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Major classes (Redirected from Biologic medical product)

Extracted from living systems

"Biologics" redirects here. For the journal, see Biologics (journal).
Produced by recombinant DNA
A biopharmaceutical, also known as a biological medical product,[1] or biologic, is any pharmaceutical drug product manufactured in, extracted from,
Vaccines or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, they include vaccines, whole blood, blood components,
Gene therapy allergenics, somatic cells, gene therapies, tissues, recombinant therapeutic protein, and living medicines used in cell therapy. Biologics can be composed
of sugars, proteins, nucleic acids, or complex combinations of these substances, or may be living cells or tissues. They (or their precursors or
Biosimilars
components) are isolated from living sources—human, animal, plant, fungal, or microbial. They can be used in both human and animal medicine.[2][3]
Commercialization
Terminology surrounding biopharmaceuticals varies between groups and entities, with different terms referring to different subsets of therapeutics within
Large-scale production
the general biopharmaceutical category. Some regulatory agencies use the terms biological medicinal products or therapeutic biological product to
Transgenics refer specifically to engineered macromolecular products like protein- and nucleic acid-based drugs, distinguishing them from products like blood, blood
Regulation components, or vaccines, which are usually extracted directly from a biological source.[4][5][6] Biopharmaceutics is pharmaceutics that works with
biopharmaceuticals. Biopharmacology is the branch of pharmacology that studies biopharmaceuticals. Specialty drugs, a recent classification of
European Union
pharmaceuticals, are high-cost drugs that are often biologics.[7][8][9] The European Medicines Agency uses the term advanced therapy medicinal
United States products (ATMPs) for medicines for human use that are "based on genes, cells, or tissue engineering",[10] including gene therapy medicines, somatic-cell
Canada therapy medicines, tissue-engineered medicines, and combinations thereof.[11] Within EMA contexts, the term advanced therapies refers specifically to
ATMPs, although that term is rather nonspecific outside those contexts.
See also

References Gene-based and cellular biologics, for example, often are at the forefront of biomedicine and biomedical research, and may be used to treat a variety of

External links medical conditions for which no other treatments are available.[12]

In some jurisdictions, biologics are regulated via different pathways from other small molecule drugs and medical devices.[13]

Major classes [ edit ]

Extracted from living systems [ edit ]

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

Organ transplantation and tissue transplants
Stem-cell therapy
Antibodies for passive immunity (e.g., to treat a virus infection) Blood plasma is
Human reproductive cells a type of
biopharmaceutical
Human breast milk
directly extracted
Fecal microbiota from living systems.

Some biologics that were previously extracted from animals, such as insulin, are now more commonly produced by recombinant
DNA.

Produced by recombinant DNA [ edit ]

See also: Biologics for immunosuppression

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:

1. 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 insulin and its analogues.
2. Monoclonal antibodies. These are similar to the antibodies that the human immune system uses to fight off bacteria and viruses, but they are
"custom-designed" (using hybridoma technology 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.
3. Receptor constructs (fusion proteins), usually based on a naturally occurring receptor linked to the 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 rheumatology and oncology, but
also cardiology, 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 treat chronic 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 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" insulin made via recombinant DNA. Sometimes referred to as rHI, under
the trade name Humulin, was developed by Genentech, but licensed to Eli Lilly and Company, who manufactured and marketed it starting in 1982.

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:

Trade
USAN/INN Indication Technology Mechanism of action
name

abatacept Orencia rheumatoid arthritis immunoglobin CTLA-4 fusion protein T-cell deactivation

rheumatoid arthritis, ankylosing spondylitis, psoriatic

adalimumab Humira monoclonal antibody TNF antagonist
arthritis, psoriasis, ulcerative colitis, Crohn's disease

incompletely
alefacept Amevive chronic plaque psoriasis immunoglobin G1 fusion protein
characterized

anemia arising from cancer chemotherapy, chronic stimulation of red blood

erythropoietin Epogen recombinant protein
renal failure, etc. cell production

rheumatoid arthritis, ankylosing spondylitis, psoriatic recombinant human TNF-receptor fusion

etanercept Enbrel TNF antagonist
arthritis, psoriasis protein

rheumatoid arthritis, ankylosing spondylitis, psoriatic

infliximab Remicade monoclonal antibody TNF antagonist
arthritis, psoriasis, ulcerative colitis, Crohn's disease

HER2/neu (erbB2)
trastuzumab Herceptin breast cancer humanized monoclonal antibody
antagonist

psoriatic arthritis, psoriasis, ulcerative colitis, IL-12 and IL-23

ustekinumab Stelara humanized monoclonal antibody
Crohn's disease antagonist

Diphtheria toxin engineered protein

denileukin Interleukin-2 receptor
Ontak cutaneous T-cell lymphoma (CTCL) combining Interleukin-2 and Diphtheria
diftitox binder
toxin

rheumatoid arthritis, psoriatic arthritis, ankylosing

golimumab Simponi monoclonal antibody TNF antagonist
spondylitis, ulcerative colitis

vedolizumab Entyvio ulcerative colitis, Crohn's disease monoclonal antibody α4β7 integrin blocker

plaque psoriasis, psoriatic arthritis, ankylosing

ixekizumab Taltz humanized monoclonal antibody IL-17A neutralizer
spondylitis, non-radiographic axial spondyloarthritis

Vaccines [ edit ]

Main article: Vaccine

Many vaccines are grown in tissue cultures.

Gene therapy [ edit ]

Viral gene therapy involves artificially manipulating a virus to include a desirable piece of genetic material.

Biosimilars [ edit ]

Main article: Biosimilar

With the expiration of many patents for blockbuster biologics between 2012 and 2019, the interest in biosimilar production, i.e., follow-on biologics, has
increased.[16] Compared to small molecules that consist of chemically identical active 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.[17][18] 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.[19]

In 2003, the European Medicines Agency introduced an adapted pathway for biosimilars, termed similar biological medicinal products. This pathway is
based on a thorough demonstration of comparability of the product to an existing approved product.[20] Within the United States, the Patient 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.[19][21] Researchers are optimistic that the introduction of biosimilars will reduce medical expenses to patients
and the healthcare system.[16]

Commercialization [ edit ]

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 [ edit ]

Biopharmaceuticals may be produced from microbial cells (e.g., recombinant E. coli or yeast cultures), mammalian cell lines (see Cell culture) and plant
cell cultures (see Plant tissue culture) and moss plants in bioreactors of various configurations, including photo-bioreactors.[26] Important issues of
concern are cost of production (low-volume, high-purity products are desirable) and microbial contamination (by bacteria, viruses, mycoplasma).
Alternative platforms of production which are being tested include whole plants (plant-made pharmaceuticals).

Transgenics [ edit ]

Main article: Pharming (genetics)

A potentially controversial method of producing biopharmaceuticals involves transgenic organisms, particularly plants and animals that have been
genetically 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 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 [ edit ]

European Union [ edit ]

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 microorganisms, mammalian cells, nucleic acids, proteinaceous, or polysaccharide components 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 [ edit ]

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 [ edit ]

In Canada, biologics (and radiopharmaceuticals) are reviewed through the Biologics and Genetic Therapies Directorate within Health Canada.[32]

See also [ edit ]

Antibody-drug conjugate Host cell protein List of recombinant proteins

Genetic engineering List of pharmaceutical companies Nanomedicine

References [ edit ]

1. ^ "Biological" . Oxford Dictionaries. Archived from the original on 17. ^ Schiestl M, Stangler T, Torella C, Cepeljnik T, Toll H, Grau R (April 2011).
October 19, 2019. "Acceptable changes in quality attributes of glycosylated
2. ^ Walsh, Gary (2018). "Biopharmaceutical benchmarks 2018" . Nature biopharmaceuticals" . Nature Biotechnology. 29 (4): 310–2.
Biotechnology. 36 (12): 1136–1145. doi:10.1038/nbt.4305 . ISSN 1087- doi:10.1038/nbt.1839 . PMID 21478841 .
0156 . PMID 30520869 . 18. ^ Lamanna WC, Holzmann J, Cohen HP, Guo X, Schweigler M, Stangler T,
3. ^ Ryan, Michael P.; Walsh, Gary (2012). "Veterinary-based Seidl A, Schiestl M (April 2018). "Maintaining consistent quality and clinical
biopharmaceuticals" . Trends in Biotechnology. 30 (12): 615–620. performance of biopharmaceuticals" . Expert Opinion on Biological
doi:10.1016/j.tibtech.2012.08.005 . PMID 22995556 . Therapy. 18 (4): 369–379. doi:10.1080/14712598.2018.1421169 .
4. ^ Rader RA (July 2008). "(Re)defining biopharmaceutical" . Nature PMID 29285958 .
Biotechnology. 26 (7): 743–51. doi:10.1038/nbt0708-743 . 19. ^ a b Nick C (2012). "The US Biosimilars Act: Challenges Facing Regulatory
PMID 18612293 . Approval" . Pharm Med. 26 (3): 145–152. doi:10.1007/bf03262388 .
5. ^ "Drugs@FDA Glossary of Terms" . Food and Drug Administration. 2 Feb S2CID 14604362 . Retrieved 2012-06-13.
2012. Retrieved 8 April 2014. 20. ^ EMA (2008-10-30). "Questions and answers on biosimilar medicines
6. ^ Walsh G (2003). Biopharmaceuticals: Biochemistry and Biotechnology, (similar biological medicinal products)" (PDF). European Medicines
Second Edition. John Wiley & Sons Ltd. ISBN 978-0-470-84326-0. Agency. Archived from the original (PDF) on 2017-03-15. Retrieved

7. ^ Gleason PP, Alexander GC, Starner CI, Ritter ST, Van Houten HK, 2014-10-11.
Gunderson BW, Shah ND (September 2013). "Health plan utilization and 21. ^ 75 FR 61497 ; United States Food and Drug Administration (2010-10-
costs of specialty drugs within 4 chronic conditions" . Journal of Managed 05). "Approval Pathway for Biosimilar and Interchangeable Biological
Care Pharmacy. 19 (7): 542–8. doi:10.18553/jmcp.2013.19.7.542 . Products" (PDF). Public Hearing; Request for Comments.
PMC 10437312 . PMID 23964615 . 22. ^ Foster, Luke. "Patenting in the Biopharmaceutical Industry—comparing the
8. ^ Thomas, Kate; Pollack, Andrew (15 July 2015). "Specialty Pharmacies US with Europe" . Archived from the original on 2006-03-16. Retrieved
Proliferate, Along With Questions" . New York Times. Sinking Spring, Pa. 2006-06-23.
Retrieved 5 October 2015. 23. ^ "Growth and Policies Behind Biopharmaceutical Innovation" . phrma.org.
9. ^ Murphy CO. "Specialty Pharmacy Managed Care Strategies" (PDF). PhRMA. Retrieved 11 April 2018.
Retrieved 24 September 2015. 24. ^ Carlyle, Erin. "The Guys Who Trade Your Blood For Profit" . Forbes.
10. ^ European Medicines Agency, "tooltip definition of advanced therapy Retrieved 2016-09-29.
medicinal products", Committee for Advanced Therapies (CAT) , retrieved 25. ^ "Sperm Donors Australia | Donate Sperm" .
2017-05-15. spermdonorsaustralia.com.au. Retrieved 2016-09-29.
11. ^ European Medicines Agency, Advanced therapy medicinal products: 26. ^ Decker EL, Reski R (January 2008). "Current achievements in the
Overview , retrieved 2017-05-15. production of complex biopharmaceuticals with moss bioreactors".
12. ^ Center for Biologics Evaluation and Research (2010-04-01). "What is a Bioprocess and Biosystems Engineering. 31 (1): 3–9. doi:10.1007/s00449-
biological product?" . U.S. Food and Drug Administration. Retrieved 007-0151-y . PMID 17701058 . S2CID 4673669 .
2014-02-09. 27. ^ Dove A (October 2000). "Milking the genome for profit". Nature
13. ^ United States Food and Drug Administration (August 2008). Biotechnology. 18 (10): 1045–8. doi:10.1038/80231 . PMID 11017040 .
"Supplemental applications proposing labeling changes for approved drugs, S2CID 10154550 .
biologics, and medical devices. Final rule" (PDF). Federal Register. 73 28. ^ Phillip B. C. Jones. "European Regulators Curdle Plans for Goat Milk
(164): 49603–10. PMID 18958946 . Human Antithrombin" (PDF). Retrieved 2006-06-23.
14. ^ Kerr LD (2010). "The use of biologic agents in the geriatric population" . 29. ^ "Go-ahead for 'pharmed' goat drug" . BBC News. 2006-06-02. Retrieved
J Musculoskel Med. 27: 175–180. 2006-10-25.
15. ^ BriskFox Financial. "Biopharmaceutical sector sees rising R&D despite 30. ^ The Commission of the European Communities (2003-06-25).
credit crunch, finds analysis" . Archived from the original on 2018-10-03. "Commission Directive 2003/63/EC amending Directive 2001/83/EC of the
Retrieved 2009-03-11. European Parliament and of the Council on the Community code relating to
16. ^ a b Calo-Fernández B, Martínez-Hurtado JL (December 2012). medicinal products for human use" (PDF). Official Journal of the
"Biosimilars: company strategies to capture value from the biologics European Union. p. L 159/62.
market" . Pharmaceuticals. 5 (12): 1393–408. doi:10.3390/ph5121393 . 31. ^ Kingham R, Klasa G, Carver K (2014). Key Regulatory Guidelines for the
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32. ^ "Biologics and Genetic Therapies Directorate" . Retrieved 2019-01-20.

External links [ edit ]

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.

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This page was last edited on 10 November 2023, at 19:42 (UTC).

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