Toxtree and T.E.S.T. software to avoid the animals bioexperiment., (Copyright © 2018. Published by Elsevier Inc.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The advent of single-use bioprocess systems used for the delivery, storage or manufacture of biopharmaceuticals has introduced a new potential source for extractables and leachables (E&L) as these systems are comprised of polymeric materials. Several industry working groups, the FDA and USP have issued guidance and draft guidance on E&L analyses for a variety of applications. These documents typically indicate that mass spectrometry should be applied for discovery of E&L's but provide little guidance as to the exact analytical methodology which should be used. We investigated the extractable profiles of a model single-use bioprocessing system consisting of a single-use bioprocess bag, connector tubing, and a hydrophilic disk filter including filter housing. Extractions were performed in water, ethanol, ethanol/water (50:50) and saline solutions. Extracts were analyzed using a stepwise analytical methodology including a variety of screening and mass spectrometry methods We then used this model system to demonstrate the use of recursive feature finding to automatically detect unique extractables followed by statistical filtering to focus on differentially present extractables which were above the analytical evaluation threshold (AET). We further show the significant affects of standard selection on the number of compounds determined to be above AET when reducing liquid chromatography-mass spectrometry (LC/MS) data. A relative response factor database consisting of 14 structurally diverse commercially available polymer additives was used to arrive at an LC/MS identification threshold. The results of this study demonstrate that significant care should be taken when selecting standards for LC/MS analysis to avoid under reporting of extractables and leachables., (Copyright © 2017 Elsevier B.V. All rights reserved.)

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., (© PDA, Inc. 2017.)

Pharmaceutical products are packaged in containers so that they can be manufactured, distributed, and used. Because extractables from such containers are precursors of leachable impurities in the product, extractables represent potential hazards to user safety. Polypropylene resins are frequently used as materials of construction for packaging of liquid parenteral drug products. Thus, extractables profiling of polypropylene resins may be an effective means of hazard identification associated with the resin's safe use. Twenty-one polypropylene resins were extracted using aqueous and organic extraction solvents, and the resulting extracts were screened for extractables using appropriate general chemistry, chromatographic, and spectroscopic methodologies. The resulting extractables profiles were toxicologically reviewed by a defined process to identify potential hazards given a specified therapeutic application involving long-term use of a large-volume aqueous parenteral drug product. The organic extractables profiles of individual polypropylene resins were variable in terms of the individual extractable identified and their extracted levels, consistent with high variability in polypropylene resin formulations and pharmaceutical product manufacturing. However, the profiles were similar in terms of the groups of extractables measured. Thus, for example, all the resins had extractables associated with antioxidants, as all the resins contained antioxidants but the specific extractables for a given resin depended on the specific antioxidants present in that resin. Few of the targeted extractable elements were present in the extracts at measurable levels, although most resins had measurable levels of extracted aluminum, silicon, and alkali and alkaline earths. A worst-case extractables profile (all the extractables measured in individual resins at their highest levels) was toxicologically reviewed considering an aqueous large-volume parenteral drug product. This review established certain extractables as potential hazards whose actual toxicological safety risk assessment would require more rigorous data and a more rigorous process than those used for hazard identification. LAY ABSTRACT: Packages used to contain aqueous parenteral drug products may be made of polypropylene. During storage, extractables from the polypropylene may leach out of the container and accumulate in the drug product, where they could affect product quality and/or safety. In this study, 21 polypropylene resins were characterized with respect to their organic and elemental extractables profiles. A worst-case extractables profile (highest level of all the extractables identified) was toxicologically assessed to establish potentially hazardous extractables. Certain extractables were established as potential hazards whose actual toxicological safety risk assessment would require more rigorous data and a more rigorous process than those used for hazard identification., (© PDA, Inc. 2017.)

When drug products contact plastic manufacturing components, packaging systems, and/or delivery devices, leachables from the plastics can accumulate in the drug product, potentially affecting its key quality attributes. Given practical issues associated with screening drug products for leachables, potential leachables are frequently surfaced as extractables revealed in extraction studies. To facilitate extractables discovery and identification and to shorten extraction times, extraction studies can be exaggerated and/or accelerated. One means of exaggerating an extraction is to increase the test article's extracted surface area to extraction solution volume ratio (SA/V), as it is generally accepted that an extractable's concentration in an extract is proportional to SA/V in a 1 to 1 manner. However, as the relationship between an extractable's concentration and SA/V depends on the extractable's plastic/solvent partition coefficient (k p/l ), the effect of SA/V on the extractable's concentrations can be either under- or over-estimated if a 1 to 1 proportion is used. This article presents the theoretical relationship between SA/V, concentration, and k p/l ; illustrates theory with a case study; and suggests proper exaggeration strategies. LAY ABSTRACT: When drug products are manufactured, stored, or delivered in systems that contain plastics, substances can be leached from the plastics and remain in the drug product, where they might affect the product's key quality attributes. To discover and identify these leached substances, the plastics are extracted under laboratory conditions and the extracts are appropriately tested. To facilitate this process, extracts may be generated under laboratory conditions that exaggerate or accelerate the drug product's clinical conditions of manufacturing or use. The proper use of the ratio of the extracted item's surface area to the volume of the extracting solution as an exaggeration parameter is discussed in this paper., (© PDA, Inc. 2017.)

A simulating leaching (migration) study was performed on a model container-closure system relevant to parenteral and ophthalmic drug products. This container-closure system consisted of a linear low-density polyethylene bottle (primary container), a polypropylene cap and an elastomeric cap liner (closure), an adhesive label (labeling), and a foil overpouch (secondary container). The bottles were filled with simulating solvents (aqueous salt/acid mixture at pH 2.5, aqueous buffer at pH 9.5, and 1/1 v/v isopropanol/water), a label was affixed to the filled and capped bottles, the filled bottles were placed into the foil overpouch, and the filled and pouched units were stored either upright or inverted for up to 6 months at 40 °C. After storage, the leaching solutions were tested for leached substances using multiple complementary analytical techniques to address volatile, semi-volatile, and non-volatile organic and inorganic extractables as potential leachables.The leaching data generated supported several conclusions, including that (1) the extractables (leachables) profile revealed by a simulating leaching study can qualitatively be correlated with compositional information for materials of construction, (2) the chemical nature of both the extracting medium and the individual extractables (leachables) can markedly affect the resulting profile, and (3) while direct contact between a drug product and a system's material of construction may exacerbate the leaching of substances from that material by the drug product, direct contact is not a prerequisite for migration and leaching to occur. LAY ABSTRACT: The migration of container-related extractables from a model pharmaceutical container-closure system and into simulated drug product solutions was studied, focusing on circumstances relevant to parenteral and ophthalmic drug products. The model system was constructed specifically to address the migration of extractables from labels applied to the outside of the primary container. The study demonstrated that (1) the extractables that do migrate can be correlated to the composition of the materials used to construct the container-closure systems, (2) the extent of migration is affected by the chemical nature of the simulating solutions and the extractables themselves, and (3) even though labels may not be in direct contact with a contained solution, label-related extractables can accumulate as leachables in those solutions., (© PDA, Inc. 2017.)

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Unlabelled: The risk mitigation of extractables and leachables presents significant challenges to regulators and drug manufacturers with respect to the development, as well as the lifecycle management, of drug products. A holistic program is proposed, using a science- and risk-based strategy for testing extractables and leachables from primary containers, drug delivery devices, and single-use systems for the manufacture of biotechnology products. The strategy adopts the principles and concepts from ICH Q9 and ICH Q8(R2). The strategy is phase-appropriate, progressing from extractables testing for material screening/selection/qualification through leachables testing of final products. The strategy is designed primarily to ensure patient safety and product quality of biotechnology products. The holistic program requires robust extraction studies using model solvents, with careful consideration of solvation effect, pH, ionic strength, temperature, and product-contact surface and duration. From a wide variety of process- and product-contact materials, such extraction studies have identified and quantified over 200 organic extractable compounds. The most commonly observed compounds were siloxanes, fatty acid amides, and methacrylates. Toxicology assessments were conducted on these compounds using risk-based decision analysis. Parenteral permitted daily exposure limits were derived, as appropriate, for the majority of these compounds. Analysis of the derived parenteral permitted daily exposure limits helped to establish action thresholds to target high-risk leachables in drug products on stability until expiry. Action thresholds serve to trigger quality investigations to determine potential product impact. The holistic program also evaluates the potential risk for immunogenicity. This approach for primary drug containers and delivery devices is also applicable to single-use systems when justified with a historical knowledge base and understanding of the manufacturing processes of biotechnology products., Lay Abstract: In the development of a drug product, careful consideration is given to impurities that may originate from manufacturing equipment, process components, and packaging materials. The majority of such impurities are common chemical additives used to improve the physicochemical properties of a wide range of plastic materials. Suppliers and drug manufacturers conduct studies to extract chemical additives from the plastic materials in order to screen and predict those that may leach into a drug product. In this context, the term extractables refers to a profile of extracted compounds observed in studies under harsh conditions. In contrast, the term leachables refers to those impurities that leach from the materials under real-use conditions and may be present in final drug products. The purpose of this article is to present a holistic approach that effectively minimizes the risk of leachables to patient safety and product quality., (© PDA, Inc. 2015.)

Inorganic extractables from glass vials may cause particle formation in the drug solution. In this study, the ability of eluting Al ion from borosilicate glass vials, and tendencies of precipitation containing Al were investigated using various pHs of phosphate, citrate, acetate and histidine buffer. Through heating, all of the buffers showed that Si and Al were eluted from glass vials in ratios almost the same as the composition of borosilicate glass, and the amounts of Al and Si from various buffer solutions at pH 7 were in the following order: citrate > phosphate > acetate > histidine. In addition, during storage after heating, the Al concentration at certain pHs of phosphate and acetate buffer solution decreased, suggesting the formation of particles containing Al. In citrate buffer, Al did not decrease in spite of the high elution amount. Considering that the solubility profile of aluminum oxide and the Al eluting profile of borosilicate glass were different, it is speculated that Al ion may be forced to leach into the buffer solution according to Si elution on the surface of glass vials. When Al ions were added to the buffer solutions, phosphate, acetate and histidine buffer showed a decrease of Al concentration during storage at a neutral range of pHs, indicating the formation of particles containing Al. In conclusion, it is suggested that phosphate buffer solution has higher possibility of forming particles containing Al than other buffer solutions.

Unlabelled: Studies of the extractable profiles of bioprocessing components have become an integral part of drug development efforts to minimize possible compromise in process performance, decrease in drug product quality, and potential safety risk to patients due to the possibility of small molecules leaching out from the components. In this study, an effective extraction solvent system was developed to evaluate the organic extractable profiles of single-use bioprocess equipment, which has been gaining increasing popularity in the biopharmaceutical industry because of the many advantages over the traditional stainless steel-based bioreactors and other fluid mixing and storage vessels. The chosen extraction conditions were intended to represent aggressive conditions relative to the application of single-use bags in biopharmaceutical manufacture, in which aqueous based systems are largely utilized. Those extraction conditions, along with a non-targeted analytical strategy, allowed for the generation and identification of an array of extractable compounds; a total of 53 organic compounds were identified from four types of commercially available single-use bags, the majority of which are degradation products of polymer additives. The success of this overall extractables analysis strategy was reflected partially by the effectiveness in the extraction and identification of a compound that was later found to be highly detrimental to mammalian cell growth., Lay Abstract: The usage of single-use bioreactors has been increasing in biopharmaceutical industry because of the appealing advantages that it promises regarding to the cleaning, sterilization, operational flexibility, and so on, during manufacturing of biologics. However, compared to its conventional counterparts based mainly on stainless steel, single-use bioreactors are more susceptible to potential problems associated with compound leaching into the bioprocessing fluid. As a result, extractable profiling of the single-use system has become essential in the qualification of such systems for its use in drug manufacturing. The aim of this study is to evaluate the effectiveness of an extraction solvent system developed to study the extraction profile of single-use bioreactors in which aqueous-based systems are largely used. The results showed that with a non-targeted analytical approach, the extraction solvent allowed the generation and identification of an array of extractable compounds from four commercially available single-use bioreactors. Most of extractables are degradation products of polymer additives, among which was a compound that was later found to be highly detrimental to mammalian cell growth., (© PDA, Inc. 2015.)

Introduction: Use of pre-filled syringes as both a packaging and delivery system for pharmaceutical drug products is accelerating. Pre-filled syringes must meet the quality and suitability for use requirements for both systems, including compatibility with the drug product. Relevant incompatibilities between pre-filled syringes and drug products include the safety of syringe-based leachables that accumulate in drug products and the ability of leachables to interact with the drug product's ingredients as such interactions can affect safety, efficacy, stability and physical viability., Areas Covered: Relevant suitability considerations for pre-filled syringes are discussed herein and specific examples of suitability for use issues for pre-filled syringes are cited, focusing on extractables associated with pre-filled syringes and leachables derived from such syringes. Aspects considered include the toxicological impact of leachables, their ability to alter the efficacy of drug products and to produce other undesirable outcomes such as aggregation and immunogenic responses., Expert Opinion: Materials used in pre-filled syringes and the conditions of use minimize the traditional safety risk associated with leachables. However, drug products that use pre-filled syringes are prone to non-traditional interactions such as disruption of protein conformation, leading to potential efficacy, safety and quality issues. In order to qualify pre-filled syringes for use, the traditional approach of measuring extractables and leachables and inferring their effect must be augmented by rigorous compatibility testing. Research into the fundamental relationship between leachables and drug substances will be necessary so the more time- and cost-efficient 'measure and infer' approach can be widely implemented.

Technical Abstract: Glass is the ideal material for parenteral packaging because of its chemical durability, hermeticity, strength, cleanliness, and transparency. Alkali borosilicate glasses have been used successfully for a long time, but they do have some issues relating to breakage, delamination, and variation in hydrolytic performance. In this paper, alkali aluminosilicate glasses are introduced as a possible alternative to alkali borosilicate glasses. An example alkali aluminosilicate glass is shown to meet the compendial requirements, and to have similar thermal, optical, and mechanical attributes as the current alkali borosilicate glasses. In addition, the alkali aluminosilicate performed as well or better than the current alkali borosilicates in extractables tests and stability studies, which suggests that it would be suitable for use with the studied liquid product formulation., Lay Abstract: The physical, mechanical, and optical properties of glass make it an ideal material for packaging injectable drugs and biologics. Alkali borosilicate glasses have been used successfully for a long time for these applications, but there are some issues. In this paper, alkali aluminosilicate glasses are introduced as a possible alternative to alkali borosilicate glasses. An example alkali aluminosilicate glass is shown to meet the requirements for packaging injectable drugs and biologics, and to be suitable for use with a particular liquid drug., (© PDA, Inc. 2014.)

Demonstrating suitability for intended use is necessary to register packaging, delivery/administration, or manufacturing systems for pharmaceutical products. During their use, such systems may interact with the pharmaceutical product, potentially adding extraneous entities to those products. These extraneous entities, termed leachables, have the potential to affect the product's performance and/or safety. To establish the potential safety impact, drug products and their packaging, delivery, or manufacturing systems are tested for leachables or extractables, respectively. This generally involves testing a sample (either the extract or the drug product) by a means that produces a test method response and then correlating the test method response with the identity and concentration of the entity causing the response. Oftentimes, analytical tests produce responses that cannot readily establish the associated entity's identity. Entities associated with un-interpretable responses are termed unknowns. Scientifically justifiable thresholds are used to establish those individual unknowns that represent an acceptable patient safety risk and thus which do not require further identification and, conversely, those unknowns whose potential safety impact require that they be identified. Such thresholds are typically based on the statistical analysis of datasets containing toxicological information for more or less relevant compounds. This article documents toxicological information for over 540 extractables identified in laboratory testing of polymeric materials used in pharmaceutical applications. Relevant toxicological endpoints, such as NOELs (no observed effects), NOAELs (no adverse effects), TDLOs (lowest published toxic dose), and others were collated for these extractables or their structurally similar surrogates and were systematically assessed to produce a risk index, which represents a daily intake value for life-long intravenous administration. This systematic approach uses four uncertainty factors, each assigned a factor of 10, which consider the quality and relevance of the data, differences in route of administration, non-human species to human extrapolations, and inter-individual variation among humans. In addition to the risk index values, all extractables and most of their surrogates were classified for structural safety alerts using Cramer rules and for mutagenicity alerts using an in silico approach (Benigni/Bossa rule base for mutagenicity via Toxtree). Lastly, in vitro mutagenicity data (Ames Salmonella typimurium and Mouse Lymphoma tests) were collected from available databases (Chemical Carcinogenesis Research Information and Carcinogenic Potency Database). The frequency distributions of the resulting data were established; in general risk index values were normally distributed around a band ranging from 5 to 20 mg/day. The risk index associated with 95% level of the cumulative distribution plot was approximately 0.1 mg/day. Thirteen extractables in the dataset had individual risk index values less than 0.1 mg/day, although four of these had additional risk indices, based on multiple different toxicological endpoints, above 0.1 mg/day. Additionally, approximately 50% of the extractables were classified in Cramer Class 1 (low risk of toxicity) and approximately 35% were in Cramer Class 3 (no basis to assume safety). Lastly, roughly 20% of the extractables triggered either an in vitro or in silico alert for mutagenicity. When Cramer classifications and the mutagenicity alerts were compared to the risk indices, extractables with safety alerts generally had lower risk index values, although the differences in the risk index data distributions, extractables with or without alerts, were small and subtle., Lay Abstract: Leachables from packaging systems, manufacturing systems, or delivery devices can accumulate in drug products and potentially affect the drug product. Although drug products can be analyzed for leachables (and material extracts can be analyzed for extractables), not all leachables or extractables can be fully identified. Safety thresholds can be used to establish whether the unidentified substances can be deemed to be safe or whether additional analytical efforts need to be made to secure the identities. These thresholds are typically based on the statistical analysis of datasets containing toxicological information for more or less relevant compounds. This article contains safety data for over 500 extractables that were identified in laboratory characterizations of polymers used in pharmaceutical applications. The safety data consists of structural toxicity classifications of the extractables as well as calculated risk indices, where the risk indices were obtained by subjecting toxicological safety data, such as NOELs (no observed effects), NOAELs (no adverse effects), TDLOs (lowest published toxic dose), and others to a systematic evaluation process using appropriate uncertainty factors. Thus the risk index values represent daily exposures for the lifetime intravenous administration of drugs. The frequency distributions of the risk indices and Cramer classifications were examined. The risk index values were normally distributed around a range of 5 to 20 mg/day, and the risk index associated with the 95% level of the cumulative frequency plot was 0.1 mg/day. Approximately 50% of the extractables were in Cramer Class 1 (low risk of toxicity) and approximately 35% were in Cramer Class 3 (high risk of toxicity). Approximately 20% of the extractables produced an in vitro or in silico mutagenicity alert. In general, the distribution of risk index values was not strongly correlated with the either extractables' Cramer classification or by mutagenicity alerts. However, extractables with either in vitro or in silico alerts were somewhat more likely to have low risk index values., (© PDA, Inc. 2014.)

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., (© PDA, Inc. 2014.)

This paper describes an approach of extractables determination and gives information on extractables profiles for gamma-sterilized single-use bags with polyethylene inner contact surfaces from five different suppliers. Four extraction solvents were chosen to capture a broad spectrum of extractables. An 80% ethanol extraction was used to extract compounds that represent the bag resin and the organic additives used to stabilize or process the polymer films which would not normally be water-soluble. Extractions with1 M HCl extract, 1 M NaOH extract, and 1% polysorbate 80 were used to bracket potential leachables in biopharmaceutical process fluids. The objective of this study was to obtain extractables data from different bags under identical test conditions. All the bags had a nominal capacity of 5 L, were gamma-irradiated prior to testing, and were tested without modification except that connectors, if any, were removed prior to filling. They were extracted at 40 °C for 30 days. Extractables from all bag extracts were identified and the concentration estimated using headspace gas chromatography-mass spectrometry and flame ionization detection for volatile compounds and for semi-volatile compounds, and liquid chromatography-mass spectrometry for targeted compounds. Metals and other elements were detected and quantified by inductively coupled plasma mass spectrometry analysis. The results showed a variety of extractables, some of which are not related to the inner polyethylene contact layer. Detected organic compounds included oligomers from polyolefins, additives and their degradation products, and oligomers from the fill tubing. The concentrations of extractables were in the range of parts-per-billion to parts-per-million per bag under the applied extraction conditions. Toxicological effects of the extractables are not addressed in this paper., Lay Abstract: Extractables and leachables characterization supports the validation and the use of single-use bags in the biopharmaceutical manufacturing process. This paper describes an approach for the identification and quantification of extractable substances for five commercially available single-use bags from different suppliers under identical analytical conditions. Four test formulations were used for the extraction, and extractables were analyzed with appropriately qualified analytical techniques, allowing for the detection of a broad range of released chemical compounds. Polymer additives such as antioxidants and processing aids and their degradation products were found to be the source of most of the extracted compounds. The concentration of extractables ranged from parts-per-billion to parts-per-million under the applied extraction conditions., (© PDA, Inc. 2014.)

Extracts of plastic packaging, manufacturing, and delivery systems (or their materials of construction) are analyzed by chromatographic methods to establish the system's extractables profile. The testing strategy consists of multiple orthogonal chromatographic methods, for example, gas and liquid chromatography with multiple detection strategies. Although this orthogonal testing strategy is comprehensive, it is not necessarily complete and members of the extractables profile can elude detection and/or accurate identification/quantification. Because the chromatographic methods rarely indicate that some extractables have been missed, another means of assessing the completeness of the profiling activity must be established. If the extracts are aqueous and contain no organic additives (e.g., pH buffers), then they can be analyzed for their total organic carbon content (TOC). Additionally, the TOC of an extract can be calculated based on the extractables revealed by the screening analyses. The measured and calculated TOC can be reconciled to establish the completeness and accuracy of the extractables profile. If the reconciliation is poor, then the profile is either incomplete or inaccurate and additional testing is needed to establish the complete and accurate profile. Ten test materials and components of systems were extracted and their extracts characterized for organic extractables using typical screening procedures. Measured and calculated TOC was reconciled to establish the completeness of the revealed extractables profile. When the TOC reconciliation was incomplete, the profiling was augmented with additional analytical testing to reveal the missing members of the organic extractables profile. This process is illustrated via two case studies involving aqueous extracts of sterile filters., Lay Abstract: Plastic materials and systems used to manufacture, contain, store, and deliver pharmaceutical products are extracted and the extracts analyzed to establish the materials' (or systems') organic extractables profile. Such testing typically consists of multiple chromatographic approaches whose differences help to ensure that all organic extractables are revealed, measured, and identified. Nevertheless, this rigorous screening process is not infallible and certain organic extractables may elude detection. If the extraction medium is aqueous, the process of total organic carbon (TOC) reconciliation is proposed as a means of establishing when some organic extractables elude detection. In the reconciliation, the TOC of the extracts is both directly measured and calculated from the chromatographic data. The measured and calculated TOC is compared (or reconciled), and the degree of reconciliation is an indication of the completeness and accuracy of the organic extractables profiling. If the reconciliation is poor, then the extractables profile is either incomplete or inaccurate and additional testing must be performed to establish the complete and accurate profile. This article demonstrates the TOC reconciliation process by considering aqueous extracts of 10 different test articles. Incomplete reconciliations were augmented with additional testing to produce a more complete TOC reconciliation., (© PDA, Inc. 2014.)

The Product Quality Research Institute (PQRI) is a non-profit consortium of organizations working together to generate and share timely, relevant, and impactful information that advances drug product quality and development. The collaborative activities of PQRI participants have, in the case of orally inhaled and nasal drug products (OINDPs), resulted in comprehensive and widely-accepted recommendations for leachables assessments to help ensure patient safety with respect to this class of packaged drug products. These recommendations, which include scientifically justified safety thresholds for leachables, represent a significant milestone towards establishing standardized approaches for safety qualification of leachables in OINDP. To build on the success of the OINDP effort, PQRI's Parenteral and Ophthalmic Drug Products (PODP) Leachables and Extractables Working Group was formed to extrapolate the OINDP threshold concepts and best practice recommendations to other dosage forms with high concern for interaction with packaging/delivery systems. This article considers the general aspects of leachables and their safety assessment, introduces the PODP Work Plan and initial study Protocol, discusses the laboratory studies being conducted by the PODP Chemistry Team, outlines the strategy being developed by the PODP Toxicology Team for the safety qualification of PODP leachables, and considers the issues associated with application of the safety thresholds, particularly with respect to large-volume parenterals. Lastly, the unique leachables issues associated with biologics are described., Lay Abstract: The Product Quality Research Institute (PQRI) is a non-profit consortium involving industry organizations, academia, and regulatory agencies that together provide recommendations in support of regulatory guidance to advance drug product quality. The collaborative activities of the PQRI Orally Inhaled and Nasal Drug Products Leachables and Extractables Working Group resulted in a systematic and science-based approach to identify and qualify leachables, including the concept of safety thresholds. Concepts from this widely accepted approach, formally publicized in 2006, are being extrapolated to parenteral and ophthalmic drug products. This article provides an overview of extractables and leachables in drug products and biologics and discusses the PQRI Work Plan and Protocols developed by the PQRI Parenteral and Ophthalmic Drug Products Leachables and Extractables Working Group.

In 2006, the Product Quality Research Institute's (PQRI) Leachables and Extractables Working Group released a comprehensive and detailed recommendation document related to leachables and extractables for inhalation drug products. The document includes best pharmaceutical development practice recommendations regarding container closure/delivery system component composition and selection, controlled extraction studies, drug product leachables studies, and routine extractables testing for component release. Also included in the document are two safety-based thresholds for leachables in inhalation drug products, the qualification threshold (QT) and the safety concern threshold (SCT), the first such safety-based thresholds for leachables in any drug product type. A process was described for converting the SCT into an analytically useful threshold for leachables/extractables characterization, the analytical evaluation threshold (AET), with consideration of individual drug product dosing parameters and container closure system component characteristics. This commentary presents the history and evolution of this recommendation document starting from the propellant changeover (chlorofluorocarbons to hydrofluorocarbons) in metered dose inhaler drug products, which helped prompt interest in inhalation drug product leachables, through the work process of the PQRI group. The overall positive acceptance of the PQRI recommendations is discussed, along with a brief summary of regulatory initiatives influenced by the recommendations. Also presented and discussed are certain key issues and questions that have arisen since the recommendation document was released. The extension and application of best practice recommendations to other high risk drug product types (e.g., large and small volume parenterals, ophthalmics), led by the PQRI Parenteral and Ophthalmic Drug Product Working Group, is introduced and considered., Lay Abstract: The recommendation document released by the Product Quality Research Institute's (PQRI) Leachables and Extractables Working Group in 2006 includes the first safety-based thresholds for leachables in any drug product type, along with comprehensive best practice recommendations for inhalation drug product pharmaceutical development related to extractables and leachables. The best practice recommendations encompass a number of important functional areas, including container closure/delivery system component composition and selection, controlled extraction studies, drug product leachables studies, and routine extractables testing for component release. This commentary presents the history and evolution of this recommendation document starting from the propellant changeover (chlorofluorocarbons to hydrofluorocarbons) in metered dose inhaler drug products, which helped prompt interest in inhalation drug product leachables, through the work process of the PQRI group. The overall positive acceptance of the PQRI recommendations is discussed, along with a brief summary of regulatory initiatives influenced by the recommendations. Also presented and discussed are certain key issues and questions that have arisen since the recommendation document was released. The extension and application of best practice recommendations to other drug product types (e.g., large- and small-volume parenterals, ophthalmics), led by the PQRI Parenteral and Ophthalmic Drug Product Working Group, is introduced and considered.

Polymeric and elastomeric materials are commonly encountered in medical devices and packaging systems used to manufacture, store, deliver, and/or administer drug products. Characterizing extractables from such materials is a necessary step in establishing their suitability for use in these applications. In this study, five individual materials representative of polymers and elastomers commonly used in packaging systems and devices were extracted under conditions and with solvents that are relevant to parenteral and ophthalmic drug products (PODPs). Extraction methods included elevated temperature sealed vessel extraction, sonication, refluxing, and Soxhlet extraction. Extraction solvents included a low-pH (pH = 2.5) salt mixture, a high-pH (pH = 9.5) phosphate buffer, a 1/1 isopropanol/water mixture, isopropanol, and hexane. The resulting extracts were chemically characterized via spectroscopic and chromatographic means to establish the metal/trace element and organic extractables profiles. Additionally, the test articles themselves were tested for volatile organic substances. The results of this testing established the extractables profiles of the test articles, which are reported herein. Trends in the extractables, and their estimated concentrations, as a function of the extraction and testing methodologies are considered in the context of the use of the test article in medical applications and with respect to establishing best demonstrated practices for extractables profiling of materials used in PODP-related packaging systems and devices., Lay Abstract: Plastic and rubber materials are commonly encountered in medical devices and packaging/delivery systems for drug products. Characterizing the extractables from these materials is an important part of determining that they are suitable for use. In this study, five materials representative of plastics and rubbers used in packaging and medical devices were extracted by several means, and the extracts were analytically characterized to establish each material's profile of extracted organic compounds and trace element/metals. This information was utilized to make generalizations about the appropriateness of the test methods and the appropriate use of the test materials.