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Hospital condition; Long-term stability study; Teduglutide Condició hospitalària; Estudi d'estabilitat a llarg termini; Teduglutida Condición hospitalaria; Estudio de estabilidad a largo plazo; Teduglutida Teduglutide, the active ingredient of the medicine Revestive® (5 mg), is a recombinant therapeutic peptide that mimics the effects of the endogenous glucagon-like peptide 2 (GLP-2). It stimulates intestinal growth, adaptation and function in patients with Short Bowel Syndrome who are dependent on parenteral nutrition. The Summary of Product Characteristics recommends immediate use of the reconstituted solutions and the discarding of any subsequent surplus. This study aims to carry out a long-term stability study that reproduces hospital conditions of use which provide sound evidence regarding the use of teduglutide surplus beyond the Summary Product Characteristics recommendations. We conducted a stability study of teduglutide solutions prepared from a 5 mg vial of Revestive®. Some of the solutions were stored in their original vial after reconstitution, while others were repackaged in plastic syringes to evaluate their physicochemical stability over time. For this purpose, we applied a set of previously validated analytical methodologies to evaluate the main critical quality attributes of teduglutide, i.e., primary (including post-tralational modifications), secondary and tertiary structures, aggregates, particulate, concentration and pH. The results indicate that the solutions maintain high physicochemical stability over time, regardless of the storage temperature (4ºC or −20ºC) or the storage container (vials or syringes). This research provides new data on the stability of Revestive® that will be of great value to hospital pharmacists. This comprehensive assessment of the physicochemical long-term stability of TGT has demonstrated that under the storage conditions and over the period studied here, the medicine maintains its quality, efficacy and safety profiles. Fundación Andaluza de Farmacia Hospitalaria (Spain); Hospital Paediatrics Pharmacy Unit of the Hospital Vall d′ Hebron (Barcelona, Spain); Junta de Andalucia (Spain), Universidad de Granada (Spain).

This study was partially funded by Project FIS: PI-17/00547 (Institute of Health 'Carlos III', Ministry of Economy and Competitiveness, Spain), which means that it was also partially supported by European Regional Development Funds (ERDF)., Major efforts have been made in the search for effective treatments since the outbreak of the COVID-19 infection in December 2019. Extensive research has been conducted on drugs that are already available and new treatments are also under development. Within this context, therapeutic monoclonal antibodies (mAbs) have been the subject of widespread investigation focusing on two target-based groups, i.e., non-SARS-CoV-2 specific mAbs, that target immune system responses, and SARS-CoV-2 specific mAbs, designed to neutralize the virus protein structure. Here we review the latest literature about the use of mAbs in order to describe the state of the art of the clinical trials and the benefits of using these biotherapeutics in the treatment of COVID-19. The clinical trials considered in the present review include both observational and randomized studies. We begin by presenting the studies conducted using non-SARS-CoV-2 specific mAbs for treating different immune disorders that were already on the market. Within this group of mAbs, we focus particularly on anti-IL-6/IL-6R. This is followed by a discussion of the studies on SARS-CoV-2 specific mAbs. Our findings indicate that SARS-CoV-2 specific mAbs are significantly more effective than non-specific ones., Institute of Health 'Carlos III', Ministry of Economy and Competitiveness, Spain - European Regional Development Funds (ERDF) FIS: PI-17/00547

The study was entirely funded by Project FIS: PI-17/00547(Instituto Carlos III, Ministerio de Economia y Competitividad, Spain), which means that it was also partially supported by European Regional Development Funds (ERDF)., A range of biopharmaceutical products are used to target Vascular Endothelial Growth Factor (VEGF), including Eylea (R) (aflibercept, AFL) and Zaltrap (R) (ziv-aflibercept, ziv-AFL). The first is indicated for ophthalmological diseases such as neovascular (wet) age-related macular degeneration, while the second is used in the treatment of metastatic colorectal cancer. The stability of AFL in prefilled syringes has been widely studied; however, no research has yet been done on the stability of ziv-AFL in polyolefin infusion bags. Therefore, the purpose of the present research is to evaluate the stability of ziv-AFL (Zaltrap (R)) clinical solutions prepared under aseptic conditions in polyolefin infusion bags at two different concentrations, i.e. 4.0 and 0.6 mg/mL, and stored refrigerated in darkness at 2-8 degrees C for 14 days. With that aim, the ziv-AFL clinical solutions were assessed by analysing changes in its physicochemical and functional properties. The distribution of the particulates was studied over a range of 0.001-10 mu m by Dynamic Light Scattering (DLS); oligomers were analysed by Size-Exclusion High-Performance Chromatography with Diode Array Detection (SE/HLPC-DAD); the secondary structure of the protein was studied by far UV Circular Dichroism (CD) and the tertiary structure by Intrinsic Tryptophan Fluorescence (IT-F) and Intrinsic Protein Fluorescence (IP-F); charge variants were assessed by Strong Cation Exchange Ultra High-Performance Chromatography with UV detection (SCX/UHPLC-UV); functionality was evaluated by ELISA by measuring the biological activity as manifested in the extension of the immunological reaction of the ziv-AFL with its antigen (VEGF). Neither aggregation nor oligomerization were detected by the techniques mentioned above. Secondary and tertiary structures remained unchanged over the 14-day period, as did charge variants. The functionality observed initially was maintained along time. Therefore, it could be proposed that the ziv-AFL clinical solutions studied showed great physicochemical and functional stability over a period of two weeks, regardless of the concentration, i.e. 4 or 0.6 mg/mL., Project FIS (Instituto Carlos III, Ministerio de Economia y Competitividad, Spain) PI-17/00547, European Commission

COVID-19, a disease caused by the novel coronavirus SARS-CoV-2, has produced a serious emergency for global public health, placing enormous stress on national health systems in many countries. Several studies suggest that cytokine storms (interleukins) may play an important role in severe cases of COVID19. Neutralizing key inflammatory factors in cytokine release syndrome (CRS) could therefore be of great value in reducing the mortality rate. Tocilizumab (TCZ) in its intravenous (IV) form of administration -RoActemra® 20 mg/mL (Roche)-is indicated for treatment of severe CRS patients. Preliminary investigations have concluded that inhibition of IL-6 with TCZ appears to be efficacious and safe, with several ongoing clinical trials. This has led to a huge increase in demand for IV TCZ for treating severe COVID-19 patients in hospitals, which has resulted in drug shortages. Here, we present a comparability study assessing the main critical physicochemical attributes of TCZ solutions used for infusion, at 6 mg/ mL and 4 mg/mL, prepared from RoActemra® 20 mg/mL (IV form) and from RoActemra® 162 mg (0.9 mL solution pre-filled syringe, subcutaneous(SC) form), to evaluate the use of the latter for preparing clinical solutions required for IV administration, so that in a situation of shortage of the IV medicine, the SC form could be used to prepare the solutions for IV delivery of TCZ. It is important to remember that during the current pandemic all the medicines are used off-label, since none of them has yet been approved for the treatment of COVID-19., Instituto Carlos III, Ministerio de Economia y Competitividad, Spain FIS: PI-17/00547, European Union (EU), Ministry of Universities, Spain FPU18/03131, University of Granada (Spain)

Background and importance Rituximab (RTX) is a therapeutic monoclonal antibody used for the treatment of certain types of cancer. As a complex protein, routine handling or unintentional mishandling of its solutions may cause degradation that could remain unnoticed but could potentially compromise the clinical safety and efficacy of the drug product.1 Aim and objectives To assess the impact on the RTX (Mabthera) aggregation process promoted by slight modification in the concentration of the compound (NaCl 0.9% and glucose 5%) used to prepare the clinical diluted solution of RTX 1.0 mg/mL. Also, to assess the impact on the aggregation of RTX clinical diluted solutions (1.0 mg/mL in NaCl 0.9% and glucose 5%) promoted by manual shaking. Material and methods RTX (Mabthera 10 mg/mL) was diluted to 1 mg/mL using different NaCl (from 0.5% to 1.5%) and glucose (from 1% to 10%) concentrations. Manual gentle shaking was performed for 10 minutes. Particulate was tracked by dynamic light scattering (DLS) and readings were carried out in a protein solution DynaPro-99 system dynamic light scattering module equipped with a temperature control micro sampler (Wyatt, Santa Barbara, California, USA) for obtaining the hydrodynamic radius (HR) and polydispersity. Results Reference 1.0 mg/mL RTX samples diluted in NaCl 0.9% and glucose 5% showed a single particulate population with a HR of 10.51±2.210 nm and 10.72±2.694 nm, respectively, attributed to monomers of RTX. No significant changes were obtained for HR when the concentration of the diluents was changed. Also, no significant changes were observed when the samples were shaken, with the HR values always within the interval of the size of the monomers. Polydispersity remained unchanged in all of the samples analysed. Conclusion and relevance Variation in NaCl and glucose concentrations around clinical concentrations of 0.9% and 5% did not promote aggregation in a 1 mg/mL RTX solution detected by DLS. Also, shaking did not have any impact on aggregation in this clinical RTX solution. References and/or acknowledgements 1. Nejadnik MR, et al. J Pharm Sci 2018;107:2013–2019. Funded by Project FIS: PI-17/00547 (Instituto Carlos III, Spain), which means that it was also partially supported by the European Regional Development Funds. No conflict of interest.

This study was entirely funded by Project FIS: PI-17/00547 (Instituto Carlos III, Ministerio de Economia y Competitividad, Spain), which means that it was also partially supported by European Regional Development Funds (ERDF)., Aflibercept (AFL) is an Fc fusion protein used in the treatment of colorectal cancers and different ophthalmological diseases. There are two medicines in which AFL is the active substance: Zaltrap and Eylea, referred as ziv-AFL and AFL respectively. No proper accelerated degradation studies were published on either AFL or ziv-AFL. These studies are essential during research, development and manufacturing stages. Here, we characterized ziv-AFL and submitted it to different stress conditions: light, 60 °C, freeze-thaw cycles, changes in pH, high hypertonic solution and strong denaturing conditions. We used an array of techniques to detect aggregation (SE-HPLC/DAD and DLS), changes in secondary structure (Far-UV circular dichroism), changes in conformation or tertiary structure (Intrinsic tryptophan fluorescence) and alterations in functionality (ELISA). Results indicate that aggregation is common degradation pathway. Two different types of aggregates were detected: dimers and high molecular weight aggregates attributed to β-amyloid-like structures. Secondary structure was maintained in most of the stress tests, while conformation was altered by almost all the tests except for the freeze-thaw cycles. Functionality, evaluated by its immunochemical reaction with VEGF, was found to be stable but with decrease when exposed to light and with likely partial inactivation of the drug when pH was altered., European Union (EU) FIS: PI-17/00547

There are two products in which infliximab is the active pharmaceutical ingredient. These are Remicade® (INF; reference product) and Remsima™/Inflectra™ (CT-P13; infliximab biosimilar). Remsima™/Inflectra™ are bioidentical products. Different recommendations have been made for the clinical solutions of each brand (Remicade® or Remsima™/Inflectra™) despite the manufacturer of the biosimilar claiming high levels of similarity to the innovator. The objective of this study was to assess and compare stability against degradation and over time of different clinical infliximab solutions prepared from Remicade® and from Remsima™/Inflectra™ using a suitable set of characterization methods in line with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) recommendations. Reconstituted solutions of INF and CT-P13 and dilutions as used in hospital were stored in glass vials (10 and 2 mg/mL) or in polyolefin infusion bags (0.4 mg/mL) refrigerated between 2 and 8 °C for 2 weeks. Regarding the physicochemical properties, the distribution of the particulates were studied over a range of 0.001–1 µm by dynamic light scattering (DLS) and oligomers up to 8 monomer were analyzed by native size-exclusion ultra-high-performance liquid chromatography with ultraviolet (UV)-visible detection coupled to (native) mass spectrometry (SE/UHPLC-UV-(native) MS); mass spectrometry was also used to evaluate natural aggregates and isoform profile; DLS was also employed to detect gross conformational changes by tracking the hydrodynamic radius (HR). The secondary structure of the proteins was studied by far UV circular dichroism (CD). The tertiary structure was investigated by intrinsic tryptophan fluorescence (IT-F). Reverse-phase ultra-high-performance liquid chromatography with UV detection (RP/UHPLC-UV) was used to analyze intact INF and CT-P13 for quantification purposes. Functionality was evaluated via the biological activity measured by the extension of the immunological reaction of the INF and the CT-P13 with its antigen, i.e., the tumor necrosis factor-α by enzyme-linked immunosorbent assay (ELISA). The stress applied to INF and CT-P13 solutions showed similar levels of aggregate formation, structural variation, and chemical modifications. The only noteworthy difference between INF and CT-P13 was detected in their behavior to freeze–thaw cycles, in which CT-P13 showed slightly more robustness. INF and CT-P13 showed identical CD spectra, similar to those reported for IgG1 in which there is dominance in β sheet secondary structures; this typical conformation remained unmodified over time in INF and CT-P13. No significant changes were detected in the tertiary structure and no aggregates process was noticed over the time studied. Polydispersity slightly increased for the most concentrated solutions, while there were no meaningful differences in the HR in the solutions over time. The concentration of INF and CT-P13 also remained constant. Differences in the native isoform MS profile were detected, as expected by the different glycosylation pattern, with no important modification over time. Functionality was maintained over the test period (60 days) and was similar in all the solutions tested, with no differences between INF and biosimilar solutions. High levels of similarity were noticed in the behavior of INF and CT-P13 when subjected to stress. When stored refrigerated at between 2 and 8 °C and prepared as normally used in the hospital pharmacy, all solutions showed physicochemical and functional stability for all the concentrations tested and all containers, at least for the 14-day test period.