title: A compilation of safety impact information for extractables associated with materials used in pharmaceutical packaging, delivery, administration, and manufacturing systems.
abstract: 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.
  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.
authors.affiliation: Baxter Healthcare Corporation, Round Lake, IL dennis_jenke@baxter.com.
authors.forename: Dennis
authors.initials: D
authors.lastname: Jenke
authors.affiliation: Baxter Healthcare Corporation, Round Lake, IL.
authors.forename: Tage
authors.initials: T
authors.lastname: Carlson
mesh_terms: D000818:Animals; D003257:Consumer Product Safety; D004305:Dose-Response Relationship, Drug; D004340:Drug Contamination; D016503:Drug Delivery Systems; D004349:Drug Packaging; D004867:Equipment Design; D006801:Humans; D009152:Mutagenicity Tests; D019055:No-Observed-Adverse-Effect Level; D009930:Organic Chemicals / Q000009:adverse effects / Q000032:analysis*; D061214:Patient Safety; D004364:Pharmaceutical Preparations / Q000032:analysis*; D018570:Risk Assessment; D013678:Technology, Pharmaceutical / Q000295:instrumentation*; D013997:Time Factors
chemical_list: D009930:Organic Chemicals; D004364:Pharmaceutical Preparations
keywords: Extractables; Leachables; Risk index (RI); Safety assessment; Thresholds; Toxicological risk assessment