Biopharmaceutical
A biopharmaceutical, also known as a biological medical product,
Terminology surrounding biopharmaceuticals varies between groups and entities, with different terms referring to different subsets of therapeutics within the general biopharmaceutical category. Some
Gene-based and cellular biologics, for example, often are at the forefront of
In some jurisdictions, biologics are regulated via different pathways from other small molecule drugs and medical devices.[13]
Major classes
Extracted from living systems
Some of the oldest forms of biologics are extracted from the bodies of animals, and other humans especially. Important biologics include:[citation needed]
- Whole blood and other blood components
- tissue transplants
- Stem-cell therapy
- Antibodies for passive immunity (e.g., to treat a virus infection)
- Human reproductive cells
- Human breast milk
- Fecal microbiota
Some biologics that were previously extracted from animals, such as insulin, are now more commonly produced by recombinant DNA.
Produced by recombinant DNA
Biologics can refer to a wide range of biological products in medicine. However, in most cases, the term is used more restrictively for a class of therapeutics (either approved or in development) that are produced using biological processes involving recombinant DNA technology. These medications are usually one of three types:
- Substances that are (nearly) identical to the body's key signaling proteins. Examples are the blood-production stimulating protein erythropoetin, or the growth-stimulating hormone named "growth hormone" or biosynthetic human insulinand its analogues.
- hybridomatechnology or other methods) and can therefore be made specifically to counteract or block any given substance in the body, or to target any specific cell type; examples of such monoclonal antibodies for use in various diseases are given in the table below.
- Receptor constructs (immunoglobulin frame. In this case, the receptor provides the construct with detailed specificity, whereas the immunoglobulin structure imparts stability and other useful features in terms of pharmacology. Some examples are listed in the table below.
Biologics as a class of medications in this narrower sense have had a profound impact on many medical fields, primarily
Older patients who receive biologic therapy for diseases such as rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis are at increased risk for life-threatening infection, adverse cardiovascular events, and malignancy.[14]
The first such substance approved for therapeutic use was biosynthetic "human"
Major kinds of biopharmaceuticals include:
- Blood factors (Factor VIII and Factor IX)
- Thrombolytic agents (tissue plasminogen activator)
- Hormones (insulin, glucagon, growth hormone, gonadotrophins)
- Haematopoietic growth factors (Erythropoietin, colony-stimulating factors)
- Interferons (Interferons-α, -β, -γ)
- Interleukin-based products (Interleukin-2)
- Vaccines (Hepatitis B surface antigen)
- Monoclonal antibodies (Various)
- Additional products (tumour necrosis factor, therapeutic enzymes)
Research and development investment in new medicines by the biopharmaceutical industry stood at $65.2 billion in 2008.[15] A few examples of biologics made with recombinant DNA technology include:
INN
|
Trade name | Indication | Technology | Mechanism of action |
---|---|---|---|---|
abatacept | Orencia | rheumatoid arthritis | CTLA-4 fusion protein
|
T-cell deactivation
|
adalimumab | Humira | rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease | monoclonal antibody | TNF antagonist
|
alefacept | Amevive | chronic plaque psoriasis | immunoglobin G1 fusion protein | incompletely characterized |
erythropoietin | Epogen | chronic renal failure , etc.
|
recombinant protein
|
stimulation of red blood cell production |
etanercept | Enbrel | rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis | recombinant human TNF-receptor fusion protein | TNF antagonist |
infliximab | Remicade | rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease | monoclonal antibody | TNF antagonist |
trastuzumab | Herceptin | breast cancer | humanized monoclonal antibody | HER2/neu (erbB2) antagonist
|
ustekinumab | Stelara | psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease | humanized monoclonal antibody | IL-12 and IL-23 antagonist |
denileukin diftitox | Ontak | cutaneous T-cell lymphoma (CTCL) | Diphtheria toxin engineered protein combining Interleukin-2 and Diphtheria toxin | Interleukin-2 receptor binder
|
golimumab | Simponi | rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis | monoclonal antibody | TNF antagonist
|
vedolizumab | Entyvio | ulcerative colitis, Crohn's disease | monoclonal antibody | α4β7 integrin blocker |
ixekizumab | Taltz | non-radiographic axial spondyloarthritis
|
humanized monoclonal antibody | IL-17A neutralizer
|
Vaccines
Many vaccines are grown in tissue cultures.
Gene therapy
Biosimilars
With the expiration of many
Biosimilars require a different regulatory framework compared to small-molecule generics. Legislation in the 21st century has addressed this by recognizing an intermediate ground of testing for biosimilars. The filing pathway requires more testing than for small-molecule generics, but less testing than for registering completely new therapeutics.[19]
In 2003, the
Commercialization
When a new biopharmaceutical is developed, the company will typically apply for a patent, which is a grant to exclusive manufacturing rights. This is the primary means by which the drug developer can recover the investment cost for development of the biopharmaceutical. The patent laws in the United States and Europe differ somewhat on the requirements for a patent, with the European requirements perceived as more difficult to satisfy. The total number of patents granted for biopharmaceuticals has risen significantly since the 1970s. In 1978 the total patents granted was 30. This had climbed to 15,600 in 1995, and by 2001 there were 34,527 patent applications.[22] In 2012 the US had the highest IP (Intellectual Property) generation within the biopharmaceutical industry, generating 37 percent of the total number of granted patents worldwide; however, there is still a large margin for growth and innovation within the industry. Revisions to the current IP system to ensure greater reliability for R&D (research and development) investments is a prominent topic of debate in the US as well.[23] Blood products and other human-derived biologics such as breast milk have highly regulated or very hard-to-access markets; therefore, customers generally face a supply shortage for these products. Institutions housing these biologics, designated as 'banks', often cannot distribute their product to customers effectively.[24] Conversely, banks for reproductive cells are much more widespread and available due to the ease with which spermatozoa and egg cells can be used for fertility treatment.[25]
Large-scale production
Biopharmaceuticals may be produced from microbial cells (e.g., recombinant
Transgenics
A potentially controversial method of producing biopharmaceuticals involves
One potential approach to this technology is the creation of a transgenic mammal that can produce the biopharmaceutical in its milk, blood, or urine. Once an animal is produced, typically using the pronuclear microinjection method, it becomes efficacious to use cloning technology to create additional offspring that carry the favorable modified genome.[27] The first such drug manufactured from the milk of a genetically modified goat was ATryn, but marketing permission was blocked by the European Medicines Agency in February 2006.[28] This decision was reversed in June 2006 and approval was given August 2006.[29]
Regulation
European Union
In the European Union, a biological medicinal product[30] is one of the active substance(s) produced from or extracted from a biological (living) system, and requires, in addition to physicochemical testing, biological testing for full characterisation. The characterisation of a biological medicinal product is a combination of testing the active substance and the final medicinal product together with the production process and its control. For example:
- Production process – it can be derived from biotechnology or from other technologies. It may be prepared using more conventional techniques as is the case for blood or plasma-derived products and a number of vaccines.
- Active substance – consisting of entire proteinaceous, or polysaccharidecomponents originating from a microbial, animal, human, or plant source.
- Mode of action – therapeutic and immunological medicinal products, gene transfer materials, or cell therapy materials.
United States
In the United States, biologics are licensed through the biologics license application (BLA), then submitted to and regulated by the FDA's Center for Biologics Evaluation and Research (CBER) whereas drugs are regulated by the Center for Drug Evaluation and Research. Approval may require several years of clinical trials, including trials with human volunteers. Even after the drug is released, it will still be monitored for performance and safety risks. The manufacture process must satisfy the FDA's "Good Manufacturing Practices", which are typically manufactured in a cleanroom environment with strict limits on the amount of airborne particles and other microbial contaminants that may alter the efficacy of the drug.[31]
Canada
In Canada, biologics (and radiopharmaceuticals) are reviewed through the Biologics and Genetic Therapies Directorate within Health Canada.[32]
See also
- Antibody-drug conjugate
- Genetic engineering
- Host cell protein
- List of pharmaceutical companies
- List of recombinant proteins
- Nanomedicine
References
- ^ "Biological". Oxford Dictionaries. Archived from the original on October 19, 2019.
- PMID 30520869.
- PMID 22995556.
- PMID 18612293.
- ^ "Drugs@FDA Glossary of Terms". Food and Drug Administration. 2 Feb 2012. Retrieved 8 April 2014.
- ISBN 978-0-470-84326-0.
- PMID 23964615.
- ^ Thomas, Kate; Pollack, Andrew (15 July 2015). "Specialty Pharmacies Proliferate, Along With Questions". New York Times. Sinking Spring, Pa. Retrieved 5 October 2015.
- ^ Murphy CO. "Specialty Pharmacy Managed Care Strategies" (PDF). Retrieved 24 September 2015.
- ^ European Medicines Agency, "tooltip definition of advanced therapy medicinal products", Committee for Advanced Therapies (CAT), retrieved 2017-05-15.
- ^ European Medicines Agency, Advanced therapy medicinal products: Overview, retrieved 2017-05-15.
- ^ Center for Biologics Evaluation and Research (2010-04-01). "What is a biological product?". U.S. Food and Drug Administration. Retrieved 2014-02-09.
- PMID 18958946.
- ^ Kerr LD (2010). "The use of biologic agents in the geriatric population". J Musculoskel Med. 27: 175–180.
- ^ BriskFox Financial. "Biopharmaceutical sector sees rising R&D despite credit crunch, finds analysis". Archived from the original on 2018-10-03. Retrieved 2009-03-11.
- ^ PMID 24281342.
- PMID 21478841.
- PMID 29285958.
- ^ S2CID 14604362. Retrieved 2012-06-13.
- ^ EMA (2008-10-30). "Questions and answers on biosimilar medicines (similar biological medicinal products)" (PDF). European Medicines Agency. Archived from the original (PDF) on 2017-03-15. Retrieved 2014-10-11.
- ^ 75 FR 61497; United States Food and Drug Administration (2010-10-05). "Approval Pathway for Biosimilar and Interchangeable Biological Products" (PDF). Public Hearing; Request for Comments.
- ^ Foster, Luke. "Patenting in the Biopharmaceutical Industry—comparing the US with Europe". Archived from the original on 2006-03-16. Retrieved 2006-06-23.
- ^ "Growth and Policies Behind Biopharmaceutical Innovation". phrma.org. PhRMA. Retrieved 11 April 2018.
- ^ Carlyle, Erin. "The Guys Who Trade Your Blood For Profit". Forbes. Retrieved 2016-09-29.
- ^ "Sperm Donors Australia | Donate Sperm". spermdonorsaustralia.com.au. Retrieved 2016-09-29.
- S2CID 4673669.
- S2CID 10154550.
- ^ Phillip B. C. Jones. "European Regulators Curdle Plans for Goat Milk Human Antithrombin" (PDF). Retrieved 2006-06-23.
- ^ "Go-ahead for 'pharmed' goat drug". BBC News. 2006-06-02. Retrieved 2006-10-25.
- ^ The Commission of the European Communities (2003-06-25). "Commission Directive 2003/63/EC amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use" (PDF). Official Journal of the European Union. p. L 159/62.
- ^ Kingham R, Klasa G, Carver K (2014). Key Regulatory Guidelines for the Development of Biologics in the United States and Europe (PDF). John Wiley & Sons, Inc. pp. 75–88. Retrieved 11 April 2018.
- ^ "Biologics and Genetic Therapies Directorate". Retrieved 2019-01-20.
External links
- Biological Products at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Debbie Strickland (2007). "Guide to Biotechnology" (PDF). Biotechnology Industry Organization (BIO). Archived from the original (PDF) on 2007-09-27. Retrieved 2007-12-17.
- Timothy B. Coan; Ron Ellis (2001-06-01). "Report for USA Specialty Pharmaceuticals: Generic Biologics: The Next Frontier" (PDF). Consumer Project on Technology. Retrieved 2007-12-17.
- "About biologics". National Psoriasis Foundation. 2006-11-01. Archived from the original on 2006-01-01. Retrieved 2007-12-17.