Statistical considerations on real time and extended controlled temperature conditions (ECTC) stability data analysis of vaccines.

BACKGROUND: Although maintaining vaccines in a strict cold chain has cost and logistical implications in low- and middle-income countries, only a few vaccines have obtained approval for extended controlled temperature conditions (ECTC) application, which permits the administration of vaccines after storage outside of the cold chain for a defined period. We developed a methodology to evaluate stability data and calculate minimum release potency (MRP) in support of ECTC application. METHODS: The methodology is focused on statistical considerations consisting of stability data collection, statistical analysis plan, statistical modelling, and statistical report. It uses mock stability data from a hypothetical product and may serve as a helpful guide for other products. The statistical data analysis is performed using the R program which is an open-source program and validated using the SAS software. RESULTS: We developed a stability data testing scheme that included 24 lots with six-time points for up to 24 months under real-time and real condition (RT) in the cold chain samples stored at 2-8 °C and 12 lots with six timepoints for 14 days under ECTC samples stored at 40 °C. The log-transformed stability data met the linear regression assumptions and were poolable from representative lots with no significant lot variation. The linear regression analysis model with a common slope and intercept confirmed the stable antigen content over time under RT and ECTC by the mean regression line and 95% confidence interval. Based on the fitted models and the estimated coefficients, the antigen content value of 966 was derived as the MRP under RT for 24 months followed by 14 days under ECTC. CONCLUSION: The presented framework of statistical considerations, with practical methods and R program codes to perform statistical analysis, may serve as a guide for developing the CTC data for a vaccine's stability evaluation prospectively.

A universal tool for stability predictions of biotherapeutics, vaccines and in vitro diagnostic products.

It is of particular interest for biopharmaceutical companies developing and distributing fragile biomolecules to warrant the stability and activity of their products during long-term storage and shipment. In accordance with quality by design principles, advanced kinetic modeling (AKM) has been successfully used to predict long-term product shelf-life and relies on data from short-term accelerated stability studies that are used to generate Arrhenius-based kinetic models that can, in turn, be exploited for stability forecasts. The AKM methodology was evaluated through a cross-company perspective on stability modeling for key stability indicating attributes of different types of biotherapeutics, vaccines and biomolecules combined in in vitro diagnostic kits. It is demonstrated that stability predictions up to 3 years for products maintained under recommended storage conditions (2-8 °C) or for products that have experienced temperature excursions outside the cold-chain show excellent agreement with experimental real-time data, thus confirming AKM as a universal and reliable tool for stability predictions for a wide range of product types.

Assessment of Functional and Physical Performances of Pre-filled Syringes in Deep Cold Storage Conditions.

The recent emergence of new drug technologies such as messenger ribonucleic acid-based vaccines developed to fight the outbreak of the COVID-19 global pandemic has driven increased demand for delivery solutions capable of withstanding deep cold storage conditions down to -50°C, and even down to -80°C. Although significant data exist for deep cold storage in vials, little evidence is available for pre-filled syringes. Because pre-filled syringes serve as both the storage container and the delivery mechanism, there are additional risks to performance that must be evaluated, such as plunger gliding performance, syringe lubrication, silicone layer stability, and container closure integrity (CCI). In the present study, a comprehensive assessment of functional and physical performances of pre-filled syringes (PFS filled with water) was performed after one or multiple freeze/thaw (F/T) cycles between ambient temperature and various temperature cycles including -40°C, -50°C or -80°C for both 'staked needle' and 'luer lock' configurations. The experiments were guided by historical normative methods such as ISO 11040-4 and USP <1207> and combined with headspace gas analysis for barrel-stopper tightness testing. In addition, they were complemented with a novel approach, namely in situ real-time optical imagery, to track plunger stopper movement during the F/T cycle. The findings indicated that there is no significant impact on the functional performances from F/T down to -80°C, whereas no CCI risk was found after F/T down to -50°C.

Triazine-based porous organic polymers for reversible capture of iodine and utilization in antibacterial application.

The capture and safe storage of radioactive iodine (129I or 131I) are of a compelling significance in the generation of nuclear energy and waste storage. Because of their physiochemical properties, Porous Organic Polymers (POPs) are considered to be one of the most sought classes of materials for iodine capture and storage. Herein, we report on the preparation and characterization of two triazine-based, nitrogen-rich, porous organic polymers, NRPOP-1 (SABET = 519 m2 g-1) and NRPOP-2 (SABET = 456 m2 g-1), by reacting 1,3,5-triazine-2,4,6-triamine or 1,4-bis-(2,4-diamino-1,3,5-triazine)-benzene with thieno[2,3-b]thiophene-2,5-dicarboxaldehyde, respectively, and their use in the capture of volatile iodine. NRPOP-1 and NRPOP-2 showed a high adsorption capacity of iodine vapor with an uptake of up to 317 wt % at 80 °C and 1 bar and adequate recyclability. The NRPOPs were also capable of removing up to 87% of iodine from 300 mg L-1 iodine-cyclohexane solution. Furthermore, the iodine-loaded polymers, I2@NRPOP-1 and I2@NRPOP-2, displayed good antibacterial activity against Micrococcus luteus (ML), Escherichia coli (EC), and Pseudomonas aeruginosa (PSA). The synergic functionality of these novel polymers makes them promising materials to the environment and public health.

In-use stability of diluted thiamazole (methimazole) infusion solutions in prefilled 0.9% sodium chloride infusion bags for continuous infusion.

OBJECTIVE: In patients with severe hyperthyroidism unable to tolerate oral antithyroid therapy, diluted thiamazole infusion solutions (dose 120-240 mg) are administered by continuous infusion over 24 hours. Information about the type of diluent and compatibility/stability of the ready-to-administer thiamazole preparation is missing in the summary of product characteristics of the injection concentrate marketed in Germany. We studied the in-use stability of diluted infusion solutions over 24 hours. METHODS: Thiamazol 40 mg inject. Henning was diluted in prefilled polyolefin infusion bags containing 250 mL 0.9% sodium chloride (NaCl) infusion solution and kept for 24 hours at room temperature and diffuse room light. Content of the diluted infusion solutions (0.48 and 0.96 mg/mL) was analysed every 4 hours over the course of 24 hours by reversed-phase high-performance liquid chromatography. pH was measured after 0, 12 and 24 hours. The infusion bags were regularly inspected for visible particles. Subvisible particles were measured by particle counting. RESULTS: Thiamazole infusion solutions of the nominal concentrations 0.48 and 0.96 mg/mL in 0.9% NaCl diluent, kept at room temperature under diffuse room light, are physicochemically stable over a period of at least 24 hours. No evidence of colour change, particle formation or pH change was observed throughout the observation period. CONCLUSION: Dilution of 120 or 240 mg doses of licensed thiamazole injection concentrate with 0.9% NaCl infusion solution in prefilled polyolefin containers is recommendable for continuous infusion over 24 hours in the treatment of thyrotoxicosis.

Exploring Challenges to COVID-19 Vaccination in the Darfur Region of Sudan.

The current COVID-19 pandemic has affected the ability of health systems to provide essential services globally. The Darfur region, located in the western part of Sudan, has been largely devastated by the war that began in 2003 and has been drawing considerable attention from the international community. The war, which erupted as a result of environmental, political, and economic factors, has led to tragic outcomes. Collapsing health-care infrastructures, health workforce shortages, lack of storage facilities for medicines and medical products, and inadequate access to health services are some of the effects of the war. After Sudan received the AstraZeneca COVID-19 vaccine through the COVID-19 Vaccines Global Access facility, significant challenges have been implicated in the delivery, storage, and use of the vaccine in the Darfur region. Lack of vaccine storage and transportation facilities, vaccination hesitancy, inequity in the distribution to health facilities, and shortage of health-care professionals resulting from insecurity and instability have added an extra layer of burden on local authorities and their ability to manage COVID-19 vaccinations in the region adequately. Addressing the impact of COVID-19 requires an effectively managed vaccination program. In the face of current challenges in Darfur, ensuring a fully vaccinated population might remain far-fetched and improbable if meaningful efforts are not put in place by all stakeholders and actors to address some of the challenges identified.

Storage of Medications: A Survey of Families in the Pediatric Emergency Department.

OBJECTIVES: To evaluate caregivers' practice of prescription medication storage, particularly of opioid medications, as well as to provide educational materials to families about the opioid crisis. METHODS: Caregivers of patients in a pediatric emergency department were asked to participate in a survey about medication storage practices and beliefs, focusing on opioid medications. Data were collected through a survey documenting demographic data along with knowledge and behaviors of medication storage. Brief education about the US opioid crisis and safe storage was provided. RESULTS: In total, 233 families participated; 3 families declined; 11.5% of caregivers reported storing prescribed medications in a locked or latched place, although most store them "out of reach." Most believed their child or children's friends could not easily access their medications (81.8%). Families who did not keep their medications in locked or latched places had never thought about it (39.7%). In total, 33% of respondents were unaware of the opioid crisis; 87.4% of caregivers said they would use a medication lock box if given one. CONCLUSIONS: Many caregivers are not aware of the opioid crisis and do not keep opioid medications locked up. Half of the caregivers surveyed stated they "never thought about" locking up medications. Most parents would use a lock box if given to them. This opens the door to further study, education, and interventions.

Maintaining a High-Quality Screening Collection: The GSK Experience.

The storage of screening collections in DMSO is commonplace in the pharmaceutical industry. To ensure a high-quality screening collection, and hence effective and efficient high-throughput screening, all compounds entering the GlaxoSmithKline (GSK) screening collection undergo a liquid chromatography-mass spectrometry (LC-MS) quality control (QC). It is generally accepted that even under optimal conditions, a small percentage of these compounds are unstable after prolonged storage in DMSO. This article presents how these QC data can be mined using a data-driven clustering algorithm to identify chemical substructures likely to cause degradation in DMSO. This knowledge provides new structural filters for use in excluding compounds with these undesirable substructures from the collection. This information also suggests an efficient, targeted approach to compound collection clean-up initiatives. Stability studies are also designed to maintain a high-quality screening collection. To define the best practice for the storage and handling of solution samples, GSK has undertaken stability experiments for two decades, initially to support the implementation of new automated liquid stores and, subsequently, to enhance storage and use of compounds in solution through an understanding of compound degradation under storage and assay conditions.

[Effect of Shelf Life on the Physical Stability of Suspended Ophthalmic Solutions].

Quality changes associated with physical changes in suspended eye drops are difficult to predict. In this study, we attempted to evaluate the aggregation and redispersability in commercially available suspended eye drops (fluorometholone ophthalmic solutions). The 0.1% fluorometholone ophthalmic solutions (the original product and 4 generic products) were gently mixed by hand after short-term (4 months) or long-term (40 months) storage, and the drug concentration in the first drop and physical stability (redispersability and particle size) were measured. All eye drops produced a cloudy precipitate on the bottom surface of the container, and the amount of precipitate decreased with mixing time. The drug concentration per drop in the original product was approximately 70% of the labeled value after mixing 10 times, and the drug particle size was approximately 4 µm. After mixing the generic products stored short-term 10 times, the concentration ranged from less than 50% to almost 100%. In addition, some generic products after long-term storage had a reduced redispersion ability and labeled concentration. These results suggested that at least 10 mixing were required before the using of fluorometholone original product. In addition, some generic products may not provide sufficient drug exposure even when mixed in the same manner as the original products.

Essential Oils from Piper lhotzkyanum Kunth Leaves from Brazilian Atlantic Forest: Chemical Composition and Stability in Different Storage Conditions.

This work aimed to evaluate the impact of different storage conditions and light and temperature exposures on the visual aspect and chemical composition of the essential oil (EO) of Piper lhotzkyanum Kunth, obtained from leaves by hydrodistillation from a region of high altitude. For this purpose, aliquots of the EO were stored for up to 90 days (a) under a refrigerator condition of 5 ± 3°C, (b) under a long-term (LT) condition of 30 ± 2°C and 75 ± 5% relative humidity (RH) and an accelerated condition (AS) of 40 ± 2°C and 75 ± 5% RH, and (c) in a photostability test achieved in amber and colorless glass vials. The changes were monitored on days 0 (control), 60, and 90 for the refrigerator, LT, and AS conditions. All EO chemical analyses were assessed by GC-FID and GC-MS for quantification and identification, respectively. It is reported, for the first time, that the EO of P. lhotzkyanum is rich in the sesquiterpenes ß-elemene and α-zingiberene. No significant changes in the EO was observed, revealing a minimal impact of temperature on the sample at the different storage conditions. However, there was a change in the content of α-zingiberene to bicyclogermacrene after exposure to light. The visual appearance of the samples was altered for all test conditions except the refrigerator condition. These results can potentially contribute to the product development of a bioactive EO from leaves of P. lhotzkyanum, a sesquiterpene rich natural material.

Deployment of response surface methodology to optimize microencapsulation of peroxidases from turnip roots (Brassica rapa L.) by double emulsion in PLA polymer.

In order to improve the preservation conditions and stability of peroxidase catalytic properties, a number of immobilization techniques have been widely developed. In this context, we set as objective, the optimization of synthesis and stability of microcapsules of peroxidases (POD) from turnip using polylactic acid (PLA) polymer with the double emulsion technique. The surfactant, polymer, and peroxidase concentrations were the optimized parameters. According to the results obtained using the Box-Behnken design, the optimal parameters found were 1.55% of PVA, 55 mg/mL of peroxidases, and 30 mg/mL of PLA polymer with an encapsulation efficiency of 57.29%. The scanning electron microscopy morphological characterization of the optimized microcapsules showed a regular spherical structure. Fourier transform infrared spectroscopy identified the specific functional groups and chemical bonds before and after microencapsulation. The elaborated microcapsules were characterized by an average size of 200 µm (mainly from 150 to 500 µm) with a low residual moisture content (2.26%) and the encapsulated peroxidases showed better thermal stability. The in vitro release of peroxidases confirmed that the microcapsules have an excellent sustained release in simulated gastric digestion. Encapsulated peroxidases' storage under 25 and 4 °C displays a good residual POD activity with about 60% of initial activities during 80 days of storage, whereas free POD losses its initial activity within 15 and 30 days, respectively. The obtained results are promising for the development of effective therapeutic treatment of some intestinal troubles due to oxidative stress. PRACTICAL APPLICATION: Brassica rapa L. root is well known for its richness on peroxidases and thus presents an interesting potential for developing high added value products. In order to preserve the activity of extracted peroxidases (POD) from turnip roots, microencapsulation was optimized using a polylactic acid polymer. The encapsulated POD showed the maintenance of its activity under the effect of different storage conditions (time and temperature) and demonstrated resistance to gastric acidity. According to the obtained results, the encapsulation of peroxidases opens up medicine and pharmaceutical applications such as intestinal and colic protection against inflammations.

Glass-like protein condensate for the long-term storage of proteins.

Long-term storage of proteins at ambient temperature is required for applications in pharmaceutics and biotechnology. Lyophilization is a versatile approach for stabilizing proteins at ambient temperature, although its freezing and drying processes negatively affect the protein structure. In this study, we show a glass-like protein condensate (GLPC) as a new method for protein stabilization at ambient temperature. Various protein types, including immunoglobulin G, gamma globulin, albumin, and chymotrypsin, formed a glassy state during ultracentrifugation and natural drying, while proteins that tend to crystalize, such as hen egg-white lysozyme, did not. The GLPCs were characterized by a transparent solid state, similar to a dry glass ball. Importantly, the GLPCs were dissolved easily in saline solution at a physiological concentration, thereby retaining their native structures and functions. The GLPCs preserved their native structures even after 1 year of incubation at ambient temperature. These results provide a framework for the development of protein preservation methods at ambient temperature other than lyophilization.

[Contribution of a hospital pharmacy team to critical care of patients infected with SARS-CoV-2]. / Contribution d'une équipe de pharmacie hospitalière à la prise en charge en réanimation des patients infectés par le SARS-CoV-2.

With regard to the hospital drug supply chain, the safest system is the individual automated drug dispensing one provided by the pharmacy. For several years we have been trying to convince hospital decision-makers to set it up. In the meantime, to mitigate the risks of medication errors incurred by patients and caregivers, we have set up several work teams within the care units. These teams, made up of one pharmacist and one or two hospital pharmacy technicians, who notably manage the medicine cabinets in care units. The close collaboration with doctors and nurses developed over the years was a determining factor when it became necessary to provide the newly created additional intensive care units with drugs and medical devices (MDs) in order to cope with the crisis triggered by the SARS-CoV-2 epidemic. Daily monitoring of the drugs consumed by each patient, particularly neuromuscular blocking agents and MDs was a key element in managing stocks and anticipating changes of drugs, packaging and/or devices references. These facts give weight to the Claris report published in France which recognizes that the interactions of pharmacy technicians and pharmacists in the care units have positive effects in terms of quality and safety of patient care. They highlight the dangers to which patients and caregivers are exposed on Saturdays, Sundays and holidays when the pharmacy is closed. They legitimize the question of extending the opening of the pharmacy with a full team 365 days a year.