Submitted: 23 June 2020; Revised: 29 June 2020; Accepted: 29 June 2020; Published online first: 10 July 2020
The past 40 years has seen a revolution in recombinant DNA (rDNA)-based and related biotechnologies and opened the door to new and exciting vistas of global public health, disease diagnosis, treatment, prevention and correction of defective genes. Amongst the successes of these technologies has been the development of platforms for the rapid development of candidate DNA and RNA vaccines as well as viral vector vaccines of particular interest in the current global COVID-19 pandemic . rDNA-derived biotherapeutic proteins are likewise now key components of modern medical practice. They are at the cutting edge of biomedical research and a rapidly growing sector of pharmaceuticals.
In the early 1980s developments in molecular biology enabled genes encoding natural biologically active proteins to be identified, modified and transferred from one organism to another and to be efficiently synthesized in different host cells. These range from bacteria, yeast, continuous cell lines of mammalian origin, insect and plant cells as well as transgenic animals and plants. In addition, rDNA technology has been used to produce clinically useful biologically active proteins which do not exist in nature, such as humanized monoclonal antibodies or other engineered biologicals like fusion proteins. Over this time period there has also been considerable development in the technologies used for purifying and characterizing these biological macromolecules and the protein sequences, secondary/tertiary structures, post-translational glycosylation, phosphorylation, oxidation and lipidation can now be defined in great detail. Even so, it is not possible to fully predict the biological properties and clinical performance of these products based simply on their physicochemical characteristics. rDNA-derived biotherapeutics have unique and diverse structural and biological properties, including species specificity, immunogenicity and unpredicted pleiotropic activities. These properties pose particular problems in relation to non-clinical testing in animals. They also mean extensive clinical evaluation covering efficacy and safety, especially immunogenicity in humans, which may have varying clinical consequences ranging from none to severe.
Regulatory measures were put in place very early on in the development of these biotechnology-derived medicines and they were regulated as biologicals. Guidelines on their development, production and quality control were also issued early on by the European Medicines Agency (EMA), the US Food and Drug Administration (FDA) and, at the global level, by the World Health Organization (WHO) [2–6]. Over time, rDNA-derived proteins became the best characterized of all biological products, as well as safe and effective medicines. The basic regulatory procedures put in place reflected long-term experience with biologicals in general and, over the years, they have provided a framework for moving forward with novel biotechnologies. Emphasis was on guidelines (or points to consider), not prescription, to allow for further innovative developments. The original concepts are still in place today, updated, expanded and refined to take into account new knowledge and new technologies, and similar guidelines have been developed by many other agencies. Guidelines for assuring the quality and safety of DNA vaccines were also developed in the 1990s . They are currently undergoing further revision and take into consideration the regulatory needs of public health emergencies of international concern. A useful list of WHO documents relevant to the development and evaluation of SARS-CoV-2 vaccines and other biologicals is also now available . Documents relevant to the current Covid-19 pandemic are additionally available on the websites of EMA and FDA and other major regulators.
Since the majority of rDNA-derived therapeutic proteins need to be glycosylated for their activity and/or for half-life considerations, they are produced in animal cells, including continuous cell lines or insect cells, as are many viral vaccines. This involves using well-characterized master and working cell banks and paying attention to genetic stability issues. A major concern regarding the safety of such products is the possible presence of adventitious viruses in cell substrates or raw materials used in production which could find their way into the product. Detailed recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological products, for the characterization of cell banks and for the control of raw materials used in production are available from WHO , the International Council for Harmonization (ICH)  and national regulatory authorities. Guidelines on the reduction and/or inactivation of possible contaminants in rDNA-derived products are also available, although inactivation or reduction technologies cannot be applied to live viral vaccines. Together, these recommendations have enabled the field to develop and many key vaccines and biotherapeutics are produced in mammalian cells. However, viral contamination has occasionally occurred during production  but usually contained. Nevertheless, even if prevented from getting into a product, contamination of cell lines and intermediate production materials can have huge economic consequences for a manufacturer and might lead to supply issues with considerable public health impact [12–14]. Adherence to good manufacturing practices (GMP) and Quality by Design (QbD) principles as well as the availability of increasingly sensitive technologies for the detection of adventitious agents should make these events increasingly rare although when they happen manufacturers need to deal with them promptly. As new inexperienced manufacturers come into operation it is essential that they understand the need for great care and attention regarding the development and production of biological products. Good cell culture practice, which includes documentation and traceability, are all key aspects of this work and staff training in cell culture processes is vital to ensure that correct procedures are adhered to under GMP. The role of National Regulatory Authorities (NRAs) in overseeing these developments is critical and GMP inspection is a key aspect of this oversight.
In recent years, increasing numbers of patents/data protection on innovator products have been expiring and biopharmaceuticals ‘similar’ to the originals are increasingly coming to the market. The key question was how to handle the licensing of these products, recognizing that biologicals cannot meet the criteria for true generics. Following a period of intense consultation, guidelines on the evaluation of similar biotherapeutic products (SBP, biosimilars) were developed, first by EMA [15, 16], then by countries such as Canada, and by WHO . More recently, FDA developed draft updated guidelines  and several other jurisdictions, such as Health Canada and EMA, have updated their guidance [19, 20]. Generally, the various guidelines and regulations reflect increasing convergence in the field. In all cases the intention is that licensing rely, in part, on data from an approved innovator product, the Reference Biological Product (RBP), and this has stimulated a lot of manufacturer and regulatory interest worldwide. Biosimilars are expected to be more affordable than the innovator products and contribute to increased access, as encouraged by the World Health Assembly Resolution of 2014 . Some rDNA biotherapeutics and biosimilars are now listed in WHO’s Essential Drugs List.
The success of biosimilars has depended on improved technologies which can now be used to characterize complex biological macromolecules in exquisite detail “3D structures of proteins and glycans, oxidations and other post-translational modifications. Whilst there is a need to show similarity between the RBP and the biosimilar/SBP it is necessary also to identify any differences. There will be differences between an SBP and RBP since, by definition, these macromolecules are highly similar but not identical. Introducing manufacturing changes to approved biotherapeutic products may likewise result in analytical differences between the pre- and post-changes product. Predicting the impact of structural differences, and the level of differences, on biological activity and clinical performance is the difficult part, especially in the case of multifunctional products, such as monoclonal antibodies. Much work is now ongoing in the area of biotherapeutics, driven by the issues of biosimilars and the field is moving towards a better understanding of the structure/function relationships of rDNA-derived proteins. Knowing which parameters affect Critical Quality Attributes, and which do not, may help refine non-clinical or clinical supporting data needs and provide confidence in the quality, safety and efficacy of biosimilars and in the extrapolation of indications, as well as post-approval manufacturing changes to biotherapeutics. This is indicated by the increasing complexity of licensed biosimilars, the first being Omnitrope (somatropin) (21 kDa) in 2006 and from 2013 onwards several much larger and complex monoclonal antibodies, such as infliximab (144.2 kDa). Data are now available to show that, at least in the situation examined, switching from innovator to biosimilar has no negative impact on efficacy, safety or immunogenicity, enhances confidence in the use of biosimilars and reduces the cost of biotherapeutic treatment . Currently, there is interest in the potential role of IL-6 antagonists, such as tocilizumab, a monoclonal antibody against the IL-6 receptor (IL-6 R), in the clinical management of severe COVID-19 infection, where some patients develop a ‘cytokine storm’ syndrome; clinical trials are ongoing [23–25]. The patents for tocilizumab have expired and several biosimilar versions are in development in a number of countries which, if successful, may offer access to more affordable treatment.
Driven by these successes and by the need for affordable biopharmaceuticals, rDNA-derived medicines, biosimilars and vaccines are increasingly being, produced and used worldwide, including in low- and middle-income countries (LMICs). This often means new manufacturers with less experience of biotherapeutics as well as NRAs with less expertise/experience and capacity to evaluate these complex products. Less experienced NRAs will therefore become the ‘first regulatory entry point’ for some complex biotherapeutics and they may need support. WHO provides support by promoting regulatory convergence at the global level by developing standards and encouraging their use through implementation workshops and the publication of case studies [6, 26–32]. GaBI also has provided support in the form of a series of interactive workshops on the regulatory assessment of biosimilars, such as the ones in Bangkok, Thailand in 2017 and Ankara, Turkey in 2018 [33, 34]. Many regulatory agencies across the globe are assessing how policy and regulations can be developed and improved to ensure that these critical and technically demanding medicines are of appropriate quality, safety and efficacy. The production of any pharmaceutical needs to be carried out using GMP and the GMP inspection is a critical and integral component of the licensing of both pharmaceutical and biological medicinal products and in ensuring their ongoing quality, safety and efficacy. However, this is especially challenging for modern day biological products which include sophisticated rDNA-derived biotherapeutics, biosimilars and vaccines. Due to the complexity of rDNA products, the inherent variability of biological production processes, depending as they do on cell culture, as well as the bioassays used in the characterization of such products, special considerations are needed in order to maintain consistency in product quality and clinical performance. A very timely and comprehensive overview of the global challenges in the manufacture, regulation and international harmonization of GMP and Quality Standards is presented by Sia CH et al. in GaBI Journal . In particular, the review covers the biopharmaceutical industry and regulatory frameworks of countries in the Association of South East Asian Nations (ASEAN) and strongly advocates improving harmonization of regulatory efforts and creating a culture of quality within the organization to meet the common challenges in dealing with these innovative and critical biological medicines. This will be particularly important for dealing with novel, technically demanding cell therapies and other advanced therapy medicinal products (ATMPs) which hold much promise to health at the personal level .
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
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Author: Elwyn Griffiths, DSc, PhD, Consultant in Vaccines and Biotherapeutics, Kingston upon Thames, Surrey, UK
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