Abiopharmaceutical, also known as abiological medical product,[1] orbiologic, is anypharmaceutical drug product manufactured in, extracted from, orsemisynthesized frombiological sources. Different fromtotally synthesized pharmaceuticals, they includevaccines,whole blood, blood components,allergenics,somatic cells,gene therapies,tissues,recombinant therapeutic protein, andliving medicines used incell therapy. Biopharmaceuticals can be composed ofsugars,proteins,nucleic acids, or complex combinations of these substances, or may be living cells or tissues. They (or theirprecursors or components) are isolated fromliving sources—human, animal, plant, fungal, or microbial. They can be used in both human and animal medicine.[2][3]
Terminology surrounding biopharmaceuticals varies between groups and entities, with different terms referring to different subsets of therapeutics within the general biopharmaceutical category. The termbiologics is often used more restrictively to mean biopharmaceuticals that are produced using recombinant DNA technology. Someregulatory agencies use the termsbiological medicinal products ortherapeutic biological product to refer specifically to engineeredmacromolecular products like protein- andnucleic acid-baseddrugs, distinguishing them from products like blood, blood components, or vaccines, which are usually extracted directly from a biological source.[4][5][6]Biopharmaceutics ispharmaceutics that works with biopharmaceuticals.Biopharmacology is the branch ofpharmacology that studies biopharmaceuticals.Specialty drugs, a recent classification of pharmaceuticals, are high-cost drugs that are often biologics.[7][8][9] TheEuropean Medicines Agency uses the termadvanced therapy medicinal products (ATMPs) for medicines for human use that are "based on genes, cells, or tissue engineering",[10] including gene therapy medicines, somatic-cell therapy medicines, tissue-engineered medicines, and combinations thereof.[11] Within EMA contexts, the termadvanced therapies refers specifically to ATMPs, although that term is rather nonspecific outside those contexts.
Gene-based and cellular biologics, for example, often are at the forefront ofbiomedicine andbiomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available.[12]
Building on the market approvals and sales of recombinant virus-based biopharmaceuticals for veterinary and human medicine, the use of engineered plant viruses has been proposed to enhance crop performance and promote sustainable production.[13]
In some jurisdictions, biologics are regulated via different pathways from other small molecule drugs andmedical devices.[14]
Some of the oldest forms of biologics are extracted from the bodies of animals, and other humans especially. Important biologics include:[citation needed]
Some biologics that were previously extracted from animals, such as insulin, are now more commonly produced byrecombinant 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 involvingrecombinant DNA technology. These medications are usually one of three types:
Biologics as a class of medications in this narrower sense have had a profound impact on many medical fields, primarilyrheumatology andoncology, but alsocardiology,dermatology,gastroenterology,neurology, and others. In most of these disciplines, biologics have added major therapeutic options for treating many diseases, including some for which no effective therapies were available, and others where previously existing therapies were inadequate. However, the advent of biologic therapeutics has also raised complex regulatory issues (see below), and significant pharmacoeconomic concerns because the cost for biologic therapies has been dramatically higher than for conventional (pharmacological) medications. This factor has been particularly relevant since many biological medications are used to treatchronic diseases, such as rheumatoid arthritis or inflammatory bowel disease, or for the treatment of otherwise untreatable cancer during the remainder of life. The cost of treatment with a typical monoclonal antibody therapy for relatively common indications is generally in the range of €7,000–14,000 per patient per year.
Older patients who receive biologic therapy for diseases such asrheumatoid arthritis,psoriatic arthritis, orankylosing spondylitis are at increased risk for life-threatening infection, adverse cardiovascular events, andmalignancy.[15]
The first such substance approved for therapeutic use was biosynthetic "human"insulin made viarecombinant DNA. Sometimes referred to as rHI, under thetrade nameHumulin, was developed byGenentech, but licensed toEli Lilly and Company, who manufactured and marketed it starting in 1982.
Major kinds of biopharmaceuticals include:
Research and development investment in new medicines by the biopharmaceutical industry stood at $65.2 billion in 2008.[16] A few examples of biologics made withrecombinant DNA technology include:
| USAN/INN | Trade name | Indication | Technology | Mechanism of action |
|---|---|---|---|---|
| abatacept | Orencia | rheumatoid arthritis | immunoglobinCTLA-4fusion protein | T-cell deactivation |
| adalimumab | Humira | rheumatoid arthritis,ankylosing spondylitis,psoriatic arthritis, psoriasis,ulcerative colitis,Crohn's disease | monoclonal antibody | TNFantagonist |
| alefacept | Amevive | chronic plaquepsoriasis | immunoglobin G1 fusion protein | incompletely characterized |
| erythropoietin | Epogen | anemia arising from cancerchemotherapy,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 andIL-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 | TNFantagonist |
| vedolizumab | Entyvio | ulcerative colitis,Crohn's disease | monoclonal antibody | α4β7integrin blocker |
| ixekizumab | Taltz | plaque psoriasis,psoriatic arthritis,ankylosing spondylitis,non-radiographic axial spondyloarthritis | humanized monoclonal antibody | IL-17A neutralizer |
Many vaccines are grown in tissue cultures.
Viral gene therapy involves artificially manipulating avirus to include a desirable piece of genetic material.
Viral gene therapies using engineered plant viruses have been proposed to enhance crop performance and promote sustainable production.[13]
With the expiration of manypatents forblockbuster biologics between 2012 and 2019, the interest in biosimilar production, i.e., follow-on biologics, has increased.[17] Compared tosmall molecules that consist of chemically identicalactive ingredients, biologics are vastly more complex and consist of a multitude of subspecies. Due to their heterogeneity and the high process sensitivity, originators and follow-on biosimilars will exhibit variability in specific variants over time. The safety and clinical performance of both originator and biosimilar biopharmaceuticals must remain equivalent throughout their lifecycle.[18][19] Process variations are monitored by modern analytical tools (e.g.,liquid chromatography,immunoassays,mass spectrometry, etc.) and describe a unique design space for each biologic.[citation needed]
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.[20]
In 2003, theEuropean Medicines Agency introduced an adapted pathway for biosimilars, termedsimilar biological medicinal products. This pathway is based on a thorough demonstration of comparability of the product to an existing approved product.[21] Within the United States, thePatient Protection and Affordable Care Act of 2010 created an abbreviated approval pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed reference biological product.[20][22] Researchers are optimistic that the introduction of biosimilars will reduce medical expenses to patients and the healthcare system.[17]
When a new biopharmaceutical is developed, the company will typically apply for apatent, 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. Thepatent laws in theUnited States andEurope 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.[23] 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.[24] 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.[25] Conversely, banks for reproductive cells are much more widespread and available due to the ease with whichspermatozoa andegg cells can be used for fertility treatment.[26]
Biopharmaceuticals may be produced from microbial cells (e.g., recombinantE. coli or yeast cultures), mammalian cell lines (seeCell culture) and plant cell cultures (seePlant tissue culture) andmoss plants inbioreactors of various configurations, includingphoto-bioreactors.[27] Important issues of concern are cost of production (low-volume, high-purity products are desirable) and microbial contamination (bybacteria,viruses,mycoplasma). Alternative platforms of production which are being tested include whole plants (plant-made pharmaceuticals).
A potentially controversial method of producing biopharmaceuticals involvestransgenic organisms, particularly plants and animals that have beengenetically modified to produce drugs. This production is a significant risk for its investor due to production failure or scrutiny from regulatory bodies based on perceived risks and ethical issues. Biopharmaceutical crops also represent a risk of cross-contamination with non-engineered crops, or crops engineered for non-medical purposes.
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 thepronuclear microinjection method, it becomes efficacious to use cloning technology to create additional offspring that carry the favorable modified genome.[28] The first such drug manufactured from the milk of a genetically modifiedgoat wasATryn, but marketing permission was blocked by theEuropean Medicines Agency in February 2006.[29] This decision was reversed in June 2006 and approval was given August 2006.[30]
In theEuropean Union, a biological medicinal product[31] 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:
In theUnited States, biologics are licensed through the biologics license application (BLA), then submitted to and regulated by the FDA'sCenter for Biologics Evaluation and Research (CBER) whereas drugs are regulated by theCenter for Drug Evaluation and Research. Approval may require several years ofclinical 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 acleanroom environment with strict limits on the amount of airborne particles and other microbial contaminants that may alter the efficacy of the drug.[32]
InCanada, biologics (and radiopharmaceuticals) are reviewed through the Biologics and Genetic Therapies Directorate withinHealth Canada.[33]
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