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Protein pharmaceuticals have become a significant class of marketed drug products and are expected to grow steadily over the next decade. Development of a commercial protein product ...is, however, a rather complex process. A critical step in this process is formulation development, enabling the final product configuration. A number of challenges still exist in the formulation development process. This review is intended to discuss these challenges, to illustrate the basic formulation development processes, and to compare the options and strategies in practical formulation development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Trehalose, a disaccharide of glucose, has been reported to accumulate in many organisms that can withstand extended periods of inanimation. Since this discovery, the properties of trehalose have been ...examined extensively to understand its role and abundance in nature. The unique features of this sugar became clearer with each new finding which demonstrated its ability to sustain and preserve a wide array of biological molecules. Trehalose has been used in a variety of research applications and is contained in several commercially available therapeutic products, including Herceptin®, Avastin®, Lucentis®, and Advate®. Currently, there is a growing interest in the use of trehalose in solid dosage formulations, most notably in quick-dissolving tablets. Furthermore, trehalose has found its use in several food and cosmetic products, and new applications capitalizing on its unique properties are being developed and implemented in everyday-use products. As trehalose is an approved ingredient in all major markets, there is no significant barrier to its use. Extensive work with trehalose has been conducted in the three major industries, however with little overlap. Further understanding of the role of trehalose in the various applications may lead to an increase in the number of trehalose-containing products.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Drying is a commonly used processing technique for the manufacture of biotherapeutic products. Removal of water provides numerous benefits, including ease of handling and storage, reduction in ...transportation costs, and improved stability, to name a few. Typically, drying is accomplished through freeze-drying, as evidenced by the availability of several lyophilized products on the market. There are, however, several drawbacks to lyophilization, including the lengthy process time required for drying, low energy efficiency, and the high cost of purchasing and maintaining the equipment. Furthermore, lyophilization is a batch process and may be challenging to adapt and implement within a continuous manufacturing process scheme. These limitations have led to the search for next-generation drying technologies that can be applied to the manufacture of biotherapeutic products. Several alternative drying methods are reviewed herein with particular emphasis on the advantages and disadvantages of each technology in comparison to lyophilization and the potential of each to be utilized for drying biotherapeutic compounds.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The continuous increase in the number of approved monoclonal antibody (mAb)-based therapy suggests that mAbs, and their derivatives, will continue to be the focus of the biotherapeutics industry for ...years to come. Although vast improvements in our capability to manufacture, characterize, and stabilize mAbs have been achieved, there are still challenges to be overcome. These include analytical and stabilization approaches associated with the development of high concentration mAb formulations. In addition, several mAb-based modalities are under development, including antibody drug conjugates (ADCs), fusion proteins, and bispecific antibodies (bsAbs), all designed to overcome the limitations encountered with mAb therapy. The current status of their development, with emphasis on manufacturing challenges as well as preliminary clinical results, will be reviewed.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose
The goal of this research is to develop stable formulations for live attenuated influenza vaccines (LAIV) by employing the drying methods freeze drying, spray drying, and foam drying.
Methods
...Formulated live attenuated Type-A H1N1 and B-strain influenza vaccines with a variety of excipient combinations were dried using one of the three drying methods. Process and storage stability at 4, 25 and 37°C of the LAIV in these formulations was monitored using a TCID
50
potency assay. Their immunogenicity was also evaluated in a ferret model.
Results
The thermal stability of H1N1 vaccine was significantly enhanced through application of unique formulation combinations and drying processes. Foam dried formulations were as much as an order of magnitude more stable than either spray dried or freeze dried formulations, while exhibiting low process loss and full retention of immunogenicity. Based on long-term stability data, foam dried formulations exhibited a shelf life at 4, 25 and 37°C of >2, 1.5 years and 4.5 months, respectively. Foam dried LAIV Type-B manufactured using the same formulation and process parameters as H1N1 were imparted with a similar level of stability.
Conclusion
Foam drying processing methods with appropriate selection of formulation components can produce an order of magnitude improvement in LAIV stability over other drying methods.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Evaluation of the physical characteristics of vaccines formulated in the presence of adjuvants, such as aluminum salts (Alum), is an important step in the development of vaccines. Depending on the ...formulation conditions and the associated electrostatic interactions of the adjuvant particles, the vaccine suspension may transition between flocculated and deflocculated states. The impact of practical formulation parameters, including pH, ionic strength, and the presence of model antigens, has been correlated to the sedimentation behavior of aluminum phosphate suspensions. A novel approach for the characterization of suspension properties of Alum has been developed to predict the flocculated state of the system using a sedimentation analysis-based tool (Turbiscan®). Two sedimentation parameters, the settling onset time (Sonset) and the sedimentation volume ratio (SVR) can be determined simultaneously in a single measurement. The results demonstrate the suspension characteristics to be significantly altered by solution conditions (pH and ionic strength) and the charge state of bound antigens. Formulation conditions that promote the flocculated state of the suspension are characterized by faster Sonset and higher SVR, and are generally easy to resuspend. The Turbiscan® method described herein is a useful tool for the characterization of aluminum-containing suspensions and may be adapted for screening and optimization of suspension-based vaccine formulations in general.
Recombinant technology has ushered in a new era for the pharmaceutical industry. Protein therapeutics, including plasma-derived products and antibodies obtained from the serum of infected patients, ...have been successfully adopted and utilized to treat various indications. The development of recombinant technology and the subsequent improvement in expression, purification, and formulation technologies have enabled the generation of highly purified proteins in a scalable and cost-effective manner. The discovery and development of several recombinant proteins, such as growth factors and cytokines, will be described followed by a brief review of monoclonal antibodies and enzyme replacement therapy. Recombinant protein-based vaccine, which is the focus of the current review, is described in detail with particular emphasis on several viral and bacterial infections. Challenges and new approaches in their use as a replacement for the currently available vaccines are discussed.
In this paper, we propose a built-in self-diagnosis (BISD) mechanism for delay faults induced by degradation. This mechanism solely generates expected signatures using slower clock on the fly and ...requires no memory for storing pre-computed expected signatures. In our experiment, the proposed BISD mechanism is applied to benchmark circuits. Area overhead and diagnostic resolution are evaluated.
A variety of excipients are used to stabilize proteins, suppress protein aggregation, reduce surface adsorption, or to simply provide physiological osmolality. The stabilizers encompass a wide ...variety of molecules including sugars, salts, polymers, surfactants, and amino acids, in particular arginine. The effects of these excipients on protein stability in solution are mainly caused by their interaction with the protein and the container surface, and most importantly with water. Some excipients stabilize proteins in solution by direct binding, while others use a number of fundamentally different mechanisms that involve indirect interactions. In the dry state, any effects that the excipients confer to proteins through their interactions with water are irrelevant, as water is no longer present. Rather, the excipients stabilize proteins through direct binding and their effects on the physical properties of the dried powder. This review will describe a number of mechanisms by which the excipients interact with proteins in solution and with various interfaces, and their effects on the physical properties of the dried protein structure, and explain how the various interaction forces are related to their observed effects on protein stability.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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