Simon Ruini, London
After having completed the last round of consultation with the public, WHO expert group is about to publish the approved and final version of the Guidelines on the Quality, Safety, and Efficacy of Biotherapeutic Products Prepared by Recombinant DNA Technology.
These guidelines apply, in principle, to all biologically active protein products used in the treatment of human diseases and which are prepared by recombinant DNA technology. They also apply to protein products used in diagnosis (e.g. for monoclonal antibody products including in vivo diagnosis and ex vivo treatment, but excluding in vitro diagnosis) and those intentionally modified by for example pegylation or modification or rDNA sequences. They set out regulatory expectations both for clinical trials and for licensing, as well as for changes in products already on the market. However, the level of data submitted for a product for clinical trials will have to take into account the nature of the product and its stage of development.
Although the principles outlined in this document (e.g. in Part A) apply to vaccines made by rDNA technology, there are more detailed guidelines/recommendations on vaccine evaluation in terms of quality, safety, and efficacy. For example, vaccines such as yeast derived hepatitis B vaccine or malaria vaccine produced by rDNA technology are available at WHO (http://www.who.int/biologicals/vaccines/en/). The present guidelines are not intended to apply to genetically modified live organisms designed to be used directly in humans, such as recombinant viral vectors or live attenuated vaccines, nor to gene transfer products. A WHO guideline on DNA vaccines for therapeutic as well as for prophylactic use, adopted by the WHO Expert Committee on Biological Standardization in 2005, are available. Products produced in transgenic animals are also excluded. Part A sets out updated guidelines for the manufacture and quality control of rDNA- derived biotherapeutics, including consideration of the effects of manufacturing changes and of devices used in delivery on the product and its stability. The nature and extent of characterization and testing (Part A) required for a product undergoing nonclinical and clinical studies will vary depending on the nature of the product and its stage of development. Part A may also apply to vaccines prepared by rDNA technology. However, neither Part B nor C applies to the vaccines.
Background
Developments in molecular genetics and nucleic acid chemistry have enabled genes encoding natural biologically active proteins to be identified, modified and transferred from one organism to another so as to obtain highly efficient synthesis of their products. This has led to the production of new rDNA-derived biological medicines using a range of different expression systems such as bacteria, yeast, transformed cell lines of mammalian origin, insect and plant cells, as well as transgenic animals. rDNA technology is also used to produce non-native biologically active proteins such as chimeric, humanized or fully human monoclonal antibodies, or antibody-related proteins or other engineered biological medicines such as fusion proteins. There has also been great progress in the ability to purify biologically active macromolecules. In addition, analytical technologies have improved tremendously since the early days of biotechnology, allowing the detailed characterization of many biological macromolecules including its protein, lipid and oligosaccharide components.Together these technologies have enabled the production of large quantities of medicinal products that are difficult to prepare from natural sources or were previously unavailable.
Nevertheless, it is still not possible to fully predict biological properties and clinical performance of these macromolecules from physicochemical characteristics alone. In addition, the production processes are biological systems which are known to be inherently variable, a feature which has important consequences for the safety and efficacy of the resulting product. A pre-requisite, therefore, for introducing such biologicals into the clinic is to ensure consistency of quality from lot to lot and for this purpose robust manufacturing processes are developed based on process understanding and characterization, including appropriate in-process controls. Process understanding and consistency is critical since slight changes can occasionally lead to major adverse effects, such as immunogenicity, with serious safety implications associated with immunogenicity. As with many other new technologies, a new set of safety issues for consideration both by industry and NRAs has been generated by these particular biotechnologies. Potential safety concerns arose from the novel processes used in manufacture, from product and process related impurities and from the complex structural and biological properties of the products themselves. Factors that have received particular attention include the possible presence of contaminating oncogenic host cell DNA in products derived from transformed mammalian cells, and the presence of adventitious viruses. Since the nature and production of these products are highly sophisticated, they require similar sophisticated laboratory techniques to ensure their proper standardization and control.
Although comprehensive characterization of the drug product is expected, considerable emphasis must also be given to process validation and in-process control. Adequate control measures relating to the starting materials and manufacturing process are, therefore, as important as analysis of the drug product. Thus data on the host cell quality, purity, freedom from adventitious agents, adequate in-process testing during production, and effectiveness of test methods are required for licensing.
At a very early stage in the development of rDNA-derived medicines, the European Medicines Agency and the US Food and Drug Administration produced guidelines and points to consider, respectively, for the development and evaluation of these new products. Such guidelines, based as they were on long experience with traditional biologicals, set the scene for regulatory expectations both for clinical trials and for licensing. At the global level, the WHO produced a series of guidance documents on the quality, safety and efficacy of rDNA-derived products, including specific guidance for products such as interferons and monoclonal antibodies. These regulatory concepts have been instrumental in establishing the quality, safety and efficacy of rDNA-derived biotherapeutics which now play a major role in today’s medical practice. As patents and data protection measures on biotechnology products have expired, or neared expiration, considerable attention has turned to producing copies of the innovator products with the view to making more affordable products which may improve global access to these medicines. Since by definition it is not possible to produce identical biologicals, the normal method of licensing generic medicines, which relies primarily on bioequivalence data, is not appropriate for licensing such products and the term similar biological product, or biosimilar product, came into existence. The concept of similar biological medicinal products was introduced first by the European Medicines Agency and subsequently by other national regulatory authorities (although the actual term used has varied slightly from agency to agency). WHO guidelines on the evaluation of similar biotherapeutic products were produced in 2010, and provided a set of globally acceptable principles regarding the regulatory evaluation of biosimilars, although it was recognized that they will not by themselves resolve all issues. During international consultations on the development of the biosimilar guidelines and also their implementation, it became clear that there was a need to update WHO guidance on the quality, safety and efficacy of rDNA-derived medicines and biotechnology products in general. In 2010, the International Conference of Drug Regulatory Authorities noted that WHO should supplement its guidance on the evaluation of similar biotherapeutic products by providing up-to-date guidelines for the evaluation of biotherapeutic products in general. The present guidelines have been developed through international consultation and are intended as a replacement of those in Annex 3, TRS No 814, 1991. They are considered to be a replacement and not a revision of those guidelines because they contain new sections on nonclinical and clinical evaluation of rDNA-derived biotherapeutics which were lacking in the original document.
Finally, a section on issues related to manufacturing changes both during development and once the product is on the market has also been introduced since considerable improvements to the production process and to the product itself can take place during the later stages of development and post licensure, especially in the immediate post licensing years. These changes can unintentionally impact the clinical performance of the product and need to be handled carefully from a regulatory perspective.
Pharma Design Limited offers regulatory and strategic advice on recombinant DNA vaccines and monoclonal antibodies. Simon Ruini is director of PhD limited.