There is continuing interest in the development and application of various microsampling technologies for drug development. The AAPS bioanalytical community microsampling subgroup and the European Bioanalysis Forum conducted a survey of their members (39 individual organizations). This gives a snapshot of current practices and demonstrates that implementation of microsampling approaches is becoming increasingly commonplace, but not universal. Greater adoption was observed for nonclinical studies, particularly nonregulatory. A number of respondents reported that they have included microsampling data in regulatory submissions. Another important observation was that where microsampling is employed for clinical studies, dried blood approaches predominate, reflecting the interest in their use where they enable sample collection which is not feasible with standard approaches or to derive richer data sets.
LC-MS/MS has been investigated to quantify protein therapeutics in biological matrices. The protein therapeutics is digested by an enzyme to generate surrogate peptide(s) before LC-MS/MS analysis. One challenge is isolating protein therapeutics in the presence of large number of endogenous proteins in biological matrices. Immunocapture, in which a capture agent is used to preferentially bind the protein therapeutics over other proteins, is gaining traction. The protein therapeutics is eluted for digestion and LC-MS/MS analysis. One area of tremendous potential for immunocapture-LC-MS/MS is to obtain quantitative data where ligand-binding assay alone is not sufficient, for example, quantitation of antidrug antibody complexes. Herein, we present an overview of recent advance in enzyme digestion and immunocapture applicable to protein quantitation.
Nonclinical dose formulation analysis methods are used to confirm test article concentration and homogeneity in formulations and determine formulation stability in support of regulated nonclinical studies. There is currently no regulatory guidance for nonclinical dose formulation analysis method validation or sample analysis. Regulatory guidance for the validation of analytical procedures has been developed for drug product/formulation testing; however, verification of the formulation concentrations falls under the framework of GLP regulations (not GMP). The only current related regulatory guidance is the bioanalytical guidance for method validation. The fundamental parameters for bioanalysis and formulation analysis validations that overlap include: recovery, accuracy, precision, specificity, selectivity, carryover, sensitivity, and stability. Divergence in bioanalytical and drug product validations typically center around the acceptance criteria used. As the dose formulation samples are not true “unknowns”, the concept of quality control samples that cover the entire range of the standard curve serving as the indication for the confidence in the data generated from the “unknown” study samples may not always be necessary. Also, the standard bioanalytical acceptance criteria may not be directly applicable, especially when the determined concentration does not match the target concentration. This paper attempts to reconcile the different practices being performed in the community and to provide recommendations of best practices and proposed acceptance criteria for nonclinical dose formulation method validation and sample analysis.
The concept of using the modulation mechanisms of a material’s optical properties for annihilation photon detection has been proposed as a potential method to significantly improve the coincidence time resolution (CTR) of positron emission tomography detectors. However, the possibility of detecting individual 511 keV photons with largely improved CTR using the proposed detection method has not yet been demonstrated, either experimentally or theoretically. In addition, the underlying physical picture of the optical modulation effects induced by annihilation photons has not been fully understood. In this work, we perform simulation studies including generation of the annihilation photon-induced ionization energy deposition trajectory, estimation of the charge carrier cascade time and temporal variance, simulation of the distribution of ionization-induced charge carrier density, and calculation of the strength of the modulation of two optical parameters: the absorption coefficient and the refractive index, as well as evaluation of the resulting optical intensity and phase change experienced by a probe laser beam. Our simulation results show that the average absorption coefficient modulation induced by individual 511 keV photon interactions is around 0.04 cm−1, and the average refractive index change is 3.6 × 10−5, leading to modulations in the probe laser intensity of around 0.1% and phase modulation of around 0.05 radians. We have also found that the ionization process induced by a single 511 keV photon interaction occurs within 2.3 ps with a temporal variance of 0.4 ps. The fundamental limit on CTR using the optical property modulation-based detection mechanism is estimated to be around 1.2 ps full width at half maximum. Our simulation results indicate that with proper experiment design, it is possible to detect the ionization produced by an individual 511 keV photon with significantly improved CTR using the optical property modulation-based detection concept.
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