Biopharmaceutical

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A biopharmaceutical, also known as a biological medical product, [1] or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, they include vaccines, whole blood, blood components, 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 components) are isolated from living sources—human, animal, plant, fungal, or microbial. They can be used in both human and animal medicine. [2] [3]

Contents

Terminology surrounding biopharmaceuticals varies between groups and entities, with different terms referring to different subsets of therapeutics within the general biopharmaceutical category. Some regulatory agencies use the terms biological medicinal products or therapeutic biological product to refer specifically to engineered macromolecular products like protein- and nucleic acid-based drugs, distinguishing them from products like blood, blood 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 pharmaceuticals, are high-cost drugs that are often biologics. [7] [8] [9] The European Medicines Agency uses the term advanced 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 term advanced 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 of biomedicine and biomedical 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 and medical devices. [14]

Major classes

Blood plasma is a type of biopharmaceutical directly extracted from living systems. FreshFrozenPlasma.JPG
Blood plasma is a type of biopharmaceutical directly extracted from living systems.

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 ]

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:

  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. [15]

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:

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 with recombinant DNA technology include:

USAN/INN Trade nameIndicationTechnologyMechanism of action
abatacept Orencia rheumatoid arthritis immunoglobin CTLA-4 fusion protein T-cell deactivation
adalimumab Humirarheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease monoclonal antibody TNF antagonist
alefacept Amevivechronic plaque psoriasis immunoglobin G1 fusion proteinincompletely characterized
erythropoietin Epogen anemia arising from cancer chemotherapy, chronic renal failure, etc. recombinant protein stimulation of red blood cell production
etanercept Enbrelrheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasisrecombinant human TNF-receptor fusion proteinTNF antagonist
infliximab Remicaderheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis, Crohn's disease monoclonal antibodyTNF 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 Ontakcutaneous 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 antibodyα4β7 integrin blocker
ixekizumab Taltz plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis humanized monoclonal antibody IL-17A neutralizer

Vaccines

Many vaccines are grown in tissue cultures.

Gene therapy

Viral gene therapy involves artificially manipulating a virus 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]

Biosimilars

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. [17] 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. [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, 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. [21] 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. [20] [22] Researchers are optimistic that the introduction of biosimilars will reduce medical expenses to patients and the healthcare system. [17]

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. [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 which spermatozoa and egg cells can be used for fertility treatment. [26]

Large-scale production

Stainless steel bioreactor for production plants Production bioreactor.jpg
Stainless steel bioreactor for production plants

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. [27] 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

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. [28] 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. [29] This decision was reversed in June 2006 and approval was given August 2006. [30]

Regulation

European Union

In the European 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:

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. [32]

Canada

In Canada, biologics (and radiopharmaceuticals) are reviewed through the Biologics and Genetic Therapies Directorate within Health Canada. [33]

See also

Related Research Articles

<span class="mw-page-title-main">Medication</span> Substance used to diagnose, cure, treat, or prevent disease

A medication is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and relies on the science of pharmacology for continual advancement and on pharmacy for appropriate management.

<span class="mw-page-title-main">Monoclonal antibody</span> Antibodies from clones of the same blood cell

A monoclonal antibody is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.

Etanercept, sold under the brand name Enbrel among others, is a biologic medical product that is used to treat autoimmune diseases by interfering with tumor necrosis factor (TNF), a soluble inflammatory cytokine, by acting as a TNF inhibitor. It has US Food and Drug Administration (FDA) approval to treat rheumatoid arthritis, juvenile idiopathic arthritis and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. Tumor necrosis factor alpha (TNFα) is the "master regulator" of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha.

<span class="mw-page-title-main">Rituximab</span> Biopharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion.

<span class="mw-page-title-main">Recombinant DNA</span> DNA molecules formed by human agency at a molecular level generating novel DNA sequences

Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination that bring together genetic material from multiple sources, creating sequences that would not otherwise be found in the genome.

Pharming, a portmanteau of farming and pharmaceutical, refers to the use of genetic engineering to insert genes that code for useful pharmaceuticals into host animals or plants that would otherwise not express those genes, thus creating a genetically modified organism (GMO). Pharming is also known as molecular farming, molecular pharming, or biopharming.

<span class="mw-page-title-main">Biocon</span> Indian multinational biopharmaceutical company

Biocon Limited is an Indian biopharmaceutical company based in Bangalore. It was founded by Kiran Mazumdar-Shaw in 1978. The company manufactures generic active pharmaceutical ingredients (APIs) that are sold in approximately 120 countries, including the United States and Europe. It also manufactures novel biologics as well as biosimilar insulins and antibodies, which are sold in India as branded formulations. Biocon's biosimilar products are also sold in both bulk and formulation forms in several emerging markets.

This page provides an alphabetical list of articles and other pages about biotechnology.

<span class="mw-page-title-main">Biological therapy for inflammatory bowel disease</span>

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

<span class="mw-page-title-main">Factor VIII (medication)</span> Pharmaceutical drug

Factor VIII is a medication used to treat and prevent bleeding in people with hemophilia A and other causes of low factor VIII. Certain preparations may also be used in those with von Willebrand's disease. It is given by slow injection into a vein.

Biological response modifiers (BRMs) are substances that modify immune responses. They can be endogenous or exogenous, and they can either enhance an immune response or suppress it. Some of these substances arouse the body's response to an infection, and others can keep the response from becoming excessive. Thus they serve as immunomodulators in immunotherapy, which can be helpful in treating cancer and in treating autoimmune diseases, such as some kinds of arthritis and dermatitis. Most BRMs are biopharmaceuticals (biologics), including monoclonal antibodies, interleukin 2, interferons, and various types of colony-stimulating factors. "Immunotherapy makes use of BRMs to enhance the activity of the immune system to increase the body's natural defense mechanisms against cancer", whereas BRMs for rheumatoid arthritis aim to reduce inflammation.

A biosimilar is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved versions of original "innovator" products and can be manufactured when the original product's patent expires. Reference to the innovator product is an integral component of the approval.

Passive immunization is a medical strategy long employed to provide temporary protection against pathogens. Early implementations involved recovering ostensibly cell-free plasma from the blood of human survivors or from non-human animals deliberately exposed to a specific pathogen or toxin. These approaches resulted in crude purifications of plasma-soluble proteins including antibodies.

<span class="mw-page-title-main">Sarfaraz K. Niazi</span> Pakistani academic

Sarfaraz Khan Niazi he migrated to Karachi, Pakistan in 1962, and to the United States in 1970. He is an expert in biopharmaceutical manufacturing and has worked in academia, industry, and as an entrepreneur. He has written books in pharmaceutical sciences, biotechnology, consumer healthcare, and poetry. He has translated ghazals of the Urdu poet Ghalib.

Moxetumomab pasudotox, sold under the brand name Lumoxiti, is an anti-CD22 immunotoxin medication for the treatment of adults with relapsed or refractory hairy cell leukemia (HCL) who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog. Moxetumomab pasudotox is a CD22-directed cytotoxin and is the first of this type of treatment for adults with HCL. The drug consists of the binding fragment (Fv) of an anti-CD22 antibody fused to a toxin called PE38. This toxin is a 38 kDa fragment of Pseudomonas exotoxin A.

Bioproduction is the production of biologics-based therapeutic drugs including protein-based therapeutics, vaccines, gene therapies as well as cell therapies; drugs so complex they can only be made in living systems or indeed are a living system. In practice, ‘bioproduction’ has become loosely synonymous with ‘bioprocessing’ as a way to describe the manufacturing process using, cell culture, chromatography, formulation and related analytical testing for large molecule drugs, vaccines and cellular therapies. Many combinations of reactor types and culture modes are now available for use in bioproduction: e.g., pharming, rocking wave-agitated bag batch, stirred-tank or air-lift fed-batch, and hollow-fiber or spin-filter perfusion. No single production format is inherently superior; that determination depends on many manufacturing capabilities, requirements, and goals. New cell lines, concerns about product quality and safety, emerging biosimilars, worldwide demand for vaccines, and cellular medicine drive new innovative solutions in bioproduction.

Celltrion, Inc. is a biopharmaceutical company headquartered in Incheon, South Korea. Celltrion Healthcare conducts worldwide marketing, sales, and distribution of biological medicines developed by Celltrion. Celltrion's founder, Seo Jung-jin, is the richest person in South Korea.

Recombinant antibodies are antibody fragments produced by using recombinant antibody coding genes. They mostly consist of a heavy and light chain of the variable region of immunoglobulin. Recombinant antibodies have many advantages in both medical and research applications, which make them a popular subject of exploration and new production against specific targets. The most commonly used form is the single chain variable fragment (scFv), which has shown the most promising traits exploitable in human medicine and research. In contrast to monoclonal antibodies produced by hybridoma technology, which may lose the capacity to produce the desired antibody over time or the antibody may undergo unwanted changes, which affect its functionality, recombinant antibodies produced in phage display maintain high standard of specificity and low immunogenicity.

Host cell proteins (HCPs) are process-related protein impurities that are produced by the host organism during biotherapeutic manufacturing and production. During the purification process, a majority of produced HCPs are removed from the final product. However, residual HCPs still remain in the final distributed pharmaceutical drug. Examples of HCPs that may remain in the desired pharmaceutical product include: monoclonal antibodies (mAbs), antibody-drug-conjugates (ADCs), therapeutic proteins, vaccines, and other protein-based biopharmaceuticals.

<span class="mw-page-title-main">Cell engineering</span>

Cell engineering is the purposeful process of adding, deleting, or modifying genetic sequences in living cells to achieve biological engineering goals such as altering cell production, changing cell growth and proliferation requirements, adding or removing cell functions, and many more. Cell engineering often makes use of DNA technology to achieve these modifications as well as closely related tissue engineering methods. Cell engineering can be characterized as an intermediary level in the increasingly specific disciplines of biological engineering which includes organ engineering, tissue engineering, protein engineering, and genetic engineering.

References

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