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.

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

Elemental impurities in drug products can arise from a number of different sources and via a number of different means, including the active pharmaceutical ingredient, excipients, the vehicle, and leaching of elemental entities that are present in the drug product's manufacturing or packaging systems. Thus, knowledge about the presence, level, and likelihood of leaching of elemental entities 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, a joint team from the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) has conducted a review of the available literature on elemental entities in pharmaceutically relevant polymers and the presence of these elemental entities in material extracts and/or drug products. This review article contains the information compiled from the available body of literature 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? Conclusions drawn from the compiled data are as follows: (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 elemental entities during their production. (2) Unless the elemental entities are parts of the materials themselves (for example, SiO2 in glass) or intentionally added to the materials (for example, metal stearates in polymers), their incidental amounts in the materials are generally low. (3) When elemental entities are present in materials and systems, generally only a very small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products. Thus, while sources of certain elemental impurities may be ubiquitous in the natural environment, they are not ubiquitous in materials used in pharmaceutical packaging and manufacturing systems and when they are present, they are not extensively leached under relevant conditions. The information summarized here can be utilized to aid the elemental impurity risk assessment process by providing the identities of commonly reported elements and data to support probability estimates of those becoming elemental impurities in the drug product. Furthermore, recommendations are made related to establishing elements of potential product impact for individual materials. 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 materials used in packaging systems contain elemental entities and the extent to which those entities leach into drug products to become elemental impurities, the Extractables and Leachables Safety Information Exchange (ELSIE) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) Consortia have jointly performed a literature review on this subject. Using the compiled information, it was concluded that while packaging materials may contain elemental entities, unless those entities are intentional parts of the materials, the amounts of those elemental entities are generally low. Furthermore, generally only a very small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products. Thus, risk assessment of sources of elemental impurities in drug products that may be related to materials used in pharmaceutical packaging and manufacturing systems can utilize the information and recommendations presented here.

Extractables and leachables considerations for prefilled syringes.

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.

Accumulation of organic compounds leached from plastic materials used in biopharmaceutical process containers.

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 direct contact of such containers with the product at one or more points in its lifetime raises the possibility that container leachables may accumulate in the finished product. The interaction between several commercially available container materials and numerous model test solutions (representative of buffers and media used in biopharmaceutical applications) was investigated. This paper summarizes the identification of leachables associated with the container materials and documents the levels to which targeted leachables accumulate in the test solutions under defined storage conditions.

Extractables/leachables from plastic tubing used in product manufacturing.

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 temporary storage containers) with the drug substance at some point in its production raises the possibility that plastic-related contaminants (leachables) may be present in the finished drug product. In this study, eight tubing materials potentially encountered in pharmaceutical production facilities, including six silicone materials and two Santoprene materials, were characterized for their extractable substances by static extraction coupled with comprehensive chemical characterization of the resulting extracts. Based on the extractables profiles thus generated, target leachables were identified for each tubing material. The accumulation of these target leachables was studied by subjecting the tubing to dynamic flow, simulated use extractions. The primary organic extractables from the silicone tubing were a homologous series of silicone oligomers, with most of the tubings demonstrating a unique distribution of oligomers. Several of the silicone tubings also possessed extractable dioctyl phthalate and dioctyl adipate. The primary organic extractables from the Santoprene-type tubing included a number of phthalates, a series of alkyl phenols and decomposition products of Irganox-type antioxidants. Inorganic extractables associated with many of the tubings included Ca, Mg, Zn and B. In general, the levels of targeted leachables extracted from the tubing materials under simulated use (flow) conditions was much smaller than the total amount of these leachables in the tubing.

Linking extractables and leachables in container/closure applications.

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 the origin and/or genesis of the leachable or extractable, enumerates situations in which extractables/leachables linkages are useful, ties such situations to the drug product's lifecycle, defines a hierarchy of linkages based on the rigor with which the linkages are established and justified, and establishes guidelines for how to determine what kind of linkage is appropriate for certain circumstances and situations. Additionally, this paper gives several examples of linkages relevant to flexible plastic drug product containers.

Accumulation of extractables in buffer solutions from a polyolefin plastic container.

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 direct contact of such containers with the product at one or more points in its lifetime raises the possibility that container extractables may end up in the finished product. The interaction between a polyolefin container material and several test solutions representative of buffers and media used in biopharmaceutical applications was investigated. This manuscript summarizes the identification of the major extractables associated with the polyolefin container and documents the levels to which targeted extractables accumulate in the test solutions under several storage regimes.

Nomenclature associated with chemical characterization of and compatibility evaluations for medical product delivery systems.

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 the contacted product may define the safety and/or efficacy of the product. Assessing the compatibility of the delivery system and the product is thus both necessary and desirable. The nomenclature associated with compatibility assessments has not been standardized, oftimes leading to conflicting or confusing information. This manuscript puts forth a nomenclature which classifies those chemical entities which participate in the system/product interaction and delineates the various extraction strategies which may be used in compatibility assessments.