Ebook: Rift-lines within european regulatory framework for biosimilars when taking heterogeneity and variation during lifecycle of the reference biologic and the biosimilar into account

Biopharmaceutical medicinal products (biologics) represent a huge financial market. Thus upon patent protection expiry of the innovator (reference) biologic there is interest from industry to gain a portion of this market by launching a 'similar' biologic at a reduced development cost, thus boosting potential gains. The EMA responded to this desire and lead the guidance process with industry on the topic of biosimilars. Based on the experience gained with biosimilars in the past, the EMA started to introduce a second generation series of guidance documents, which take into account the past, current and possibly future challenges of biosimilars. Those proposals were evaluated by EMA and partially incorporated into new guidance documents. This work highlights the challenges and risks associated with biosimilar submissions for large and complex bio-molecules such antibodies. Results: There are unaddressed questions for the regulator with regard to the unsolved dynamic of heterogeneity and variations of the quality profile, which have potential implications on safety and efficacy. This is neglected and not taken into account seriously enough by the stakeholders. Solution: Further, the only (in my view) progressive way to deal with such foreseeable situations from the biosimilar developer’s point of view is to incorporate a design space. Auszug aus dem Text Text Sample: Chapter 1, Introduction: 1.0. Rationale on the selection of the topic (as guide for future students) I started this course in pharmaceutical QA being aware that I would not benefit from full sponsorship from my employer. Although my financial possibilities were limited at the time, I wanted to explore the opportunity to take a step forward in my career in a meaningful way, by improving and developing my knowledge. Now, when I am close to finishing my study, looking back I realized it was the right choice as it was the gateway to a better future not only from the point of view of my knowledge but also from a personal perspective. My educational and scientific background is in immunology, as I graduated with a Diploma thesis at the Max Planck Institute for Immunology in Freiburg. I wanted to use this scientific background to find a proper topic for my study project. On the other hand, I also wanted to focus on a topic I am personally interested in and that will help me find better career opportunities. The search for a proper study topic started very early. I was asked by my teachers where do I want to be in 5-years time and what topic really interested me, and yet would allow me to gain further competencies and scientific skills. Finding the answer to this question took some time, but going through this process was deeply revealing and gave me clarity about my future career path. At the end of 2010, following a lecture and an article in TOPRA, I found what I was looking for: Biosimilars. The Biosimilar topic represents a good symbiosis of the DIT course content, focused on EMA regulations, and in accordance with my background in immunology. It is an emerging top regulatory topic, as the generic biologics industry (the correct term is biosimilar industry) seeks to gain access to the highly profitable biologics market. There was a good likelihood of writing a meaningful research paper and conducting an interesting study. The regulatory framework within Europe (the leading regulatory region for biosimilars) continues to require clarification and is in need of further development, especially at the theoretical level. By commenting on EMA regulations and directly interacting with the EMA, this study bears the potential to bring a new perspective to the European biosimilar regulations, overall an excellent strategic opportunity for the elaboration of this study. 1.1 Definitions: To understand the notion of biosimilar and differences to classical small molecules, it is first required to outline the term generic. The term 'generic' medicinal product is used to describe chemicals, which are small molecules. They are structurally equivalent to an innovator medicinal product whose patent and/or data protection period has expired. Bioequivalence of the generic medicine with a reference product is required, which usually does not include clinical trial, or in the case where it does they are minimal. It is permissible for generic companies to apply for a M.A., due to the pharmacopeia data from the reference medical product outline specification and the ability to produce robustly the same molecular entity, through synthesis. This high chemical purity product is very much different to biotherapeutics/biologics which are relatively large and complex proteins that are difficult to characterize (1). 1.1.1 Definition of biological medicine and major differences to ‘classical’ chemical medicine Biologics refers to naturally occurring substances generated by animals or microorganisms, or that can be created through biotechnology — recombinant DNA technology. Biological medicines are medicinal products, which are produced using a living system or organism. Typically modern biotechnology products are proteins, since almost all life on earth is based on proteins with its manifold functional groups, thus being an ideal basis for drug development. Proteins are produced in cells using recombinant DNA technology. From the European regulatory perspective, they are defined as medicinal products that are developed based on biotechnological processes: • Recombinant DNA technology • Controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells • Hybridoma and monoclonal antibody methods Biological medicines differ from ‘classical’ chemical medicines fundamentally through the following perspective: 1) Chemical medicines are usually small molecules, which are produced using a chemical synthesis process. Aspirin, for example, has a molecular weight of ca. 0.2 kDA. Biological medicines are usually much larger. Interferon alpha, for example, has a molecular size of ca. 19kDA and the IgG molecule has a molecular size of ca. 150kDA. 2) This direct molecular size/weight difference between biological medicines (later abbreviated as biologics) and chemical medicines, results also in a more complex three-dimensional structure of biologics. 3) The complex structures of biologics are more prone to vary compared to chemical medicines and poses inherent heterogeneity , refer to section: 2.2 Life cycle in relation to heterogeneity and variation for details on that heterogeneity and variation issue. 4) Chemical medicines are well defined and need to follow specific standards, which makes it relatively easy to reproduce them if required. On the other hand, biologics are more difficult to analyze. Their production process has a high impact on the final product. 5) Related to their protein structure, biologics are usually administered by injection, whereas chemical medicines can be administered in other forms such as pills, creams, ointments and sprays, etc. 6) Due to their differences in terms of administration and the foreign nature of these particular biologically active molecules to the body, potential adverse effects (the ‘immunogenic response’ ) with biologics are always a concern. The EMA recently described biologics as: ‘A biological medicine is a medicine that contains one or more active substances made by or derived from a biological source. Some of them may be already present in the human body and examples include proteins such as insulin, growth hormone and erythropoietins. The active substances of biological medicines are larger and more complex than those of non-biological medicines. Only living organisms are able to reproduce such complexity. Their complexity as well as the way they are produced may result in a degree of variability in molecules of the same active substance, particularly in different batches of the medicine’. (2) Biographische Informationen The author works in the life-science industry for over 7 years now. His educational and scientific background is in immunology, as he graduated at the Max Planck Institute for Immunology in Freiburg. Further he completed a MSc. in pharmaceutical quality assurance and regulatory affairs at the Dublin Institute of Technology.