Orthogonal and complementary measurements of properties of drug products containing nanomaterials

Quality control of pharmaceutical and biopharmaceutical products, and verification of their safety and efficacy, depends on reliable measurements of critical quality attributes (CQAs). The task becomes particularly challenging for drug products and vaccines containing nanomaterials, where multiple complex CQAs must be identified and monitored. To reduce (i) the risk of measurement bias and (ii) the uncertainty in decision-making during product development, the combination of orthogonal and complementary analytical techniques are generally recommended by regulators. However, despite frequent reference to “orthogonal” and “complementary” in guidance documents, neither term is clearly defined. How does one determine if two analytical methods are orthogonal or complementary to one another? Definitions are needed to design a robust characterization strategy aligned to regulatory needs. Definitions for “orthogonal” and “complementary” are proposed that are compatible with existing metrological terminology and are applicable to complex measurement problems. Orthogonal methods target the quantitative evaluation of the true value of a product attribute to address unknown bias or interference. Complementary measurements include a broader scope of methods that reinforce each other to support a common decision. Examples of the application of these terms are presented, with a focus on measurement of physical properties of nano-enabled drug products, including liposomes and polymeric nanoparticles for cancer treatment, lipid-based nanoparticles (LNPs) and virus-like particles for nucleic acid delivery. The proposed framework represents a first step in advancing the assessment of the orthogonality and complementarity of two measurements and it can potentially serve as the basis for a future international standard. This framework may help product developers to implement more efficient product characterization strategies, accelerate the introduction of novel medicines to the clinic and be applicable to other therapeutics beyond nanomaterial-containing pharmaceuticals.publishedVersio

Microscopic investigation of single-wall carbon nanotube uptake by Daphnia magna

The objectives of this study were to determine the extent of absorption of functionalized single-wall carbon nanotubes (SWCNTs) across the gut epithelial cells in Daphnia magna. Several microscopic techniques were utilized, including micro-Raman spectroscopy, high-resolution transmission electron microscopy (HRTEM) and selective area diffraction (SAD). In an effort to examine the variation in uptake due to surface properties, four groups of differently functionalized SWCNTs were used: hydroxylated (OH-SWCNTs), silicon dioxide (SiO₂-SWCNTs), poly aminobenzenesulfonic acid (PABS-SWCNTs) and polyethylene glycol (PEG-SWCNTs). Raman spectroscopy was able to detect OH-SWCNTs within the gut, but lacked the spatial resolution that is needed to identify lower concentrations of SWCNTs that may have been absorbed by body tissues. Initially, low-magnification imaging of exposed D. magna sections in the TEM revealed several features, which suggested absorption of SWCNTs. However, subsequent analysis with additional techniques (HRTEM, X-ray energy-dispersive spectroscopy and SAD) indicated that these features were either artifacts produced via the specimen staining process or consisted of non-graphitic, organic structures. This latter observation emphasizes the inherent difficulty in resolving SWCNTs embedded within a complex, organic matrix, as well as the care with which imaging results must be interpreted and supplemented with other, more analytical techniques.Keywords: Nanomaterials, Electron microscopy, Absorptio

Adapting oecd aquatic toxicity tests for use with manufactured nanomaterials: key issues and consensus recommendations

The unique or enhanced properties of manufactured nanomaterials (MNs) suggest that their use in nanoenabled products will continue to increase. This will result in increased potential for human and environmental exposure to MNs during manufacturing, use, and disposal of nanoenabled products. Scientifically based risk assessment for MNs necessitates the development of reproducible, standardized hazard testing methods such as those provided by the Organisation of Economic Cooperation and Development (OECD). Currently, there is no comprehensive guidance on how best to address testing issues specific to MN particulate, fibrous, or colloidal properties. This paper summarizes the findings from an expert workshop convened to develop a guidance document that addresses the difficulties encountered when testing MNs using OECD aquatic and sediment test guidelines. Critical components were identified by workshop participants that require specific guidance for MN testing: preparation of dispersions, dose metrics, the importance and challenges associated with maintaining and monitoring exposure levels, and the need for reliable methods to quantify MNs in complex media. To facilitate a scientific advance in the consistency of nanoecotoxicology test results, we identify and discuss critical considerations where expert consensus recommendations were and were not achieved and provide specific research recommendations to resolve issues for which consensus was not reached. This process will enable the development of prescriptive testing guidance for MNs. Critically, we highlight the need to quantify and properly interpret and express exposure during the bioassays used to determine hazard values

Current ecotoxicity testing needs among selected U.S. federal agencies

U.S. regulatory and research agencies use ecotoxicity test data to assess the hazards associated with substances that may be released into the environment, including but not limited to industrial chemicals, pharmaceuticals, pesticides, food additives, and color additives. These data are used to conduct hazard assessments and evaluate potential risks to aquatic life (e.g., invertebrates, fish), birds, wildlife species, or the environment. To identify opportunities for regulatory uses of non-animal replacements for ecotoxicity tests, the needs and uses for data from tests utilizing animals must first be clarified. Accordingly, the objective of this review was to identify the ecotoxicity test data relied upon by U.S. federal agencies. The standards, test guidelines, guidance documents, and/or endpoints that are used to address each of the agencies’ regulatory and research needs regarding ecotoxicity testing are described in the context of their application to decision-making. Testing and information use, needs, and/or requirements relevant to the regulatory or programmatic mandates of the agencies taking part in the Interagency Coordinating Committee on the Validation of Alternative Methods Ecotoxicology Workgroup are captured. This information will be useful for coordinating efforts to develop and implement alternative test methods to reduce, refine, or replace animal use in chemical safety evaluations