What is a Combination Product?
Remember Jack and Jill, who went up the hill for water? Jack fell down, broke his crown and mended it with vinegar and brown paper. This rhyme is from 1765 and it alludes to a drug/device combination of cider vinegar (the drug) and brown paper (the device). Brown paper soaked in apple cider vinegar and put across the forehead can often stop a headache within a few minutes. Jack and Jill did not give however a definition of a combination product in their story. Of course, the drug/device combination products that are available today are significantly more sophisticated.
Defining Combination Products
The definition of a combination product reflects the convergence of 2 or more product types. Combination products combines two or more different single-entity products such as a drug combined with a medical device, a drug combined with a biologic, or a medical device combined with both a drug and a biologic.
Combination products combines two or more different single-entity products such as a drug combined with a medical device, a drug combined with a biologic, or a medical device combined with both a drug and a biologic. The US regulations contain a definition for combination products, which can be found in Title 21 of the Code of Federal Regulations (21 CFR), Part 3.2(e)1. There is no formal definition for combination products in European Union (EU) legislation, however.
To find out more about the FDA regulations for combination products, complete Introduction to FDA cGMP Requirements for Drug/Device Combination Products Online Training Course.
There is no formal definition for combination products in European Union legislation.
Combination products come in many shapes and sizes, some more complex than others. For example, products that incorporate or are used to administer a drug, may be regulated as a medical device or as a medicinal product or as a combination product, depending on the principal intended function of the product, the method by which this action is achieved and where it is to be marketed (i.e. in the USA or the EU).
For example, one may consider the case of syringes used to administer medicinal products. A syringe marketed empty is classified as a medical device both in the USA and the EU. In the EU a syringe marketed pre-filled is classified as a medicinal product. In the USA it is classified as a combination product.
Drug Eluting Stent Combination Products
An example of a combination product is the drug – eluting stent. The metal stent (the medical device) is coated with a drug used in the treatment of coronary disease. Its primary mode of action is to mechanically open a vessel (thus, operating primarily as a medical device). The drug component then provides a pharmacological means of preventing scar tissue from forming in the vessel (thus, functioning secondarily as a drug).
Figure 1 shows how a Drug Eluting Stent works. The stent is mounted on a balloon catheter and advanced to the diseased, narrowed portion of the heart artery. The balloon is inflated and the stent is expanded, which opens the narrowed section of the artery. The balloon is deflated and removed; the stent is embedded into the wall of the artery and stays in position. Medication coats drug-eluting stents and reduces the chance of renarrowing, or restenosis, of the blood vessel.
Orthopedic Combination Products
The most common drug device combinations products in the combination product sector is antibiotic-loaded bone cement (ALBC). The primary aim of ALBC is infection control (Bistolfi et al., 2011). It has been used for more than 30 years as a delivery device for antibiotics in the treatment of musculoskeletal infections. Cement was originally used as a spacer to preserve the joint space and soft-tissue tension for later reconstruction (figure 2).
The addition of it to the cement, results in their elution into the involved tissue area, thus aiding the prevention of infection. As use of ALBCs grew, doctors began to add antibiotics to the cement when reimplanting a previously infected total joint. This positioning at the surgical site allows the administration of a high concentration of the drug, which would cause complications and toxicity if administered venously. A combination of medical device and pharmaceutical companies dominate the antibiotic market.
Transdermal Patches Combination Products
Transdermal drug delivery systems (figure 3) consist of self contained, individual dosage forms which, when put directly on skin, deliver the drug(s), through the skin, at an optimal rate to systemic circulation (Jain, 1997).
Transdermal drug delivery systems offer many advantages over standard pharmaceutical dosage forms, for example elimination of first pass metabolism, continuous drug delivery, decreased frequency of administration, decreased side effects, and enhanced patient compliance (Hadgraft and Lane, 2005). Developments in synthetic materials and patch design have resulted in patches that are more aesthetically acceptable to patients and that deliver controlled dosing of active compounds in a less invasive manner. The FDA approved the first transdermal system for systemic delivery—a patch that elutes scopolamine to combat motion sickness—for general use in 1979. Ten years afterwards, nicotine patches were the earliest transdermal blockbuster, increasing the popularity of transdermal delivery. Transdermal drug delivery is used in a variety of areas, including pain management, endocrinology, and motion sickness. Estrogen patches are approved for menopausal indications in addition to post-menopausal osteoporosis.
Learn about the 21 CFR Part 4 (Subpart A) cGMP requirements for combination products, 21 CFR Part 4 (Subpart A) – cGMP for Combination Products Online Training Course.
Wound Care Combination Products
Wound care products are primarily aimed at ensuring timely wound healing and effective infection control. The rapid spread of modern epidemics such as diabetes and obesity (both leading causes of chronic wounds) the rise of hospital-acquired infections, and an increasing elderly population are driving demand for advanced wound care products (Singer and Dagum 2008). Drug/device combination products typically provide treatment for burns or wounds caused by underlying illnesses, as these types of wounds usually require more specialized treatments such as moist or active wound healing products. Created to treat wounds such as diabetic foot ulcers, pressure ulcers and venous leg ulcers, products such as Advanced Moist Wound Healing Products (alginate dressing, film dressing, foam dressing, hydrogel dressing), Active Wound Healing Products (Skin replacements, cell-based replacement, collagen dressings, growth factors) and Antimicrobial Dressings (Silver antimicrobial dressing non-silver antimicrobial dressing). A mix of medical device and pharmaceutical companies dominate.
Prefilled Syringes Combination Products
Syringe and vial is the most common delivery system for injection but has limitations; it is easy to make errors in preparation and delivery of drugs (Makwana, Basu et al. 2011). To address this, more advanced drug/device combination products like insulin pens were developed in the 1980s to allow for convenient, safe self-administration of drugs. Around the same time, autoinjectors such as EpiPen were also developed for emergency treatment of anaphylaxis. More recently, auto-injectors were developed for the delivery of drugs for the treatment of other chronic diseases such as rheumatoid arthritis and multiple sclerosis.
Inhaler Combination Products
Since ancient times pulmonary routes have been used to treat respiratory diseases. Ancient remedies included employing leaves from plants, vapours from aromatic plants, balsam, and myrrh. Targeting the delivery of a drug into the lungs is one of the most important aspects of local or systemic drug delivery systems (Hickey 2013). The use of inhaled aerosols allows selective treatment of the lungs, achieving high drug concentrations in the airway and reducing systemic adverse effects (figure 4). Not only is aerosol therapy used to treat lung disease, but increasingly inhalation is being explored as a method for systemic drug delivery (e.g., inhaled insulin and inhaled narcotics). Furthermore, inhaled drug delivery is used to treat pulmonary vascular disease in addition to pulmonary infection and airway diseases.
The effectiveness of inhaled drugs depends not only on the formulation, but perhaps even more on the delivery device and the patient’s ability to use the device correctly. A deficient technique leads to decreased drug delivery and potentially reduced efficacy. An significant disadvantage of inhaled drug delivery is that the correct use of inhaler devices requires specific techniques (Hess 2005). The asthma market is estimated to be worth approximately $6 billion worldwide, and consists largely of inhaled products—bronchodilators and corticosteroids. It is a growing market because the prevalence of asthma is growing, particularly in developed countries.
Conclusion
It is clear that combination products cover a wide range of medical areas. That is why we at The Learning Reservoir have developed a suite of e-learning courses about combination products.
If you want to learn about Combination Products check out our selection of courses on the topic: The Learning Reservoir Combination Product Course Catalog
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Dr. Fiona Masterson
Fiona is the Managing Director and founder of The Learning Reservoir. Fiona has over 20+ years of experience in the Life Sciences, Food and Drink industries and third level education. Her Doctorate focused on the regulation of drug/device combinations products in the US and European Union. She has also published peer review publication on combination products.