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Strategic collaborations are critical to the success of efforts aimed at discovering new drugs and therapies in the biopharmaceutical industry. These collaborations aim to leverage domain expertise, asymmetries in production costs and/or capabilities to improve efficiency. Despite increasing collaborations, the biopharmaceutical industry lacks a structured guideline for choosing contracts. We present contract models with effort-based formulations that capture the key characteristics of biopharmaceutical operations and analyse incentive mechanisms such as fixed payment, revenue-sharing, risk-sharing, and cost-sharing in biopharmaceutical collaborations. We show that traditional incentive schemes do not achieve supply chain coordination, although they are commonly used in the industry. We introduce a new contract model called fee-for-effort-and-output contract that encourages the parties to exert higher efforts by offering discounts on their operating costs, and show that this contract achieves coordination with an appropriate selection of contract parameters. We also investigate the efficiency of noncoordinating contracts with traditional incentive schemes and identify the capability and cost structures under which they achieve the highest efficiency possible, to both determine the next-best alternatives and explain their popularity in practice. [ABSTRACT FROM AUTHOR]

Regulatory authorities in biopharmaceutical industry emphasize process design by process understanding but applicable tools that are easy to implement are still missing. Soft sensors are a promising tool for the implementation of the Quality by Design (QbD) approach and Process Analytical Technology (PAT). In particular, the correlation between viable cell counting and oxygen consumption was investigated, but problems remained: Either the process had to be modified for excluding CO 2 in pH control, or complex k L a models had to be set up for specific processes. In this work, a non-invasive soft sensor for simplified on-line cell counting based on dynamic oxygen uptake rate was developed with no need of special equipment. The dynamic oxygen uptake rates were determined by automated and periodic interruptions of gas supply in DASGIP® bioreactor systems, realized by a programmed Visual Basic script in the DASware® control software. With off-line cell counting, the two parameters were correlated based on linear regression and led to a robust model with a correlation coefficient of 0.92. Avoidance of oxygen starvation was achieved by gas flow reactivation at a certain minimum dissolved oxygen concentration. The soft sensor model was established in the exponential growth phase of a Chinese Hamster Ovary fed-batch process. Control studies showed no impact on cell growth by the discontinuous gas supply. This soft sensor is the first to be presented that does not require any specialized additional equipment as the methodology relies solely on the direct measurement of oxygen consumed by the cells in the bioreactor. • Non-invasive soft sensor method for simplified on-line cell counting. • Implemented in exponential growth phase of CHO cells. • Dynamic oxygen uptake rate as only predictor resulted in a correlation coefficient of 0.92. • No negative influences on cell growth as oxygen starvation was prevented. • 5-k cross validation showed RMSE of 0.7 × 106 cells/mL. [ABSTRACT FROM AUTHOR]

As a responsible business philosophy, sustainable management is becoming a widely accepted management mode among managers, practitioners, stakeholders, and customers. The sustainable development of business management calls for the practice of the environmental, social, and governance (ESG) principle. Companies that neglect ESG criteria in their business operations may face unexpected consequences. Therefore, the ESG sustainable performance of the company is becoming a benchmark to evaluate environmental and social responsibility of companies worldwide. This paper proposes an integrated MCDM framework combining the interval type-2 fuzzy analytic hierarchy process (IT2FAHP) and the interval type-2 fuzzy combined compromise solution (IT2F-CoCoSo) method for evaluating the ESG sustainable performance of listed companies. In the integrated MCDM framework, the interval type-2 fuzzy sets serve as an effective tool to transform qualitative linguistic evaluation into quantitative expression, the criteria weights are obtained using the IT2FAHP, and the rankings of alternatives are determined by the IT2F-CoCoSo method. The proposed method is applied in a case study on the ESG sustainable performance evaluation of five medical listed companies, which are evaluated based on three aspects: E, S, and G and further divided into 14 criteria. Results reveal that the most important criterion in the E, S, and G aspects are pollution treatment, health and safety, and risk management. It suggests that the Pfizer biopharmaceutical company has the best ESG sustainable performance among the five alternative medical listed companies. We perform a sensitivity analysis with random criteria weights and different parameter values to show the stability of the proposed approach. A comparison is also performed between our approach and some existing methods for validating the proposed approach. This analysis shows that the proposed approach is efficient and well-consistent with the other methods. [ABSTRACT FROM AUTHOR]

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]

The impact of orbitally shaking bioreactors (OSRs) on the biopharmaceutical industry is becoming increasingly important. In the preliminary exploration of the orbitally shaking bioreactor performance, the vessel wall shape has a crucial influence on the mixing and mass transfer in the bioreactor. However, the shape of OSRs still maintains a cylindrical structure, significantly limiting the advantages of the orbital shaking mixing. Therefore, in order to further improve the mixing and mass transfer performance of OSRs, a novel wall shape is proposed in this paper. This novel wall shape consists of cylindrical and square parts and looks like a square tank with a large circular chamfer (STCC), which was found could effectively enhance the efficiency of material mixing and mass transfer theoretically. Based on the same specific volumetric power consumption, a comparative analysis was conducted on the mixing time and oxygen transfer efficiency of OSRs with different shape walls using simulation and experimental methods. The results showed that the OSR with STCC was expected to perform higher mixing and oxygen transfer efficiency than the OSR with cylindrical wall. These findings suggested a promising prospect for the future application of the OSRs with STCC. • Developing a novel wall structure (STCC) improving the mixing performance of OSRs. • Both oxygen mass transfer and mixing efficiency were increased with the STCC effect. • Improving the bioreactor performance with low calculated shear stress. • Mixing speed was found significantly lower in the vortex center than other regions. • Promising prospect for the future application of the OSRs with STCC. [ABSTRACT FROM AUTHOR]

Background: The study presents two distinct analytical methods tailored for the precise determination of curcumin (CUR) and nicotinamide (NIC) within liposomal formulations, addressing the needs of researchers and analysts in the biomedical and food supplement sectors. Method: UV spectrophotometry provides a swift and cost-effective solution for quantification, while HighPerformance Liquid Chromatography (HPLC) offers enhanced specificity and sensitivity, particularly in complex matrices. Method validation, especially for HPLC, ensures reliability and suitability for rigorous analysis, advancing the field of Analytical Chemistry and strengthening development and quality assurance processes in the pharmaceutical and biotechnology industries. Results: The encapsulation efficiencies of CUR and NIC into liposomes, primarily composed of DPPC and CHO, were found to be 30% ± 6% and 80% ± 5%, respectively. The developed analytical methods using UV spectrophotometry and reverse-phase HPLC demonstrated robustness and efficiency, allowing for the simultaneous analysis of CUR and NIC with high specificity, accuracy, and p recision. Validation according to ICH Q2 guidelines revealed excellent system suitability, linearity, and robustness, with relative standard deviation consistently below 2%. Stability studies over three weeks at 4°C showed minimal changes in liposomal characteristics, indicating good stability. Furthermore, release studies at 37°C demonstrated enhanced solubility and increased release of curcumin, suggesting the potential of the liposomal formulation for drug delivery applications. Conclusion: This study developed straightforward, time-efficient, and cost-effective analytical methods using UV spectrophotometry and reverse-phase HPLC to quantify CUR and NIC encapsulated in liposomal formulations. [ABSTRACT FROM AUTHOR]

CRISPR-based high-throughput genome-wide loss-of-function screens are a valuable approach to functional genetics and strain engineering. The yeast Komagataella phaffii is a host of particular interest in the biopharmaceutical industry and as a metabolic engineering host for proteins and metabolites. Here, we design and validate a highly active 6-fold coverage genome-wide sgRNA library for this biotechnologically important yeast containing 30,848 active sgRNAs targeting over 99% of its coding sequences. Conducting fitness screens in the absence of functional non-homologous end joining (NHEJ), the dominant DNA repair mechanism in K. phaffii , provides a quantitative means to assess the activity of each sgRNA in the library. This approach allows for the experimental validation of each guide's targeting activity, leading to more precise screening outcomes. We used this approach to conduct growth screens with glucose as the sole carbon source and identify essential genes. Comparative analysis of the called gene sets identified a core set of K. phaffii essential genes, many of which relate to metabolic engineering targets, including protein production, secretion, and glycosylation. The high activity, genome-wide CRISPR library developed here enables functional genomic screening in K. phaffii , applied here to gene essentiality classification, and promises to enable other genetic screens. • Designed and validated a high activity genome-wide CRISPR-Cas9 library for K. phaffii. • Disabling non-homologous end joining (NHEJ) DNA repair enables the generation of genome-wide guide activity profiles. • Activity-corrected fitness screens identify a high confidence set of essential genes in K. phaffii. • Protein production, secretion, and glycosylation pathways are essential in K. phaffii but not in other yeasts. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are crucial regulators of gene expression involved in various pathophysiological processes. Their ability to modulate multiple pathways simultaneously and their involvement in numerous diseases make miRNAs attractive tools and targets in therapeutic development. Significant efforts have been made to advance miRNA research in the preclinical stage, attracting considerable investment from biopharmaceutical companies. Consequently, an increasing number of miRNA-based therapies have entered clinical trials for both diagnostic and therapeutic applications across a wide range of diseases. While individual miRNAs can regulate a broad array of mRNA targets, this also complicates the management of adverse effects seen in clinical trials. Several candidates have been discontinued due to toxicity concerns, underscoring the need for comprehensive risk assessments of miRNA therapeutics. Despite no miRNA-based strategies have yet received approval from regulatory agencies, prominent progress in the miRNA modulation approaches and in the nano-delivery systems have been made in the last decade, leading to the development of novel safe and well-tolerated miRNA drug candidates. In this review, we present recent advances in the development of miRNA therapeutics currently in preclinical or clinical stages for treating both rare genetic disorders and multifactorial common conditions. We also address the challenges related to the safety and targeted delivery of miRNA therapies, as well as the identification of the most effective therapeutic candidates in preclinical and clinical trials. [ABSTRACT FROM AUTHOR]

Background: Phase 1 oncology trials provide access to new therapies and may improve cancer outcomes. Phase 1 trials conducted in the Asian‐Pacific region are increasing at a faster rate than the global trend. This study aimed to describe the changing landscape of phase 1 oncology trials in Australia in the last decade. Methods: This cross‐sectional study reviewed phase 1 oncology trials registered on ClinicalTrials.gov conducted in Australia. Phase 1 trials were included for analysis if they enrolled adults with solid organ malignancies, used at least one systemic agent, and were first registered between January 1, 2012, and December 31, 2022. The number of trials, site locations, sponsor type, and drug class were analyzed using descriptive statistics. Results: Over the 10‐year period, ClinicalTrials.gov included 493 phase 1 clinical trials across 71 Australian sites. Most sites were in metropolitan locations; in Melbourne, trials were concentrated within selected sites, while in Sydney, trials were spread across a larger number of sites. The number of phase 1 trials per annum increased from 18 in 2012 to 75 in 2022. Since 2020, emerging biopharmaceutical companies have become the predominant sponsor type, a trend that is also seen globally. While most trial sponsors were North American (42%), there was increasing representation from Asian sponsors over the 10‐year period (6% in 2012 to 39% in 2022). Immunomodulatory (45%) and targeted approaches (44%) accounted for most drug classes used alone or in combination. Conclusions: There are an increasing number of phase 1 trials conducted within Australia. Sponsors of phase 1 trials are increasingly from Asian countries and are more likely to be emerging biopharmaceutical companies. [ABSTRACT FROM AUTHOR]

Polysorbate (PS) degradation in monoclonal antibody (mAb) formulations poses a significant challenge in the biopharmaceutical industry. PS maintains protein stability during drug product's shelf life but is vulnerable to breakdown by low-abundance residual host cell proteins (HCPs), particularly hydrolytic enzymes such as lipases and esterases. In this study, we used activity-based protein profiling (ABPP) coupled with mass spectrometry to identify acyl-protein thioesterase-1 (APT-1) as a polysorbate-degrading HCP in one case of mAb formulation with stability problems. We validated the role of APT1 by matching the polysorbate degradation fingerprint in the mAb formulation with that of a recombinant APT1 protein. Furthermore, we found an agreement between APT1 levels and PS degradation rates in the mAb formulation, and we successfully halted PS degradation using APT1-specific inhibitors ML348 and ML211. APT1 was found to co-purify with a specific mAb via hitchhiking mechanism. Our work provides a streamlined approach to identifying critical HCPs in PS degradation, supporting quality-by-design principles in pharmaceutical development. [ABSTRACT FROM AUTHOR]

Advanced therapy medicinal products (ATMPs) are rapidly evolving to offer new treatment options. The scientific, technical, and clinical complexities subject drug regulatory authorizes to regulatory challenges. To advance the regulatory capacity for ATMPs, the National Medical Products Administration in China made changes to the drug regulatory system and developed regulatory science with the goal of addressing patient needs and encouraging innovation. This study aimed to systematically identify the regulatory evidence on ATMPs in China under the guidance of an overarching framework from the World Health Organization Global Benchmarking Tool. It was found that China's administrative authorities at all levels have issued a number of policy documents to promote the development of ATMPs, covering biopharmaceutical products research and development (n = 14), biopharmaceutical industry development (n = 9), high-quality development of medical institutions (n = 1), specific development plans/projects (n = 6) and specific regional development (n = 4). The legal and regulatory framework of ATMPs in China has been established and is subject to continuous adjustment in various aspects including regulations (n = 3), departmental rules or administrative normative documents (n = 22), and technical guidance (n = 15). As the regulatory reform continues, the drug review processes have been revised, and various technical standards have been launched, which aim to establish a regulatory approach that oversees the full life-cycle development of ATMPs in the country. The limited number of investigational new drug applications and approved ATMPs suggests a lag remains between the translation of advanced therapeutic technologies into clinically available medical products. To accelerate the translational research of ATMP in countries such as China, developing and adopting real-world evidence generated from clinical use in designated healthcare facilities to support scientific decision-making in ATMP regulation is warranted. The enhancement of regulatory capacity building and multi-stakeholder collaborations should also be encouraged to facilitate the timely evaluation of promising ATMPs to meet more patient needs. [ABSTRACT FROM AUTHOR]

Purpose: Indirect knowledge leakage to rivals located near alliance partners represents a significant risk that has received limited scholarly attention. Hence, the question of how to manage this risk – which the authors term "partner-rival co-location risk" – in nonequity alliances remains unanswered, and this study aims to suggest establishing a steering committee to oversee the partnership. Design/methodology/approach: Drawing on the agglomeration economies and alliance governance literatures, the authors develop a set of hypotheses and perform a series of empirical tests on 470 nonequity alliances in the US biopharmaceutical industry. Findings: The authors propose that there is a positive linkage between partner-rival co-location risk and the formation of a steering committee in a nonequity alliance, which receives strong empirical support. Further, this relationship is significantly moderated by the breadth (alliance scope) but not the depth (reciprocal interdependence) of interaction between the partnering firms. Originality/value: This paper is a pioneer to shed light on "partner-rival co-location risk" and how partner-rival co-location risk affects the governance decision of whether to establish a steering committee in a nonequity alliance, thus offering important theoretical and practical insights into competition and cooperation in alliance management. [ABSTRACT FROM AUTHOR]

Engineered circular RNAs (circRNAs) are a class of single-stranded RNAs with head-to-tail covalently linked structures that integrate open reading frames (ORFs) and internal ribosome entry sites (IRESs) with the function of coding and expressing proteins. Compared to mRNA vaccines, circRNA vaccines offer a more improved method that is safe, stable, and simple to manufacture. With the rapid revelation of the biological functions of circRNA and the success of Severe Acute Respiratory Coronavirus Type II (SARS-CoV-2) mRNA vaccines, biopharmaceutical companies and researchers around the globe are attempting to develop more stable circRNA vaccines for illness prevention and treatment. Nevertheless, research on circRNA vaccines is still in its infancy, and more work and assessment are needed for their synthesis, delivery, and use. In this review, based on the current understanding of the molecular biological properties and immunotherapeutic mechanisms of circRNA, we summarize the current preparation methods of circRNA vaccines, including design, synthesis, purification, and identification. We discuss their delivery strategies and summarize the challenges facing the clinical application of circRNAs to provide references for circRNA vaccine-related research. [ABSTRACT FROM AUTHOR]

Bioreactor scale‐up and scale‐down have always been a topical issue for the biopharmaceutical industry and despite considerable effort, the identification of a fail‐safe strategy for bioprocess development across scales remains a challenge. With the ubiquitous growth of digital transformation technologies, new scaling methods based on computer models may enable more effective scaling. This study aimed to evaluate the potential application of machine learning (ML) algorithms for bioreactor scale‐up, with a specific focus on the prediction of scaling parameters. Factors critical to the development of such models were identified and data for bioreactor scale‐up studies involving CHO cell‐generated mAb products collated from the literature and public sources for the development of unsupervised and supervised ML models. Comparison of bioreactor performance across scales identified similarities between the different processes and primary differences between small‐ and large‐scale bioreactors. A series of three case studies were developed to assess the relationship between cell growth and scale‐sensitive bioreactor features. An embedding layer improved the capability of artificial neural network models to predict cell growth at a large‐scale, as this approach captured similarities between the processes. Further models constructed to predict scaling parameters demonstrated how ML models may be applied to assist the scaling process. The development of data sets that include more characterization data with greater variability under different gassing and agitation regimes will also assist the future development of ML tools for bioreactor scaling. [ABSTRACT FROM AUTHOR]

Recent advances in messenger ribonucleic acid (mRNA) vaccines and gene therapy vectors have increased the need for rapid plasmid DNA (pDNA) screening and production within the biopharmaceutical industry. High‐throughput (HT) fermentor systems, such as the Ambr® 250 HT, can significantly accelerate process development timelines of pDNA upstream processes compared to traditional bench‐scale glass fermentors or small‐scale steam‐in‐place (SIP) fermentors. However, such scale‐down models must be qualified to ensure that they are representative of the larger scale process similar to traditional small‐scale models. In the current study, we developed a representative scale‐down model of a Biostat® D‐DCU 30 L pDNA fermentation process in Ambr® 250 HT fermentors using three cell lines producing three different constructs. The Ambr scale‐down model provided comparable process performance and pDNA quality as the 30 L SIP fermentation process. In addition, we demonstrated the predictive value of the Ambr model by two‐way qualification, first by accurately reproducing the prior trends observed in a 30 L process, followed by predicting new process trends that were then successfully reproduced in the 30 L process. The representative and predictive scale‐down Ambr model developed in this study would enable a faster and more efficient approach to strain/clone/host‐cell screening, pDNA process development and characterization studies, process scale‐up studies, and manufacturing support. [ABSTRACT FROM AUTHOR]

Host cell proteins (HCPs) are process‐related impurities in a therapeutic protein expressed using cell culture technology. This review presents biopharmaceutical industry trends in terms of both HCPs in the bioprocessing of monoclonal antibodies (mAbs) and the capabilities for HCP clearance by downstream unit operations. A comprehensive assessment of currently implemented and emerging technologies in the manufacturing processes with extensive references was performed. Meta‐analyses of published downstream data were conducted to identify trends. Improved analytical methods and understanding of "high‐risk" HCPs lead to more robust manufacturing processes and higher‐quality therapeutics. The trend of higher cell density cultures leads to both higher mAb expression and higher HCP levels. However, HCP levels can be significantly reduced with improvements in operations, resulting in similar concentrations of approx. 10 ppm HCPs. There are no differences in the performance of HCP clearance between recent enhanced downstream operations and traditional batch processing. This review includes best practices for developing improved processes. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) used in biomedical research and therapeutic applications are primarily produced by Chinese hamster ovary (CHO) cells via fed-batch culture. The growing need for elevated quantities of biologics mandates the continual optimization of the mAb production process. The development of an effective process control method is indispensable for the production of specified mAbs by CHO cells. In this study, the effects of the pH control strategy on CHO cell fed-batch culture to produce an antibody (EA5) were first investigated in a 3 L bioreactor. The results indicate that controlling the culture pH at 7.2 during the fed-batch stage could produce a higher EA5 titer of 6.1 g/L with a lower Man5 ratio of 2.2% by day 14. Based on this, an optimized CHO cell fed-batch culture was conducted in a 15 L bioreactor to verify its effectiveness and stability. In this case, on day 14, an EA5 titer of 6.5 g/L was achieved with productivity of 0.46 g/L/day, which was 1.07-fold higher compared to that of the culture in the 3 L bioreactor. Furthermore, regarding the product quality, a monomer abundance of 96.0%, a main peak of 55.0%, and a Man5 proportion of 2.4% were maintained in the 15 L bioreactor. In addition, different cell clarification processes were evaluated using the CHO cell culture broth from the 3 L and 15 L bioreactors to further improve productivity and economic performance. Overall, this study provides some directions for process intensification and improving the quality of mAbs produced by CHO cells in the biopharmaceutical industry. [ABSTRACT FROM AUTHOR]

This paper examines how the fragmented ownership of complementary intellectual property (IP) rights affects firms' acquisition behaviour. We theorize that as the ownership of complementary IP rights fragments, the rate at which a focal firm engages in technology acquisitions will increase. Our predictions suggest that firms will expand their IP portfolios through acquisitions as a strategy to continue innovating when the ownership over strategic IP becomes exceedingly spread among technology holders. Furthermore, we propose that this positive relationship between fragmentation and acquisitions will be stronger for firms whose patent portfolios hold relatively less value compared to their peers, owing primarily to their diminished control over strategic IP. Using a unique longitudinal dataset from the biopharmaceutical industry, we find empirical support for our hypotheses. [ABSTRACT FROM AUTHOR]

Chinese hamster ovary (CHO) cells are popular in the pharmaceutical industry for their ability to produce high concentrations of antibodies and their resemblance to human cells in terms of protein glycosylation patterns. Current data indicate the relevance of CHO cells in the biopharmaceutical industry, with a high number of product commendations and a significant market share for monoclonal antibodies. To enhance the production capabilities of CHO cells, a deep understanding of their cellular and molecular composition is crucial. Genome sequencing and proteomic analysis have provided valuable insights into the impact of the bioprocessing conditions, productivity, and product quality. In our investigation, we conducted a comparative analysis of proteomic profiles in high and low monoclonal antibody–producing cell lines and studied the impact of tunicamycin (TM)-induced endoplasmic reticulum (ER) stress. We examined the expression levels of different proteins including unfolded protein response (UPR) target genes by using label-free quantification techniques for protein abundance. Our results show the upregulation of proteins associated with protein folding mechanisms in low producer vs. high producer cell line suggesting a form of ER stress related to specific protein production. Further, Hspa9 and Dnaja3 are notable candidates activated by the mitochondria UPR and play important roles in protein folding processes in mitochondria. We identified significant upregulation of Nedd8 and Lgmn proteins in similar levels which may contribute to UPR stress. Interestingly, the downregulation of Hspa5/Bip and Pdia4 in response to tunicamycin treatment suggests a low-level UPR activation. Key points: • Proteome profiling of recombinant CHO cells under mild TM treatment. • Identified protein clusters are associated with the unfolded protein response (UPR). • The compared cell lines revealed noticeable disparities in protein expression levels. [ABSTRACT FROM AUTHOR]

Successful development of nucleic acid therapeutics requires effective manufacturing strategies tailored to the production and purification of RNA and DNA. Membrane processes can be used for initial clarification, removal of smaller host cell proteins and transcription factors, concentration and buffer exchange, and sterile filtration. Transmission of DNA and RNA in ultrafiltration is governed by both the effective size and elongational flexibility of the nucleic acids. Sterile filtration of DNA/RNA therapeutics can present unique challenges due to their large size and shear sensitivity. Nucleic acid therapeutics have the potential to revolutionize the biopharmaceutical industry, providing highly effective vaccines and novel treatments for cancers and genetic disorders. The successful commercialization of these therapeutics will require development of manufacturing strategies specifically tailored to the purification of nucleic acids. Membrane technologies already play a critical role in the downstream processing of nucleic acid therapeutics, ranging from clarification to concentration to selective purification. This review provides an overview of how membrane systems are currently used for nucleic acid purification, while highlighting areas of future need and opportunity, including adoption of membranes in continuous bioprocessing. [ABSTRACT FROM AUTHOR]

The biopharmaceutical industry in Korea is considered a key strategic industry following the semiconductor industry. However, success in the biopharmaceutical industry depends on the outcome of research and development processes that require long periods and substantial investment, resulting in a success rate of only around 2.5%–4% for new drug development. Consequently, rational strategic choices, such as determining key capabilities to pursue business, deciding where to position within the value chain and identifying collaboration partners and strategies, are more crucial in the biopharmaceutical industry compared to other industries. In this study, we divided Korean biopharmaceutical companies into research and development groups and Integrated groups, which perform both research and production, and compared their productivity using the meta-frontier methodology to verify the significance of technology gap ratio (TGR) values between groups. We also investigated the influence of open innovation activities, including the type, partners and timing, on the TGR of each group with Tobit analysis. The investigation revealed that productivity and its influencing elements varied depending on the business model. This finding suggests that this information can be utilised to develop efficient industrial policies. [ABSTRACT FROM AUTHOR]

In the traditional clinical research model, patients are typically involved only as participants. However, there has been a shift in recent years highlighting the value and contributions that patients bring as members of the research team, across the clinical research lifecycle. It is becoming increasingly evident that to develop research that is both meaningful to people who have the targeted condition and is feasible, there are important benefits of involving patients in the planning, conduct, and dissemination of research from its earliest stages. In fact, research funders and regulatory agencies are now explicitly encouraging, and sometimes requiring, that patients are engaged as partners in research. Although this approach has become commonplace in some fields of clinical research, it remains the exception in clinical pain research. As such, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials convened a meeting with patient partners and international representatives from academia, patient advocacy groups, government regulatory agencies, research funding organizations, academic journals, and the biopharmaceutical industry to develop consensus recommendations for advancing patient engagement in all stages of clinical pain research in an effective and purposeful manner. This article summarizes the results of this meeting and offers considerations for meaningful and authentic engagement of patient partners in clinical pain research, including recommendations for representation, timing, continuous engagement, measurement, reporting, and research dissemination. [ABSTRACT FROM AUTHOR]

In recent years, multivariate data analysis (MVDA) has been widely used for process characterization and fault diagnosis in the biopharmaceutical industry. This study aims to investigate the feasibility of using MVDA for the development and scale-up of a perfusion process for HEK293 cell-based recombinant adenovirus zoster vaccine (Ad-HER) production. The Principal Component Analysis (PCA) results suggested comparable performance among the ATF, PATFP, and BFP perfusion systems in benchtop-scale stirred-tank bioreactor (STR). Then a Batch Evolution Model (BEM) was built using representative data from 10 L STR with a BFP system to assess the Ad-HER perfusion process performance at pilot-scale bioreactor (50 L STR and 50 L wave bioreactor). Furthermore, another BEM model and Batch Level Model (BLM) were built to monitor process parameters over time and predict the final adenovirus titer in 50 L wave bioreactor. The loading plot revealed that lactate dehydrogenase activity, viable cell diameter, and base-added during the virus production phase could be used as preliminary indicators of adenovirus yield. Finally, an adenovirus titer of 2.0±0.3×1010 IFU/mL was achieved in the 50 L wave bioreactor with BFP system, highlighting the robustness of the Ad-HER perfusion process at pilot-scale. Overall, this study emphasizes the effectiveness of MVDA as a tool for advancing the understanding of recombinant adenovirus vaccine perfusion production process development and scale-up. [ABSTRACT FROM AUTHOR]

As the need for higher volumetric productivity in biomanufacturing grows, biopharmaceutical companies are increasingly investing in a perfusion cell culture process, most commonly one that uses a hollow fiber filter as the cell retention device. A current challenge with using hollow fiber filters is fouling of the membrane, which reduces product sieving and can increase transmembrane pressure (TMP) past process limitations. In this work, the impact of hollow fiber filter geometries on product sieving and hydraulic membrane resistance profiles is evaluated in a tangential flow filtration (TFF) perfusion system. The hollow fibers tested had lengths ranging from 19.8 to 41.5 cm, inner diameters (IDs) ranging from 1.0 to 2.6 mm, and pore sizes of 0.2 or 0.65 μm. The results showed that the shortest hollow fibers experienced higher product sieving while larger IDs contributed to both higher product sieving and lower hydraulic membrane resistances, illustrating the impact of filter geometry on process performance. The results also showed 0.2 μm pore size filters maintain higher product sieving, but also higher membrane resistances compared to 0.65 μm pore size filters. This study highlights the need for optimized hollow fiber filter geometries to maximize use of the membrane area, which in turn can reduce production costs and increase scalability of the perfusion process. [ABSTRACT FROM AUTHOR]

This article provides a comparative analysis of the prevention of pharmaceutical patenting abuse in the United States, Japan, and France. It discusses the regulatory regimes in each country and the issues they face. In the United States, concerns about product hopping are raised, while Japan deals with reverse payment settlements, and France faces denigration of generic drugs. The article compares the prevention efforts in these countries and highlights the different attitudes towards pharmaceutical settlement agreements. Each country has implemented different measures to address these issues based on their existing policy and regulatory regimes. [Extracted from the article]

The development of media for cell culture is a major issue in the biopharmaceutical industry, for the production of therapeutics, immune-modulating molecules and protein antigens. Chemically defined media offer several advantages, as they are free of animal-derived components and guarantee high purity and a consistency in their composition. Microorganisms of the genus Leishmania represent a promising cellular platform for production of recombinant proteins, but their maintenance requires supplements of animal origin, such as hemin and fetal bovine serum. In the present study, three chemically defined media were assayed for culturing Leishmania tarentolae, using both a wild-type strain and a strain engineered to produce a viral antigen. Among the three media, Schneider's Drosophila Medium supplemented with Horseradish Peroxidase proved to be effective for the maintenance of L. tarentolae promastigotes, also allowing the heterologous protein production by the engineered strain. Finally, the engineered strain was maintained in culture up to the 12th week without antibiotic, revealing its capability to produce the recombinant protein in the absence of selective pressure. [ABSTRACT FROM AUTHOR]

Ultrasound has attracted attention in recent years as a green and effective non-thermal processing technique used in various fields, especially in the food, biotechnology and biopharmaceutical industries. It is important to determine the effects of ultrasonication on enzymatic reactions that have important applications in these industries. While intense ultrasonication conditions cause enzyme inactivation, it has been reported that enzyme activity can be increased under mid-ultrasound conditions (i.e. low intensity and short duration). Ultrasound treatment can be applied to free enzyme, substrate and immobilized enzyme. Ultrasonication may have a positive effect on the structure of molecules, increasing enzyme activity and product yield. In this review, information is given about the changes in molecular structure and enzyme activation that occur as a result of the application of ultrasound treatment to free enzyme, immobilized enzyme and substrate, the mechanisms of these changes and the factors that affect these mechanisms. [ABSTRACT FROM AUTHOR]

The objective of this research was to propose actions for the solution of failures in critical equipment of the Unit of Capsules and Suspensions of the Pharmaceutical Laboratory "8 de Marzo". Initially, the most critical assets were identified from the application of a technology for the hierarchy of systems and technological assets for biopharmaceutical companies. For this, techniques from the field of research were used such as bibliographic search, document review, technology for the priority order of systems and technological assets in biopharmaceutical companies; in addition to Pareto analysis and Cause-Effect Diagram; applying the latter to equipment failures. Brainstorming work sessions were organized with the workers of the laboratories, maintenance department and the group of experts, yielding as the main conclusion of 8 actions to solve the problems of failure of the most critical assets and consequently the reduction of stops for this concept and its corresponding improvement in the general availability of the plant. [ABSTRACT FROM AUTHOR]

Producing solid-state formulations of biologics remains a daunting task despite the prevalent use of lyophilization and spray drying technologies in the biopharmaceutical industry. The challenges include protein stability (temperature stresses), high capital costs, particle design/controllability, shortened processing times and manufacturing considerations (scalability, yield improvements, aseptic operation, etc.). Thus, scientists/engineers are constantly working to improve existing methodologies and exploring novel dehydration/powder-forming technologies. Microglassification™ is a dehydration technology that uses solvent extraction to rapidly dehydrate protein formulations at ambient temperatures, eliminating the temperature stress experienced by biologics in traditional lyophilization and spray drying methods. The process results in microparticles that are spherical, dense, and chemically stable. In this study, we compared the molecular stability of a monoclonal antibody formulation processed by lyophilization to the same formulation processed using Microglassification™. Both powders were placed on stability for 3 months at 40 °C and 6 months at 25 °C. Both dehydration methods showed similar chemical stability, including percent monomer, charge variants, and antigen binding. These results show that Microglassification™ is viable for the production of stable solid-state monoclonal antibody formulations. [Display omitted] [ABSTRACT FROM AUTHOR]

Monoclonal antibodies require careful formulation due to their inherent stability limitations. Polysorbates are commonly used to stabilize mAbs, but they are prone to degradation, which results in unwanted impurities. KLEPTOSE® HPβCD (hydroxypropyl beta-cyclodextrin) has functioned as a stable stabilizer for protein formulations in our previous research. The current study investigates the collaborative impact of combining polysorbates and HPβCD as excipients in protein formulations. The introduction of HPβCD in formulations showed it considerably reduced aggregation in two model proteins, bevacizumab and ipilimumab, following exposure to various stress conditions. The diffusion interaction parameter revealed a reduction in protein–protein interactions by HPβCD. In bevacizumab formulations, the subvisible particle counts per 0.4 mL of samples in commercial formulations vs. formulations containing both HPβCD and polysorbates subjected to distinct stressors were as follows: agitation, 87,308 particles vs. 15,350 particles; light, 25,492 particles vs. 6765 particles; and heat, 1775 particles vs. 460 particles. Isothermal titration calorimetry (ITC) measurement indicated a weak interaction between PS 80 and HPβCD, with a KD value of 74.7 ± 7.5 µM and binding sites of 5 × 10–3. Surface tension measurements illustrated that HPβCD enhanced the surface activity of polysorbates. The study suggests that combining these excipients can improve mAb stability in formulations, offering an alternative for the biopharmaceutical industry. [ABSTRACT FROM AUTHOR]

Mechanism models and model‐assisted process optimization play a vital role in biopharmaceutical industry. However, the parameter estimation remains a challenging task in modeling due to the presence of multiple local optima and ill‐conditioning. In this study, we firstly presented a comparative evaluation of particle swarm optimization (PSO), genetic algorithm (GA), and simulated annealing (SA) for parameter estimation and confirmed PSO was the most efficient approach. Then an improved PSO algorithm using second‐order oscillation and particle replacement strategies was developed to enhance fitting performance in fed‐batch cell culture modeling. The results of fitting and model validation demonstrated that the improved PSO could explore more reasonable parameters and leading to a significantly enhancement in predictive accuracy throughout the entire cell culture process under varying conditions. Moreover, 10 diverse fed‐batch experiments were conducted to validate the fitting abilities on different process condition and clones, the improved PSO method exhibited improvements in accuracy and universality of parameter estimation for modeling various cultivation processes, particularly those lacking any prior knowledge. This improved algorithm is implemented to make it available to both the scientific community and industry, offering customized solutions for specific projects. [ABSTRACT FROM AUTHOR]

• Melatonin, a natural signaling compound (hormone) is present in animals, plants, bacteria even in Fungi. • In fungi, it regulates circadian rhythms, growth, development and morphogenesis by maintaining cellular homeostasis. • Melatonin has potential in crop production, mushroom biotechnology and pharmaceutical industry as antioxidant, antimicrobial and anticancer metabolite. • Fungal melatonin has advantageous over animal and plant sources. Melatonin performs a critical part in the reduction of biotic and abiotic stressors of plants, triggering defence systems and pathogen diminutions. As there are lot of reports available on the effects on melatonin on plants and animals, our decision is to focus primarily on fungi. A diverse group of melatonin producer fungi from unicellular Saccharomyces to filamentous Trichoderma , even the advanced basidiomycetous edible mushroom Agaricus, Pleurotus etc. provide an enriched panorama for exploration. This review article is composed of the report about the properties of melatonin, their role on the plant-fungal interactions, covering its effects on fungi from various ecological niche viz. soil/leaf-borne pathogenic fungi, endophytes as well as the fungi occurring in arbuscular mycorrhiza (AM). There were both positive as well as negative impacts of melatonin on the fungal mycelia, primordia, fruiting bodies and spores. The biotechnological applications of melatonin in enhancing abiotic stress responses, signalling pathways, antioxidant and probable secondary metabolite productions and developing biocontrol agents have also been discussed. Melatonin plays an essential role in cultivation of edible mushroom. Melatonin and its homologues also possess anti-cancerous activity and can be used in different therapeutic applications as an anti-fungal, antibacterial, anti-viral, anti-inflammatory and anti-ageing agents. [ABSTRACT FROM AUTHOR]

Process Analytical Technologies (PATs) are taking a key role in the run for automatization in the biopharmaceutical industry. Spectroscopic methods such as Raman spectroscopy or mid‐infrared (MIR) spectroscopy are getting more recognition in the recent years for inline monitoring of bioprocesses due to their ability to measure various molecules simultaneously. However, their dependency on laborious model calibration making them a challenge to implement. In this study, a novel one‐point calibration that requires a single reference point prior to the inline monitoring of glucose and lactate in bioprocesses with MIR spectroscopy is assessed with 22 mammalian cell perfusion (PER) processes in two different scales and four different products. Concentrations are predicted over all PERs runs with a root mean square error (RMSE) of 0.29 g/L for glucose and 0.24 g/L for lactate, respectively. For comparison conventional partial least square regression (PLSR) models were used and trained with spectroscopic data from six bioreactor runs in two different scales and three products. The general accuracy of those models (RMSE of 0.41 g/L for glucose and 0.16 g/L for lactate) are in the range of the accuracy of the one‐point calibration. This shows the potential of the one‐point calibration as an approach making spectroscopy more accessible for bioprocess development. [ABSTRACT FROM AUTHOR]

Novel, eco-saving and low-cost food sources are a global priority, such as edible insects. This work sets a valorization pathway for frass and Tenebrio molitor adult insects using solid-state fermentation (SSF) to obtain fungal proteases, which are highly used in food, beverages, cosmetics, pharmaceutical and biotechnology industries. Initial screening experiments demonstrated that Aspergillus uvarum MUM 08.01 was the most efficient proteases producer. Small-scale SSF with frass resulted in high proteases activity (65 U g'1), which increased 52% when BSG was mixed with frass (1:1, w/w). The proteases activity attained in this study using only frass or mixed with BSG was superior compared to other activities observed when using agroindustry by-products (such as rapeseed, sunflower, soybean, among others) and other species of Aspergillus genus. The optimal conditions from full factorial design using frass:BSG mixture resulted in 152 U g'1 of proteases activity, which is in full accordance with the value predicted by the model. SSF scale-up with 50 g of frass:BSG increased proteases activity up to 202.2 U g'1. This study presents an innovative utilization of insects' by-products in the field of enzymes production, in full accordance with the circular economy guidelines. [ABSTRACT FROM AUTHOR]

The biopharmaceutical industry is rapidly advancing, driven by the need for cutting‐edge technologies to meet the growing demand for life‐saving treatments. In this context, Model Predictive Control (MPC) has emerged as a promising solution to address the complexity of modern biopharmaceutical production processes. Its ability to optimize operations and ensure consistent product yields has made it an attractive option for manufacturers in this sector. Furthermore, MPC's alignment with the Process Analytical Technology (PAT) initiative provides an additional layer of assurance, facilitating real‐time monitoring and enabling swift adjustments to maintain process integrity. This comprehensive review delves into the various applications of MPC, ranging from robust control to stochastic model predictive control, thereby equipping biotechnologists and process engineers with a powerful toolset. By harnessing the capabilities of MPC, as elucidated in this review, manufacturers can confidently navigate the intricate bioprocessing landscape and unlock this approach's full potential in their production processes. [ABSTRACT FROM AUTHOR]

Steering committees are pivotal for governing complex collaborations by consensus to facilitate coordination and knowledge sharing. Although consensus-based governance promotes mutuality, it can also cause deadlocks, stalling expeditious decision making. We examine the conditions under which alliance partners delegate decision-making authority to steering committees as well as the conditions under which authority over discordant matters can be relocated to one of the alliance partners. We argue that joint coordination concerns increase the likelihood of authority delegation, whereas the higher costs and stakes associated with decision stalemates provide grounds for authority reversion. Empirical analyses of strategic alliances in the biopharmaceutical industry support our arguments. Our paper demonstrates the versatility of contractually defined administrative interfaces in alliance governance, allowing partners to coordinate bilaterally and adapt hierarchically as and when required. [ABSTRACT FROM AUTHOR]

Recent studies in the biopharmaceutical industry have shown an increase in the productivity and production efficiency of recombinant proteins by continuous culture. In this research, a new upstream fermentation process was developed for the production of recombinant uricase in the methylotrophic yeast Pichia pastoris. Expression of recombinant protein in this system is under the control of the AOX1 promoter and therefore requires methanol as an inducing agent and carbon/energy source. Considering the biphasic growth characteristics of conventional fed‐batch fermentation, physical separation of the growth and induction stages for better control of the continuous fermentation process resulted in higher dry‐cell weight (DCW) and enhanced recombinant urate oxidase activity. The DCW and recombinant uricase activity enzyme for fed‐batch fermentation were 79 g/L and 6.8 u/mL. During the continuous process, in the growth fermenter at a constant dilution rate of 0.025 h−1, DCW increased to 88.39 g/L. In the induction fermenter, at methanol feeding rates of 30, 60, and 80 mL/h, a recombinant uricase activity was 4.13, 7.2, and 0 u/mL, respectively. The optimum methanol feeding regime in continuous fermentation resulted in a 4.5‐fold improvement in productivity compared with fed‐batch fermentation from 0.04 u/mL/h (0.0017 mg/mL/h) to 0.18 u/mL/h (0.0078 mg/mL/h). [ABSTRACT FROM AUTHOR]

Purposes: Highly concentrated monoclonal antibody (mAb) formulations for subcutaneous administration are becoming increasingly preferred within the biopharmaceutical industry for ease of use and improved patient compliance. A common phenomenon observed in the industry is that osmolality detected via freezing-point depression (FPD) in high-concentration mAb formulations is much higher than the theoretical concentrations, yet the occurrence of this phenomenon and its possible safety issues have been rarely reported. Methods: The current study summarized theoretical osmolality of U.S. Food and Drug Administration approved high-concentration mAb formulations and evaluated effects of high osmolality on safety using hemolysis experiments for the first time. Two mAbs formulated at 150 mg/mL were used as models and configured into two isotonic solutions: a, a theoretically calculated molarity in the isotonic range (H) and b, an osmolality value measured via the FPD in the isotonic range (I). The H and I formulations of each mAb were individually subjected to hemolysis experiments, and the hemolysis rates of the two formulations of the same mAb were compared. Besides, the effect of mAb concentration on osmolality detected by FPD was explored as well. Results: The results indicated that the hemolysis rates were similar between the H and I formulations of mAbs at the same sample addition volume, and the osmolality values increased approximately linearly with the increase in mAb concentration. Conclusions: High osmolality for high-concentration mAb formulations would not affect product safety and the excipients could be added at relatively high levels to maintain product stability, especially for labile products. [ABSTRACT FROM AUTHOR]

The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Consequently, RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy. Moreover, advancements in RNA chemistry and delivery methods have been pivotal in shaping the landscape of RNA-based immunotherapy, including miRNA-based approaches. Consequently, the biotechnology and pharmaceutical industry has witnessed a resurgence of interest in incorporating RNA-based immunotherapies and miRNA therapeutics into their development programs. Despite substantial progress in preclinical research, the field of miRNA-based therapeutics remains in its early stages, with only a few progressing to clinical development, none reaching phase III clinical trials or being approved by the US Food and Drug Administration (FDA), and several facing termination due to toxicity issues. These setbacks highlight existing challenges that must be addressed for the broad clinical application of miRNA-based therapeutics. Key challenges include establishing miRNA sensitivity, specificity, and selectivity towards their intended targets, mitigating immunogenic reactions and off-target effects, developing enhanced methods for targeted delivery, and determining optimal dosing for therapeutic efficacy while minimizing side effects. Additionally, the limited understanding of the precise functions of miRNAs limits their clinical utilization. Moreover, for miRNAs to be viable for cancer treatment, they must be technically and economically feasible for the widespread adoption of RNA therapies. As a result, a thorough risk evaluation of miRNA therapeutics is crucial to minimize off-target effects, prevent overdosing, and address various other issues. Nevertheless, the therapeutic potential of miRNAs for various diseases is evident, and future investigations are essential to determine their applicability in clinical settings. [ABSTRACT FROM AUTHOR]

There is a growing interest in perfusion or continuous processes to achieve higher productivity of biopharmaceuticals in mammalian cell culture, specifically Chinese hamster ovary (CHO) cells, towards advanced biomanufacturing. These intensified bioprocesses highly require concentrated feed media in order to counteract their dilution effects. However, designing such condensed media formulation poses several challenges, particularly regarding the stability and solubility of specific amino acids. To address the difficulty and complexity in relevant media development, the biopharmaceutical industry has recently suggested forming dipeptides by combining one from problematic amino acids with selected pairs to compensate for limitations. In this study, we combined one of the lead amino acids, L-tyrosine, which is known for its poor solubility in water due to its aromatic ring and hydroxyl group, with glycine as the partner, thus forming glycyl-L-tyrosine (GY) dipeptide. Subsequently, we investigated the utilization of GY dipeptide during fed-batch cultures of IgG-producing CHO cells, by changing its concentrations (0.125 × , 0.25 × , 0.5 × , 1.0 × , and 2.0 ×). Multivariate statistical analysis of culture profiles was then conducted to identify and correlate the most significant nutrients with the production, followed by in silico model-guided analysis to systematically evaluate their effects on the culture performance, and elucidate metabolic states and cellular behaviors. As such, it allowed us to explain how the cells can more efficiently utilize GY dipeptide with respect to the balance of cofactor regeneration and energy distribution for the required biomass and protein synthesis. For example, our analysis results uncovered specific amino acids (Asn and Gln) and the 0.5 × GY dipeptide in the feed medium synergistically alleviated the metabolic bottleneck, resulting in enhanced IgG titer and productivity. In the validation experiments, we tested and observed that lower levels of Asn and Gln led to decreased secretion of toxic metabolites, enhanced longevity, and elevated specific cell growth and titer. Key points: • Explored the optimal Tyr dipeptide for the enhanced CHO cell culture performance • Systematically analyzed effects of dipeptide media by model-guided approach • Uncovered synergistic metabolic utilization of amino acids with dipeptide [ABSTRACT FROM AUTHOR]

Transient gene expression (TGE) in mammalian cells is a well-known approach to the fast expression of recombinant proteins. The human cell line HEK (human embryonic kidney) 293F is widely used in this field, due to its adaptability to grow in suspension to high cell densities in serum-free media, amenability to transfection, and production of recombinant proteins in satisfactory quantities for functional and structural analysis. Amounts of plasmid DNA (pDNA) required in transfections for TGE remain high (usually 1 µg pDNA/mL, or even higher), representing a noticeable proportion of the overall cost. Thus, there is an economic need to reduce amounts of coding pDNA in TGE processes. In this work, amounts of both pDNA and transfecting agent used for TGE in HEK 293F cells have been explored in order to reduce them without compromising (or even improving) the productivity of the process in terms of protein yield. In our hands, minimal polyethyleneimine (PEI) cytotoxicity and optimum protein yields were obtained when transfecting at 0.5 µg pDNA/mL (equal to 0.5 µg pDNA/million cells) and a DNA-to-PEI ratio of 1:3, a trend confirmed for several unrelated recombinant proteins. Thus, carefully tuning pDNA and transfecting agent amounts not only reduces the economic costs but also results in higher recombinant protein yields. These results surely have a direct application and interest for the biopharmaceutical industry, always concerned in increasing productivity while decreasing economic costs. Key points: • Mammalian cells are widely used to produce recombinant proteins in short times. • Tuning DNA and transfecting agent are of great interest to optimize economic costs. • Reducing DNA and transfecting agent amounts result in higher protein yields. [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]

Cancer medicines have become one of the most dominant global medical technologies. They generate huge profits for the biopharmaceutical industry as well as fuel the research and advocacy activities of public funders, patient organisations, clinical and scientific communities and entire federal political ecosystems. The mismatch between the price, affordability and value of many cancer medicines and global need has generated significant policy debate, yet we see little change in behaviours from any of the major actors from public research funders through to regulatory authorities. In this policy analysis we examine whether, considering the money and power inherent in this system, any rationale global consensus and policy can be achieved to deliver affordable and equitable cancer medicines that consistently deliver clinically meaningful benefit. [ABSTRACT FROM AUTHOR]

The intact‐mass MS measurements are becoming increasingly popular in characterization of a range of biopolymers, especially those of interest to biopharmaceutical industry. However, as the complexity of protein therapeutics and other macromolecular medicines increases, the new challenges arise, one of which is the high levels of structural heterogeneity that are frequently exhibited by such products. The very notion of the molecular mass measurement loses its clear and intuitive meaning when applied to an extremely heterogenous system that cannot be characterized by a unique mass, but instead requires that a mass distribution be considered. Furthermore, convoluted mass distributions frequently give rise to unresolved ionic signal in mass spectra, from which little‐to‐none meaningful information can be extracted using standard approaches that work well for homogeneous systems. However, a range of technological advances made in the last decade, such as the hyphenation of intact‐mass MS measurements with front‐end separations, better integration of ion mobility in MS workflows, development of an impressive arsenal of gas‐phase ion chemistry tools to supplement MS methods, as well as the revival of the charge detection MS and its triumphant entry into the field of bioanalysis already made impressive contributions towards addressing the structural heterogeneity challenge. An overview of these techniques is accompanied by critical analysis of the strengths and weaknesses of different approaches, and a brief overview of their applications to specific classes of biopharmaceutical products, vaccines, and nonbiological complex drugs. [ABSTRACT FROM AUTHOR]

Purpose: Technology acquisition is a common phenomenon of acquiring external knowledge, but we have a limited understanding of conditions in which the acquirer integrates the target or not. On one hand, the acquirer may have a policy to integrate the target to benefit from its prior knowledge. On the other hand, the target may face challenges in continuing its knowledge creation and the acquirer may want to provide it autonomy to not disrupt it. This paper aims to identify conditions in which targets tend to be less integrated after acquisitions, allowing them to maintain more autonomy and contribute more to knowledge creation. Design/methodology/approach: We test our arguments in the empirical setting of the global biopharmaceutical industry using a difference-in-difference approach on a longitudinal dataset of matched patents. We examine self-cites received by patents belonging to acquirers and the targets before and after the acquisitions. Findings: We find that, on average, the targets' prior patents do not receive more self-cites after the acquisition. We conclude that this is because their R&D activities are disrupted, suggesting a higher level of post-acquisition integration. However, more nuanced findings reveal that it may not be the case all the time. When the target has more research experience, is international or is specialized in complementary technologies, prior patents of targets continue to receive more self-cites after the acquisition. It indicates that the targets in such conditions continue knowledge creation, suggesting a lower level of post-acquisition integration. Originality/value: Our findings contribute to post-acquisition integration research. While post-acquisition integration downside is common, we present conditions in which such a downside may be less likely. We highlight that the context of an acquisition may be an important determinant of the extent of integration of the target. Moreover, we supplement the integration research (cultural, structural and human resource and leadership perspectives of integration) by adding a knowledge-based perspective to it. Such dynamics have important implications for acquirers and targets in deriving value from the acquisition. [ABSTRACT FROM AUTHOR]

The halotolerant non-conventional yeast Debaryomyces hansenii can grow in media containing high concentrations of salt (up to 4 M), metabolize alternative carbon sources than glucose, such as lactose or glycerol, and withstand a wide range of temperatures and pH. These inherent capabilities allow this yeast to grow in harsh environments and use alternative feedstock than traditional commercial media. For example, D. hansenii could be a potential cell factory for revalorizing industrial salty by-products, using them as a substrate for producing new valuable bioproducts, boosting a circular economy. In this work, three different salty by-products derived from the dairy and biopharmaceutical industry have been tested as a possible feedstock for D. hansenii 's growth. The yeast was not only able to grow efficiently in all of them but also to produce a recombinant protein (Yellow Fluorescent Protein, used as a model) without altering its performance. Moreover, open cultivations at different laboratory scales (1.5 mL and 1 L) were performed under non-sterile conditions and without adding fresh water or any nutritional supplement to the cultivation, making the process cheaper and more sustainable. [Display omitted] • D. hansenii can thrive in high-salt containing feedstocks for producing recombinant proteins. • Side-streams with high salt content are used without sterilization in lab-scale fermentations. • No addition of fresh water to the media is needed, waste-streams can be used directly from the source. [ABSTRACT FROM AUTHOR]

Molecular biological methods have emerged as inevitable tools to accompany the process of cell line development for the generation of stable and highly productive manufacturing cell lines in the biopharmaceutical industry. PCR-based methods are especially useful for screening and characterization of cell lines due to their low cost, scalability, precision and propensity for multidimensional read-outs. In this study, the diverse applications of droplet digital PCR (ddPCR) as a molecular biological tool for cell line development are demonstrated. Specifically, it is shown that ddPCR can be used to enable precise, sensitive and reproducible absolute quantification of genomically integrated transgene copies during cell line development and cell bank characterization. Additionally, an amplitude multiplexing approach is applied to simultaneously run multiple assays on different genetic targets in a single reaction and advance clonal screening by measuring gene expression profiles to predict the assembly and homogeneity of difficult-to-express (DTE) proteins. The implementation of ddPCR-based assays during cell line development allows for early screening at a transcriptional level, particularly for complex, multidomain proteins, where balanced polypeptide chain ratios are of primary importance. Moreover, it is demonstrated that ddPCR-based genomic characterization improves the robustness, efficiency and comparability of absolute transgene copy number quantification, an essential genetic parameter that must be demonstrated to regulatory authorities during clinical trial and market authorization application submissions to support genetic stability and consistency of the selected cell substrate. • Gene expression analysis by ddPCR can predict the assembly of bispecific antibodies. • Amplitude-multiplexing allows for a simultaneous quantification of several genes. • Precise and sensitive absolute quantification of transgene copy numbers. • High correlation between RNA sequencing, ddPCR and capillary gel electrophoresis. [ABSTRACT FROM AUTHOR]