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Over the last decade, biopharmaceuticals' research, development, production, and sale have involved high risks and costs for companies. Hence companies have moved toward reaping the benefits of open innovation models. Open innovation is a paradigm that forces the company to use internal and external ideas to accelerate and upgrade its technology and product innovation. This study attempts to identify and explain the open innovation model in the biopharmaceutical industry by studying the successful experiences of two prominent Iranian companies. Also, 22 companies were identified and 19 questionnaires were completed finally. The results of this study showed that the value chain in this industry consists of four major links (including research/discovery, development, production, and sales) and nine sub-links. Based on this, the conceptual model of open innovation in the value chain of Iran's biopharmaceutical industry is drawn with emphasis on four main actors including foreign patent companies, accelerators, large bio-companies, and distribution companies. Meanwhile, despite numerous problems, this industry has been able to move in the direction of open innovation. [ABSTRACT FROM AUTHOR]

Hydroxylation of prolines to 4-trans-hydroxyproline (Hyp) is mediated by prolyl-4 hydroxylases (P4Hs). In plants, Hyps occur in Hydroxyproline-rich glycoproteins (HRGPs), and are frequently O-glycosylated. While both modifications are important, e.g. for cell wall stability, they are undesired in plant-made pharmaceuticals. Sequence motifs for prolyl-hydroxylation were proposed but did not include data from mosses, such as Physcomitrella. We identified six moss P4Hs by phylogenetic reconstruction. Our analysis of 73 Hyps in 24 secretory proteins from multiple mass spectrometry datasets revealed that prolines near other prolines, alanine, serine, threonine and valine were preferentially hydroxylated. About 95 % of Hyps were predictable with combined established methods. In our data, AOV was the most frequent pattern. A combination of 443 AlphaFold models and MS data with 3000 prolines found Hyps mainly on protein surfaces in disordered regions. Moss-produced human erythropoietin (EPO) exhibited O-glycosylation with arabinose chains on two Hyps. This modification was significantly reduced in a p4h1 knock-out (KO) Physcomitrella mutant. Quantitative proteomics with different p4h mutants revealed specific changes in protein amounts, and a modified prolyl-hydroxylation pattern, suggesting a differential function of the Physcomitrella P4Hs. Quantitative RT-PCR revealed a differential effect of single p4h KOs on the expression of the other five p4h genes, suggesting a partial compensation of the mutation. AlphaFold-Multimer models for Physcomitrella P4H1 and its target EPO peptide superposed with the crystal structure of Chlamydomonas P4H1 suggested significant amino acids in the active centre of the enzyme and revealed differences between P4H1 and the other Physcomitrella P4Hs.

Building technological capabilities is influenced by different factors, notably policies. This paper explains the co-evolution of policies, i.e. policy tools, on the technological capabilities in Iran's biopharmaceutical sector from 1995 to 2022. By adopting a qualitative research method, we gathered primary data through thirty-nine semi-structured as well as secondary data from reports and statistics. This paper explains technological capabilities enhancement from operational capabilities to innovative capabilities based on our proposed framework, which includes six levels. While the lack of an efficient policy tools, until the mid-2000s, was decisive in the inertia of biopharmaceutical sector capabilities, a proactive policy tools in recent years led to considerable promising results in terms of manufacturing and exporting advanced biosimilar products. Our findings shed light on the role of government support in the acceleration and directionality of technological capabilities building. Achieving advanced levels of technological capabilities requires learning, international collaboration, and export-oriented policies. [ABSTRACT FROM AUTHOR]

Asparagine is a non-essential amino acid crucial for protein biosynthesis and function, and therefore cell maintenance and growth. Furthermore, this amino acid has an important role in regulating several metabolic pathways, such as tricarboxylic acid cycle and the urea cycle. When compared to normal cells, tumor cells typically present a higher demand for asparagine, making it a compelling target for therapy. In this review article, we investigate different facets of asparagine bioavailability intricate role in malignant tumors raised from solid organs. We take a comprehensive look at asparagine synthetase expression and regulation in cancer, including the impact on tumor growth and metastasis. Moreover, we explore asparagine depletion through L-asparaginase as a potential therapeutic method for aggressive solid tumors, approaching different formulations of the enzyme and combinatory therapies. In summary, here we delve into studies about endogenous and exogenous asparagine availability in solid cancers, analyzing therapeutic implications and future challenges. [ABSTRACT FROM AUTHOR]

Copyright of Xinjiang Agricultural Sciences is the property of Xinjiang Agricultural Sciences Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Microalgae are promising production platforms for the cost-effective production of recombinant proteins. We have recently established that the red alga Porphyridium purpureum provides superior transgene expression properties, due to the episomal maintenance of transformation vectors as multicopy plasmids in the nucleus. Here, we have explored the potential of Porphyridium to synthesize complex pharmaceutical proteins to high levels. Testing expression constructs for a candidate subunit vaccine against the hepatitis C virus (HCV), we show that the soluble HCV E2 glycoprotein can be produced in transgenic algal cultures to high levels. The antigen undergoes faithful posttranslational modification by N-glycosylation and is recognized by conformationally selective antibodies, suggesting that it adopts a proper antigenic conformation in the endoplasmic reticulum of red algal cells. We also report the experimental determination of the structure of the N-glycan moiety that is attached to glycosylated proteins in Porphyridium. Finally, we demonstrate the immunogenicity of the HCV antigen produced in red algae when administered by injection as pure protein or by feeding of algal biomass. [ABSTRACT FROM AUTHOR]

Reducing the dimensions, when other additives are present, shows potential as a method to improve the dissolution and solubility of biopharmaceutical classification system class II drugs that have poor solubility. In this investigation, the process involved grinding naproxen with nicotinamide with the aim of improving solubility and the rate of dissolution. Naproxen was subjected to co-milling with urea, dimethylurea, and nicotinamide using a planetary ball mill for a duration of 90 min, maintaining a 1:1 molar ratio for the excipients (screening studies). The co-milled combinations, naproxen in its pure milled form, and a physical mixture were subjected to analysis using X-ray powder diffraction (XRPD), scanning electron microscopy (SEM), and solubility assessment. The mixture displaying the highest solubility (naproxen-nicotinamide) was chosen for further investigation, involving testing for intrinsic dissolution rate (IDR) and Fourier-transform infrared spectroscopy (FTIR) after co-milling for both 90 and 480 min. The co-milled combination, denoted as S-3b and consisting of the most substantial ratio of nicotinamide to naproxen at 1:3, subjected to 480 min of milling, exhibited a remarkable 45-fold increase in solubility and a 9-fold increase in IDR. XRPD analysis of the co-milled samples demonstrated no amorphization, while SEM images portrayed the aggregates of naproxen with nicotinamide. FTIR outcomes negate the presence of any chemical interactions between the components. The co-milled sample exhibiting the highest solubility and IDR was used to create a tablet, which was then subjected to comprehensive evaluation for standard attributes. The results revealed improved compressibility and dissolution properties. [ABSTRACT FROM AUTHOR]

AbstractThe present study was designed to develop a self-micellizing solid dispersion (SMSD) containing Thymoquinone (TQM), a phytonutrient obtained from Nigella sativa seeds, aiming to improve its biopharmaceutical and nephroprotective functions. The apparent solubility of TQM in polymer solutions was used to choose an appropriate amphiphilic polymer that could be used to make an SMSD system. Based on the apparent solubility, Soluplus® was selected as an appropriate carrier, and mixing with TQM, SMSD-TQM with different loadings of TQM (5–15%) was made by solvent evaporation and freeze-drying techniques, respectively, and the formulations were optimized. The optimized SMSD-TQM was evaluated in terms of particle size distribution, morphology, release characteristics, pharmacokinetic behavior, and nephroprotective effects in a rat model of acute kidney injury. SMSD-TQM significantly improved the dissolution characteristics (97.8%) of TQM in water within 60 min. Oral administration of SMSD-TQM in rats exhibited a 4.9-fold higher systemic exposure than crystalline TQM. In a cisplatin-induced (6 mg/kg, i.p.) acute kidney-damaged rat model, oral SMSD-TQM (10 mg/kg) improved the nephroprotective effects of TQM based on the results of kidney biomarkers and histological abnormalities. These findings suggest that SMSD-TQM might be efficacious in enhancing the nephroprotective effect of TQM by overcoming biopharmaceutical limitations.

The role of mass spectrometry (MS) has become more important in most application domains in recent years. Pharmaceutical analysis is specific due to its stringent regulation procedures, the need for good laboratory/manufacturing practices, and a large number of routine quality control analyses to be carried out. The role of MS is, therefore, very different throughout the whole drug development cycle. While it dominates within the drug discovery and development phase, in routine quality control, the role of MS is minor and indispensable only for selected applications. Moreover, its role is very different in the case of analysis of small molecule pharmaceuticals and biopharmaceuticals. Our review explains the role of current MS in the analysis of both small‐molecule chemical drugs and biopharmaceuticals. Important features of MS‐based technologies being implemented, method requirements, and related challenges are discussed. The differences in analytical procedures for small molecule pharmaceuticals and biopharmaceuticals are pointed out. While a single method or a small set of methods is usually sufficient for quality control in the case of small molecule pharmaceuticals and MS is often not indispensable, a large panel of methods including extensive use of MS must be used for quality control of biopharmaceuticals. Finally, expected development and future trends are outlined. [ABSTRACT FROM AUTHOR]

Copyright of Current Biotechnology (2095-2341) is the property of Chinese Academy of Agricultural Sciences, Institute of Biotechnology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Forced degradation, also known as stress testing, is used throughout pharmaceutical development for many purposes including assessing the comparability of biopharmaceutical products according to ICH Guideline Q5E. These formal comparability studies, the results of which are submitted to health authorities, investigate potential impacts of manufacturing process changes on the quality, safety, and efficacy of the drug. Despite the wide use of forced degradation in comparability assessments, detailed guidance on the design and interpretation of such studies is scarce. The BioPhorum Development Group is an industry-wide consortium enabling networking and sharing of common practices for the development of biopharmaceuticals. The BioPhorum Development Group Forced Degradation Workstream recently conducted several group discussions and a benchmarking survey to understand current industry approaches for the use of forced degradation studies to assess comparability of protein-based biopharmaceuticals. The results provide insight into the design of forced degradation studies, analytical characterization and testing strategies, data evaluation criteria, as well as some considerations and differences for non-platform modalities (e.g., non-traditional mAbs). This article presents survey responses from several global companies of various sizes and provides an industry perspective and experience regarding the practicalities of using forced degradation to assess comparability. [ABSTRACT FROM AUTHOR]

Drug repurposing refers to the process of discovering new therapeutic uses for existing medicines. Compared to traditional drug discovery, drug repurposing is attractive for its speed, cost, and reduced risk of failure. However, existing approaches for drug repurposing involve complex, computationally‐intensive analytical methods that are not widely used in practice. Instead, repurposing decisions are often based on subjective judgments from limited empirical evidence. In this article, we develop a novel Bayesian network meta‐analysis (NMA) framework that can predict the efficacy of an approved treatment in a new indication and thereby identify candidate treatments for repurposing. We obtain predictions using two main steps: first, we use standard NMA modeling to estimate average relative effects from a network comprised of treatments studied in both indications in addition to one treatment studied in only one indication. Then, we model the correlation between relative effects using various strategies that differ in how they model treatments across indications and within the same drug class. We evaluate the predictive performance of each model using a simulation study and find that the model minimizing root mean squared error of the posterior median for the candidate treatment depends on the amount of available data, the level of correlation between indications, and whether treatment effects differ, on average, by drug class. We conclude by discussing an illustrative example in psoriasis and psoriatic arthritis and find that the candidate treatment has a high probability of success in a future trial. [ABSTRACT FROM AUTHOR]

• Biopharmaceutical industries are important sources of VOCs emission. • The types and emissions of VOCs are related to the processes adopted by enterprises. • Health risks was emulated based on the simulation of pollutants diffusion. • The VB12 process led to considerable ozone formation potential. • Benzene and chlorobenzene cause significant SOA formation potential. The biopharmaceutical industry contributes substantially to volatile organic compounds (VOCs) emissions, causing growing concerns and social developmental conflicts. This study conducted an on-site investigation of the process-based emission of VOCs from three biopharmaceutical enterprises. In the workshops of the three enterprises, 26 VOCs were detected, which could be sorted into 4 classes: hydrocarbons, aromatic hydrocarbons, oxygen-containing compounds, and nitrogen-containing compounds. Ketones were the main components of waste gases, accounting for 44.13%–77.85% of the overall VOCs. Process-based source profiles were compiled for each process unit, with the fermentation and extraction units of tiamulin fumarate being the main source of VOC emissions. Dimethyl heptanone, vinyl acetate, diethylamine, propylene glycol methyl ether (PGME), and benzene were screened as priority pollutants through a fuzzy comprehensive evaluation system. Ground level concentration simulation results of the Gauss plume diffusion model demonstrated that the diffusivity of VOCs in the atmosphere was relatively high, indicating potential non-carcinogenic and carcinogenic risks 1.5–2 km downwind. Furthermore, the process-based formation potentials of ozone and secondary organic aerosols (SOAs) were determined and indicated that N -methyl-2-pyrrolidone, dimethyl heptanone, and PGME should be preferentially controlled to reduce the ozone formation potential, whereas the control of benzene and chlorobenzene should be prioritized to reduce the generation of SOAs. Our results provide a basis for understanding the characteristics of VOC emission by biopharmaceutical industries and their diffusion, potentially allowing the development of measures to reduce health risks and secondary pollution. [Display omitted] [ABSTRACT FROM AUTHOR]

Flow imaging microscopy (FIM) is widely used to characterize biopharmaceutical subvisible particles (SVPs). The segmentation threshold, which defines the boundary between the particle and the background based on pixel intensity, should be properly set for accurate SVP quantification. However, segmentation thresholds are often subjectively and empirically set, potentially leading to variations in measurements across instruments and operators. In the present study, we developed an objective method to optimize the FIM segmentation threshold using poly(methyl methacrylate) (PMMA) beads with a refractive index similar to that of biomolecules. Among several candidate particles that were evaluated, 2.5-µm PMMA beads were the most reliable in size and number, suggesting that the PMMA bead size analyzed by FIM could objectively be used to determine the segmentation threshold for SVP measurements. The PMMA bead concentrations measured by FIM were highly consistent with the indicative concentrations, whereas the PMMA bead size analyzed by FIM decreased with increasing segmentation threshold. The optimal segmentation threshold where the analyzed size was closest to the indicative size differed between an instrument with a black-and-white camera and that with a color camera. Inter-instrument differences in SVP concentrations in acid-stressed recombinant adeno-associated virus (AAV) and protein aggregates were successfully minimized by setting an optimized segmentation threshold specific to the instrument. These results reveal that PMMA beads can aid in determining a more appropriate segmentation threshold to evaluate biopharmaceutical SVPs using FIM. [ABSTRACT FROM AUTHOR]

Patients with psoriasis are more likely to experience depression and suicidality compared to non-psoriatic patients, though systemic therapies have been shown to improve depressive symptoms. It is unclear whether or not biologic or oral agents are more effective at improving such depressive symptoms in psoriasis patients, however. We aimed to determine an estimate of the odds of incident depression in psoriasis patients on different systemic therapies by performing a cross-sectional analysis of postmarketing data. The reporting odds ratio (ROR) for 15 different systemic agents was calculated using reports from the Food and Drug Administration Adverse Events Reporting System (FAERS). After excluding brodalumab and apremilast due to high risk of reporting bias, we found oral agents were associated with a significantly higher ROR of depression compared to biologics (OR = 2.42, 95% confidence interval: 1.93–3.04). These results suggest biologics may be more effective at reducing incident depression than oral agents. Future controlled trials are needed to confirm these findings.

Red ginger is a biopharmaceutical that is demanded greatly by the public. The quality of ginger rhizome is determined by its phytochemical content. Most of the ginger rhizomes farmers produce are not from environmentally friendly cultivations. This research is essential to determine the increase in the phytochemical content of red ginger cultivated using eco-enzymes. The study was arranged using a completely randomized design (CRD) in three replications with no eco-enzyme treatment (control), and eco-enzyme concentration of 0.25%, 0.50%, and 0.75%. Agronomic character variables of the ginger plants and the phytochemical content of the rhizomes were observed. Data analysis used Analysis of Variance (ANOVA) at the significant level. A Duncan's Multiple Range Test was performed at the significant level to determine the significant differences between treatments. The results showed that applying eco-enzymes to ginger plants increased the number of tillers, root dry weight, and rhizome dry weight. Also, the application of eco-enzymes increases the phenolic content markedly. Therefore, ecoenzymes are recommended for red ginger cultivation to improve the quality and yield of rhizomes. [ABSTRACT FROM AUTHOR]

Despite steam sterilisation in autoclaves being a common industrial method of sterilisation, very little research has been conducted into quantifying the resources these processes demand and their associated environmental impacts. This paper aims to investigate industrial steam sterilisation in autoclaves with particular application to the biopharmaceutical industry. A mathematical model of a steam autoclave was developed to examine relationships between load size, load material properties and autoclave capacity with energy consumption, environmental impact and cost of sterilisation. The two main energy requirements are thermal energy to produce the clean steam for sterilising, and electrical energy for the vacuum pump. The study showed that thermal energy is dominant, particularly as load increases. The percentage of the maximum load at which the autoclave is operated has a major impact on the specific energy requirement or the energy required to sterilise per unit mass of load. For a given autoclave, the energy requirement increases with increased load but the specific energy requirement decreases. This in turn impacts on the emissions and the energy cost. It is thus shown that it is much more energy efficient to operate at higher loads, making the autoclave much more energy and cost effective, and with less environmental impact. There is potential for applying the analysis presented in this work for conducting optimisation studies for determining the sizes of autoclaves that could minimise the energy requirement, environmental impact and economic cost (3E) of investments for specified load versus time profiles. [ABSTRACT FROM AUTHOR]

L-asparaginase (ASNase) is an efficient inhibitor of tumor development, used in chemotherapy sessions against acute lymphoblastic leukemia (ALL) tumor cells; its use results in 80% complete remission of the disease in treated patients. Saccharomyces cerevisiae's L-asparaginase II (ScASNaseII) has a high potential to substitute bacteria ASNase in patients that developed hypersensitivity, but the endogenous production of it results in hypermannosylated immunogenic enzyme. Here we describe the genetic process to acquire the ScASNaseII expressed in the extracellular medium. Our strategy involved a fusion of mature sequence of protein codified by ASP3 (amino acids 26–362) with the secretion signal sequence of Pichia pastoris acid phosphatase enzyme; in addition, this DNA construction was integrated in P. pastoris Glycoswitch® strain genome, which has the cellular machinery to express and secrete high quantity of enzymes with humanized glycosylation. Our data show that the DNA construction and strain employed can express extracellular asparaginase with specific activity of 218.2 IU mg−1. The resultant enzyme is 40% more stable than commercially available Escherichia coli's ASNase (EcASNaseII) when incubated with human serum. In addition, ScASNaseII presents 50% lower cross-reaction with anti-ASNase antibody produced against EcASNaseII when compared with ASNase from Dickeya chrysanthemi. [ABSTRACT FROM AUTHOR]

Biopharmaceutical protein production using transgenic plant cell bioreactor processes offers advantages over microbial and mammalian cell culture platforms in its ability to produce complex biologics with simple chemically defined media and reduced biosafety concerns. A disadvantage of plant cells from a traditional batch bioprocessing perspective is their slow growth rate which has motivated us to develop semicontinuous and/or perfusion processes. Although the economic benefits of plant cell culture bioprocesses are often mentioned in the literature, to our knowledge no rigorous technoeconomic models or analyses have been published. Here we present technoeconomic models in SuperPro Designer® for the large-scale production of recombinant butyrylcholinesterase (BChE), a prophylactic/therapeutic bioscavenger against organophosphate nerve agent poisoning, in inducible transgenic rice cell suspension cultures. The base facility designed to produce 25 kg BChE per year utilizing two-stage semicontinuous bioreactor operation manufactures a single 400 mg dose of BChE for $263. Semicontinuous operation scenarios result in 4-11% reduction over traditional two-stage batch operation scenarios. In addition to providing a simulation tool that will be useful to the plant-made pharmaceutical community, the model also provides a computational framework that can be used for other semicontinuous or batch bioreactor-based processes.

Abstract The COVID-19 pandemic has once again brought the significance of biopharmaceutical and medical technology sectors to the spotlight. Seeing that some of the most critical medical breakthroughs such as the speedy mRNA vaccine development were results of cross-border patenting collaboration, we have proposed in a previous work a new method to identify the cross-border collaborative regional centres in the patent networks, using a clustering comparison approach based on adjusted mutual information (AMI). In this paper, we focus on the UK industrial landscape. We use the UK bioscience and health technology sector statistics from 2015 to 2020 and look into the regional growth of each postcode area. We compare the top growth regions with the cross-border collaborative centres identified using AMI comparison at the postcode area level, and find that both long-term and short-term AMI gains show an increase in the correlation with regional annual growth rates of firm numbers in the studied sectors from 2016 to 2020, and the increase is more consistent with the short-term AMI gain. We also found that areas more central in the long-term cross-regional R&D collaboration demonstrate a stronger association with more developed industrial settings indicated by more firms and, potentially more employment and turnover in the field. However, AMI gains are found to have negative correlations with the industrial growths as a sign of possible trade-offs of being central.

Objectives: Solid biopharmaceutical products can circumvent lower temperature storage and transport and increase remote access with lower carbon emissions and energy consumption. Saccharides are known stabilizers in a solid protein produced via lyophilization and spray drying (SD). Thus, it is essential to understand the interactions between saccharides and proteins and the stabilization mechanism. Methods: A miniaturized single droplet drying (MD) method was developed to understand how different saccharides stabilize proteins during drying. We applied our MD to different aqueous saccharide-protein systems and transferred our findings to SD. Results: The poly- and oligosaccharides tend to destabilize the protein during drying. The oligosaccharide, Hydroxypropyl β-cyclodextrin (HPβCD) shows high aggregation at a high saccharide-to-protein molar ratio (S/P ratio) during MD, and the finding is supported by nanoDSF results. The polysaccharide, Dextran (DEX) leads to larger particles, whereas HPBCD leads to smaller particles. Furthermore, DEX is not able to stabilize the protein at higher S/P ratios either. In contrast, the disaccharide Trehalose Dihydrate (TD) does not increase or induce protein aggregation during the drying of the formulation. It can preserve the protein's secondary structure during drying, already at low concentrations. Conclusion: During the drying of S/P formulations containing the saccharides TD and DEX, the MD approach could anticipate the in-process (in) stability of protein X at laboratory-scale SD. In contrast, for the systems with HPβCD, the results obtained by SD were contradictory to MD. This underlines that depending on the drying operation, careful consideration needs to be applied to the selection of saccharides and their ratios. [ABSTRACT FROM AUTHOR]

Attractive self‐interactions of therapeutic proteins are linked to problematic solution behaviors at high protein concentrations such as reversible or irreversible aggregation, high viscosity, opalescence, phase separation, and low solubility. Prediction of attractive self‐interactions early in development can improve the processes of formulation development and candidate selection. To that end, a coarse‐grained model with explicit representation of charged sites was used to accurately predict a broad range of protein self‐interactions at high protein concentrations (up to 160 mg/ml) for multiple monoclonal antibodies and formulations, including strong electrostatic attractions, with static light scattering measurements at low protein concentrations as the only experimental input. In addition, Mayer‐weighted electrostatic energies for charged residues from these simulations can contribute to understanding of electrostatic interactions and guide the development of protein variants. [ABSTRACT FROM AUTHOR]

Technological catch-up is a very complex and time-consuming process that requires all kinds of capabilities to be acquired by the latercomer firms in order to successfully complete the various stages. This process is influenced by various factors that determine its failure or success. Considering the factors affecting the successful and unsuccessful cases in the catch-up process can gain a good insight for companies and countries that want to go through this path successfully. In this regard, in the present study, with the help of a systematic review of the literature, a framework of factors affecting the success of pharmaceutical, biopharmaceutical and knowledge-based industries was extracted in order to make a comparative comparison with the catch-up situation in the biopharmaceutical industry in Iran. Quantitative support of foreign and domestic studies of each of the factors by Shannon entropy method is calculated and compared with each other to identify gaps in the catch-up of the Iranian biopharmaceutical industry. The obtained results show that there is a high similarity between domestic and international articles in terms of entropy in terms of institutional environment, capability building, and technological regimes. It is also necessary to improve the unfavorable position of the domestic industry in the factors of the market catch-up, organizational issues and the catch-up strategies with the help of the proposed solutions.

Process models are mathematical formulations (essentially a set of equations) that try to represent the real system/process in a digital or virtual form. These are derived either based on fundamental physical laws often combined with empirical assumptions or learned based on data. The former has been existing for several decades in chemical and process engineering while the latter has recently received a lot of attention with the emergence of several artificial intelligence/machine learning techniques. Hybrid modeling is an emerging modeling paradigm that explores the synergy between existing these two paradigms, taking advantage of the existing process knowledge (or engineering know-how) and information disseminated by the collected data. Such an approach is especially suitable for systems and industries where data generation is significantly resource intensive while at the same time fundamentally not completely deciphered such as the processes involved in the biopharmaceutical pipeline. This technology could, in fact, be the enabler to meeting the demands and goals of several initiatives such as Quality by design, Process Analytical tools, and Pharma 4.0. In addition, it can aid in different process applications throughout process development and Chemistry, Manufacturing, and Control (CMC) to make it more strategic and efficient. This article focuses on providing a step-by-step guide to the different considerations to be made to develop a reliable and applicable hybrid model. In addition, the article aims at highlighting the need for such tools in the biopharmaceutical industry and summarizes the works that advocate its implications. Subsequently, the key qualities of hybrid modeling that make it a key enabler in the biopharmaceutical industry are elaborated with reference to the literature demonstrating such qualities.

The global market for biopharmaceuticals is currently growing, and lyophilization is becoming increasingly important. Lyophilization is a time- and cost-consuming process for which the programs and recipes must be optimized to ensure product quality with minimum process time. However, a sufficient number of experiments for optimization of production-scale lyophilizers have not been performed due to limitations in actual pharmaceutical development, and a breakthrough approach is required to establish optimal lyophilization conditions with the limited experimental data available. Although there are a great number of published works associated with lyophilization of pharmaceutical products, the scale-up/tech transfer of the lyophilization process for biopharmaceuticals is still difficult. This review aims to discuss the difficulty of process development of lyophilization from an industry perspective and to introduce promising novel technologies and approaches and new findings related to successful lyophilization of biopharmaceuticals. [ABSTRACT FROM AUTHOR]

Various industries ranging from water purification to pharmaceutical production have experienced multi separation steps that impose more process time and contamination possibility by batch operation. We propose a developed microfluidic particle sorter (miniaturized hydrocyclone) that adopts centrifugal force as it has ability to decline the number of separation steps and the risk of extrinsic contamination in continuous process. While biological industries have not relied on mini hydrocyclones considerably because of low efficiency and microfabrication difficulties, current work has been planned to conquer these obstacles. In this research, biomass separation from fermentation broth by 3 mm hydrocyclones was investigated. The effect of apex size, feed flow rate, hydrocyclone geometry were analyzed numerically in four mini-hydrocyclones. The most efficient mini-hydrocyclone was chosen to be made by elegant additive manufacturing technology and studied experimentally. The separation efficiency was achieved up to 90% while the concentration ratio of heavy stream (apex) to dilute stream (vortex finder) was reached more than twofold. The mini hydrocyclone performance in view of energy target was studied by Euler-Reynolds-Efficiency plots. The 4 μm cut size was achieved that is promising high throughput separation for biological particles. [ABSTRACT FROM AUTHOR]

The enzyme L-asparaginase (L-asparagine amidohydrolase) catalyzes the breakdown of L-asparagine into aspartate and ammonia, which leads to an anti-neoplastic activity stemming from its capacity to deplete L-asparagine concentrations in the bloodstream, and it is therefore used in cases of acute lymphoblastic leukemia (ALL) to inhibit malignant cell growth. Nowadays, this anti-cancer enzyme, largely produced by Escherichia coli, is well established on the market. However, E. coli L-asparaginase therapy has side effects such as anaphylaxis, coagulation abnormality, low plasma half-life, hepatotoxicity, pancreatitis, protease action, hyperglycemia, and cerebral dysfunction. This review provides a perspective on the use of filamentous fungi as alternative cell factories for L-asparaginase production. Filamentous fungi, such as various Aspergillus species, have superior protein secretion capacity compared to yeast and bacteria and studies show their potential for the future production of proteins with humanized N-linked glycans. This article explores the past and present applications of this important enzyme and discusses the prospects for using filamentous fungi to produce safe eukaryotic asparaginases with high production yields. [ABSTRACT FROM AUTHOR]

Copyright of Pedagogía Profesional is the property of Universidad de Ciencias Pedagogicas "Enrique Jose Varona" Facultad de Ciencias Tecnicas and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

We review medical economics literature presented at the 2023 annual AEA-ASSA convention, the largest gathering of economists worldwide. Pharmacoeconomic papers addressed a wide range of issues, including gender and racial gaps in clinical trials, hospital credit financing, drug rebates, covid-19 vaccine equality, and the opioid epidemic. Yet, they had some common identifiable themes. We examine them in the context of the "twin towers" of biopharmaceutical innovation: discovery and commercialization. Implementation outcomes and relative success of innovative solutions — whether in terms of products and services, structural design and arrangements, or policies — depend on how adequately they respond to questions and challenges that arise in drug discovery and commercialization, and who gains from them. That innovation's beneficiaries might not equally gain from its intended advantages is another unifying theme in the reviewed literature. Against this backdrop, biopharmaceutical innovation can breed new challenges and opportunities. And health policy can perform a critical, leveling function that reduces cost, increases access, and ensures quality of biopharmaceutical solutions. [ABSTRACT FROM AUTHOR]

Pharmaceuticals, biotechnology, and technological advances are currently a new paradigm with ample potential to provide therapeutic solutions to multiple diseases. The purpose of this study was to survey granted patents related to biopharmaceutical products. The most important results show that most of these inventions are concentrated in the United States, and European and Asian countries, and that US companies are the clear leaders in this area of knowledge, reaffirming its position as one of the most important technological markets in the world. Additionally, the technological classes, established according to search criteria, that have shown the most progress over time has to do with medicinal preparations containing antigens or antibodies, as well as those associated with peptides. Finally, the role of the Latin American market is not relevant for the production of this group of technologies; consequently, it is important to define strategies for their inclusion in countries in the region and to promote cooperation in terms of research and development. This course of action will provide the region with the possibility of increasing technological capabilities that will allow it to innovate within the sector. [ABSTRACT FROM AUTHOR]

The biopharmaceutical industry is evolving with a shift in focus from recombinant proteins and antibodies towards more complex cell and gene therapies. To be competitive globally, biomanufacturers need to focus on aligning with global standards with regard to drug quality, reducing manufacturing failures and delivering drugs to market quickly. Building these capabilities requires a multifaceted approach that includes improvements in operations, quality compliance, and control strategies. To address these needs, the US Pharmacopeia (USP), the Department of Biotechnology (DBT) India, and the Confederation of Indian Industry (CII) held a symposium to discuss the requirements and gaps in the biotechnology and pharmaceutical sectors in India and other developing countries. A panel of experts from academia, manufacturing, and governmental agencies identified several drivers needed for capability building, including a skilled workforce, public–private partnerships, advanced manufacturing technologies, novel biologics, and favorable policies. This article summarizes the recommendations put forward by this panel. [ABSTRACT FROM AUTHOR]

[Display omitted] • A hollow PVDF fiber was modified into a Janus membrane through UV-irradiation. • The water flux can be increased through the reduction of membrane fouling. • The Janus membrane can remove on 20-nm-scale viruses. • The membranes were modified with anionic-hydrophobic/anionic-hydrophilic modifiers. • The initial log reduction value (LRV) and filtration efficiency were excellent against viruses. In this study, a hollow polyvinylidene fluoride (PVDF) fiber was developed and modified into a Janus membrane (Janus-VM) and an entirely hydrophobic membrane (Hydrophobic-VM) for removing 20-nm-scale viruses during biopharmaceutical processing. The Janus-VM has anionic properties on the outer and feed hydrophilic surfaces, and the inner pore surface (I.P.S) maintains the anionic-hydrophobic properties of the PVDF. Theoretically, an electrostatic repulsion force might be formed between the surface of the strong anionic membrane and anionic bacteriophages, preventing bacteriophages from adsorbing to the membrane surface. As a result, water flux can be increased through the reduction of membrane fouling. The PVDF membrane was modified through UV-irradiation, which causes –OH radicals to form on the membrane surface, and chemical grafting with anionic-hydrophobic/anionic-hydrophilic modifiers, which enhances the membrane's anion characteristics (−27, −48 mV). Additionally, the average pore size was reduced from 34 nm to less than 20 nm through chemical surface modification, after which the Janus membrane showed an excellent initial water flux, with the protein recovery ratio (PRR) approaching 98.9 %. UV absorbance analysis revealed 100 % removal efficiency for 20- and 40-nm gold particles on the membranes. Furthermore, the initial log reduction value (LRV) was observed through flux performance using MS2 and PP7 bacterial phages, for which the Janus membrane showed an excellent virus removal performance (LRV > 6.8 and 6.5). [ABSTRACT FROM AUTHOR]

The aim of the study was to examine the benefit of combination of organic (manure) and an organic fertilizer (NPK) along with the use of biofertilizer to improve cardamon growth and performance as Covid-19 biopharmaceutical raw material. The results showed that the application of NPK fertilizer in combination with NPK fertilizer had a significant effect on the observed variables, including: plant height, number of leaves, number of shoots per clump, number of flowers per clump, but had no significant effect on the observed variable number of stems. The best treatment was found at P5 treatment (200% NPK fertilizer + 200% manure) for observation variables of plant height, number of leaves, and number of shoots per clump, while the best treatment for the observation variable of the number of flowers per clump was found in the treatment P9 (NPK fertilizer 200%). The use of multivariate analysis has been successfully grouped and positioned each treatment in 2 dimensional graphs.

Pharmaceuticals, biotechnology, and technological advances are currently a new paradigm with ample potential to provide therapeutic solutions to multiple diseases. The purpose of this study was to survey granted patents related to biopharmaceutical products. The most important results show that most of these inventions are concentrated in the United States, and European and Asian countries, and that US companies are the clear leaders in this area of knowledge, reaffirming its position as one of the most important technological markets in the world. Additionally, the technological classes, established according to search criteria, that have shown the most progress over time has to do with medicinal preparations containing antigens or antibodies, as well as those associated with peptides. Finally, the role of the Latin American market is not relevant for the production of this group of technologies; consequently, it is important to define strategies for their inclusion in countries in the region and to promote cooperation in terms of research and development. This course of action will provide the region with the possibility of increasing technological capabilities that will allow it to innovate within the sector.

Polysorbate (also known as "Tween") 80 (PS80) is the most common surfactant in biopharmaceuticals. Here, we report a sensitive, and specific platform analytical method using reversed-phase high performance liquid chromatography employing a charged aerosol detector (HPLC-CAD), that offers the ability to quantitate intact PS80 and can distinguish between low recovery of PS80 and degraded PS80 by also monitoring several PS80 degradants which offers multiple improvements over various previously reported polysorbate analytical methods. The method employs protein/monoclonal antibody precipitation and is designed to be a quality control (QC) lab-friendly method. The method is distinguishable from other published methods because the quantification of the PS80 mono-esters is free from interference from known PS80 degradants. The method has demonstrated acceptable accuracy, precision, specificity, and sensitivity through qualification studies. The specificity afforded by the method allows for employment in forced degradation studies to discern kinetic information. Lastly, the method also has promising applications with other polysorbates (PS60, PS40, and all-laurate PS20) and shows acceptable performance with several types of biopharmaceutical proteins. [ABSTRACT FROM AUTHOR]

Biomacromolecules are viewed as promising drugs due to their specific functions in biological processes, biocompatibility, and pharmacological efficacy. Injective administration, chosen to avoid intestinal barriers, may in turn lead to immediate decay in the circulation system, unreliable targeting performance, or the induction of immune responses. For some biomacromolecules, chemically modified proteins have been developed for practical use. Various cargo or carrier systems are under development but have been delayed by technical difficulties. We present self-assembled nanocapsules with diameters ranging from 100 to 500 nm that can be deployed in physiological buffers to enclose various substances present in the buffers at the same time. Our amphiphilic nanocapsule, consisting of silole-core dendrimer products as the hydrophobic part and green fluorescent protein (GFP) derivatives as the hydrophilic part, connects and assembles spontaneously when mixed in solutions while engulfing dissolved or dispersed compounds together in a dose-dependent manner and shows unique optical characteristics because the dendrimer products exhibit aggregation-induced emission. Furthermore, the emission of the dendrimer causes considerable fluorescence resonance energy transfer (FRET) to GFP derivatives upon association. We could easily monitor assemblies by FRET states and particle sizes and have confirmed a stable presence in the buffer for at least a month. Further tracking of nanocapsules by fluorescence confirmed efficient uptake into some cancer cells. Nanocapsules based on GFP variants with or without a cell-surface-specific tag demonstrated that the tag improved the potential for specific targeted delivery. There were also indications that the nanocapsules became unstable after cellular uptake in the intracellular environment. We report here the simple preparation of traceable, stable, and biocompatible self-assembled nanocapsules as the basis for a versatile drug delivery system.

Background: Supply chain risk management can help companies detect potential hazards,mitigate potential risks, and thereby increase supply chain efficiency. The biopharmaceuticalindustry in Iran has a generic-based pharmerging market. Therefore, identifying risksassociated with the supply chain of those drugs can significantly boost the possibility of successof biopharmaceutical companies. This study is conducted to determine the supply chain riskfactors of biopharmaceuticals companies in Iran. Methods: The current research work is a qualitative-quantitative study. A systematic review andinterview with experts (n=14) were conducted to identify potential supply chain risks in thebiopharmaceutical industries. To determine the significance of identified risks, Fuzzy screeningmethod was employed to collect the opinions of experts (n=16) in the biopharmaceuticalindustries. Results: By systematic review and interviews with the biopharmaceutical industry experts, 100 potential risks in the biopharmaceutical industry supply chain were identified. These risks weredivided into two general categories namely macro and micro risks. Based on experts’ judgment,77 out of 100 identified risks were eliminated and 23 significant risks were determined. Themost important risks are the Ministry of health (as the regulatory body) conflict of interest, USsanctions, lack of domestic suppliers of essential materials, pseudo-productivity, and moneytransfer related to the bank’s sanctions. Conclusion: Due to the multitude of present risks and the impossibility of controlling all ofthem, it is recommended that managers and producers focus more on controlling the identifiedsignificant risks.

Introduction: The biomedical industry has grown significantly both globally and in China; however, there are still challenges. This study aimed at evaluating the biopharmaceutical sector of China, in terms of ability to innovate, current sales volume, investment, and R&D expenditure, as well as providing a case study detailing the progress and challenges of the industry in Shaanxi province. Method: A cross-sectional mixed-method study design was used to generate a comprehensive profile of the nature of biopharmaceutical innovation capacity and development in China by triangulating country-wide survey and interview data from Shaanxi province. Only biopharmaceutical companies that are currently marketing or conducting research and development were eligible for inclusion, and Shaanxi province was selected for conducting the interviews. Categorical and continuous variables were analyzed descriptively. Interviews were thematically analyzed by using NVivo version 12. Results: The analysis includes responses from 77 biopharmaceutical enterprises; the majority (36, 46.8%) are in Eastern China, followed by 26 (33.8%) in Central China. In 2018, the total sales of biological products amounted to 26.28 billion yuan, and in 2019, a slight increase was observed (30.34 billion); the amount doubled in 2020 to about 67.91 billion yuan. The top three biopharmaceutical products on sale in 2020 were Camrelizumab (5.14 billion yuan), human albumin (4.56 billion yuan), and human immunoglobulin for injection (3.78 billion yuan). Expenditure on R&D has also increased; it amounted to 1657.7 million yuan in 2018, which more than doubled in 2019 to 3572.1 million yuan and further increased to 5857.7 million yuan in 2020. Nonetheless, the progress is not uniform across all provinces, as shown from the results from Shaanxi province, because of lack of local government policies that will impact on the funding, incentives, and market share that motivate the producers.Conclusion: China’s biopharmaceutical industry has expand significantly. The increase in sales indicates that there is an increase in demand for biologicals; moreover, R&D funding is increasing. These are key indicators that influence innovation and development. However, the sector’s capacity to innovate and develop needs to be improved, particularly in the western region, where research and production are relatively weak. [ABSTRACT FROM AUTHOR]

[Display omitted] The availability of rapid methods that can accurately define and quantify biopharmaceutical critical quality attributes has been the driving force for the implementation of mass spectrometry techniques throughout the development and production pipeline. While the multi-attribute method (MAM) has become widely adopted and developed, some critical information cannot be monitored through this workflow, such as correct chain assembly or the presence of fragments or aggregates. In this study, we combine intact protein mass spectrometry and the multi-attribute method to create an intact multi-attribute method – or iMAM. Using a CFR Part 11 compliant data system, we evaluated the proposed workflow using several intact analysis approaches under both denaturing and native conditions. As for the standard MAM approach, iMAM involves the generation of an intact protein target workbook which is created from the analysis of a reference sample, with ID confirmation obtained from deconvolution results and chromatographic retention times, while quantitation is obtained from the intensities of the m / z of most abundant charge states. The created processing method is then applied to the analysis of subsequent samples. New peak detection can also be performed, monitoring the number of components revealed after each analysis. The entire data process can be automated to generate a report within the chromatography data system software. Three case studies presented herein show the potential of iMAM for implementation at different stages of the production pipeline, from product development to stability testing and batch release. [ABSTRACT FROM AUTHOR]

Liquid biopharmaceuticals including monoclonal antibodies (mAbs) have been widely acknowledged to undergo various stresses during shipping/handling and long-term storage. Several mechanical stresses including shaking during shipping has been widely known to cause protein aggregation and sub-visible particle (SbVP) formation in liquid biopharmaceutical formulations. However, shaking-induced degradation of freeze-dried (FD) biopharmaceuticals has seldomly been reported in the literature and therefore this type of stress is widely overlooked in industry due to their presumed high stability, especially when the formulations and freeze-drying processes are fully optimized. In this Lessons Learned article, we report an interesting phenomenon in which the optimized FD biopharmaceutical formulations of three typical mAbs showed much degradation and SbVP formation under shaking stress compared with their liquid counterparts. This is a striking deviation to the notion that mAbs are generally more stable in the FD formulations than in the liquid ones. Therefore, shaking stress experiment should be considered a critical stress condition for early-stage selection of liquid versus FD mAb formulations. [ABSTRACT FROM AUTHOR]