Dennis Jenke

Triad Scientific Solutions

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 sugg...

Drug products and medical devices can contain impurities, termed leachables, which could produce an adverse patient health effect during clinical use. To establish patient exposure to leachables, drug products, packaging or manufacturing system extracts are analytically screened for extractables or leachables. Similarly, medical device contact medi...

Once an extract or leachate has been generated, the sample must be analytically tested to establish its levels of extracted or leached substances. This chapter focuses on the largely chromatographic methods that are used for testing samples for organic compounds. Testing processes including screening, targeting, and targeted screening are discussed...

During manufacturing, process streams are chemically and physically altered to produce the finished drug product. Drug product production operations typically put the process stream into contact with polymeric manufacturing components such as filters, tubing, connectors, reactors, storage containers, and related items. During contact, chemicals may...

The generation of chemical characterization data is an unproductive process until the data is assessed for impact, either the impact of leachables on human health and safety or the impact of extractables on an item's manufacturability or quality. Toxicological (safety) risk assessment (TRA) is the process of establishing the likely safety impact of...

Medical devices contact the body, either directly or indirectly through a medium, during their clinical use. During use, chemicals present in the medical device can leach and be administered to the device's user, potentially adversely affecting user health and safety. The ISO 10993 series of standards establishes the biocompatibility qualification...

The process of chemical characterization, addressing extractables and leachables, is introduced in terms of purpose and process. Key terms are defined and key documents, such as regulatory guidelines, compendial monographs, and industry‐driven best demonstrated practices, are reviewed. The high‐level process of chemical characterization is establis...

Chemical characterization is a two‐step process, generating the article for testing (extract or drug product) followed by testing of the generated article. This chapter focuses on generating the article for testing. Considering extraction, the chapter delineates the types of extractions, provides examples of extraction processes, and considers the...

As chemical characterization matures as a science‐based and practical field of endeavor, one anticipates that practices and principles will evolve to take advantage of developing insights and principles and to address current deficiencies or inefficiencies in science and/or practice. In this chapter, the author provides his vision for the future of...

Packaged drug products and medical devices are commercialized through a long and complicated process of development, optimization, and registration. Effective and efficient product development and commercialization requires that extractables and leachables be addressed via a well‐planned, sequential process, pictorially represented by the Chemical...

Pharmaceutical drug products and medical devices are packaged to ensure their integrity and stability during post‐production shipping and storage prior to clinical use. As packaging directly or indirectly contacts the drug product or medical device during shipping and storage, the packaging and packaged item can interact via transfer of chemicals....

In addition to organic compounds, extractables and leachables can include elemental and inorganic substances. This chapter deals with the testing of samples for extracted elements and ionic extractables. The mandate for extractable elements testing is provided, considering both regulations and material composition and properties. Extraction paramet...

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...

Leachables in drug products or from medical devices could 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...

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...

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 leach...

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...

Elemental impurities in drug products arise from different sources and via a number of different means, including leaching of elemental entities (including 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...

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 no...

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 qu...

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...

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...

Pharmaceutical drug products are packaged in containers so that they can be manufactured, distributed and stored. During these events in a drug product's lifecycle, the drug product and it's packaging could interact, resulting in substances leaching from the plastic and accumulating in the drug product. As the leached substances could adversely imp...

The safety aspects of elemental impurities in finished drug products is 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 syste...

Pharmaceutical drug products (DP) can contain foreign impurities due to contact with manufacturing, storage, distribution and administration systems. These foreign impurities (leachables) are leached from these systems by the drug product and can be linked to extractables measured in the systems during laboratory investigations. Assessing the impac...

The intent of this Stimuli article is to provide the rationale for the proposed changes to USP Elastomeric Closures for Injections (381) and a summary of the proposed revisions. The current chapter was revised in 2009 to align with European Pharmacopoeia 3.2.9 Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders and for F...

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 li...

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 extr...

A simulating leaching (migration) study was performed on a model container-closure system relevant to parenteral and ophthalmic drug products (PODP). 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...

Organic extractables and leachables (E&L) from drug product packaging, manufacturing components, and delivery devices are of concern as they could impact product quality and/or user safety. Proper E&L assessment involves chromatographic profiling of a drug product or extraction solvent, including liquid chromatography with UV absorption and mass sp...

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 det...

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...

Unlabelled: Ethanol/water mixtures are frequently used as simulating solvents in extractables studies. However, the basis for determining and justifying the right ethanol proportion in a simulating solvent for a particular drug product or solution has not been previously established.A solvent strength model has been developed in this study, based...

Lay abstract: Extraneous impurities in drug products provide no therapeutic benefit and thus should be known and controlled. Elemental impurities can arise from a number of sources and by a number of means, including the leaching of elemental entities from drug product packaging and manufacturing systems. To understand the extent to which material...

One source of elemental impurities in drug products is substances leached from the product’s packaging system. The maximum amount of elemental entities that can be leached into a packaged drug product is the total pool of the elemental entity in the packaging system; the actual amount that is leached is established by testing the packaged drug pr...

The effective management of leachables in pharmaceutical products is a critical aspect of their development. This can be facilitated if extractables information on the materials used in a packaging or delivery system is available to assist companies in selecting materials that will be compatible with the drug product formulation and suitable for th...

Purpose: To develop and justify a Risk Evaluation Matrix for estimating the safety risk associated with extractables from plastic materials used in pharmaceutical applications and to apply that matrix to approximately 510 extractables to assess the risk that they would accumulate in drug products at levels sufficiently high to affect patient safet...

Unlabelled: 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...

The release of extractables from multi-layered plastic films such as those used in containers for liquid drug products has been investigated. Targeted extractables were chosen from the film's extractable profile, as elucidated by a controlled extraction study. The total available pool of targeted extractables was ascertained via exhaustive sequenti...

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 i...

Unlabelled: 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...

Leachables present in packaged drug products may affect the safety and quality of such products. The process by which leachables compounds are discovered, identified and quantified in a finished drug product, termed chemical assessment, consists of a series of actions which include characterizing a system's materials of construction for their ingre...

Unlabelled: 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 (O...

Unlabelled: 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 m...

Unlabelled: Nearly 100 individual test articles, representative of materials used in pharmaceutical applications such as packaging and devices, were extracted under exaggerated conditions and the levels of 32 metals and trace elements (Ag, Al, As, B, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Ge, Li, Mg, Mn, Mo, Na, Ni, P, Pb, S, Sb, Se, Si, Sn, Sr, Ti,...

Unlabelled: The general compatibility between various polymers (plastic and elastomeric materials) commonly used in medical devices (e.g., syringes) and common solution-based pharmaceutical products was examined. Processes affecting material/solution compatibility that were considered included drug binding and material leaching. Considering bindin...

Substances from packaging systems that are leached into packaged medical products may have a safety impact on patients to whom such medical products are administered. The potential safety impact depends on the identity and concentration of the leached substances. The concentration above which a leachable must be identified in order to assess its sa...

Organic extractables (substances extracted from materials used in pharmaceutical packaging) are discovered, identified, and quantified via screening of extracts with analytical methods including liquid chromatography with mass spectrometric detection (LC-MS). Because extractables include a large number of diverse compounds that are typically presen...

Unlabelled: During the course of their manufacturing, storage, and administration, pharmaceutical drug products come in contact with materials, components, and systems. Such contact may result in an interaction between the drug product and these entities. One such interaction is the migration of substances from these entities and into the drug pro...

Introduction An Overview of the Issue of Suitability for Intended Use Additive Interactions Utilization of Rubber and Plastic Materials in Pharmaceutical Systems: Opportunities And Issues References

Introduction and Overview Extract Generation Analysis of Extract Interpretation of the CES “Special Case” Compounds Summary of Recommended Best Practices for CESS Conclusions References

Unlabelled: An emerging trend in the biotechnology industry is the utilization of plastic components in manufacturing systems for the production of an active pharmaceutical ingredient (API) or a finished drug product (FDP). If the API, the FDP, or any solution used to generate them (for example, process streams such as media, buffers, and the like...

Ion chromatography (IC) has developed and matured into an important analytical methodology in a number of diverse applications and industries, including pharmaceuticals. This manuscript provides a review of IC applications for the determinations of active and inactive ingredients, excipients, degradation products, and impurities relevant to pharmac...

Polymers utilized in medical or pharmaceutical applications (e.g., manufacturing, packaging, delivery systems, and devices) contain additives and impurities due to their formulation and/or processing. Under conditions of use, these ingredients and other extractables may leach from the polymers and accumulate in pharmaceutical products. In order to...

Unlabelled: The accumulation of organic compounds associated with plastic materials into pharmaceutical products and their associated solutions has important suitability for use consequences for those pharmaceutical solutions, most notably in terms of safety and efficacy. The interaction between the pharmaceutical solution and the plastic material...

Unlabelled: The concept of quality by design (QbD) reflects the current global regulatory thinking related to pharmaceutical products. A cornerstone of the QbD paradigm is the concept of a design space, where the design space is a multidimensional combination of input variables and process parameters that have been demonstrated to provide the assu...

Plastic materials are widely used in medical items such as solution containers, infusion sets, transfer tubing, devices, processing equipment and systems, filters, and the like. Components in medical items can leach out of such items when they are contacted by a therapeutic product or product-related solution. Stearic acid and stearate salts are co...

Tinuvin 770 is a light stabilizer present in numerous polymers utilized in medical or pharmaceutical applications (e.g., manufacturing, packaging, delivery systems and devices). Under conditions of use, Tinuvin 770 and its related substances may leach from the polymers and accumulate in pharmaceutical products that are administered to subjects to p...

The organic extractables profile of a synthetic polyisoprene material being considered for use as a closure on a bag-type packaging system has been delineated. The predominant organic extractables associated with the test material were bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate (Tinuvin 770), several Tinuvin-related substances, fatty acids, and...

Material/water equilibrium binding constants (E(b)) were determined for 11 organic solutes and 2 plastic materials commonly used in pharmaceutical product containers (plasticized polyvinyl chloride and polyolefin). In general, solute binding by the plasticized polyvinyl chloride material was greater, by nearly an order of magnitude, than the bindin...

Material/water equilibrium binding constants (Eb) were determined for 14 organic solutes and 17 plastic raw materials that could be used in pharmaceutical product container systems. Correlations between the measured binding constants and the organic solute's octanol/water and hexane/water partition coefficients were obtained. In general, while the...

This paper deals with validation of chromatographic methods for quantitation of leachables and extractables in pharmaceutical solutions. Guidelines are presented for designing, implementing, and interpreting validations.

The term “leachables” refers to impurities in pharmaceutical products whose origin is the pharmaceutical container closure system in either direct or indirect contact with the formulation. Potential leachables identified through laboratory studies of pharmaceutical container closure system components are referred to as “extractables.” Extractables...

General: The Migration StudyDesign of the Migration StudyInterpretation of the Migration Study: Toxicological AssessmentDisaster ManagementSpecificity Check in Drug Product Analysis Methods Product Stability Issues Associated with LeachablesReferences

GeneralDiscussion of the Components of the Master Flow DiagramObservationsApplication of the Process Map

Half TitleTitleCopyrightDedicationContentsPreface

The use of prefilled syringes is a growing trend in the pharmaceutical industry.The nature of their application and their mode of use mean that prefilled syringes meet the regulatory definitions of immediate packaging or container-closure systems. Therefore, they fall under the suitability-for-use requirements for such systems. The author discusses...

A review is provided on the general topic of the compatibility of plastic materials with pharmaceutical products, with specific emphasis on the safety aspects associated with extractables and leachables related to such plastic materials.

A chromatographic method for the quantitation of organic compounds leached from a plastic solution container and its associated secondary packaging is described and its validation is enumerated.

Plastic materials are widely used in medical items, such as solution containers, transfusion sets, transfer tubing, and devices. An emerging trend in the biotechnology industry is the utilization of plastic containers to prepare, transport, and store an assortment of solutions including buffers, media, and in-process and finished product. The direc...

The performance of an ion chromatographic method for measuring citrate and phosphate in pharmaceutical solutions is evaluated. Performance characteristics examined include accuracy, precision, specificity, response linearity, robustness, and the ability to meet system suitability criteria. In general, the method is found to be robust within reasona...

Leaching of plastic materials, packaging, or containment systems by finished drug products and/or their related solutions can happen when contact occurs between such materials, systems, and products. While the drug product vendor has the regulatory/legal responsibility to demonstrate that such leaching does not affect the safety, efficacy, and/or c...

While the ability of packaging systems to contribute leached substances to finished drug products is well established, increasing interest is being focused on the potential contamination of drug substances by plastic materials encountered during their production. The direct contact of such plastic parts (such as tubing, gaskets, filters and tempora...

This is an updated review related to the identification and/or accumulation of organic and inorganic extractable substances from di(2-ethylhexyl) phthalate (DEHP)-plasticized polyvinyl chloride (PVC), polyolefin, and various other plastic materials. The review considers the identification of such extractables, their reported levels in material extr...

Material/water equilibrium interaction constants (E(b)) were determined for 12 organic model solutes and a plastic material used in pharmaceutical product containers (non-PVC polyolefin). An excellent correlation was obtained between the measured interaction constants and the organic solute's octanol/water partition coefficient. The effect of solve...

Distribution coefficient (Ks) and diffusivity [diffusion coefficient (D)] values for 19 nonvolatile solutes were previously reported for three ethylene–vinyl acetate (EVA) copolymers. In this article, the interaction properties of these solutes are compared with their octanol/water partition coefficient (Po/w) values. Adequate linear log/log correl...

A multi-layered, laminated plastic material, similar to those used in flexible intravenous solution containers, was loaded to contain known amounts of 15 model compounds whose partitioning behaviors were previously established. The loaded material was extracted with eight different extracting solutions including water (ambient pH); pH 3, 4, 5, and...

Container/closure systems are extensively characterized in terms of their propensity to contribute leachable substances to the drug products they contain. Such a characterization is relevant until a change occurs in the composition or production of the container/closure system itself or the raw materials it is comprised of. When such a change occur...

Establishing a link between extractables and leachables may be necessary to understand, interpret, assess, quantify, or control the interaction between a drug product and its container/closure system. This paper considers the various factors that affect the rigor with which such a linkage is established and justified. Such an assessment considers t...

Plastic materials are widely used in medical items, such as solution containers, transfusion sets, transfer tubing and devices. An emerging trend in the biotechnology industry is the utilization of large plastic containers to prepare, transport and store an assortment of solutions including buffers, media and in-process and finished products. The d...

Cyclic oligomers of caprolactam were isolated from a multilayered polyolefin plastic film containing a nylon-6 layer and subsequently characterized. Nylon-6 was extracted with aqueous solutions and the levels of the oligomers were measured in the resulting extracts. Oligomers up to n = 5 were present at high and comparable levels in all the nylon-6...

Chromatographic methods for the identification of organic compounds leached from a plastic material used in solution containers in the pharmaceutical industry are described. Based on a set of compounds identified in extracts of a multilayered polyolefin film, targeted leachables are delineated for accumulation assessments, and methods to perform ta...

The leaching of several target organic acids from an irradiated ethylene vinyl acetate material, such as those used as a solution product container, is examined as a function of solution pH and polarity. The targeted compounds included highly soluble weak acids such as acetic and formic acids, and larger, more lipophillic acids such as myristic, pa...

Since its introduction in 1975, ion chromatography (IC) has developed and matured into an important analytical methodology in a number of diverse applications and industries. This article briefly describes IC principles and instruments and also provides a review of IC applications developed and validated for the determination of active and inactive...

Triton X-100 (octoxynol 9) is a commercially available surfactant used as a solvent detergent in numerous pharmaceutical applications including virus inactivation. A byproduct formed during its synthesis is 1,4-dioxane, the cyclic dimer of ethylene oxide and a possible carcinogen to humans. The United States Pharmacopoeia (USP) contains a labor-int...

In this paper, methods for identification and quantitation of organic polymer additives are presented. Information is given in convenient tabular form and detailed references are provided. Reprinted from the Encyclopedia of Chromatography, Jack Cazes, Ed., Marcel Dekker, Inc. (© 2003); URL: http://www.dekker.com./servlet/product/productid/E‐ECHR

A review is provided, related to the chromatographic methods used to assess the accumulation of leachable substances from packaging materials used for pharmaceutical products. The review considers methods used to identify and/or quantify such leachables in actual products or product simulating solvent systems. Reprinted from the Encyclopedia of Chr...

The interaction of model compounds with a polyolefin plastic material was examined in binary mixtures of ethanol/water to assess the impact of the solvent polarity on the magnitude of the interaction. The interactions investigated included both compound sorption from the solution by the plastic material and leaching of plastic components into the s...

Delivery systems are used to store, contain, and/or administer liquid pharmaceutical products. Gaining an understanding of the chemical composition of such a delivery system is necessary with respect to effective system development, registration, and production. Additionally, the ability of the delivery system to impact the chemical composition of...