Comparison of permitted daily exposure (PDE) values for active pharmaceutical ingredients (APIs) - Evidence of a robust approach.

Permitted Daily Exposure Limits (PDEs) are set for Active Pharmaceutical Ingredients (APIs) to control cross-contamination when manufacturing medicinal products in shared facilities. With the lack of official PDE lists for pharmaceuticals, PDEs have to be set by each company separately. Although general rules and guidelines for the setting of PDEs exist, inter-company variations in the setting of PDEs occur and are considered acceptable within a certain range. To evaluate the robustness of the PDE approach between different pharmaceutical companies, data on PDE setting of five marketed APIs (amlodipine, hydrochlorothiazide, metformin, morphine, and omeprazole) were collected and compared. Findings show that the variability between PDE values is within acceptable ranges (below 10-fold) for all compounds, with the highest difference for morphine due to different Point of Departures (PODs) and Adjustment Factors (AFs). Factors of PDE variability identified and further discussed are: (1) availability of data, (2) selection of POD, (3) assignment of AFs, (4) route-to-route extrapolation, and (5) expert judgement and differences in company policies. We conclude that the investigated PDE methods and calculations are robust and scientifically defensible. Additionally, we provide further recommendations to harmonize PDE calculation approaches across the pharmaceutical industry.

Deriving harmonised permitted daily exposures (PDEs) for paracetamol (acetaminophen) CAS #: 103-90-2.

In the pharmaceutical industry, cleaning criteria are required for multipurpose manufacturing facilities. These Health Based Exposure Limits (HBELs), also called permitted daily exposures (PDEs) values, are derived from toxicological and pharmacological evaluation of the active pharmaceutical ingredients (APIs). The purpose of this publication is to show an example of how authors from different companies evaluate a generic drug, paracetamol, and discuss different approaches and relevance of the nonclinical studies for deriving PDEs. PDE limits of 25 mg/day for the oral route, and 20 mg/day for the intravenous (i.v.) and inhalation (inhal.) routes, respectively, were established herein. However, it has been already recognised that there are acceptable differences in the PDE calculations, which may be based on data accessibility, company-specific science-policy decisions or expert judgments. These differences can cause up to a 3-fold lower or higher values. If unnecessarily high factors are applied, this would result in a very conservative PDE value and unneeded additional cleaning and higher manufacturing costs. The PDE values presented are considered to be protective against adverse and pharmacological effects observed in clinical trials and in this case, a very long postmarketing period of paracetamol.

What to consider for a good quality PDE document?

For the handling of active pharmaceutical ingredients (APIs) and production of medicinal products in shared facilities, the European Medicines Agency (EMA) has introduced the determination of permitted daily exposure (PDE) values to provide limits for cross-contamination. APIs have a desired pharmacological effect in the patient who intendedly uses a certain medicinal product. However, this effect is undesired in a patient that receives this API unintendedly as a cross-contamination of another medicinal product. In particular, for approved APIs for human use, a multitude of data is available on the pharmacological activity as well as adverse effects, which have to be taken into account in PDE setting. Thus, the setting of PDEs for APIs needs a structured scientific evaluation of all properties and identification of the most critical effect, which is the basis for PDE calculation. In this publication, we provide guidance on points for consideration when setting PDEs for APIs, or when evaluating the quality of documents describing the derivation of PDEs received, e.g. by third parties.

Applicability of surface sampling and calculation of surface limits for pharmaceutical drug substances for occupational health purposes.

Within the context of Occupational Hygiene (OH), surface sampling has been employed as a method to assess surface levels of Active Pharmaceutical Ingredients (APIs). There are potentially a number of reasons surface samples are collected including assessing potential health risks, housekeeping and cleaning effectiveness. There are no internationally accepted standards relating to collecting or interpreting surface samples for OH purposes. In the past, surface sampling results have been applied not only for estimating risks due to dermal contact, but also for other routes of exposure (e.g. inhalation, ingestion, etc). In this publication, we provide a decision tree to support the decision and value of performing surface sampling. For scenarios without conceivable skin exposure due to applied risk mitigation measures or for substances that do not penetrate the skin, surface sampling may not be needed. If the workers' health is determined to be at risk for systemic effects via skin, we propose to use the skin Permitted Daily Exposure (PDEskin), a safe skin dose independent of the exposure scenario that takes into consideration skin absorption properties of substances. For the purpose of OH monitoring, the likelihood of dermal exposure has to be understood before taking any samples, using both the PDEskin to calculate the surface limit and appropriate validated monitoring method for the surface.

Combined in situ quartz crystal microbalance with dissipation monitoring, indirect nanoplasmonic sensing, and vibrational sum frequency spectroscopic monitoring of alkanethiol-protected copper corrosion.

In this study, we have applied three techniques to simultaneously and in situ study the initial stage of corrosion of copper protected by a self-assembled monolayer of octadecanethiol (ODT). We combined quartz crystal microbalance with dissipation monitoring (QCM-D), indirect nanoplasmonic sensing (INPS), and vibrational sum frequency spectroscopy (VSFS) and obtained complementary information about mass uptake and optical and spectroscopic changes taking place during the initial corrosion phase. All three techniques are very sensitive to the formation of a corrosion film (thickness in the range 0-0.41 nm) under mildly corrosive conditions (dry air, <0.5% relative humidity). The three techniques yield information about the viscoelasticity of the corrosion film (QCM-D), the homogeneity of the corrosion reaction on the surface (INPS), and the stability of the ODT protection layer (VSFS). Furthermore, by also studying the corrosion process in humid air (ca. 70% relative humidity), we illustrate how the combination of these techniques can be used to differentiate between simultaneously occurring processes, such as water adsorption and corrosion product formation.

Localized and propagating plasmons in metal films with nanoholes.

The occurrence of plasmon resonances in thin (~20 nm) Al and Au films, perforated with nanoholes, was studied. In both metals, two plasmon resonances were observed: (i) A surface plasmon polariton mode associated with a maximum in extinction and (ii) a localized resonance in the nanohole associated with a minimum in extinction. By varying the diameter of the nanoholes, the scaling of the peak positions of the plasmon resonances was determined as a function of hole diameter. In the large nanohole limit, the plasmon peak positions depend only on the nanohole diameter being independent of the material. On the other hand, for small nanoholes the plasmon peak positions are material and size dependent. In contrast to Al films where the localized plasmons can be excited from the near-IR to the UV, no plasmon resonances were observed for Au at energies above the interband threshold (2.4 eV). The interaction between a distinct interband transition in Al at 1.5 eV and the localized plasmon resonance is considered in detail. We observe for the first time experimentally a noncrossing behavior of the interband transition and the localized plasmon resonance. The energy (size) dependence of surface plasmon peak width, being a measure for the decay/damping of the latter, is very different for the two metals. This can be explained by considering the different decay mechanisms active in the two metals. Apart from these basic plasmonics results, we test the potential of using the shifts of the plasmon resonances in perforated Al films to follow the atmospheric oxidation/corrosion kinetics of Al. The results are quantified by model calculations. The obtained kinetic law for the oxide growth is in good agreement with a previous XPS study on plain Al films. This suggests that the nanohole-induced plasmon resonances can be a sensitive and simple measure for Al corrosion and metal corrosion in general.

Diffraction from arrays of plasmonic nanoparticles with short-range lateral order.

We have measured the angular distribution of light scattered off 2D plasmonic Al nanoparticle ensembles. We created these samples with disk-like nanoparticles, 175 and 500 nm in diameter, respectively, using hole-mask colloidal lithography and electron beam lithography. The nanoparticle arrangements in the samples display the short-range order (but no long-range order) characteristic for an ensemble formed by random sequential adsorption. As a consequence of this, the ensemble scattering patterns can be quantitatively well described by combining the single-particle scattering pattern with a static structure factor that carries information about the diffraction effects caused by the short-range order of the ensemble. We also performed sensing experiments in which we monitored changes in the angle-resolved scattering intensity for a fixed wavelength as a function of the thickness of an ultrathin SiO(2) coating covering the Al nanoparticles. The data show that the angle and strength of the main diffraction peak vary linearly with SiO(2) coating thickness in the range 1.5-4.5 nm and suggest that measurements of the scattering profile could be a competitive alternative to traditional transmission measurements in terms of sensitivity.

LSPR study of the kinetics of the liquid-solid phase transition in Sn nanoparticles.

Using the localized surface plasmon resonance as a probe in solid and liquid Sn nanoparticles of 107 nm diameter and 52 nm height, we have studied their kinetics of melting and freezing at temperature ramps and, for the first time, at fixed temperatures. During temperature ramps, the kinetics exhibit distinct hysteresis. The melting occurs near the bulk melting point while the freezing is observed at much lower temperatures so that the undercooling interval is approximately 130 K. The time scale of the freezing kinetics measured at different fixed temperatures rapidly decreases as the latter are lowered. All these findings have been quantitatively described by assuming the nucleation to occur on the edges of nanoparticles and employing the classical nucleation theory with the corresponding modifications.

Localized surface plasmon resonances in aluminum nanodisks.

The plasmonic properties of arrays of supported Al nanodisks, fabricated by hole-mask colloidal lithography (HCL), are analyzed for the disk diameter range 61-492 nm at a constant disk height of 20 nm. Strong and well-defined (UV-vis-NIR) localized surface plasmon resonances are found and experimentally characterized with respect to spectral peak positions, peak widths, total cross sections, and radiative and nonradiative decay channels. Theoretically, the plasmon excitations are described by electrostatic spheroid theory. Very good qualitative and quantitative agreement between model and experiment is found for all these observables by assuming a nanoparticle embedded in a few nanometer thick homogeneous (native) aluminum oxide shell. Other addressed aspects are: (i) the role of the strong interband transition in Al metal, located at 1.5 eV, for the plasmonic excitations of Al nanoparticles, (ii) the role of the native oxide layer, and (iii) the possibility of using the plasmon excitation as an ultrasensitive, remote, real-time probe for studies of oxidation/corrosion kinetics in metal nanoparticle systems.