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PubMed1996

Safety of biopharmaceuticals: a current perspective.

The impetus for this conference comes in large measure from the continuing development of the ICH Viral Safety document concerned with testing and evaluation of the viral safety of biotechnology products derived from characterized cell lines of human or animal origin [1]. My opening remarks for this conference were, I think, suggested by the organizers in the belief that George Santayana's quote, "Those who cannot remember the past are condemned to repeat it" has validity for this effort. In this brief review I have tried to recall some past unfortunate episodes and outline the lessons that they might have for us. I have also attempted to outline a number of issues which I believe are critical to the success of efforts to guarantee, as much as humanly possible, the safety that we seek balanced against our ability to develop and use important new products.

Animals↗
PubMed1997

Is the biopharmaceutical quality of extracts adequate for clinical pharmacology?

According to definition, an extract is a multi-substance mixture from a medicinal plant obtained by extraction of specific parts of the plant. Corresponding to the active ingredients in each case, each extract exhibits, qualitatively and quantitatively, a specific content spectrum, so that an extract is not just any extract. With an increasing demand for demonstrating the clinical efficacy of plant-based substances, extracts or extract fractions, we necessarily confront the problem of phytogenerics, i.e. extract-identical preparations for exchange versus the innovator. Up to now, pharmacognosic experts, phytochemists, and pharmacists have dealt with the problem as to the bioequivalence of phytopharmaceuticals within the context of pharmaceutical and biopharmaceutical/technological equivalence. In the meantime, however, from a number of plant extracts, the active ingredients determining their efficacy are known and analytical methods have been established, so that bioavailability/bioequivalence studies similar to those for chemical/synthetic substances are now possible.

Guidelines as Topic↗
PubMed1997

[Biopharmaceutical studies of similar theophylline products in the national market].

BACKGROUND: Theophylline has a narrow therapeutic margin, therefore it should be formulated as a sustained release pharmaceutical form. In Chile there are several brands of sustained release theophylline forms that have not been tested. AIM: To perform in vitro release-dissolution studies of sustained release theophylline forms commercialized in Chile. MATERIALS AND METHODS: Five sustained release products were studied according to the specifications of the seventh supplement of The United States Pharmacopoeia Convention. Release and dissolution rates were compared with a rapid release aminophylline form. The identity, validation and active principle content of each product was also studied. RESULTS: All the studied forms complied with the quality requirements of the USP XII. The dissolution rate constants of the products at pH 6 ranged from 0.0583 to 0.2130, compared with 7.1 for the rapid release form. The dissolution of all products, except one, was pH dependent. CONCLUSIONS: These results underscore the need to systematically study the quality of pharmaceutical products, considered similar, whose differences could have potential risks for patients.

Bronchodilator Agents↗
PubMedDate not supplied

Technology and biopharmaceutical availability of solid ocular inserts containing sulfadicramide and some promoters.

Technology for obtaining solid ocular inserts made of poly(vinyl alcohol), containing sulfadicramide and some sorption promoters, was worked out. The rate of drug release was studied by assuming the pseudo-first order kinetics to hold true. An isolated animal cornea was used to measure the coefficients of permeability and the efficiency of sulfadicramide penetration through these corneas.

Amides↗
PubMed1998

[Experiences with the rectal use of a chemotherapeutic agent. 1. In vitro biopharmaceutical examinations; selection of the optimal vehicle].

The factors influencing in vitro liberation (Part 1) and in vivo absorption (Part 2) from trimethoprim-containing rectal suppositories and the authors' results related to them are reported in this two-part publication. Special emphasis was laid on selecting the optimal suppository base which is harmless physiologically yet not indifferent pharmacologically. From among the 24 compositions studied, a lipophilic mixture containing a surface active additive (Witepsol W 35) and a hydrophilic (Macrogolum) mixture were found to be the best in all respects. Liberation from the trimethoprim-containing rectal suppositories was measured with in vitro dynamic diffusion and spectrophotometrically. A power relation was found to exist between the quantity of the released pharmacon and the diffusion time, and a significant negative exponential relation was observed between the doses and their respective in vitro availability values.

Administration, Rectal↗
PubMed1995

Recent developments and perspectives of biotechnology-derived products.

Recent advances in molecular biology especially in the area of rDNA, gene transfer, polymerase chain reaction and hybridoma techniques have provided the necessary molecular tools for the development of a new class of biopharmaceuticals. These biopharmaceuticals include antisense drugs, carbohydrate-based macromolecules and agents that interfere with apoptosis pathways. Cytokines and other immunomodulators also represent an exciting class of new therapeutic entities. The safety evaluation, efficacy, manufacturing and quality control of these complex biopharmaceuticals represent a challenge to the pharmacologist and toxicologist. Finally, the regulatory issues associated with the new biopharmaceuticals need to be addressed to insure the safety of these evolving therapeutic substances.

Apoptosis↗
PubMed2005

Fractionation of follicle stimulating hormone charge isoforms in their native form by preparative electrophoresis technology.

Complex glycoprotein biopharmaceuticals, such as follicle stimulating hormone (FSH), erythropoietin and tissue plasminogen activator consist of a range of charge isoforms due to the extent of sialic acid capping of the glycoprotein glycans. Sialic acid occupies the terminal position on the oligosaccharide chain, masking the penultimate sugar residue, galactose from recognition and uptake by the hepatocyte asialoglycoprotein receptor. It is therefore well established that the more acidic charge isoforms of glycoprotein biopharmaceuticals have higher in vivo potencies than those of less acidic isoforms due to their longer serum half-life. Current strategies for manipulating glycoprotein charge isoform profile involve cell engineering or altering bioprocesss parameters to optimise expression of more acidic or basic isoforms, rather than downstream separation of isoforms. A method for the purification of a discrete range of bioactive recombinant human FSH (rhFSH) charge isoforms based on Gradiflowtrade mark preparative electrophoresis technology is described. Gradiflowtrade mark electrophoresis is scaleable, and incorporation into glycoprotein biopharmaceutical production bioprocesses as a potential final step facilitates the production of biopharmaceutical preparations of improved in vivo potency.

Animals↗
PubMed2002

Analysis methods of polysorbate 20: A new method to assess the stability of polysorbate 20 and established methods that may overlook degraded polysorbate 20.

PURPOSE: Polysorbate 20 is a commonly used excipient in biopharmaceutical formulations, some of which may have an enzymatic activity. The action(s) of polysorbate 20 in biopharmaceutical formulations as a stabilizer require this surfactant to maintain its intact structure. This manuscript evaluates a new analytic method for the analysis of polysorbate 20 degradation in the format of a biopharmaceutical formulation and makes a comparison with several established methods of analysis. METHODS: Polysorbate 20 samples were degraded in a controlled environment utilizing the enzyme pancreatic lipase to generate degradants that included lauric acid and the sorbitan polyoxyethylene side chain. A new method was developed with sufficient sensitivity to analyze the degraded solutions. Lauric acid was derivatized with the fluorescent reagent 9-anthryldiazomethane to form 9-anthrylmethylethyl ester. The derivatized lauric acid was separated by reversed-phase chromatography and detected by fluorescence or UV spectroscopy. Three established methods utilized to measure polysorbate 20 were evaluated for their ability to detect degraded polysorbate 20. These methods were: (1) fluorescence analysis with N-phenyl-1-naphthylamine fluorescent dye; (2) UV spectroscopy with ammonium cobaltothiocyanate colorimetric reagent; and (3) nuclear magnetic resonance (NMR). RESULTS: Polysorbate 20 incubation with lipase resulted in degraded polysorbate 20 as determined by the derivatized lauric acid assay. The UV spectroscopy assay utilizing ammonium cobaltothiocyanate reagent was not able to detect the degradation of polysorbate 20 in the samples. The fluorescence method of analysis detected polysorbate 20 degradation as an approximate 50% decrease in micelles in comparison to standard nondegraded polysorbate 20 solutions. NMR analysis resulted in similar proton peak areas for both degraded and nondegraded polysorbate 20 samples. NMR spectra did contain minor differences between the samples. CONCLUSIONS: It is essential to choose the appropriate method of polysorbate 20 evaluation to assess the content, stability, and compatibility of a formulation. Current established methods to assess polysorbate 20 may overlook and do not necessarily monitor the potential degradation of this surfactant, which results in the formation of lauric acid. Because this type of degradation may occur in a formulation by an enzymatically active biopharmaceutical, a new method of analysis has been established.

Chemistry, Pharmaceutical↗
PubMedDate not supplied

The role of the toxicologic pathologist in the preclinical safety evaluation of biotechnology-derived pharmaceuticals.

Biotechnology-derived pharmaceuticals, or biopharmaceuticals, represent a special class of complex, high molecular weight products, such as monoclonal antibodies, recombinant proteins, and nucleic acids. With these compounds, it is not appropriate to follow conventional safety testing programs, and the preclinical "package" for each biopharmaceutical needs to be individually designed. In addition to standard histopathology, the use of molecular pathology techniques is often required either in conventional animal studies or in in vitro tests. In this review, the safety evaluation of biopharmaceuticals is discussed from the perspective of the toxicologic pathologist, and appropriate examples are given of the use of molecular pathology procedures. Examples include the use of in situ hybridization to localize gene therapy vectors, the assessment of vector integration into genomic DNA by the polymerase chain reaction (PCR), and the use of immunohistochemistry to evaluate the potential cross-reactivity of monoclonal antibodies. In situ PCR techniques may allow for confirmation of the germ cell localization of nucleic acids and may therefore facilitate the risk assessment of germline transmission. Increased involvement with biopharmaceuticals will present challenging opportunities for the toxicologic pathologist and will allow for much greater use of molecular techniques, which have a critical role in the preclinical development of these compounds.

Animals↗
PubMed2003

Conference on plant-made pharmaceuticals. 16-19 March 2003, Québec City, Québec, Canada.

The Conference on Plant-Made Pharmaceuticals was an inaugural event organized by Molecular Farming Association Inc, a non-profit organization created in 2000 to support the emergence of plant-made biopharmaceuticals and plant-factory companies. The meeting was sponsored by the Government of Canada, the Gouvermement du Québec and the Société Générale de Financement, along with 20 companies involved in plant-made pharmaceuticals and related activities. Although there was very little discussion of new biopharmaceuticals under development with these systems, this was the first meeting where participants could survey the entire breadth of technologies and approaches that are being taken to produce biopharmaceuticals in transgenic plants. Participants also heard about the technical, manufacturing and regulatory issues confronting transgenic plant expression systems, as well as from 'new technology' companies that hav not previously presented in a public forum. There was a clear sense emerging from the meeting that the hurdles currently facing the industry will be overcome and that transgenic plant systems will eventually move into the mainstream of biopharmaceutical manufacturing technologies.

Animals↗
PubMed1990

Large-scale animal cell culture: a biological perspective.

It is generally recognized that no one cell culture system can be universally applied to all cell types commonly used for biopharmaceutical manufacture. The analogous concept that no single cell type may be useful for the expression of all biopharmaceutical products may also gain credence in the biotechnology community. It may be that like specialized bioreactors, there will come to exist a variety of cell types that will be used for the production of different types of biopharmaceutical products. In addition, it may not be enough in the future just to demonstrate the stability of expression of the amino acid backbone of the protein only; the carbohydrate portion of the molecule may become the subject of real scrutiny. Questions such as how the carbohydrate side chain affects the performance of the molecule in vivo are being asked of more DNA constructs. The next question becomes, how can we control the expression of carbohydrate moieties on the molecule? Such questions are in the future of the biotech manufacturing field. Aside from those examples mentioned above dealing with the insertion of receptors, other more subtle attempts at modifying cellular metabolism are taking place. It was reported at a recent meeting that the sialyltransferase gene was inserted into a CHO line which did not normally express this enzyme (116). The transfected line was capable of expressing the transferase and, more importantly, the enzyme functioned correctly in sialylating glycoproteins. Other very complex relationships exist between the substratum and the cell that could have very direct consequences on culture maintenance. For example, researchers recently published results indicating that collagenase synthesis and secretion is stimulated in rabbit fibroblasts by autocrine factors. They determined that these autocrine proteins had sequence homology to serum amyloid-A and beta-2-microglobulin. It may be that using serum supplements in the medium in those systems that couple fibroblast and collagen substratum may not be prudent, especially for long-term culture. The traditional selection of a cell type for expressing heterologous proteins has generally been limited to the more "common" cell types such as CHO cells, C127 cells, and myeloma cells. In many cases these cell types were selected because there was a great deal of preexisting literature on the cell type (i.e., "cookbook" methods of transfection for the cell) or the cell was simply being carried in the lab at the time the effort was made to express a biopharmaceutical product.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Creating the next generation of protein therapeutics through rational drug design.

Biopharmaceuticals, or protein drugs, have proven to be safe and effective therapies in many disease indications. However, the first generation of biopharmaceuticals has largely been limited to replicating the functions of native human proteins, or inhibiting these functions through the use of monoclonal antibodies. Recent advances in the design of biopharmaceuticals include computational approaches to manipulate protein structure, improved screening processes to synthesize and assay libraries of novel proteins, and new methods to modify proteins post-translationally and during production. Protein drug structure and function can now be optimized in the same way that small molecules are optimized via medicinal chemistry. This review addresses recent developments in the field of protein 'medicinal biology', and provides examples of how these tools are being applied to create the next generation of biopharmaceuticals possessing optimized drug properties and novel functions.

Animals↗