Biopharmaceutical

Biopharmaceuticals (also biopharmaceuticals , biologicals , biologics , biologics or biologics ) are medicinal substances that are produced using biotechnology and genetically modified organisms . Biopharmaceuticals are among the growing business areas in the pharmaceutical and biotechnology industries . The area of biopharmaceuticals must be distinguished from this .

Principle, manufacture and areas of application

Biopharmaceuticals are manufactured with great technological effort and complex development and manufacturing methods. They are supposed to intervene specifically in the processes of the body.

Produced proteins (including monoclonal antibodies ), and nucleic acids ( DNA , RNA such as antisense RNA , and antisense oligonucleotides ). These can be used in diagnostics , but also for therapy , e.g. B. in the fight against cancer . Modified human cells can also be included: if one's own blood cells are removed from the body in the course of an adoptive cell transfer , genetically modified in the laboratory, multiplied and administered again, e.g. B. the CAT lymphocytes in the treatment of certain leukemias.

In principle, the production can take place with the help of animal or plant organisms. Biopharmaceuticals can of microorganisms (eg., Recombinant Escherichia coli or yeast ), cell lines of mammals (for. Example, CHO cells ) and plant ( vegetable tissue culture ) are produced in bioreactors. If biopharmaceuticals are produced with the help of genetically modified plants ( plant biotechnology ), the plants are called pharmaceutical plants .

Drug groups

Important groups in which biotechnologically manufactured active ingredients are used include:

• Blood clotting factors (e.g. octocog alfa, nonacog alfa)
• Fibrinolytics ( tissue-specific plasminogen activators such as alteplase )
• Hormones (e.g. insulin , gonadotropins , growth hormones such as somatotropin )
• Haematopoietic growth factors ( erythropoietin , colony stimulating factors such as G-CSF )
• Interferons (interferon-α, -β, -γ)
• Interleukin analogues, e.g. B. recombinant interleukin-2 (rIL-2, aldesleukin)
• Vaccines (e.g. hepatitis B vaccine )
• Monoclonal antibodies
• Active substances that have a direct effect on gene expression ( transcription , translation ) (e.g. transcription factors , siRNAs or microRNAs )
• Other products ( tumor necrosis factor superfamily , therapeutic enzymes)

Research and results

One goal of research and development in the field of biopharmaceuticals (the relevant branch of science is called pharmaceutical biotechnology ) is to find a safe alternative to conventional production systems, such as B. CHO cells to develop. Here are GMP conditions best met if the pharmaceuticals are cultivated in closed containers such. B. in bioreactors .

The first biopharmaceutical to be approved for therapeutic purposes was an insulin produced biosynthetically using recombinant DNA from E. coli (rHI, trade name Humulin , developed by Genentech , but licensed to Eli Lilly , launched in 1982).

The first medicine made from the milk of a genetically modified goat was ATryn . The market launch was initially stopped by the European Medicines Agency in February 2006. This decision was reversed in June 2006 and approval was granted in August 2006.

The number of patents for biopharmaceuticals has grown rapidly since the 1970s. In 1978 there were a total of 30 patents, in 1995 15,600, and in 2001 34,527 applications were filed.

Measured in terms of sales figures and the range of possible medical indications, the most important biopharmaceutical in the world today is erythropoietin . Recombinant antibodies make up about 30% of all biopharmaceuticals currently in clinical testing ; this shows the potential for the growth of biotechnology in the production of these products.

A detailed study of the Institute for Quality and Efficiency in Health Care (IQWiG) showed that nine biologics are useful for use in rheumatoid arthritis, even if long-term data and direct comparisons are still lacking. Abatacept, adalimumab, certolizumab pegol, golimumab, and tocilizumab supported remission, relieved symptoms, and increased physical function status and quality of life. There is no evidence for anakinra, etanercept, infliximab and rituximab, but there is at least some evidence that they are useful in the treatment of rheumatoid arthritis.

Biosimilars

Biosimilars are drug-like successor products to biopharmaceuticals. They do not belong to the generic product class. When approving low-molecular chemical generics, the manufacturer may refer to the pharmacological and clinical studies of the original product that were submitted when the product was first approved. Biosimilars are biotechnologically generated, protein-based copycat drugs that are approved after the patent period of an original active ingredient has expired. As biotechnology products, they are subject to natural fluctuations, for example in the isoform distribution, which means that no two batches are one hundred percent identical. Even within a single batch, there can be minimal deviations. This is why the reference product and biosimilar can never be completely identical and one speaks of similarity. Although there may be differences in the quantity of specific variants, a biosimilar must not have any clinically relevant differences from the original active ingredient and must have equivalent safety and effectiveness to the original active ingredient. Their approval requires more complex procedures and monitoring measures than with traditional generics. From the point of view of the Drugs Commission of the German Medical Association AkdÄ , evidence of efficacy, quality and harmlessness is available due to the requirements for approval. Biosimilars are equivalent to the original preparations and can be used just like these at the beginning of a treatment.

Naming

The naming of active ingredients in biosimilars is not internationally standardized and in Europe the INN system is used in the same way for an active ingredient in an original medicinal product and its biosimilar medicinal product, so that all have an identical INN name. This prevents any distinction from proprietary names, which can be problematic in certain cases.

In January 2017 the US Food and Drug Administration (FDA) published a guideline for the naming of biological drugs. As a result, a four-letter suffix with no meaning of its own is added to the INN of a biotechnologically produced active ingredient (e.g. infliximab-abda, infliximab-dyyb, infliximab-qbtv). Initially only practiced at biosimilars, newly approved original biologics are now also given such a suffix. In some cases, 3-letter prefixes were also assigned to differentiate originator variants.

In Japan, regulations also require a biosimilar active ingredient to be labeled with a unique, unprotected name ( Japanese Accepted Name , JAN). For a biosimilar active ingredient, the INN of the one in the reference product must be given, followed by the addition “biosimilar” and a consecutive number (in the order of approval) (e.g. filgrastim biosimilar 1, filgrastim biosimilar 2 etc.).

The Australian authority TGA announced in January 2018 that it would keep the existing system of the Australian Biological Name (ABN) and not use any non-proprietary markings in addition to the INN, such as the 4-letter suffix in the USA. For reports in the context of pharmacovigilance, the trade name of the preparation is mandatory in addition to the name of the active substance; for all general matters, a barcode based on the EU model is introduced to identify the drug on the packaging.

Biopharmaceutical costs

Biotechnologically manufactured drugs are associated with high annual therapy costs. In Germany, around 13 percent of pharmaceutical expenditure, which in 2011 amounted to € 27.1 billion at the expense of the statutory health insurance, is attributable to this class.

Individual evidence

1. ↑ Phillip BC Jones: European Regulators Curdle Plans for Goat Milk Human Antithrombin
2. ↑ Go-ahead for 'pharmed' goat drug , BBC, June 2, 2006.
3. ^ Luke Foster: Patenting in the Biopharmaceutical Industry - comparing the US with Europe ( Memento of November 17, 2007 in the Internet Archive ) 2002.
4. ↑ Biologika - second line therapy for rheumatoid arthritis (PDF; 488 kB).
5. ^ William C. Lamanna, Johann Holzmann, Hillel P. Cohen, Xinghua Guo, Monika Schweigler: Maintaining consistent quality and clinical performance of biopharmaceuticals . In: Expert Opinion on Biological Therapy . January 10, 2018, ISSN  1744-7682 , p. 1–11 , doi : 10.1080 / 14712598.2018.1421169 , PMID 29285958 .
6. ↑ Drugs Commission of the German Medical Association: Statement of the Drugs Commission of the German Medical Association on biosimilars. Berlin, December 9, 2008 (PDF; 124 kB).
7. ↑ B. Sträter: Drug safety: biosimilars from the point of view of the lawyer . Dtsch Arztebl 2016; 113 (9): A-373 / B-317 / C-317.
8. ^ Nonproprietary Naming of Biological Products - Guidance for Industry. FDA, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). January 2017.
9. ↑ US Food and Drug Administration: FDA-Approved Biosimilar Products , accessed April 17, 2019.
10. ↑ Naming and interchangeability for biosimilars in Japan Generics and Biosimilars Initiative (GaBI) online, October 7, 2016.
11. ↑ Submissions received and TGA response: Nomenclature of biological medicines , January 23, 2018.