Developments in biological standardization最新文献

Animal cell lines are increasingly used in the manufacture of viral vaccines. They may play a key role in the preparation of seed stock virus and vaccine production. However, the same animal cell substrates may also be used for diagnosis of viral infection and surveillance of prevalent virus strains. Quality control of cell lines intended for use in this range of procedures is vital to ensure the absence of contaminating organisms and correct identity of the substrate cells used. Furthermore, the qualification and validation of the procedures, facilities and staff involved in the cell culture and testing are also important issues addressed in regulatory guidelines and regulations. The standards to which these activities are performed are dependent on whether the cells are intended for diagnostic and surveillance work or for seed stock virus isolation and production. This paper indicates when and how some of the relevant quality standards and quality control issues apply to cell lines intended for the different procedures involved in virus isolation and vaccine production.

The Australia Influenza Vaccine Committee makes independent decisions concerning the influenza vaccine formulation for Australia. Large-scale cell culture using MDCK cells would improve response time for vaccine production in the face of a new pandemic. There must be a consensus with respect to the use of MDCK or other cells before the next pandemic. It is unrealistic to expect any national regulatory authority to determine what safety requirements should be met before approving a cell substrate for vaccine production during an influenza pandemic. Regulatory issues seen as obstacles to the approval of MDCK cells as an accepted cell substrate for influenza vaccine production are identified.

Research always depended on animals or directly on human beings for the generation of antibodies with new specificities. With the opportunity to clone the human antibody repertoire, it is now also feasible to tap the human immune system and to search for new antibody specificities in antibody gene libraries [1, 2]. Phage display technology has fostered these approaches as it allows even rare specificities to be identified in libraries of a complexity of 10(8) to 10(10) [3, 4]. While most of the work in this field is still based on immune libraries, that is, B-cells derived from immunised animals or human individuals, more recent approaches allow even the necessity for immunisation to be by-passed. Synthetic antibody libraries exist of a complexity comparable to the natural immune system of mammals, so that theoretically every imaginable antibody may be detected and then used either for diagnostic or therapeutic purposes [5-7]. Thus, these new gene technology approaches make it possible to generate antibodies completely independently of animals. It may be that animals will only be used in the future to study the immune system of the animal.

A new generation of membrane-based cell culture devices especially designed for small scale production of monoclonal antibodies (mabs) has entered the market in the last few years. In contrast to conventional perfusion hollow fibre bioreactors, these devices contain two functionally different membranes--one ultrafiltration membrane for nutrient supply and one gas-permeable membrane for direct oxygenation of cells. The latest systems of this generation are static culture systems which are of moderate cost and either better than, or equal to, the ascites mice in terms of quality and quantity of produced monoclonal antibodies. We have investigated the advantages of the perfused Tecnomouse bioreactor and the static CELLine culture flasks in comparison to ascites production and conventional roller bottle cultures.

It is important, both morally, scientifically and legally, that animal experimentation causes the minimum amount of suffering necessary to achieve the scientific objective. This paper describes an approach that facilitates the recognition and assessment of animal pain and distress through the use of clinical signs. The score sheet system can help to indicate new scientific responses, as well as to determine and to validate humane end points in the safety testing of biological products using animals. Some examples are given.

The history of cell substrates for the manufacture of biological products is directly related to a series of technical advances and challenges to the status quo, some of which were accepted quickly while others took more than a decade to resolve. The development of cell culture techniques in the 1950s opened the door to the manufacture of a wide range of biological products. The first major challenge occurred in the late 1960s when human diploid cells (HDCs) were developed and proposed as an alternative to primary cell cultures for the production of live viral vaccines such as polio, which up to that point had been produced in primary cells of various species. In the 1970s, attention was focussed on the use of continuous cell lines (CCLs) for the production of non-replicating biological products such as interferon (IFN). The next significant technical advance and challenge was the development of recombinant DNA and monoclonal antibody technologies in the 1980s, both of which required the use of CCLs. Although most of the issues relating to CCLs in the manufacture of biological products have been resolved, issues related to their use as substrates for live viral vaccines remain to be fully addressed. Those experiences in the past teach us clearly that a system in which regulatory authorities, industry, and the general biomedical community cooperate in finding solutions to problems and in reaching consensus on issues raised by technical advances is ultimately in everyone's best interest. The World Health Organization has played a major role in that regard, and it should continue to provide leadership in this area.

The potency of several novel botulinum toxin-derived biological therapeutic products now in routine medical use is determined exclusively by in vivo methods. In addition, large numbers of animals continue to be used for the potency and safety testing of therapeutic antitoxins and toxoid vaccines. There is thus an increasing need to develop acceptable alternative assays for toxicity testing of clostridia neurotoxins which could be applied to different toxin derived therapeutic agents, including vaccines. Scientific advances in the understanding of the mode of action of clostridial neurotoxins have now provided the basis for improving conventional testing procedures.