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BIOPHARMACEUTICAL analysis is the analysis of drugs in biological media. When developing an analytical method for the determination of a drug substance in a biological sample, a decision is made to determine which analytical instr...
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BIOPHARMACEUTICAL analysis is the analysis of drugs in biological media. When developing an analytical method for the determination of a drug substance in a biological sample, a decision is made to determine which analytical instrumentation is to be used.
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Raw materials, in particular cell culture media, represent a significant source of variability to biopharmaceutical manufacturing processes that can detrimentally affect cellular growth, viability and specific productivity or alte...
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Raw materials, in particular cell culture media, represent a significant source of variability to biopharmaceutical manufacturing processes that can detrimentally affect cellular growth, viability and specific productivity or alter the quality profile of the expressed therapeutic protein. The continual expansion of the biopharmaceutical industry is creating an increasing demand on the production and supply chain consistency for cell culture media, especially as companies embrace intensive continuous processing. Here, we provide a historical perspective regarding the transition from serum containing to serum-free media, the development of chemically-defined cell culture media for biopharmaceutical production using industrial scale bioprocesses and review production mechanisms for liquid and powder culture media. An overview and critique of analytical approaches used for the characterisation of cell culture media and the identification of root causes of variability are also provided, including in-depth liquid phase separations, mass spectrometry and spectroscopic methods.
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Much interest has been expressed in this work on the role of water diffusivity in the release media as a new parameter for predicting drug release. NMR was used to measure water diffusivity in different media varying in their osmo...
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Much interest has been expressed in this work on the role of water diffusivity in the release media as a new parameter for predicting drug release. NMR was used to measure water diffusivity in different media varying in their osmolality and viscosity. Water self-diffusion coefficients in sucrose, sodium chloride, and polymeric hydroxypropyl methylcellulose (HPMC) solutions were correlated with water uptake, disintegration, and drug release rates from trospium chloride immediate release tablets. The water diffusivity in sucrose solutions was significantly reduced compared to polymeric HPMC and molecular sodium chloride solutions. Water diffusivity was found to be a function of sucrose concentration in the media. Dosage form disintegration and drug release was to be affected by water diffusivity in these systems. This observation can be explained by hydrogen bonding formation between sugar molecules, an effect which was not expressed in sodium chloride solutions of equal osmolality. Water diffusivity and not media osmolality in general need to be considered to predict the effect of disintegration and dissolution media on drug release. Understanding the relevance of water diffusivity for disintegration and dissolution will lead to better parametrization of dosage form behavior in gastrointestinal (GI) aqueous and semisolid media.
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In 2012 and 2016, the first two strategic science-business media models were published (SBBMM 1.0 and 2.0). Since that time, there have been significant changes both to the media landscape and to the usage and capability of online...
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In 2012 and 2016, the first two strategic science-business media models were published (SBBMM 1.0 and 2.0). Since that time, there have been significant changes both to the media landscape and to the usage and capability of online and social media platforms. This paper seeks to describe the current bioindustry-relevant media landscape, to introduce a new media model, the Strategic Bioenterprise Media Model 2020 (SBMM 2020), which reflects this new landscape, and to present a mainstream submodel to support the latest opportunity for biotechnology media coverage: Mainstream Media. Examples are drawn from media coverage following the FDA approvals of Zulresso from Sage Therapeutics, Aimovig from Novartis and Amgen, and AquAdvantage salmon from AquAdvantage Technologies. The overall goal of this paper is to equip bioenterprise professionals with an understanding of media dynamics and the strategic potential it brings, ultimately contributing to bioenterprise success.
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The production of active pharmaceutical ingredients (APIs) is currently undergoing its biggest transformation in a century. The changes are based on the rapid and dramatic introduction of protein- and macromolecule-based drugs (co...
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The production of active pharmaceutical ingredients (APIs) is currently undergoing its biggest transformation in a century. The changes are based on the rapid and dramatic introduction of protein- and macromolecule-based drugs (collectively known as biopharmaceuticals) and can be traced back to the huge investment in biomedical science (in particular in genomics and proteomics) that has been ongoing since the 1970s. Biopharmaceuticals (or biologics) are manufactured using biological-expression systems (such as mammalian, bacterial, insect cells, etc.) and have spawned a large (>Euro35 billion sales annually in Europe) and growing biopharmaceutical industry (BioPharma). The structural and chemical complexity of biologics, combined with the intricacy of cell-based manufacturing, imposes a huge analytical burden to correctly characterize and quantify both processes (upstream) and products (downstream). In small molecule manufacturing, advances in analytical and computational methods have been extensively exploited to generate process analytical technologies (PAT) that are now used for routine process control, leading to more efficient processes and safer medicines. In the analytical domain, biologic manufacturing is considerably behind and there is both a huge scope and need to produce relevant PAT tools with which to better control processes, and better characterize product macromolecules. Raman spectroscopy, a vibrational spectroscopy with a number of useful properties (nondestructive, non-contact, robustness) has significant potential advantages in BioPharma. Key among them are intrinsically high molecular specificity, the ability to measure in water, the requirement for minimal (or no) sample pre-treatment, the flexibility of sampling configurations, and suitability for automation. Here, we review and discuss a representative selection of the more important Raman applications in BioPharma (with particular emphasis on mammalian cell culture). The review shows that the properties of Raman have been successfully exploited to deliver unique and useful analytical solutions, particularly for online process monitoring. However, it also shows that its inherent susceptibility to fluorescence interference and the weakness of the Raman effect mean that it can never be a panacea. In particular, Raman-based methods are intrinsically limited by the chemical complexity and wide analyte-concentration-profiles of cell culture media/bioprocessing broths which limit their use for quantitative analysis. Nevertheless, with appropriate foreknowledge of these limitations and good experimental design, robust analytical methods can be produced. In addition, new technological developments such as time-resolved detectors, advanced lasers, and plasmonics offer potential of new Raman-based methods to resolve existing limitations and/or provide new analytical insights.
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Abstract Due to the favorable attributes of Chinese hamster ovary (CHO) cells for therapeutic proteins and antibodies biomanufacturing, companies generate proprietary cells with desirable phenotypes. One key attribute is the abili...
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Abstract Due to the favorable attributes of Chinese hamster ovary (CHO) cells for therapeutic proteins and antibodies biomanufacturing, companies generate proprietary cells with desirable phenotypes. One key attribute is the ability to stably express multi‐gram per liter titers in chemically defined media. Cell, media, and feed diversity has limited community efforts to translate knowledge. Moreover, academic, and nonprofit researchers generally cannot study “industrially relevant” CHO cells due to limited public availability, and the time and knowledge required to generate such cells. To address these issues, a university‐industrial consortium (Advanced Mammalian Biomanufacturing Innovation Center, AMBIC) has acquired two CHO “reference cell lines” from different lineages that express monoclonal antibodies. These reference cell lines have relevant production titers, key performance outcomes confirmed by multiple laboratories, and a detailed technology transfer protocol. In commercial media, titers over 2?g/L are reached. Fed‐batch cultivation data from shake flask and scaled‐down bioreactors is presented. Using productivity as the primary attribute, two academic sites aligned with tight reproducibility at each site. Further, a chemically defined media formulation was developed and evaluated in parallel to the commercial media. The goal of this work is to provide a universal, industrially relevant CHO culture platform to accelerate biomanufacturing innovation.
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To assess in vivo behavior through in vitro method, the dissolution test is mostly used, both for quality control (QC) and for development purpose. In view of the fact that a dissolution test can hardly achieve two goals at the sa...
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To assess in vivo behavior through in vitro method, the dissolution test is mostly used, both for quality control (QC) and for development purpose. In view of the fact that a dissolution test can hardly achieve two goals at the same time, the design of dissolution testing generally varies along with the development stage of drug products and therefore the selection of dissolution media may change with the goals of the dissolution test. To serve the QC purpose, a dissolution medium is designed to provide a sink condition; for development purpose, the dissolution medium is required to simulate the physiological conditions in the gastrointestinal tract as far as possible. In this review, we intended to provide an initial introduction to the various dissolution media applied for QC and formulation development purposes for poorly water soluble drugs. We focused on these methods like addition of cosolvents, surfactants and utilization of biphasic media, applied to provide sink conditions which are difficult to be achieved by simple aqueous buffers for lipophilic drugs, and introduced the development of physiologically relevant media for human and animals like dog and rat with respect to the choice of buffers, bile salts, lipids and so on. In addition, we further discussed the influence of biorelevant dissolution media on the modification of drug Biopharmaceutical Classification System (BCS) classification, especially for BCS class II drugs with low solubility and high permeability, the solubility of which is relatively sensitive to the presence of bile salts and lipids.
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Media coverage following U.S. Food and Drug Administration (FDA) drug approvals is generally found in two sectors: bioindustry news and the financial markets. The March 19,2019 FDA announcement of its approval ofthe postpartum ant...
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Media coverage following U.S. Food and Drug Administration (FDA) drug approvals is generally found in two sectors: bioindustry news and the financial markets. The March 19,2019 FDA announcement of its approval ofthe postpartum anti-depression biopharmaceutical Zulresso from Sage Therapeutics also elicited unusually high levels of media response in the mainstream media. This case study (1) details the total media news response following the FDA approval announcement regarding Zulresso, (2) compares that media response with the mainstream media coverage for Aimovig, a Novartis and Amgen treatment, which received the most mainstream coverage in the group of 2018 FDA novel drug approvals, and (3) compares the media coverage for three recent FDA drug approvals, Mayzent, Dovato and Evenity, to demonstrate a normative media response pattern. Findings include demonstration of Zulresso coverage across all major mainstream media outlets, well in excess of its mainstream media comparator, Aimovig. The three recently-announced comparators received the anticipated media coverage in the bioindustry and financial markets segments, while the two mainstream candidates, Zulresso and Aimovig, both received more and/or more timely media coverage in the bioindustry and financial markets media sectors than three recent drug approval comparators. No determination could be made as to whether the mainstream media response to Zulresso was a singular incident, or the signaling of a sea change due to the maturation of the biotechnology industry.
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A strategy followed to integrate in vitro solubility and permeability data into a PBBM model to predict the food effect of a BCS IV zwitterionic drug (GSK3640254) observed in clinical studies is described. The PBBM model was devel...
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A strategy followed to integrate in vitro solubility and permeability data into a PBBM model to predict the food effect of a BCS IV zwitterionic drug (GSK3640254) observed in clinical studies is described. The PBBM model was developed, qualified and verified using clinical data of an immediate release (IR)-tablet (10-320 mg) obtained in healthy volunteers under fasted and fed conditions. The solubility of GSK3640254 was a function of its ionization state, the media composition and pH, whereas its permeability determined using MDCK cell lines was enhanced by the presence of mixed micelles. In vitro data alongside PBBM modelling suggested that the positive food effect observed in the clinical studies was attributed to micelle-mediated enhanced solubility and permeability. The biorelevant media containing oleic acid and cholesterol in fasted and fed levels enabled the model to appropriately capture the magnitude of the food effect. Thus, by using Simcyp? v20 software, the PBBM model accurately predicted the results of the food effect and predicted data were within a two-fold error with 70% being within 1.25-fold. The developed model strategy can be effectively adopted to increase the confidence of using PBBM models to predict the food effect of BCS class IV drugs.
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The aim of this study was to evaluate in-line Raman spectroscopy for monitoring the progress of particle size reduction in real time during wet-stirred media milling of two Biopharmaceutics Classification System (BCS) Class II dru...
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The aim of this study was to evaluate in-line Raman spectroscopy for monitoring the progress of particle size reduction in real time during wet-stirred media milling of two Biopharmaceutics Classification System (BCS) Class II drugs, griseofulvin and naproxen. To develop a validated online Raman method, Raman analyses were carried out offline by taking samples from the mill at various milling times. A multivariate linear model (partial least squares, PLS) was fitted to the raw data obtained from the Raman measurements and good linearity between online and offline Raman spectra was found. Line intensities (I) of the in-line spectra obtained during the wet media milling were processed by multivariate analyses and correlated with both the median size (d(50)) and the 90% passing particle size (d(90)), which were measured off line by laser diffraction. A two-parameter exponential growth model of the form d=exp[A(I - I-o)] was found to establish a good correlation (R-2 > 0.90) as a statistically significant model with statistically significant parameters (P < 10(-4)). The correlations were applicable to milled suspensions with particles in the approximate size range of 0.1-6 mu m for griseofulvin and 0.1-8 mu m for naproxen. These results suggest that in-line Raman spectroscopy can be used to successfully monitor the progress of particle size reduction during wet media milling.
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