Identification and quantification of medical device extractables and leachables via non-target analysis (NTA); Analytical uncertainty.

Leachables are substances that are leached from a medical device during its clinical use and are important due to the patient health-related effects they may have. Thus, medical devices are profiled for leachables (and/or extractables as probable leachables) to assess their potential impact on patient health and safety. This profiling is accomplished by screening extracts or leachates of the medical device for released organic substances via non-targeted analysis (NTA) employing chromatographic methods coupled with mass spectrometric detection. Chromatographic mass spectral response factors (RFs) for extractables and leachables vary significantly from compound to compound, complicating the quantitation of these compounds and the application of assessment strategies such as the Analytical Evaluation Threshold (AET). The analytical uncertainty resulting from response factor variation can be expressed in terms of an uncertainty factor (UF), which estimates the magnitude of response factor variation. This manuscript discusses the concept and impact of analytical uncertainty and provides best practice recommendations for the calculation and use of the uncertainty factor, UF.

Accurate or Protective: What is the Goal of Non-targeted Extractables and Leachables Quantitation and Identification?

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 under-estimated. Considering this conclusion, means of making concentration estimates and proposed identities protective are discussed.

Standardization of Chromatographic Screening Methods for Organic Extractables and Leachables by Managing Outcomes.

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.

A Practical Derivation of the Uncertainty Factor Applied to Adjust the Extractables/Leachables Analytical Evaluation Threshold (AET) for Response Factor Variation.

The analytical evaluation threshold (AET) establishes which chromatographic peaks, produced during organic extractables/leachables (E&L) screening, require toxicological safety risk assessment because the peaks are associated with compounds of potentially unacceptable toxicity. Thus, the AET protects patient safety as its proper application ensures that all potentially unsafe E&L are necessarily assessed. Generally, application of the AET involves the presumption that all organic E&L have the same detector response factor, an assumption that is not valid for any of the detection methods commonly used in E&L screening. Thus, the AET's ability to be protective is compromised for poorly responding compounds, as they will appear to be below the AET when in fact they are not. This unacceptable outcome is addressed by adjusting the AET with an uncertainty factor (UF) whose value is dictated by the magnitude of response factor variation, with a larger variation resulting in a larger UF and a lower adjusted AET. Although the concept of the UF is straightforward, setting a generally accepted, scientifically valid, and practical value for the UF has been challenging. In this article, a database of relative response factors obtained for nearly 1200 E&L via the most commonly applied chromatographic screening methods (gas chromatography/mass spectrometry [GC/MS], liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization [LC/MS-APCI], and LC/MS with electrospray ionization [LC/MS-ESI]) is used to justify UFs for these methods, individually and as a combined practice, based on the practical principle of "the point of diminishing returns". Using this concept results in nearly 92% of the compounds in the database being properly flagged as above an AET adjusted with a UF = 3. Ninety-five percent (95%) coverage of the compounds can be achieved when a UF of 4 is applied to the combination of GC/MS and LC/MS methods or with other combinations of UF values applied to the various methods individually. Coverage is increased to 97% when a UF of 4 is individually applied to the GC/MS method and a UF of 10 is individually applied to the LC/MS methods. Furthermore, the available data suggest that application of both APCI and ESI ionization in LC/MS screening (as opposed to either method separately) provides the greatest coverage of E&L.

Is Retention Time and/or Structure Matching a Solution to the Challenge of Providing Quantitative Data When Screening for Extractables and Leachables by GC/MS?

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.

A Safety Risk-Based Extractables and/or Leachables Qualification Strategy for Packaged Drug Products.

During storage and distribution of a packaged drug product, chemical substances present in or on the packaging may leach into the drug product, potentially adversely affecting the drug product's key quality attributes, including safety. Thus, the packaging is profiled for extractables as potential leachables and/or the drug product is profiled for leachables over shelf life via the process of chemical characterization. In so doing, the packaging and the packaged drug product are qualified as being suited for their intended use. It is reasonable to propose that the extent of chemical characterization required to qualify the packaging and the packaged drug product depends on the risk that leached substances could adversely affect drug product quality; the higher the risk, the more extensive and rigorous the required qualification. Although regulatory guidance supports and advocates such a risk-based approach to chemical characterization, the existing guidance is founded on an overly simplified approach to risk assessment, leading to incongruous risk classifications for certain classes of drug products. Furthermore, the existing guidance no longer links risk to current requirements concerning the extent of chemical characterization necessary to secure regulatory approval of drug product applications. To address these circumstances, this manuscript proposes and justifies a risk classification process (risk evaluation matrix) for drug products and packaging and a risk-based approach to chemical characterization requirements, linking risk to the degree and rigor of the chemical characterization process and establishing chemical characterization requirements for individual risk classes.

The Implications of Chromatographically Screening Medical Products for Organic Leachables Down to the Analytical Evaluation Threshold Adjusted for Response Factor Variation.

A drug product is chromatographically screened for organic leachables, derived from the product's packaging system, as leachables might adversely impact the health of a patient to whom the drug product is administered. Similarly, medical device and packaging system extracts are chromatographically screened for organic extractables as probable leachables. To be protective of patient health, the screening methods must produce recognizable responses for all potentially unsafe substances. To be efficient, the screening methods should provide a means of differentiating between the responses linked to likely to be safe substances and to potentially unsafe substances. The analytical evaluation threshold (AET) was established as a means of differentiating chromatographic peaks, based on concentration, that are unlikely to be unsafe (and thus do not need safety assessment) and that are possibly unsafe (and thus require safety assessment). Thus, the AET manages the competing objectives of protection and efficiency. Although the AET is based on concentration, it is applied based on response. As no chromatographic detection method applied to extractables and leachables screening produces a uniform response to all potential analytes (thus, the magnitude of the response differs across analytes), the objectives of protection or efficiency can be compromised by false negatives and positives. To ensure protection at the expense of efficiency, the AET can be adjusted to address response variation. This article addresses the practical issue that the protectiveness of the AET is affected both by response factor bias and variation and thus correction for only variation is incomplete and ineffective. The article illustrates the proper adjustment of the AET for bias and variation.

Correcting the Analytical Evaluation Threshold (AET) and Reported Extractable's Concentrations for Analytical Response Factor Uncertainty Associated with Chromatographic Screening for Extractables/Leachables.

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.

Identification and Quantitation Classifications for Extractables and Leachables.

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.

Identifying and Mitigating Errors in Screening for Organic Extractables and Leachables: Part 2-Errors of Inexact Identification and Inaccurate Quantitation.

Patients can be exposed to leachables derived from pharmaceutical manufacturing systems, packages, and/or medical devices during a clinical therapy. These leachables can adversely decrease the therapy's effectiveness and/or adversely impact patient safety. Thus, extracts or drug products are chromatographically screened to discover, identify, and quantify organic extractables or leachables. Although screening methods have achieved a high degree of technical and practical sophistication, they are not without issues in terms of accomplishing these three functions. In this Part 2 of our three-part series, errors of inexact identification and inaccurate quantitation are addressed. An error of inexact identification occurs when a screening method fails to produce an analyte response that can be used to secure the analyte's identity. The error may be that the response contains insufficient information to interpret, in which case the analyte cannot be identified or that the interpretation of the response produces an incorrect identity. In either case, proper use of an internal extractables and leachables database can decrease the frequency of encountering unidentifiable analytes and increase the confidence that identities that are secured are correct. Cases of identification errors are provided, illustrating the use of multidimensional analysis to increase confidence in procured identities. An error of inaccurate quantitation occurs when an analyte's concentration is estimated by correlating the responses of the analyte and an internal standard and arises because of response differences between analytes and internal standards. The use of a database containing relative response factors or relative response functions to secure more accurate analyte quantities is discussed and demonstrated.

Identifying and Mitigating Errors in Screening for Organic Extractables and Leachables: Part 1-Introduction to Errors in Chromatographic Screening for Organic Extractables and Leachables and Discussion of the Errors of Omission.

Substances leached from materials used in pharmaceutical manufacturing systems, packages, and/or medical devices can be administered to a patient as part of a clinical therapy. These leachables can have an undesirable effect on the effectiveness of the therapy and/or patient safety. Thus, relevant samples such as material extracts or drug products are chromatographically screened for foreign organic impurities, where screening is the analytical process of discovering, identifying, and quantifying these unspecified foreign impurities. Although screening methods for organic extractables and leachables have achieved a high degree of technical and practical sophistication, they are not without issues with respect to their ability to accomplish the aforementioned three functions. In this first part of a series of three manuscripts, the process of screening is examined, limitations in screening are identified, and the concept of using an internally developed analytical database to identify, mitigate, or correct these errors is introduced. Furthermore, errors of omission are described, where an error of omission occurs when a screening method fails to produce a recognizable response to an analyte present in the test sample. The error may be that no response is produced ("falling through the cracks") or that a produced response is not recognizable ("failing to see the tree for the forest"). In either case, proper use of a robust internal extractables/leachables database can decrease the frequency with which errors of omission occur. Examples of omission errors, their causes, and their possible resolution are discussed.

Identifying and Mitigating Errors in Screening for Organic Extractables and Leachables: Part 3-Considering Errors of Implementation and the Use of a Database to Judge and Promote Good Science and Efficient Practices.

Substances leached from pharmaceutical manufacturing systems, packages, and/or medical devices can be administered to a patient during a clinical therapy and can adversely affect the therapy and/or patient safety. Thus, extracts or drug products are chromatographically screened to discover, identify, and quantify these unspecified foreign impurities. Although screening methods have achieved a high degree of technical and practical sophistication, they are not without issues in terms of accomplishing these three functions. In this third (and last) part of the series, errors of implementation are addressed. An error of implementation occurs when a capable method and/or a proper data processing procedure is implemented in such a way that the intrinsic capabilities of either the method or the processing procedure (or both) are compromised. System suitability assessment establishes that a method, as executed at the time of use, has been properly set up and implemented, thus revealing errors of implementation. System suitability data, captured in a database, can be processed to establish trends in system performance, where trends in declining performance can establish a system's useful operating lifetime, serve as an early warning of imminent system failure, and/or act as a trigger for system maintenance. Additionally, this manuscript considers how the existence, size, and use of a chromatographic database provides a measure of a testing laboratory's level of "good science". Lastly, the manuscript considers the database as an enabler of advances in information management and impact assessment.

Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: An Updated Literature Review.

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., SiO2 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.

How One Might Experimentally Determine if Container Closure Systems and Their Components and Materials of Construction Contribute Elemental Impurities To Packaged Pharmaceutical Drug Products.

The safety aspects of elemental impurities in finished drug products are a topic of considerable importance in the pharmaceutical community, and guidelines such as ICH Q3D and USP <232> and <233> have been published to provide directions on how to assess finished drug products with respect to such impurities. Although a drug product's packaging system has been identified as a potential source of elemental impurities, comparable guidelines have not been established for assessing packaging systems and their materials and components of construction with respect to their potential to contribute leached elements to packaged drug products. In this commentary, the author considers the critical questions associated with selecting materials and components of construction and qualifying components and packaging with respect to their potential to add elemental impurities to packaged products and suggests means for accomplishing this objective.LAY ABSTRACT: Elemental impurities in drug products can adversely affect the drug product's quality attributes. Regulatory guidelines that establish how to assess drug products for elemental impurities have been published. Although the drug product's packaging system has been identified as a potential source of elemental impurities, no guidelines have been published to specifically address packaging. In this commentary, the author considers the key issues associated with elemental impurities derived from packaging and suggests means for selecting and qualifying packaging on the basis of extractable elements.

Application of Arrhenius Kinetics to Acceleration of Controlled Extraction Studies.

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.

Extractables Screening of Polypropylene Resins Used in Pharmaceutical Packaging for Safety Hazards.

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.

Proper Accounting for Surface Area to Solution Volume Ratios in Exaggerated Extractions.

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 (kp/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 kp/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.

Simulated Leaching (Migration) Study for a Model Container-Closure System Applicable to Parenteral and Ophthalmic Drug Products.

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.

Development and Justification of a Risk Evaluation Matrix To Guide Chemical Testing Necessary To Select and Qualify Plastic Components Used in Production Systems for Pharmaceutical Products.

UNLABELLED: An accelerating trend in the pharmaceutical industry is the use of plastic components in systems used to produce an active pharmaceutical ingredient or a finished drug product. If the active pharmaceutical ingredient, the finished drug product, or any solution used to generate them (for example, a process stream such as media, buffers, eluents, and the like) is contacted by a plastic component at any time during the production process, substances leached from the component may accumulate in the active pharmaceutical ingredient or finished drug product, affecting its safety and/or efficacy. In this article the author develops and justifies a semi-quantitative risk evaluation matrix that is used to determine the amount and rigor of component testing necessary and appropriate to establish that the component is chemically suitable for its intended use. By considering key properties of the component, the contact medium, the contact conditions, and the active pharmaceutical ingredient's or finished drug product's clinical conditions of use, use of the risk evaluation matrix produces a risk score whose magnitude reflects the accumulated risk that the component will interact with the contact solution to such an extent that component-related extractables will accumulate in the active pharmaceutical ingredient or finished drug product as leachables at levels sufficiently high to adversely affect user safety. The magnitude of the risk score establishes the amount and rigor of the testing that is required to select and qualify the component, and such testing is broadly grouped into three categories: baseline assessment, general testing, and full testing (extractables profiling). LAY ABSTRACT: Production suites used to generate pharmaceuticals can include plastic components. It is possible that substances in the components could leach into manufacturing solutions and accumulate in the pharmaceutical product. In this article the author develops and justifies a semi-quantitative risk evaluation matrix that can be used to determine the amount and rigor of component testing that may be necessary and appropriate to establish that the component is suitable for its intended use. Use of the risk evaluation matrix allows a user of a component to determine the type and amount of testing that should be performed to establish the patient safety risk associated with using that component in order to manufacture an active pharmaceutical ingredient or a finished drug product.

Moving Forward towards Standardized Analytical Methods for Extractables and Leachables Profiling Studies.

This commentary considers the standardization of analytical methods used in extractables and leachables screening and proposes that method standardization is not the end goal but rather the necessary first step for enabling efficient, effective, robust, and consistent extractables and leachables profiling. Standardized methods are the platform upon which a knowledge set and a knowledge management process can be built, and it is the combination of the methods, the set, and the process that facilitates extractables and leachables profiling.