Biopharmaceuticals are among the growing business segments of the pharmaceutical and biotechnology industries. Since its introduction in 1982, biopharmaceutical drugs have revolutionized the treatment of a broad spectrum of diseases and are increasingly used in nearly all branches of medicine.
What are Biopharmaceuticals?
Biopharmaceuticals (including biologicals, or biologics) are drugs produced in, extracted from, or semisynthesized from genetically modified organisms1. In contrast to chemical synthesis of pharmaceuticals biological sources enable the production of more complex drugs like recombinant therapeutic proteins, or even whole living cells used in cell therapy. For example, a molecule of acetylsalicylic acid is composed of 21 atoms. In contrast, biopharmaceuticals are typically 100–1000 times larger.2
The main categories of biopharmaceuticals are organisms, such as attenuated viruses, or parts and products of organisms, such as tissues, stem cells and monoclonal antibodies, as well as recombinant proteins. The two fastest growing categories are monoclonal antibodies and recombinant proteins. Among the many types of expression hosts used to generate recombinant proteins for therapeutics are mammalian cells, such as Chinese hamsters – ovarian (CHO) cell lines, insect cells, yeasts and bacteria.
Biopharmaceutical and Synthetic Medicine
The complex structure of biopharmaceuticals causes new obstacles in drug development and production and therefore higher time and money investment. Average development of biopharmaceuticals takes between seven and eight years, with expenses in the range of € 60 to € 200 million2. Chemical synthesized medicine ranges between €1.6 and €2.4 million in only two to three years. Main reasons are a high level of monitoring as well as scores of quality tests.2
The Rise of Biopharmaceuticals
Despite the immense time and financial effort required the market of biopharmaceuticals is rapidly growing. The global biopharmaceuticals market generated US$ 228 billion in 2016, a forecast for 2023 estimates to reach USD 341.16 billion3. Recombinant antibodies account for approximately 30% of all biopharmaceuticals currently under development.
Drugs against diseases that trigger a deregulation of homeostasis in cell proliferation and cell death account for the biggest growth. This includes both the field of chronic autoimmune diseases and cancer. Especially, when prior no satisfying medication existed, the demand is tremendous. With the introduction of immunotherapy antibodies such as Opdivo (nivolumab) and Keytruda (pembrolizumab), and CAR-T cell therapies, there have been remarkable therapeutic results that would be extremely difficult to emulate with conventional therapies.4
- Annually registered Studies
2005 12,800 2006 10,917 2007 12,554 2008 17,573 2009 17,017 2010 17,351 2011 17,823 2012 19,473 2013 20,447 2014 23,320 2015 24,129 2016 27,806 2017 29,195 2018 25,748
Biopharmaceuticals are manufactured by recombinant DNA technology to use a host cell to express and secrete therapeutic proteins. Several protein expression systems has been established over the years all with their own advantages and disadvantages. Chinese hamster ovary (CHO) cells are arguably the most important for therapeutic protein production. Also the cultivation and harvest is more complex and expensive in comparison to bacterial expression, CHO cells offer mammalian post-translational modification (PTM) which is crucial for the functionality of the desired protein. This is why CHO cells are used to make more than half of all therapeutic proteins on the market today.6
Host Cell Proteins
Expression systems used in the generation of biopharmaceuticals contain not only they desired pharmaceutical protein but also the whole proteome of the organism it self. These host cell proteins (HCP) pose the danger of adverse drug effects like allergic or anaphylactic reactions.7 Under some circumstances HCPs may even be biologically active in the human body or impact product stability by degradation either of the therapeutic protein or product-stabilizing excipients.
The composition of HCPs is influenced by many factors. Stages of development and culture conditions all have an impact on the proteome of cells. Determination of all HCP components represents one of the biggest challenges in drug development and production at this present time. Recombinant protein pharmaceuticals have to be purified to a high degree to meet clinical requirements. Based on risk assessments, clinical experience and manufacturing capability typically accepted levels are < 100 ppm (100 ng HCP/mg product).7
This strict regulation also applies for biosimilars. A biosimilar is a medicine that is modelled on the original biopharmaceutical (the biological reference product); however, it is not identical to it. The production process of biopharmaceuticals varies from one manufacturer to the next and as a consequence every biopharmaceutical has unique properties possibly resulting in severe product quality issues.8 Follow-on manufacturers do not have access to the originator’s materials like molecular clone and original cell bank or the exact process itself. Together with the unique nature of each host organism and complex protein structure, every biopharmaceutical has unique properties. Despite that heterogeneity, all biopharmaceuticals, including biosimilars, must maintain consistent quality and clinical performance throughout their lifecycle.
Therefore, in case of a monoclonal antibody-containing drug, extensive physicochemical and biological characterization has to be made for both, biosimilar and its reference product, in order to demonstrate their highly-similar properties. For the sake of patient´s health the regulations are very strict – in the last 12 years drug-related authorities like EMA (EU) and FDA (US) have granted marketing authorisation for only a few biosimilars in total.
- Definition of “biological” at Oxford Dictionaries
- Rader RA (2008). “(Re)defining biopharmaceutical”. in Nature Biotechnology. 26 (7): 743–51. PMID 18612293
- Ralf Otto (2014). “Rapid growth in biopharma: Challenges and opportunities”. in McKinsey. PMID 18612293
- Misra, M. (2012) Indian J. Pharmacol. 44, 12–14. PubMed
- Kaplon, H., & Reichert, J. M. (2018). Antibodies to watch in 2018. mAbs, 10(2), 183-203. PMID
- Florian M. Wurm (2004). “Production of recombinant protein therapeutics in cultivated mammalian cells. in Nature Biotechnology. 22: 1393–1398. PubMed
- Stefanie Wohlrab (2018) “Tracking Host Cell Proteins During Biopharmaceutical Manufacturing: Advanced Methodologies to Ensure High Product Quality” in APR
- Malgorzata Kesik‐Brodacka (2017). “Progress in biopharmaceutical development” in Biotechnology and Applied Biochemistry. Volume 65, Issue 3. PubMed
- Lamanna WC, Holzmann J, Cohen HP, Guo X, Schweigler M, Stangler T, Seidl A, Schiestl M (April 2018). “Maintaining consistent quality and clinical performance of biopharmaceuticals”. Expert Opinion on Biological Therapy. 18 (4): 369–379. doi:10.1080/14712598.2018.1421169. PubMed