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Nanoparticles are already used in several consumer products including food, food packaging and cosmetics, and their detection and measurement in food represent a particularly difficult challenge. In order to fill the void in the official definition of what constitutes a nanomaterial, the European Commission published in October 2011 its recommendation on the definition of ‘nanomaterial’. This will have an impact in many different areas of legislation, such as the European Cosmetic Products Regulation, where the current definitions of nanomaterial will come under discussion regarding how they should be adapted in light of this new definition. This new definition calls for the measurement of the number-based particle size distribution in the 1–100 nm size range of all the primary particles present in the sample independently of whether they are in a free, unbound state or as part of an aggregate/agglomerate. This definition does present great technical challenges for those who must develop valid and compatible measuring methods. This review will give an overview of the current state of the art, focusing particularly on the suitability of the most used techniques for the size measurement of nanoparticles when addressing this new definition of nanomaterials. The problems to be overcome in measuring nanoparticles in food and consumer products will be illustrated with some practical examples. Finally, a possible way forward (based on the combination of different measuring techniques) for solving this challenging analytical problem is illustrated. [ABSTRACT FROM PUBLISHER]

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. [Display omitted] • Orthogonal or complementary measurements often recommended to reduce bias & uncertainty in nanopharmaceutical measurements • Definitions are lacking, thus the following are proposed and explained using using examples of nano-enabled drug products: • Orthogonal measurements: use different physical principles to measure the same property of the same sample • Orthogonal measurements aim to minimize method-specific biases and interferences of a measurement of a single attribute • Complementary measurements: corroborate each other to support the same decision [ABSTRACT FROM AUTHOR]

Abstract The particle size distribution (PSD) and the stability of nanoparticles enabled medicinal products (NEP) in complex biological environments are key attributes to assess their quality, safety and efficacy. Despite its low resolution, dynamic light scattering (DLS) is the most common sizing technique since the onset of NEP in pharmaceutical technologies. Considering the limitations of the existing sizing measurements and the challenges posed by complex NEPs both scientists and regulators encourage the combination of multiple orthogonal high-resolution approaches to shed light in the NEP sizing space (e.g. dynamic light scattering, electron microscopy, field flow fractionation coupled to online sizing detectors, centrifugal techniques, particle tracking analysis and tunable resistive pulse sensing). The pharmaceutical and biotechnology developers are now challenged to find their own pragmatic characterisation approaches, which should be fit for purpose and minimize costs at the same time, in a complicated landscape where only a few standards exist. In order to support the community, the European Nanomedicine Characterisation Laboratory (EUNCL) and the US National Cancer Institute Nanotechnology Characterization Laboratory (NCI-NCL) have jointly developed multiple standard operating procedures (SOPs) for NEP assessment, including the measurements of particle size distribution, and are offering wide access to their 'state of the art' characterisation platforms, in addition to making SOPs publicly available. This joint perspective article would like to present the NCI-NCL and EUNCL multi-step approach of incremental complexity to measure particle size distribution and size stability of NEPs, consisting of a quick preliminary step to assess sample integrity and stability by low resolution techniques (pre-screening), followed by the combination of complementary high resolution sizing measurements performed both in simple buffers and in complex biological media. Test cases are presented to demonstrate: i) the need for employing at least one high-resolution sizing technique, ii) the importance of selecting the correct sizing techniques for the purpose, and iii) the robustness of utilizing orthogonal sizing techniques to study the physical properties of complex NEP samples. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

The implementation of the proposal from the European Chemical Agency (ECHA) to restrict the use of nanoplastics (NP) and microplastics (MP) in consumer products will require reliable methods to perform size and mass-based concentration measurements. Analytical challenges arise at the nanometre to micrometre interface, e.g., 800 nm–10 µm, where techniques applicable at the nanometre scale reach their upper limit of applicability and approaches applicable at the micrometre scale must be pushed to their lower limits of detection. Herein, we compared the performances of nine analytical techniques by measuring the particle size distribution and mass-based concentration of polystyrene mixtures containing both nano and microparticles, with the educational aim to underline applicability and limitations of each technique. Light scattering-based measurements do not have the resolution to distinguish multiple populations in polydisperse samples. Nanoparticle tracking analysis (NTA), nano-flowcytometry (nFCM) and asymmetric flow field flow fractionation hyphenated with multiangle light scattering (AF4-MALS) cannot measure particles in the micrometre range. Static light scattering (SLS) is not able to accurately detect particles below 200 nm, and similarly to transmission electron microscopy (TEM) and flow cytometry (FCM), is not suitable for accurate mass-based concentration measurements. Alternatives for high-resolution sizing and concentration measurements in the size range between 60 nm and 5 µm are tunable resistive pulse sensing (TRPS) and centrifugal liquid sedimentation (CLS), that can bridge the gap between the nanometre and micrometre range. [ABSTRACT FROM AUTHOR]

• Multi-detector AF4 for characterization of nanomedicines is reviewed • The development of high quality Standard Operating Procedures is presented • The process for developing validated standard test methods is discussed • Multi-detector AF4 is a robust technique for measuring quality attributes Asymmetric-flow field-flow fractionation (AF4) has been recognized as an invaluable tool for the characterisation of particle size, polydispersity, drug loading and stability of nanopharmaceuticals. However, the application of robust and high quality standard operating procedures (SOPs) is critical for accurate measurements, especially as these complex drug nanoformulations are most often inherently polydisperse. In this review we describe a unique international collaboration that lead to the development of a robust SOP for the measurement of physical-chemical properties of nanopharmaceuticals by multi-detector AF4 (MD-AF4) involving two state of the art infrastructures in the field of nanomedicine, the European Union Nanomedicine Characterization Laboratory (EUNCL) and the National Cancer Institute-Nanotechnology Characterisation Laboratory (NCI-NCL). We present examples of how MD-AF4 has been used for the analysis of key quality attributes, such as particle size, shape, drug loading and stability of complex nanomedicine formulations. The results highlight that MD-AF4 is a very versatile analytical technique to obtain critical information on a material particle size distribution, polydispersity and qualitative information on drug loading. The ability to conduct analysis in complex physiological matrices is an additional very important advantage of MD-AF4 over many other analytical techniques used in the field for stability studies. Overall, the joint NCI-NCL/EUNCL experience demonstrates the ability to implement a powerful and highly complex analytical technique such as MD-AF4 to the demanding quality standards set by the regulatory authorities for the pre-clinical safety characterization of nanomedicines. [ABSTRACT FROM AUTHOR]