Challenges for FCC-ee luminosity monitor design

For cross section measurements, an accurate knowledge of the integrated luminosity is required. The FCC-ee physics programme at and around the Z pole sets the ambitious precision goal of $$10^{-4}$$ 10 - 4 on the absolute luminosity measurement and one order of magnitude better on the relative measurement between energy scan points. The luminosity is determined from the rate of Bhabha scattering, $$\mathrm {e^+e^- \rightarrow e^+e^-}$$ e + e - → e + e - , where the final state electrons and positrons are detected in dedicated monitors covering small angles from the outgoing beam directions. The constraints on the luminosity monitors are multiple: (i) they are placed inside the main detector volume only about 1 m from the interaction point; (ii) they are centred around the outgoing beam directions and do not satisfy the normal axial detector symmetry; (iii) their coverage is limited by the beam pipe, on the one hand, and by the requirement to stay clear of the main detector acceptance, on the other; (iv) the steep angular dependence of the Bhabha scattering process imposes a precision on the acceptance limits at about 1 $$\upmu $$ μ rad, corresponding to an absolute geometrical precision of $${\mathcal {O}}(1\,\upmu \text {m})$$ O ( 1 μ m ) on the monitor radial dimensions; and v) the very high bunch-crossing rate of 50 MHz during the Z-pole operation calls for fast readout electronics. Inspired by second-generation LEP luminosity monitors, which achieved an experimental precision of $$3.4 \times 10^{-4}$$ 3.4 × 10 - 4 on the absolute luminosity measurement (Abbiendi et al. in Eur Phys J C 14:373–425, 2000), a proposed ultra-compact solution is based on a sandwich of tungsten-silicon layers. A vigorous R&D programme is needed in order to ensure that such a solution satisfies the more challenging FCC-ee requirements.

RP-HPLC Method for Quantification of Emtricitabine and Tenofovir Alafenamide Fumarate Drug Substance and Tablet Dosage Form

Aim: The primary objective of the research work is to develop a effective, sensitive, economical and simple reverse phase HPLC method to estimate Emtricitabine and tenofovir alafenamide fumarate in its pure and binary mixture of tablets. Study Design: HPLC based Quantification Studies. Place and Duration of Study: 1Department of Chemistry, Acharya Nagarjuna University,Guntur, Andhra Pradesh between April 2019 and August 2020. Methodology: Separation of the analytes were done by using Eclipse XDB-Phenyl (250 x 4.6mm, 5µ,100 A0) column and a mobile phase ratio of 30:10:70 percentage of 0.1% trifluoro acetic acid: acetonitile: methanol at a flow rate of 1 ml/min. The injected standard and sample solutions were detected 260nm wavelength. Results: The retention time of Emtricitabine and tenofovir alafenamide fumarate were found at 2.3min and 2.8 min respectively. The method has good linearity range about 50 to 150µg/ml of Emtricitabine and 6.5 to 19.5 µg/ml of tenofovir alafenamide fumarate. The method has validated as per ICH guidelines and all the validation parameterwere satisfy the ICH Q2 specification acceptance limits Conclusion: The developed method said to be highly sensitive, accurate, specific and robust, therefore this method has high probability to adopt in pharmaceutical industry for regular analysis of Emtricitabine and tenofovir alafenamide.

Similar pharmacokinetics and pharmacodynamics of a new biosimilar and reference insulin aspart in healthy Chinese males

Insulin aspart (IAsp) is one of the main therapies used to control blood glucose after a meal. This study aimed to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 2 rapid-acting IAsp products: a new IAsp biosimilar (RD10046) and NovoRapid. In a single-center, randomized, single-dose, 2-period, crossover, euglycemic clamp study (registry number: CTR20180517, registration date: 2018-05-30), healthy Chinese males were randomized to receive 0.2 U/kg of the IAsp biosimilar RD10046 and NovoRapid under fasted conditions on two separate occasions. PK and PD were assessed for up to 10 h. Of the 30 randomized subjects, all 30 completed both treatment periods. The PK (area under the curve [AUC] of total IAsp; maximum observed IAsp concentration [Cmax]) and PD (maximum glucose infusion rate [GIRmax]; total glucose infusion during the clamp [AUCGIR,0–10h]) were similar between the new IAsp biosimilar RD10046 and NovoRapid. In all cases, the 90% CIs for the ratios of the geometric means were completely contained in the prespecified acceptance limits of 0.80–1.25. No hypoglycemic events, allergic reactions, or local injection adverse reactions occurred in this trial. We concluded that the studied IAsp biosimilar (RD10046) was bioequivalent to NovoRapid.

Testing the Limits of a Portable NIR Spectrometer: Content Uniformity of Complex Powder Mixtures Followed by Calibration Transfer for In-Line Blend Monitoring

(1) Background: Portable NIR spectrometers gain more and more ground in the field of Process Analytical Technology due to the easy on-site flexibility and interfacing versatility. These advantages that originate from the instrument miniaturization, also come with a downside with respect to performance compared to benchtop devices. The objective of this work was to evaluate the performance of MicroNIR in a pharmaceutical powder blend application, having three active ingredients and 5 excipients. (2) Methods: Spectral data was recorded in reflectance mode using static and dynamic acquisition, on calibration set samples developed using an experimental design. (3) Results: The developed method accurately predicted the content uniformity of these complex mixtures, moreover it was validated in the entire calibration range using ±10% acceptance limits. With respect to at-line prediction, the method presented lower performance compared to a previously studied benchtop spectrometer. Regarding the in-line monitoring of the blending process, it was shown that the spectral variability-induced by dynamic acquisition could be efficiently managed using spectral pre-processing. (4) Conclusions: The in-line process monitoring resulted in accurate concentration profiles, highlighting differences in the mixing behaviour of the investigated ingredients. For the low dose component homogeneity was not reached due to an inefficient dispersive mixing.

Development and validation of a simple and rapid ICP-OES method for quantification of elemental impurities in voriconazole drug substance

Background The aim of the present study was to develop and validate an inductively coupled plasma optical emission spectroscopic (ICP–OES) method for quantification of elemental impurities, i.e., Lead, Palladium, and Zinc, in voriconazole drug substance, and this method was employed for the regular sample analysis of Lead, Palladium, and Zinc in voriconazole drug substance for pharmaceutical use. The method has been validated using RF power of 1150 W, auxiliary gas of 0.5 L/min, and nebulizer flow of 0.4 L/min and plasma view at axial mode for Lead and Palladium and radial mode for Zinc. The wavelength was monitored for Lead, Palladium, and Zinc at 220.3 nm, 340.4 nm, and 213.8 nm respectively. Results The method is selective and is capable of detecting desired elemental impurities with regulatory acceptance limits in the presence of other elements. The validation experiments involve the demonstration of system suitability, specificity, LOD and LOQ, linearity, precision, and accuracy experiments. The linearity results obtained ˃ 0.9990 for all three impurities. Conclusion The proposed method is simple, sensitive quality control tool for the simultaneous quantitative determination of Lead, Palladium, and Zinc at low levels in voriconazole drug substance. Graphical abstract

Evaluation and authentication for metformin HCL, Glimepride, atorvastatine by using bulk HPLC pharmaceutical dosage form

Reverse phase chromatographic techniques are used for analyzing drugs. It is advanced analytical instrumentation method used for analysis of drugs. A novel accurate, precise, simple, & selective RP- HPLC technique is established and authorized for stability representing RP – HPLC technique for simultaneous assessment of Metformin HCL, Glimepiride & Atorvastatin in bulk & pharmaceutical dosage form by RP– HPLC technique. The technique on Luna C 18, 250mm × 4.6 mm, 15 µm. Column with a mobile phase comprising of buffer and acetonitrile in ratio of (85:15 v/v) and 1.0ml/ minflow rate. The detection is 258 nm. The retention time for metformin HCL, Atorvastatin & Glimepiride are discovered to be 3.266, 5.237 and 8.457 correspondingly. The technique authorized accordingly to ICH rules for precision, specificity, LOQ, LOD, accuracy, robustness, & linearity. The technique demonstrates best recovery &reproducibility with % RSD lower than 2. The suggested technique is discovered to be precise, simple, accurate, specific, &linear. The results are within the acceptance limits of lower than 2% signified that suggested technique has best reproducibility. The toughness of developed technique is validated by altering mobile phase composition, flow rate, and changing wavelength. The % RSD was found within the limits i.e., should not be more than 2.0.

Stability of Turoctocog Alfa, a Recombinant Factor VIII Product, during Continuous Infusion In Vitro

Objective Turoctocog alfa is a recombinant factor VIII (rFVIII) for the prevention and treatment of bleeding in patients with hemophilia A, including those undergoing surgery and invasive medical procedures. This in vitro study evaluated the physical and chemical stability of turoctocog alfa during continuous infusion (CI) over 24 hours at 30°C. Materials and Methods The study was performed at 30°C ( ± 2°C). A CI system with pump speed set at either 0.6 or 1.5 mL/h was used to evaluate the stability of three turoctocog alfa strengths (500, 1,000, and 3,000 IU), equating to doses of 1.1 to 16.1 IU/h per kilogram of body weight. The following parameters were evaluated at selected time points between 0 and 24 hours: appearance of solution, clarity, pH, potency, purity, content, total high molecular weight proteins (HMWPs), and oxidized rFVIII. Results The mean potency of turoctocog alfa was maintained within the predefined acceptance criteria during CI for both pump speeds with all three strengths at 6, 12, or 24 hours (500 IU: ≥484 IU/vial; 1,000 IU: ≥1,014 IU/vial; and 3,000 IU: ≥3,029 IU/vial). Furthermore, the appearance of solution, clarity, pH, purity, content of turoctocog alfa, total HMWP, and oxidized forms were also within the predefined limits, and comparable to the reference samples (time = 0 hours) for the pump speeds and product strengths assessed. Conclusion Physical and chemical stability of turoctocog alfa was maintained during CI over 24 hours. There was only minor degradation or changes in any of the parameters tested. Potency was within the prespecified acceptance limits throughout 24 hours of infusion. These findings confirm the suitability of turoctocog alfa for CI.

Pharmacogenetic perspectives in improving pharmacokinetic profiles for efficient bioequivalence trials with highly variable drugs: a review

Conducting bioequivalence trials under traditional crossover study designs without exposing a large number of healthy volunteers to demonstrate two highly variable (%coefficient of variability greater than 30) test/reference (branded) drug products in different formulations to meet the standard 90% confidence interval criteria of relevant pharmacokinetic metrics between 0.80 and 1.25 and to maintain the consumer risk smaller than 5% has been a challenging task. Genetic polymorphisms encoding key drug-metabolizing enzymes can significantly influence absorption, distribution, metabolism and elimination of many highly variable generic drugs after administration. This article briefly reviews the case studies and examples of utilizing pharmacogenetic screening approaches in the recent literature to alleviate the resources and ethical burden of recruiting larger numbers of subjects in bioequivalence trials needed to perform pharmacokinetic studies for formulations of highly variable drug products without widening the bioequivalence acceptance limits.

Controlling the Reproducibility of AC50 Estimation during Compound Profiling through Bayesian β-Expectation Tolerance Intervals

During drug discovery, compounds/biologics are screened against biological targets of interest to find drug candidates with the most desirable activity profile. The compounds are tested at multiple concentrations to understand the dose-response relationship, often summarized as AC50 values and used directly in ranking compounds. Differences between compound repeats are inevitable because of experimental noise and/or systematic error; however, it is often desired to detect the latter when it occurs. To address this, the β-expectation tolerance interval is proposed in this article. Besides the classical acceptance criteria on assay performance, based on control compounds (e.g., quality control samples), this metric permits us to compare new estimates against historical estimates of the same study compound. It provides a measure that detects whether observed differences are likely due to systematic error. The challenge here is that limited information is available to build such compound-specific acceptance limits. To this end, we propose the use of Bayesian β-expectation tolerance intervals to validate agreement between replicate potency estimates for individual study compounds. This approach allows the variability of the compound-testing process to be estimated from reference compounds within the assay and used as prior knowledge in the computation of compound-specific intervals as from the first repeat of the compound and then continuously updated as more information is acquired with subsequent repeats. A repeat is then flagged when it is not within limits. Unlike a fixed threshold such as 0.5log, which is often used in practice, this approach identifies unexpected deviations on each compound repeat given the observed variability of the assay.

Enhanced specificity due to method specific limits for relative ion intensities in a high-performance liquid chromatography – tandem mass spectrometry method for iohexol in human serum

BackgroundAccurate assessment of kidney function is needed for a variety of clinical indications and for research. The measurement of the serum clearance of iohexol has emerged as a feasible method to reach this objective. We report the analytical validation and clinical application of a new high-performance liquid chromatography (HPLC) – tandem mass spectrometry (MS/MS) assay to quantify iohexol in human serum. Specificity was enhanced due to the use of method specific acceptance limits for relative ion (RI) intensities.MethodsThe internal standard ioversol was added to 50 μL serum prior to protein precipitation with methanol. Linear gradient elution was performed on a Waters Oasis® HLB column. Three transitions for both iohexol and ioversol were monitored allowing calculation of RIs. Measurements acquired during method validation were used as a training set to establish stricter acceptance criteria for RIs which were then tested retrospectively on clinical routine measurements (86 measurements) and on mathematically simulated interferences.ResultsThe method was linear between 5.0 μg/mL (lower limit of quantification [LLOQ]) and 100.3 μg/mL iohexol. Intraday and interday imprecision were ≤2.6% and ≤3.2%, respectively. Bias was −1.6% to 1.5%. All validation criteria were met, including selectivity, recovery, extraction efficiency and matrix effects. Retrospectively acceptance limits for RIs could be narrowed to ±4 relative standard deviations of the corresponding RIs in the training set. The new limits resulted in an enhanced sensitivity for the simulated interferences.ConclusionsCriteria for validation were met and the assay is now used in our clinical routine diagnostics and in research.