Biological medicines
Biological medicines are complex molecules made in living organisms rather than by chemical synthesis, they vary from batch to batch, and they need terms that set them apart from chemically made drugs. They have been used for more than two centuries and regulated for more than one, and most of the new ones that reached the market between 2014 and 2018 were recombinant proteins, made from the genetic code of a natural source rather than extracted from it.
What makes a medicine biological
Biological medicines are typically complex protein-based molecules that may also carry carbohydrate and lipid moieties and other post-translational modifications. They are usually generated by exploiting living organisms as production systems rather than by a defined chemical synthesis. This gives every biological medicine a degree of intrinsic variability, and biological products also vary somewhat from batch to batch, arising from variations in manufacturing steps such as fermentation, cell separation or disruption, purification and filtration. Their complex nature also means they can be used to treat serious and chronic conditions that are themselves complex, such as cancers and autoimmune diseases. They have the potential to address a range of unmet medical needs and are key enablers of the trend towards increasingly personalised medicine. Biological medicines offer treatment options for patients with chronic and often disabling conditions such as diabetes, autoimmune disease and cancer.
A biological medicinal product is a medicinal product whose active substance is a biological substance: one produced by or extracted from a biological source that needs, for its characterisation and the determination of its quality, a combination of physico-chemical-biological testing together with the production process and its control.
Biologics, or biological drugs, are products created from living organisms or that contain components of living organisms. Because they are created in living cells, they cannot be chemically synthesised like conventional drugs and their generics. A biologic is any pharmaceutical product manufactured in, extracted from or semisynthesised from biological sources, such as E coli cells. Biologics contain one or more active substances made by or derived from a biological source, such as E coli, and they often have a native counterpart in the human body, such as insulin, erythropoietin and growth hormones. The source is natural and often animal, human or bacterial in origin, and a series of complex, proprietary steps, such as cell culture, expansion, recombinant DNA technology and glycosylation, turns it into products that are not easily characterised. Biologics are complex products composed of sugars, proteins or nucleic acids, or of living cells and tissues. They are derived from microorganisms or animals, or through biotechnology techniques.
The cells that produce a biological can be yeast, bacterial, animal or plant cells. Biologics often originate from them through recombinant DNA technology, and they are large, complex molecules, such as proteins and monoclonal antibodies, with complicated primary, secondary and tertiary structures. Biological molecules are much more complex than chemical entities, and producing them in prokaryotic or eukaryotic cells is a much more complex and challenging process than a chemical synthesis. The characteristics of a biological are determined by the organism and the manufacturing process, and even minor changes to that process can have a major effect on efficacy, safety and tolerability. The manufacture of biologics is challenging and well regulated.
What biologics include
Biologics and biosimilars include monoclonal antibodies, hormones, small proteins, vaccines and fusion proteins, and those that are monoclonal antibodies or their derivatives target pro-inflammatory cytokines, most commonly tumour necrosis factor alpha. Biologics encompass vaccines, blood components, allergenics, somatic cell lines, tissues, peptides and antibodies, among others. Insulin is a typical example of a biologic. Biological medicines as the US and EU define them include recombinant products, such as bone morphogenetic proteins, enzymes, growth factors, hormones, interferons, interleukins and tumour necrosis factor, monoclonal antibodies, recombinant vaccines, and toxins and anti-toxins; blood, blood components and blood derivatives; allergenics for immunotherapy; vaccines; and advanced therapy medicinal products, such as gene therapies, somatic cells and tissue-engineered therapy. Some biological drugs use transplant or transfusion technology, such as stem cells, tissue and blood products. Pollens that cause hay fever and bee stings that cause anaphylaxis are examples of biological allergenics, and a doctor might use allergenics to identify a patient's sensitivities.
How biologics differ from chemically manufactured drugs
The larger proportion of drugs is manufactured by chemical means. Chemically manufactured drug molecules are generally smaller and less complex than biologically manufactured ones. A small-molecule medicine is chemically manufactured and typically under 900 daltons. Small molecules are single molecules of low molecular weight with a simple, well-defined structure that is independent of the manufacturing process, which is chemical synthesis, and they are easily characterised, stable and usually non-immunogenic. The well-defined chemical structure of a small-molecule drug can be analysed to determine all its components. A biologic differs from chemically synthesised drugs, whose structure is known. Most traditionally manufactured chemical drugs can receive comprehensive characterisation through physicochemical analysis.
Most biologics, unlike chemically synthesised small molecules, are not easily characterised, are sensitive to changes in manufacturing, can be costly to produce and are more likely to be immunogenic. They are also more likely to cause anaphylaxis or unexpected side effects, and their pharmacokinetics can be difficult to measure. A biologic is generally a complex milieu, and the bioequivalence rules that apply to small-molecule therapeutics do not work for biologics.
Aspirin and abciximab, both blood thinners, show the difference in size: aspirin is a chemically manufactured drug with nine carbon atoms and a molecular weight of 180.157 daltons, and abciximab a biological with 6,462 carbon atoms and a molecular weight of 145,651.1 daltons. Biological drugs contain thousands of carbon atoms and have a higher molecular weight, where non-biologicals have a few carbon atoms and a lower molecular weight. An IgG antibody has around 25,000 atoms where aspirin has 21. Biological molecules are generally larger and so less rigid, which has consequences for their stability.
Biologicals and non-biologicals follow different regulatory pathways to the market, and the pathways reflect differences in the molecules, their manufacture, their administration and their risk-benefit profiles. For many, it is difficult to imagine differences in things invisible to the eye, so the importance of these differences is not always appreciated. Biological drugs are not traditional chemical drugs, and they should not be treated as such.
Terms for biological medicines
Biologics are also called biological medicines. A biological is any drug manufactured from a biological source, such as vaccines, blood products, cells, allergens, genes, tissues and recombinant proteins, and biological, biologic and biopharmaceutical are generally interchangeable collective terms for it.
A biopharmaceutical is not any drug, chemical or biological, intended for use in humans or animals. Biopharmaceutics is the study of the physical and chemical properties of drugs, their bioavailability and their therapeutic effects. Yet in the Biopharmaceutics Classification System (BCS) and the Biopharmaceutics Drug Disposition Classification System (BDDCS), biopharmaceutics refers to any drug intended for use in humans or animals, which understandably confuses laypeople and uninitiated industry staff when they distinguish biological from non-biological drugs.
By 2020 the use of biological drugs was becoming more accepted and commonplace, and the number of biological drugs sold on the market was increasing year on year. Terms that clearly distinguish biological from non-biological drugs are increasingly necessary. Drug definitions become rigid by necessity as they are used in regulatory frameworks.
Something non-biological does not involve a biological system. Chemically manufactured drugs are also referred to as more traditionally manufactured chemical drugs, and non-biological is more practical to say. Non-biological drugs are sometimes referred to as normal drugs. Chemically manufactured drugs are at times called small molecule drugs, but the term is arbitrary: its cutoff is put anywhere between 500 and 1,000 daltons depending on the reference.
Non-biological, non-biologic and non-biopharmaceutical have no formal designation. One author who argues for their wider use in the industry holds that they are appropriate for describing all drug products that have not been manufactured biologically, and that they are descriptively agreeable and carry more intuitive meaning than biological, biologic and biopharmaceutical. Yet in 2020 non-biological was not widely used to refer to the more traditional manufacture of chemical drugs. In the same author's view the term helps to set the chemical manufacture of pharmaceuticals apart from the biological. The term is already used on supermarket shelves, where biological and non-biological washing powders are sold.
Non-biological drug names often refer to chemical elements and functional groups, as acetylsalicylic acid (aspirin) does. Functional groups often specified in their names include acetyl, alcohol, aldehyde, alkane, alkene, alkyl halide, alkyne, amide, amine, benzene ring (phenyl), carboxylic acid, ester, ether, ketone and thiol.
How long biologics have been in use
Biologics had only recently started to gain traction in the market by 2018, but they are not new. The first recorded use of a biologic was by Edward Jenner in 1796. The Biologics Control Act, passed in 1902, required inspections of the manufacturing facilities of vaccines, which were some of the earliest biologics. In 1922 Leonard Thompson, aged 14, received the first dose of insulin. By 2019 the US formulary held more than 250 approved, marketed biologics, vaccines among them.
Where biologics come from
Therapeutic proteins represent biological drugs. A therapeutic protein is concentrated and purified from a biological source that occurs in nature, or a manufacturer recombines the gene that codes for it, bypassing the natural source. Human chorionic gonadotrophin (hCG) has been made both ways. Pregnant women produce it as the placenta grows and excrete it in their urine, where it causes the positive line on a home pregnancy test. It was first purified from human urine, and concentrated hCG is used to treat women who have less success in getting pregnant. Understanding its genetic code allowed recombinant hCG to be developed, so hCG no longer always comes from the urine of pregnant women. Molecular biology techniques allow highly concentrated volumes of it to be made without urine, and by 2020 women received the recombinant form.
First-generation biologics are derived from humans and animals, and second-generation biologics are developed using recombinant DNA technology. The trend is to identify the genetic code of a natural-source biological, whatever it is, and create a recombinant form in the laboratory. This uses the natural source more sustainably: the source is not depleted, controls are engineered into the clone, purification is easier in a model organism and yields are higher. Recombinant biologicals are the highest proportion of biological drugs approved worldwide, a class that includes monoclonal antibodies, hormones, clotting factors, enzymes, vaccines, nucleic acid-based products and engineered cell-based products, with indications in cancer, inflammation-related diseases, haemophilia, diabetes, asthma, migraine, HIV and inhalational anthrax. Of 71 genuinely new biological active ingredients that came to market between January 2014 and July 2018, 62 were recombinant proteins.