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PubMed2001

Medical molecular farming: production of antibodies, biopharmaceuticals and edible vaccines in plants.

The use of plants for medicinal purposes dates back thousands of years but genetic engineering of plants to produce desired biopharmaceuticals is much more recent. As the demand for biopharmaceuticals is expected to increase, it would be wise to ensure that they will be available in significantly larger amounts, on a cost-effective basis. Currently, the cost of biopharmaceuticals limits their availability. Plant-derived biopharmaceuticals are cheap to produce and store, easy to scale up for mass production, and safer than those derived from animals. Here, we discuss recent developments in this field and possible environmental concerns.

Antibodies↗

PubMed2000

Toward the rational design of cell fate modifiers: notch signaling as a target for novel biopharmaceuticals.

Recent advances in our understanding of highly conserved mechanisms that control cell fate determination are paving the way towards rationally designed biologics that modulate specific cell fate decisions. Cell fate decisions leading to proliferation, differentiation or apoptosis are crucial elements in the pathogenesis of countless human diseases. Biopharmaceuticals designed to regulate such processes in specific cell types in vivo or ex vivo have vast potential applications in oncology, stem cell technology, immunomodulation and neuropathology. One of the most conserved mechanisms controlling cell fate determination is based upon Notch-ligand interactions and subsequent signaling events. Recent studies have shown that this mechanism regulates cell differentiation, proliferation and apoptosis in a wide variety of cell maturation processes and in neoplastic cells. These observations identify the Notch signaling network as a promising drug target for numerous indications. In this review, we describe: 1) potential drug targets in the Notch signaling network; 2) the Notch agonists and antagonists developed so far, including recombinant proteins, antibody-based agents, synthetic peptides, antisense oligonucleotides and gene therapy approaches, as well as possible strategies to design novel Notch-targeting biopharmaceuticals; 3) the possible clinical applications of such biopharmaceuticals and 4) a model strategy for the selection and developement of a Notch-targeting biopharmaceutical.

Animals↗

PubMed2001

Similarity of the Escherichia coli proteome upon completion of different biopharmaceutical fermentation processes.

A comprehensive view of the physiological state of Escherichia coli cells at the completion of fermentation processes for biopharmaceutical production was attained via two-dimensional gel electrophoretic analysis of cellular proteins. For high cell density fermentations in which phosphate is depleted to induce recombinant protein expression from the alkaline phosphatase promoter, proteome analysis confirms that phosphate limitation occurs. Known phosphate starvation inducible proteins are observed at high levels; these include the periplasmic phosphate binding protein and the periplasmic phosphonate binding protein. The phn (EcoK) locus of these E. coli K-12 strains remains cryptic, as demonstrated by failure to grow with phosphonate as the sole phosphorus source. Proteome analysis also provided evidence that cells utilize alternative carbon and energy sources during these fermentation processes. To address regulatory issues in the biopharmaceutical industry, comparative electrophoretic analyses were conducted on a qualitative basis for four different fermentation processes. Using this approach, the protein profiles for these processes were found to be highly similar, with the vast majority (85-90%) of proteins detected in all profiles. The observed similarity in proteomes suggests that multiproduct host cell protein immunoassays are a feasible means of quantifying host-derived polypeptides from a variety of biopharmaceutical fermentation processes.

Biopharmaceutics↗

PubMedDate not supplied

Contribution of biopharmaceutics and pharmacokinetics to improve drug therapy.

Efficacy, safety and costs are the elements defining the quality of pharmacological therapy. Several clinical studies have shown the contribution of pharmacokinetics and biopharmaceutics to different treatment responses. During the past few years, new drugs with very interesting properties, such as good oral bioavailability, wide tissue distribution and slow elimination rate, have been introduced. It has allowed improvement in the patient's treatment, and has introduced new therapeutic possibilities. The development of new drug delivery systems has facilitated achieving certain pharmacodynamic effects and overcoming some pharmacokinetic disadvantages of conventional formulations. This achievement has been a biopharmaceutical challenge in answer to a clinical need. Therapeutic drug monitoring in wide populations has permitted improvements in the design of new dosage regimens in order to ameliorate the therapeutic efficacy for different groups of drugs: antibiotics, antineoplastics, cardiovascular agents etc. Pharmacokinetic criteria have to be considered as a clinical strategy to increase the accuracy when making decisions about dosage individualization. Individual patients, other patient populations, and also the use of usually unmonitored drugs, take advantage of therapeutic monitoring benefits. The contribution of biopharmaceutics and pharmacokinetics has been important for obtaining maximum efficacy with minimal side-effects and cost optimization.

Biopharmaceutics↗

PubMedDate not supplied

An overview about biopharmaceutics in Europe.

In Europe, the concept of biopharmaceutics was first introduced at the end of the 70s by various highly informed young Europeans who took into full account the publications and studies carried out by the first generation of explorers in this area in the United States such as John Wagner, Gerhard Levy, and W.A. Ritschel, amongst others. Their primary aim was to develop bioavailability studies for the registration of generics or new dosage forms. They then worked on setting up a new system for drug dissolution in vitro, including in vitro and in vivo correlations to better define the formulations. All this research led to the publication of numerous reports on different congresses, the most important of these being the European Congress of Biopharmaceutics and Pharmacokinetics, which is held once every two years in a European country and includes a large number of participants with an attendance ranging from 300 to 500 persons. During this same period, books were published in French and other European languages such as English, German and Spanish, with the result that updated information was efficiently circulated throughout all European countries. In the near future, the introduction of the biopharmaceutical classification as well as new in vitro models will certainly make a positive contribution to the further development of research in this area.

Biological Availability↗

PubMed2004

Economic aspects of commercial manufacture of biopharmaceuticals.

Sustained approvals of new biopharmaceuticals supported by a sparkling pipeline are the drivers for the above-market growth of biopharmaceuticals. Due to usually high therapeutic dose of monoclonal antibodies, they are demanding for high capacity needs. This requires significant capital investment and stimulates innovation for process improvement to decrease cost of goods and to save capital investments. Such process improvements are either ongoing along the learning curve or result from significant process changes through regulatory authorities impact. Both approaches require extensive protein analytical guidance to maintain product quality, safety and equivalency. In addition to second generation processes, second generation products have the feature of optimizing the physiological principle of biopharmaceuticals to the therapeutic need and to decrease the therapeutic dose, which goes along with investment savings and lower cost of goods.

Amino Acid Sequence↗

PubMed1998

Advances in biopharmaceutical analysis in the People's Republic of China 1995-1997.

The present paper is the third biannual review in succession to the author's previous publications (Z.L. Qin, Advances in biopharmaceutical analysis in the People's Republic of China: 1991-1993, J. Pharm. Biomed Anal. 13, 1995, 1-7 and Z.L. Qin, Advances in biopharmaceutical analysis in the People's Republic of China: 1993-1995, J. Pharm. Biomed. Anal. 14, 1996, 1395-1403), regarding the methodological study and progress in biopharmaceutical analysis by RP-HPLC, GC and GC-MS selected from relative journals between April 1995 and March 1997 in P.R. China. The published methods were widely adopted in pharmacokinetic and metabolic studies. Investigation on drug metabolism were conducted more deeply, both in vitro and in vivo, for searching the structure of metabolites and drug metabolic pathways. The use of high performance CZE as a new trend for the analysis of drugs and metabolites in biofluids was also reported.

Biopharmaceutics↗

PubMed2001

Biopharmaceuticals approved in the EU 1995-1999: a European Union-United States comparison.

The European Union's (EU) centralized procedure for new drug review was implemented in 1995 to unify the regulatory process and provide EU-wide marketing authorizations for innovative medicinal products. Goals were instituted to ensure the timeliness of the various steps of the process. The EU approved 27 biopharmaceutical products through the centralized procedure during 1995-1999. This study documents the success of the EU in meeting the timeline goals for the group and for separate categories of biopharmaceuticals (recombinant proteins, monoclonal antibodies, and antisense oligonucleotides). A subset of the 27 biopharmaceuticals approved in the EU were also approved in the United States (US). We compared EU and US approval times for these products by product category and by review status (exceptional/non-exceptional circumstance in the EU and priority/standard in the US).

Biopharmaceutics↗

PubMed2006

Immunogenicity of biopharmaceuticals.

The availability of biopharmaceuticals has been increasing over the past decade and as their patents expire, the emergence of biosimilar agents approaches. The primary issue of concern for the safety of these agents is the potential for immunogenicity. Both product- and host-related factors have documented impact on the immune response, but many factors are still unknown. Although in many cases the presence of antibodies may have little clinical consequence, the upsurge of pure red cell aplasia cases further increased concerns about potential clinical consequences of extensive use of biopharmaceuticals and biosimilars. Available laboratory measurement methods are insufficient to predict biological and clinical properties of biopharmaceuticals, or even to compare their bioequivalence. Comparison of results from different studies is complicated by the variability of assay measurements, presentation of data and lack of standardization.

Animals↗

PubMed2003

The immunogenicity of biopharmaceuticals. Lessons learned and consequences for protein drug development.

Most biopharmaceuticals, including those proteins that are more or less identical to native human proteins, induce antibodies in a significant fraction of patients. The main factors contributing to immunogenicity are impurities and the presence of aggregates. Sequence divergence from the native proteins only plays a minor role except in proteins from microbial, plant or distant vertebrate origin. In the majority of cases the antibodies have no biological or clinical effects. The most common clinical effect is the loss of efficacy of the biopharmaceutical. Serious complications of immunogenicity are rare. The best method to prevent immunogenicity is optimizing production, purification and formulation of the biopharmaceutical protein to generate soluble, non-aggregated, native protein free of contaminating adjuvants. The best way to predict immunogenicity in humans is evaluation in immune tolerant transgenic mice.

Animals↗

PubMed2006

Particle engineering techniques for inhaled biopharmaceuticals.

Formulation of biopharmaceuticals for pulmonary delivery is faced with the challenge of producing particles with the optimal properties for deep lung deposition without altering the native conformation of these molecules. Traditional techniques such as milling are continuously being improved while newer and more advanced techniques such as spray drying, spray freeze drying and supercritical fluid technology are being developed so as to optimize pulmonary delivery of biopharmaceuticals. While some of these techniques are quite promising, some are harsh and impracticable. Method scale up, cost-effectiveness and safety issues are important factors to be considered in the choice of a technique. This paper reviews the presently developed techniques for particle engineering biopharmaceuticals.

Administration, Inhalation↗

PubMed2004

Second-generation biopharmaceuticals.

The majority of first generation biopharmaceuticals are unengineered murine monoclonal antibodies or simple replacement proteins displaying an identical amino acid sequence to a native human protein. While some such products continue to be approved, an increasing number of modern biopharmaceuticals are engineered, second-generation products. Engineering can entail alteration of amino acid sequence, alteration of the glycocomponent of a glycosylated protein, or the covalent attachment of chemical moieties such as polyethylene glycol. Engineering has been applied in order to alter a protein's immunological or pharmacokinetic profile, or in order to generate novel fusion products. Better understanding of the links between protein structure and function will underpin the development of an increasing number of engineered biopharmaceuticals in the future.

Animals↗

PubMed2026

Inducible flocculation in Komagataella phaffii enables enhanced biomass separation for biopharmaceutical production.

Biomass separation represents a critical bottleneck in Komagataella phaffii-based biopharmaceutical processes, as typically high cell densities of 40 - 50 % create significant operational, technical and economic challenges for harvest operations. Yeast cell aggregation (flocculation) provides a solution to accelerate cell sedimentation by increasing particle size, thus allowing to improve biomass-supernatant separation efficiency during both natural gravity settling and (continuous) centrifugation operations. This study demonstrates successful engineering of K. phaffii strains with an inducible flocculation phenotype using CRISPR/Cas9-based genome editing to integrate the Saccharomyces cerevisiae FLO1 (ScFLO1) gene under control of various regulatory elements, including methanol-inducible and derepressible promoters. Flocculation strength could be enhanced by implementing transcriptional positive feedback circuits based on the methanol-inducible AOX1 promoter. To address methanol-free production requirements, we developed alternative systems to retrofit PAOX1-based ScFLO1 expression and exploited the derepressible PDF promoter, offering broader compatibility with biopharmaceutical manufacturing facilities. Flocculating cells cultivated in a bioreactor demonstrated significantly improved sedimentation behavior, with considerably lower supernatant turbidity after short low-speed centrifugation or gravity sedimentation compared to non-flocculating controls. Crucially, cell flocculation had no negative impact on product amount and quality when expressing a multivalent NANOBODY® VHH molecule with pharmaceutical relevance. Thus, this work establishes the first genetically engineered flocculation system in K. phaffii compatible with recombinant protein production, providing the basis for an innovative approach to streamline harvest operations in biopharmaceutical processes.

Flocculation↗

PubMed1997

Plants as bioreactors for biopharmaceuticals: regulatory considerations.

Plants are one of several novel hosts that can be used for the production of recombinant biopharmaceuticals such as cytokines, hormones, monoclonal antibodies, enzymes and vaccines. The novelty of this technology and its wide range of potential applications require an assessment of possible regulatory concerns in the clinical development of plant-derived biopharmaceuticals. General principles extrapolated from experience gained with biotechnology products from other sources can serve as a foundation to develop scientifically sound strategies for the large-scale production and clinical development of safe and effective biopharmaceuticals in plant hosts.

Animals↗

PubMed1998

Biopharmaceutical characterization of oral immediate release drug products. In vitro/in vivo comparison of phenoxymethylpenicillin potassium, glimepiride and levofloxacin.

The development of in vitro dissolution tests using the paddle and basket apparatus is described with respect to the qualification/validation of the testing procedure. Three examples of immediate release products containing phenoxymethylpenicillin potassium, glimepiride, and levofloxacin providing different solubility characteristics are evaluated. The solubility was high in the case of phenoxymethylpenicillin potassium and levofloxacin and low for glimepiride according to the biopharmaceutics classification system. The permeability is studied using the human colorectal carcinoma cell line CaCo-2. The permeability (10(-6) cm/s) of phenoxymethylpenicillin potassium, glimepiride, and levofloxacin was high. The determined permeability data are confirmed by absorption data obtained by means of numerical deconvolution of plasma concentrations. Recommendations are given for the biopharmaceutical characterization of the three immediate release drug products, taking into account in vitro and in vivo comparison as well as the biopharmaceutics drug classification system. The evaluated acceptance criteria are the following: phenoxymethylpenicillin potassium (80% in 30 min), glimepiride (80% in 15 min) and levofloxacin (80% in 30 min). Typically, for immediate release formulations, one limit is specified for the dissolution to ensure the release of the active ingredient within the present time period. Since phenoxymethylpenicillin potassium and levofloxacin belong to Case 1, no in vitro/in vivo correlation is expected, absorption may be gastric emptying dependent. Glimepiride is categorized to Case 2. Nevertheless, a correlation with the in vivo dissolution profile does not exist, because of the pH-dependent low solubility of the drug. Finally, recommendations are made for the batch control of drug products in accordance with the four Cases.

Absorption↗

PubMed2004

Biopharmaceuticals derived from genetically modified plants.

Modern biotechnology has resulted in a resurgence of interest in the production of new therapeutic agents using botanical sources. With nearly 500 biotechnology products approved or in development globally, and with production capacity limited, the need for efficient means of therapeutic protein production is apparent. Through genetic engineering, plants can now be used to produce pharmacologically active proteins, including mammalian antibodies, blood product substitutes, vaccines, hormones, cytokines, and a variety of other therapeutic agents. Efficient biopharmaceutical production in plants involves the proper selection of host plant and gene expression system, including a decision as to whether a food crop or a non-food crop is more appropriate. Product safety issues relevant to patients, pharmaceutical workers, and the general public must be addressed, and proper regulation and regulatory oversight must be in place prior to commercial plant-based biopharmaceutical production. Plant production of pharmaceuticals holds great potential, and may become an important production system for a variety of new biopharmaceutical products.

Antibodies↗

PubMed2005

Biosimilar epoetins: an analysis based on recently implemented European medicines evaluation agency guidelines on comparability of biopharmaceutical proteins.

Patents of innovator biopharmaceutical products, such as epoetin, are expiring, and biosimilar versions of these products may soon enter European and American markets. Copies of these products, termed biosimilars or follow-on biologics, are not truly equivalent and cannot gain market approval through the procedure typically applied to generic drugs. We evaluated literature reports of both analytic and clinical studies conducted with biosimilar epoetin products currently marketed outside the United States and Europe in light of recently implemented European Medicines Evaluation Agency guidelines. The analytic studies reported that products differed widely in composition, did not always meet self-declared specifications, and exhibited batch-to-batch variation. Although several clinical studies demonstrated correction of anemia with biosimilar epoetins by using an open-label or placebo-controlled study design, only 4 of 22 studies were competitor controlled. Most of the studies were small (median 41 patients, range 18-1079 patients) and of short duration (median 12 wks, range 6 wks-1 yr). Clinical experience with epoetin shows that the dosage required to achieve similar hemoglobin levels varies among patients, making it impossible to demonstrate bioequivalence without a comparator. The analytic reports did not demonstrate comparability of biosimilar epoetin products with innovator epoetin alfa, and the clinical studies were not rigorous enough to show equivalent safety and efficacy of a biopharmaceutical product. The variation between products illustrates the challenge in replicating and consistently producing biopharmaceutical proteins. Immunogenic reactions with epoetin indicate that large, long-term studies are needed to adequately monitor safety.

Anemia↗

PubMed2001

Formulations strategies for biopharmaceuticals--ensuring success to market.

It was clear from the number of attendees and the broad spectrum of organizations represented at this conference, that effective formulation development for biopharmaceuticals is a critical and timely issue. From DNA-based products to antibodies, vaccines to therapeutics, administered by every route known to medicine, formulation plays a critical role in the ultimate success of biopharmaceutical products. It was obvious from the various case studies presented that effective formulation development is not often achieved as an organization enters into drug development. In fact, systematic pre-formulation work was stressed by most speakers as an effective use of company resources. In order to develop successful formulations, it is essential that appropriate analytical information is collected, that excipients are systematically evaluated, and that the developer understands the basis of stability of the drug product. In all cases, this means understanding product instability, including the physicochemical and thermodynamic basis for instability. Drugs such as therapeutic antibodies, which may require large doses to achieve the desired pharmacological effect, require ever more advanced formulation development to achieve concentrations in the 100-mg/ml range. Potent drugs, such as gene therapies and DNA vaccines, require formulation development in order to achieve effective delivery and expression. On aggregate, it is apparent that there is much to learn in formulation development, from each other as well as in the unexplored territory ahead. This conference provided an excellent forum for the exchange of ideas and information regarding effective formulation development for biopharmaceuticals.

Journal Article↗