A Retrospective Evaluation of the Use of Mass Spectrometry in FDA Biologics License Applications

The characterization sections of biologics license applications (BLAs) approved by the United States Food and Drug Administration (FDA) between 2000 and 2015 were investigated to examine the extent of the use of mass spectrometry. Mass spectrometry was found to be integral to the characterization of these biotherapeutics. Of the 80 electronically submitted monoclonal antibody and protein biotherapeutic BLAs included in this study, 79 were found to use mass spectrometric workflows for protein or impurity characterization. To further examine how MS is being used in successful BLAs, the applications were filtered based on the type and number of quality attributes characterized, the mass spectrometric workflows used (peptide mapping, intact mass analysis, and cleaved glycan analysis), the methods used to introduce the proteins into the gas phase (ESI, MALDI, or LC-ESI), and the specific types of instrumentation used. Analyses were conducted over a time course based on the FDA BLA approval to determine if any trends in utilization could be observed over time. Additionally, the different classes of protein-based biotherapeutics among the approved BLAs were clustered to determine if any trends could be attributed to the specific type of biotherapeutic.

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Building the pyramids: perfect bubble crystals

Abstract

The use of appropriate flat-sided pyramidal containers to grow ordered foams allows single crystals to be formed. In the case of face-centred cubic crystals, these have been prepared with up to 500 bubbles. Strained and deliberately defective crystals can also be grown. The growth of simple cubic and body-centred cubic crystals is limited by instability; preliminary results are presented for these, as well as ordered bidisperse foams.     

A cryogenic beam of refractory, chemically reactive molecules with expansion cooling

Cryogenically cooled buffer gas beam sources of the molecule thorium monoxide (ThO) are optimized and characterized. Both helium and neon buffer gas sources are shown to produce ThO beams with high flux, low divergence, low forward velocity, and cold internal temperature for a variety of stagnation densities and nozzle diameters. The beam operates with a buffer gas stagnation density of ～10(15)-10(16) cm(-3) (Reynolds number ～1-100), resulting in expansion cooling of the internal temperature of the ThO to as low as 2 K. For the neon (helium) based source, this represents cooling by a factor of about 10 (2) from the initial nozzle temperature of about 20 K (4 K). These sources deliver ～10(11) ThO molecules in a single quantum state within a 1-3 ms long pulse at 10 Hz repetition rate. Under conditions optimized for a future precision spectroscopy application [A. C. Vutha et al., J. Phys. B: At., Mol. Opt. Phys., 2010, 43, 074007], the neon-based beam has the following characteristics: forward velocity of 170 m s(-1), internal temperature of 3.4 K, and brightness of 3 × 10(11) ground state molecules per steradian per pulse. Compared to typical supersonic sources, the relatively low stagnation density of this source and the fact that the cooling mechanism relies only on collisions with an inert buffer gas make it widely applicable to many atomic and molecular species, including those which are chemically reactive, such as ThO.     

“Schizomorphic” Emulsion Copolymerization Particles

Cryo‐electron microscopy, atomic force microscopy, and light microscopy investigations provide experimental evidence that amphiphilic emulsion copolymerization particles change their morphology in dependence on concentration. The shape of the particles is spherical at solids content above 1%, but it changes to rod‐like, ring‐like, and web‐like structures at lower concentrations. In addition, the shape and morphology of these particles at low concentrations are not fixed but very flexible and vary with time between spheres, flexible pearl–necklace structures, and stretched rods.     

Properties of irradiated PVC plasticized with non-endocrine disruptor

Polyvinylchloride (PVC) is under heavy attack from environmentalist groups due to the use of plasticizers and its recycling difficulties. Chloro-organics and phtalates are considered now as ubiquitous global contaminants due to their potential as weak endocrine disruptor and huge consumption. In order to make PVC acceptable for the irradiation processing industry in the long term, non-toxic plasticizers should be used. PVC was added with dioctyl phtalate (DOP) and epoxy soybean oil (ESO) and irradiated up to 50 kGy. Mechanical properties, optical properties and viscosity were measured and compared. The elongation and mechanical strength were under the usual range and they didn’t show any significant change in the studied range of irradiation dose. All the samples showed a weak yellowing effect after irradiation and the molecular weight measured by viscosimetry showed only negligible changes. In conclusion, DOP and ESO were shown to be effective in stabilizing the radiolytic abstraction of HCl from PVC. Both plasticizers imparted good color stability and overall properties to the products.     

An asymmetric approach to filters in strict extensions and quotients

Filters are a fundamental tool in the study of convergence and completeness in topology. On the other hand, downsets have been used extensively for this purpose in the setting of pointfree topology. This paper investigates links between these in the asymmetric context, that is, for biframes and bispaces. We present an appropriate kind of filter for the asymmetric setting, which we call a bifilter. These form a bispace, functorially so, which proves isomorphic to the spectrum of the downset biframe. As a corollary, downset biframes are seen to be isomorphic to the opens of the bifilter bispace. Both these correspondences are natural isomorphisms. The join map from a downset biframe to its underlying biframe appears here as a universal strict quotient. We use it to show that the embedding of any T ₀ bispace in its bifilter bispace is a universal strict extension. Banaschewski and Hong [10] have established the importance of general filters for convergence and completeness in the pointfree setting. We conclude this paper with a discussion of an appropriate concept of general bifilter, and show that the right adjoint of the join map mentioned above is a universal general bifilter.     

Drainage induced convection rolls in foams

When liquid is added to a foam at sufficiently large flow rates, convective bubble motion will occur. Experiments are described in which the foam is confined in a tube which is tilted from the vertical. The theory of foam drainage is applied to this problem to show that the critical angle of tilt θ_c at which convection occurs is related to the liquid flow-rate Q by θ_c ∝Q^-3/4.     

Shear localisation with 2D viscous froth and its relation to the continuum model

Simulations of monodisperse and polydisperse (μ ₂(A) = 0.13±0.002) 2D foam samples undergoing simple shear are performed using the 2D viscous froth (VF) model. These simulations clearly demonstrate shear localisation. The dependence of localisation length on the product λV (shearing velocity V times the wall drag coefficient λ) is examined and is shown to agree qualitatively with published experimental data. A wide range of localisation lengths is found at low λV, an effect which is attributed to the existence of distinct yield and limit stresses. The general continuum model is extended to incorporate such an effect and its parameters are subsequently related to those of the VF model. A Herschel–Bulkley exponent of a = 0.3 is shown to accurately describe the observed behaviour. The localisation length is found to be independent of λV for monodisperse foam samples.     

Untersuchung von Fruchterzeugnissen

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