Medicine is continuously evolving, driven by breakthrough scientific discoveries and enabled by cutting-edge tools. It is common to think of drugs as things we buy in the pharmacy like acetaminophen or bismuth subsalicylate and to consider branded versus generic as the only option. But there is a range of drug modalities, formulations and methods of administration that reflect the vibrant evolution of our scientific advancements.
The word drug refers to “chemical compositions that impact the body or mind when administered to a human or animal”. Drugs are classed by their composition and formulation, which also impacts how a patient takes the drug (administration).
This blog presents an overview of how drugs are made and administered to patients.
The Basics
A drug product formulation contains an active pharmaceutical ingredient (API) and various excipients (inactive components required for formulation). APIs are also referred to as drug substances or therapies, and they fall into a few major categories:
- small-molecule (chemical) APIs
- large-molecule APIs or biologics (recombinant proteins and antibodies)
- nucleic acid APIs (DNA, RNA)
- cell and gene therapies
- peptides, hormones, regenerative medicines
- vaccines
Small-molecule drugs are produced chemically and are what we are used to seeing in pill or liquid bottles in the pharmacy, like the acetaminophen or bismuth subsalicylate mentioned before. All the other classes of drugs are complex biomolecules that only the machinery of living cells can make.
Complex biomolecules are most often produced in three phases:
- upstream processing (USP)
- downstream processing (DSP)
- fill and finish (F/F)
Cells engineered to produce the biomolecule are cultured and harvested in USP (often also referred to as “cell culture”), the drug product is separated and purified from the harvested cell culture in DSP and pooled in its final form as “bulk drug substance”, and then the bulk drug substance is aliquoted into doses, filled into vials or another suitable container, labeled and packaged to be shipped to the point-of-care.
Regardless of type, several steps must be completed before a final drug product reaches patients. All drugs must comply with strict regulatory requirements for the formulation, filling, and dosing of the final product. The most notable regulatory requirements include:
- Good Laboratory Practice (GLP)
- Current Good Manufacturing Practices (cGMP)
- Good Distribution Practice (GDP)
The two most followed drug authorities are the United States Federal Drug Administration (FDA) and the European Medicines Agency (EMA). Guidelines issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) are often adopted by FDA, EMA, and other health agencies. The World Health Organization (WHO) issues guidelines as well. The FDA regularly updates its regulatory requirements, and companies must be up to date and comply with the latest instance, or the current Good Manufacturing Practices (cGMP).
The FDA publishes cGMP in the Code of Federal Regulations in Title 21 as “21 CFR Part 210. Current Good Manufacturing Practice in Manufacturing Processing, Packing, or Holding of Drugs” and “21 CFR Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals.” Updates to cGMP happen continuously, so manufacturers need to follow the agency to be assured of compliance.
Suppliers of the critical raw materials used to manufacture drug substances must be identified, audited, and approved. Vendors of other formulation components (excipients, solvents) and materials consumed during production are also subjected to the same process.
Once a drug substance is produced, it must be combined with excipients in an appropriate buffer solution to generate the final formulation. Solid formulations are then formed into tablets or filled into capsules. Liquids may be filled into capsules, vials, syringes or other containers. Ointments are filled into tubes, and so on. The filled products are labelled. They may then be placed into secondary packaging along with written sales and education materials. Ultimately the products are placed in bulk packaging for distribution. Some newer therapies are made is smaller batches or personalized more locally, as appropriate.
In many cases, production operations are performed by contract development and manufacturing organizations (CDMOs). One service provider may manufacture the drug substance and drug product and manage distribution as well. It is also possible that the pharmaceutical company will rely on different providers for each aspect of the manufacturing process and for logistics management.
Classes of drug substances
Small-molecule or chemical APIs are chemical compounds with molecular weights generally below 1 kiloDalton (kD). They can be of natural or synthetic origin. Natural drug substances are extracted from plants or animals, while synthetic small-molecule APIs are constructed using a series of chemical reactions. Typically, small-molecule drug substances interfere with biochemical pathways in the body that lead to disease by binding to biomolecules (mostly proteins) and preventing them from participating in biological processes. One limitation of small-molecule drugs is they can only bind to proteins with active binding sites (“druggable targets”), which only account for a small percentage of proteins in the body.
Large-molecule APIs or biologics generally refer to recombinant proteins, which include therapeutic proteins, enzymes, monoclonal and polyclonal antibodies, multi-specific antibodies, and other antibody-based drug substances like antibody-drug conjugates. They are produced via fermentation in bacteria or yeast or grown in cell culture in a range of different cell types, including Chinese hamster ovary (CHO) and human embryonic kidney (HEK) cells. Like small-molecule drug substances, biologics are designed to bind to specific targets, but in this case those targets include small-molecule signaling compounds, other expressed proteins and antibodies, and cell receptors on the surfaces of particular types of cells. To be effective, a protein-based drug must have the correct structure, folding properties, and post-translational modifications to achieve maximum binding of the desired target with minimal side effects due to off-target interactions.
Nucleic acid APIs are based on DNA or different forms of RNA, including small interfering RNA (siRNA), microRNA (miRNA), messenger RNA (mRNA), self-amplifying mRNA (sa-mRNA), and others. Peptide nucleic acids (PNAs) are synthetic DNA analogues with high metabolic stability that bind with high specificity to their target DNA or RNA molecules and can thus block problematic protein synthesis. RNA as an active therapeutic or immunological agent modulates protein production by leveraging existing cellular machinery, rather than binding to specific targets. mRNA-based therapies are receiving the greatest attention currently given the success of the COVID-19 vaccines based on this technology.
Cell and gene therapies/advanced therapies comprise a broad category of drug products including those based on various types of stem cells and immune cells. If donor cells are collected from patients, the treatments are referred to as autologous or patient specific. If the starting cells come from healthy donors, the treatments are allogeneic, or “off-the-shelf”. Some cell therapies involve the use of cells that have undergone gene editing to add functionality, such as for binding to receptors on specific tumor cells. To date, gene editing has been performed in a central manufacturing facility, and solutions for on-site manipulation of patient cells and even in vivo gene editing of cells are being explored. Approved gene therapies are designed to deliver one gene of interest, most commonly using a viral vector (a virus that has been produced with the gene of interested packaged inside, rather than viral DNA), to target cells to replace a dysfunctional or missing gene. The goal is to develop therapies that can treat or even cure diseases caused by multiple genetic abnormalities.
Formulation and administration
Generally, drugs are classified as solid, semi-solid, and liquid. When considering the route of administration of a drug, the physical nature of the product determines available options. The specific route of administration chosen for a given drug depends on several factors, including, among others, the physicochemical properties of the drug substance, its mechanism of action (referred to as MOA), the indication, and the characteristics of the patient population. Achieving convenience and ease of use are also important, as they contribute to higher medication adherence and more positive outcomes. The patient population can also impact the ideal type of formulation. For instance, there are different concerns for an infant or child (ability to swallow, etc.) that may not be present for other patient populations.
Nearly all solid and some liquid drugs are administered orally, although for certain indications, intranasal, rectal, or vaginal administration is better. Most liquid products are delivered via injection, and semi-solids are typically applied to the surface of the body. There is also growing interest and application of inhaled formulations for therapeutics and vaccines that have traditionally been in injectable formats.
Not all drugs are shelf stable, which is determined by the formulation. Most drugs require specific storage conditions, but this is amplified in live drugs. These drugs require cold chains to keep the product viable, which can present deeper challenges in depressed or hard to access economies. This is driving more exploration of easier to store and administer methods, particularly in products like vaccines.
Implanted device delivery
Various implantable devices (implantable drug delivery systems, IDDS) have been developed that allow long-term drug delivery without the need for repeated/frequent dosing/injections. Key examples include drug-eluting stents, steroidal collars, and ocular implants.
Intranasal & inhalation administration
Administration of drugs intranasally involves spraying the drug formulation into the nose in a manner that generates tiny droplets that can be absorbed through the nasal membranes. The API then rapidly enters the bloodstream. Only drug substances that do not irritate the nasal passages can be formulated for this route of administration
Administration via inhalation allows direct delivery of medications to the lungs. It is therefore a preferred route for drugs treating lung conditions and is also used for delivering anesthetics. Inhalation is also becoming an attractive approach for vaccines because viral infections typically present in the respiratory tract and delivery by this method can stimulate a strong mucosal immune response in this region and throughout the body. The drugs are either breathed in through the mouth or mouth and nose using an inhaler and may be formulated as liquids or dry powders.
There are three main types of injections: intravenous (IV), intramuscular (IM), and subcutaneous (SC). IV administration is typically performed in a clinical setting, with the drug administered over an extended period. IM and SC administration can be performed by healthcare workers (such as for vaccines) or patients at home (such as for medications to treat chronic conditions).
Less used methods of injection include intraarterial, intrathecal, and intramyocardial, which involve injection into arteries (such as for diagnostic tests), the central nervous system (to avoid the blood-brain barrier), and to the heart, respectively.
Ocular & otic administration
Delivery of medications to the eyes (ocular) and ears (otic) is preferred as a means for realizing localized treatment. For eye diseases (glaucoma, infections, dry eye disease, etc.), drops, gels, or ointments are common, but for indications that affect the posterior (back) of the eye, injections are often necessary. Implants are now available that reduce the required frequency of injections.
Drugs administered into the ear are generally used to treat inflammation and infections and formulated as drops.
Oral administration
Oral administration is often preferred by patients and physicians as it is easy and convenient. However, drugs that are degraded in the stomach are not suitable for this approach. Oral solid dosage (OSD) medications may also not be suitable for patients with difficulty swallowing (children and the elderly) and certain mental health conditions, although delivery technologies like orally dispersible or chewable tablets, for instance, can overcome these limitations for some drug substances.
Sublingual (under the tongue) and buccal (in the cheek or below the gums) delivery may provide a means for bypassing first-pass-metabolism issues for OSD drugs that cannot be directly delivered to the stomach through swallowing, as the drug is absorbed into small blood vessels through a passive mechanism.
OSD drugs can be formulated as tablets, capsules, chewable tablets, orally dispersible tablets, minitablets that can be sprinkled onto foods, gummy tablets, and so on. Liquid oral drug products are typically suspensions or solutions.
A key challenge with oral drugs is overcoming the bitter taste of most APIs and poor mouthfeel for some OSD forms. Another is achieving a consistent amount of the drug substance. Many taste-masking and sustained/extended/controlled-release technologies are used to overcome these issues.
Parenteral administration
Parenteral drugs are liquid formulations delivered via injection. They must be produced as sterile products, which is achieved either via terminal sterilization once the drug is filled into its primary packaging, or under aseptic conditions designed to assure sterility of the product. Parenteral administration is often used for small-molecule drugs that cannot be delivered orally due to first-pass metabolism issues and for biologics, which are too large to penetrate into the bloodstream once in the stomach.
Rectal & vaginal administration
Rectal administration of suppositories is an alternative to oral delivery when oral administration cannot be used (nausea, eating restrictions after surgery) and for relevant conditions (constipation). The API is typically mixed with a waxy material that dissolves after insertion, allowing rapid adsorption.
Vaginal delivery is used to treat vaginal symptoms and to deliver estrogen during menopause. Products can be solutions, tablets, creams, gels, suppositories, or rings.
Topical administration
For many skin indications (psoriasis, eczema, infections), drugs are formulated as ointments, gels, creams, or lotions and applied topically – directly onto the skin. Transdermal administration involves systemic delivery of drug substances using a patch applied to the surface of the skin. Older technologies were needle-free, but some newer patches leverage microneedles that do not cause pain but achieve more effective delivery. This route of administration is typically only used for drugs that require delivery of small daily doses.
Progress continues
Innovation is expanding the types of drugs available and even how they are administered. More patient-friendly approaches are available for administration and even more personalized treatments are in evolution on the drug side. It is possible to track what is happening in the world of drugs by viewing these reference pages on the FDA website. Visitors can see the current list of approved medicines and status of new trials for drugs in development.
At Ensorcell, we are committed to helping drug manufacturers continue making this progress forward with better, faster, and safer tools. We are reimagining life science tools for critical bioprocessing steps, helping to make existing and new therapies more affordable and accessible.