Validation Aspects of Water Treatment Systems for Pharmaceutical Products

The goal of conducting validation is to demonstrate that a process, when operated within established limits, produces a product of consistent and specified quality with a high degree of assurance. Validation of water treatment systems is necessary to obtain water with all desired quality attributes. This also provides a framework to establish a total control over the process which monitors safety, efficacy and ultimately, the process outcomes. The present overview is an attempt to discuss various aspects of validation including different approaches, components of water treatment systems, equipment qualifications, phases of performance testing, documentation and post-validation monitoring.Keywords: Validation; Water treatment systems; Quality attributes; Pharmaceutical product

Ethanol Induced Disordering of Pancreatic Acinar Cell Endoplasmic Reticulum: An ER Stress/Defective Unfolded Protein Response Model.

Background & aimsHeavy alcohol drinking is associated with pancreatitis, whereas moderate intake lowers the risk. Mice fed ethanol long term show no pancreas damage unless adaptive/protective responses mediating proteostasis are disrupted. Pancreatic acini synthesize digestive enzymes (largely serine hydrolases) in the endoplasmic reticulum (ER), where perturbations (eg, alcohol consumption) activate adaptive unfolded protein responses orchestrated by spliced X-box binding protein 1 (XBP1). Here, we examined ethanol-induced early structural changes in pancreatic ER proteins.MethodsWild-type and Xbp1+/- mice were fed control and ethanol diets, then tissues were homogenized and fractionated. ER proteins were labeled with a cysteine-reactive probe, isotope-coded affinity tag to obtain a novel pancreatic redox ER proteome. Specific labeling of active serine hydrolases in ER with fluorophosphonate desthiobiotin also was characterized proteomically. Protein structural perturbation by redox changes was evaluated further in molecular dynamic simulations.ResultsEthanol feeding and Xbp1 genetic inhibition altered ER redox balance and destabilized key proteins. Proteomic data and molecular dynamic simulations of Carboxyl ester lipase (Cel), a unique serine hydrolase active within ER, showed an uncoupled disulfide bond involving Cel Cys266, Cel dimerization, ER retention, and complex formation in ethanol-fed, XBP1-deficient mice.ConclusionsResults documented in ethanol-fed mice lacking sufficient spliced XBP1 illustrate consequences of ER stress extended by preventing unfolded protein response from fully restoring pancreatic acinar cell proteostasis during ethanol-induced redox challenge. In this model, orderly protein folding and transport to the secretory pathway were disrupted, and abundant molecules including Cel with perturbed structures were retained in ER, promoting ER stress-related pancreas pathology

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children <18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p<0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p<0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p<0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer

Indirect search for dark matter from the Galactic Center and halo with the Super-Kamiokande detector

We present a search for an excess of neutrino interactions due to dark matter in the form of weakly interacting massive particles (WIMPs) annihilating in the Galactic center or halo based on the data set of Super-Kamiokande-I, -II, -III and -IV taken from 1996 to 2016. We model the neutrino flux, energy, and flavor distributions assuming WIMP self-annihilation is dominant to ν ¯ ν , μ + μ − , b ¯ b , or W + W − . The excess is in comparison to atmospheric neutrino interactions which are modeled in detail and fit to data. Limits on the self-annihilation cross section ⟨ σ A V ⟩ are derived for WIMP masses in the range 1 GeV to 10 TeV, reaching as low as 9.6 × 10 − 23     cm 3   s − 1 for 5 GeV WIMPs in b ¯ b mode and 1.2 × 10 − 24     cm 3   s − 1 for 1 GeV WIMPs in ν ¯ ν mode. The obtained sensitivity of the Super-Kamiokande detector to WIMP masses below several tens of GeV is the best among similar indirect searches to date

Diffuse supernova neutrino background search at Super-Kamiokande

A new search for the diffuse supernova neutrino background (DSNB) flux has been conducted at Super-Kamiokande (SK), with a $22.5\times2970$-kton$\cdot$day exposure from its fourth operational phase IV. The new analysis improves on the existing background reduction techniques and systematic uncertainties and takes advantage of an improved neutron tagging algorithm to lower the energy threshold compared to the previous phases of SK. This allows for setting the world's most stringent upper limit on the extraterrestrial $\bar{\nu}_e$ flux, for neutrino energies below 31.3 MeV. The SK-IV results are combined with the ones from the first three phases of SK to perform a joint analysis using $22.5\times5823$ kton$\cdot$days of data. This analysis has the world's best sensitivity to the DSNB $\bar{\nu}_e$ flux, comparable to the predictions from various models. For neutrino energies larger than 17.3 MeV, the new combined $90\%$ C.L. upper limits on the DSNB $\bar{\nu}_e$ flux lie around $2.7$ cm$^{-2}$$\cdot$$\text{sec}^{-1}$, strongly disfavoring the most optimistic predictions. Finally, potentialities of the gadolinium phase of SK and the future Hyper-Kamiokande experiment are discussed.Comment: 42 pages, 37 figures, 14 table

Searching for supernova bursts in Super-Kamiokande IV

Super-Kamiokande has been searching for neutrino bursts characteristic of core-collapse supernovae continuously, in real time, since the start of operations in 1996. The present work focuses on detecting more distant supernovae whose event rate may be too small to trigger in real time, but may be identified using an offline approach. The analysis of data collected from 2008 to 2018 found no evidence of distant supernovae bursts. This establishes an upper limit of 0.29 yr−1 on the rate of core-collapse supernovae out to 100 kpc at 90% C.L. For supernovae that fail to explode and collapse directly to black holes the limit reaches to 300 kpc

Search for neutrinos in coincidence with gravitational wave events from the LIGO–Virgo O3a observing run with the Super-Kamiokande detector

The Super-Kamiokande detector can be used to search for neutrinos in time coincidence with gravitational waves detected by the LIGO–Virgo Collaboration (LVC). Both low-energy (7–100 MeV) and high-energy (0.1–105 GeV) samples were analyzed in order to cover a very wide neutrino spectrum. Follow-ups of 36 (out of 39) gravitational waves reported in the GWTC-2 catalog were examined; no significant excess above the background was observed, with 10 (24) observed neutrinos compared with 4.8 (25.0) expected events in the high-energy (low-energy) samples. A statistical approach was used to compute the significance of potential coincidences. For each observation, p-values were estimated using neutrino direction and LVC sky map; the most significant event (GW190602_175927) is associated with a post-trial p-value of 7.8% (1.4σ). Additionally, flux limits were computed independently for each sample and by combining the samples. The energy emitted as neutrinos by the identified gravitational wave sources was constrained, both for given flavors and for all flavors assuming equipartition between the different flavors, independently for each trigger and by combining sources of the same nature

Impact of operational systems on supplier's response under performance-based contracts

Performance-based contract has developed into a new service strategy in after-market operations that aims to compensate for performance outcomes. One of the key components of a performance-based contract is performance measure that is affected by factors such as base stock, reliability and response time. To achieve a desired performance level, the supplier has to improve the component reliability and the repair time. The component reliability in a repairable part inventory system is a function of the number of operational systems and the service capacity. In this research, we consider a single echelon repairable part inventory system and conduct a parametric analysis to evaluate the impact of the total number of systems on the supplier's decisions under a performance contract. The results show that the numbers of systems plays a key role on the supplier's response when the customer uses the average number of backorders as the negative incentive.Published versio

A study of repairable parts inventory system operating under performance-based contract

Performance-Based Logistics (PBL) is becoming a dominant logistics support strategy, especially in the defense industry. PBL contracts are designed to serve the customer's key performance measures, while the traditional contracts for after-sales services, such as Fixed-price (FP) and Cost-plus (C+), only provide insurance or incentive. In this research, we develop an inventory model for a repairable parts system operating under a PBL contract. We model the closed-loop inventory system as an M/M/m queue in which component failures are Poisson distributed and the repair times at the service facility are exponential. Our model provides the supplier and the customer increased flexibility in achieving target availability. Analysis of key parameters suggests that to improve the availability of the system with repairable spare parts, the supplier should work to improve the components reliability and efficiency of repair facility, rather than the base stock level, which has minimal impact on system availability.Logistics Base stock Component reliability Repair facility