American Pharmaceutical Review Supplement, April 2015
Pressures from consumers, investors, insurance companies, regulators, and governments to drive down costs and improve product performance (efficacy, ease of use, patient adherence, etc.) are driving pharmaceutical companies to consider all aspects of a formulated drug, including the use of advanced drug delivery technologies (DDTs) and unique packaging solutions, much earlier in the drug development cycle.
In addition to having a more patient-centric focus, the pharmaceutical industry is also shifting to greater outsourcing of research and manufacturing activities. Drug manufacturers are therefore seeking custom manufacturing organizations that can, in addition to fill finish operations, offer unique DDTs and approaches to product packaging combined with formulation development and analytical support to ensure that patients get the medicine they need in the dosage form they prefer.
Introduction
Numerous changes are occurring in the pharmaceutical industry today. Drug manufacturers face significant pressure to reduce costs from governments, insurers, and patients. The shift in growth from mature to emerging markets, where the demand for low-cost therapeutics is predominant, is adding to the downward pricing pressure. Poor patient adherence (taking medication as prescribed) is a further problem that is contributing significantly to rising healthcare costs.1 Investors, meanwhile, want to see much lower failure rates for candidate drugs and a higher return on drugs that do make it to the market.
In response, drug manufacturers are looking for ways to determine the likelihood of success much earlier in the drug development cycle. The industry has also adopted a more patient-centric focus, paying closer attention to the development of drugs that are more likely to not only be preferred by patients, but actually taken as intended by their doctors.2,3 Consequently, dosing regimens (particularly single-unit dosing), delivery methods, and product packaging are now being considered much earlier in the drug development cycle.4
This approach can be challenging, however, given that the level of outsourcing of drug development and manufacturing activities has increased dramatically. This trend is in part due to the fact that drug companies see outsourcing as a mechanism for reducing costs. It can also be attributed to the growing complexity of drug candidates, the production of which often requires specialized capabilities that most pharmaceutical manufacturers do not have.
While growing numbers of contract manufacturing organizations (CMOs) purport to offer “integrated” services from discovery through commercial manufacturing, in general CMOs tend to focus either on the synthesis and production of pharmaceutical intermediates and active pharmaceutical ingredients (APIs, drug substances) or the production of formulated drug products. This separation is even more pronounced for products that require sterile manufacturing conditions due to the need for more advanced equipment and more extensive control procedures to ensure sterility throughout the entire process. In addition, while some secondary CMOs (formulated product producers) are involved in the development of drug delivery technology, many are not, and even fewer are involved in the development of packaging solutions.
As a result, sponsor companies are looking for CMOs that have the capability to develop novel drug delivery and packaging technologies and an awareness of patient needs and expectations, and can work closely with the drug development group throughout the development cycle to ensure that the best possible solution is developed for the patient.4
The Problem of Poor Patient Adherence
There have been numerous studies in the US highlighting the level of patient non adherence and its potential impact on the patients themselves as well as the healthcare system in general. For example, it has been found that over 50% of prescribed medications are taken incorrectly or not at all.6 One- to two-thirds of hospital emissions resulting from drug-related adverse events are related to poor medication compliance7, up to 40% of nursing home admissions can be attributed to non-adherence8, and as many as 125,000 deaths per year in the US alone may be due to non-adherence.7 Given these statistics, it is not surprising that the financial consequences are significant—over $200 billion annually, according to a 2013 report by the IMS Institute for Healthcare Informatics.1
Those numbers don’t include non-prescription medicines. They also don’t reveal the fact that medication errors of all kinds typically affect children and seniors more significantly than other age groups.4 In fact, a recent study of data from the US National Poison Database System revealed that during the period 2002 to 2012, 696,937 children under 6 years old experienced out-of-hospital medication errors, which equates to 1 child every 8 minutes.9 The majority (80%) were liquid doses, and the causes ranged from “inadvertently taking or being given medication twice,” “incorrect dose,” “confused unit of measure,” to “wrong medication taken or given.” Fortunately, most cases were resolved outside of a healthcare facility (>93%), but 25 children died as a result of the medication error.
Taking Patient Preferences Into Account
The idea of patient-centricity is receiving growing attention, and there are many interpretations of its meaning. The main idea, however, is that patient preferences and needs should be considered early on in the drug development process. One of the primary drivers of this movement is the increasing access that people have to medical information and the ability to learn from other people about their experiences. As a result, patients actively seek a say in their treatment and are more vocal about expressing their level of satisfaction.
Both the US Food and Drug Administration (FDA) and insurance companies have also been pushing for a more patient-centric approach to drug development. For instance, the Patient Focused Drug Development initiative from the FDA is a program that gets patients involved in the design of clinical trials.10,11 Insurance companies, on the other hand, are looking for evidence from patients that the drug products they use provide value.12
Many factors contribute to that sense of value; efficacy, safety, minimal side effects, and cost are obvious issues. There are additional opportunities for drug manufacturers, however, to address patient expectations around ease of use, portability, and even level of comfort taking their medicine in a public location. Self administered drugs, for example, are often preferred because trips to the doctor’s office or hospital can be eliminated, which saves time and money. However, self administered drugs must be easy to use if they are to be taken correctly, while improving the ease-of-use of such therapies can help reduce patient non-adherence.
The Dose Matters
One of the problems with many types of medications is that they are distributed in multi-dose packaging formats. It is interesting to note that in hospitals, which must distribute many different medications to a large number of patients every day, medication errors are reduced through the use of single-dose packaging. Clear labeling of an accurately pre-measured dose are the two most notable benefits of single-use doses, but there are others as well: reduced risk of contamination, reduced drug waste, and greater ease and convenience for self-administration.
Packages designed to hold a single dose come in many shapes and sizes for oral, topical, and injectable drugs. Blister or pouch packages are widely used for tablets, capsules, and other oral solid formulations. Single-dose packaging units for oral liquids include plastic syringes with rubber tips and squeeze tubes. Single-dose stick packs are also now available for both the oral and topical administration of liquids. Typical unit-dose containers for injectable drugs include prefilled syringes and cartridges.
Drug Delivery and Packaging Technologies Make a Difference
Advanced drug delivery and packaging solutions are, in fact, receiving significant attention, and growth in these sectors of the pharmaceutical market is expected to be quite strong. According to BCC Research, the global market for advanced drug delivery systems was $181.9 billion in 2013 and is expected to grow at a compound annual growth rate (CAGR) of 3.2% to $212.8 billion in 2018.13 The advantages of advanced drug delivery systems over traditional systems, according to the market research firm, include more convenient routes of administration, greater efficacy and duration of drug activity, decreased dosing frequency, improved targeting, and reductions in toxic metabolites.14
Focusing on topical drug delivery systems, Micromarket Monitor estimates that in 2013 the global topical drug delivery market was valued at $9.44 billion and predicts it will grow at a CAGR of 3.50% to reach $11.21 billion by 2018.15 Growth in this sector is driven by patent cliffs, increased incidence of chronic diseases, increasing competition, improving patient compliance, and huge investments made by key pharmaceutical companies, according to the market research firm.
Meanwhile, Markets and Markets estimates that the global pharmaceutical packaging market will grow at a CAGR of 6.7% from 2013 to 2018, reaching a value of $78.8 billion.16 This value includes drug delivery systems that are also considered to be product packaging. This sector of the packaging market is growing at an even faster CAGR of 9.1% due to increasing demand for delivery/packaging solutions as many drugs come off-patent in the coming years, according to the market research firm.
The Blow-Fill-Seal Solution
Blow-Fill-Seal (BFS) technology allows the creation and filling of a variety of plastic containers on one piece of automated equipment without human intervention. It is recognized as an advanced aseptic process by FDA and the European Medicines Agency (EMA) and involves container molding followed by product filling, and then hermetic sealing. The areas for both container molding and filling have minimal exposure to the environment, and the container is sealed with a sterile boundary and then sterilized in place.
In addition to increased safety of the aseptic production process, BFS offers several other advantages over conventional glass containers. The plastic resins used in BFS processes are recyclable. In addition, because plastic is used for the packaging of BFS drug products, there is no worry about glass shattering, and concerns about particulates, which have increased in recent years,17 are much less of an issue.18 Furthermore, less energy is typically used in a BFS process because the three steps are combined and fully automated compared to conventional container manufacture, filling, and sealing. Finally, because the drug product is immediately and hermetically sealed in the container, there is no need for the use of preservatives, which can cause allergic reactions in some patients.
BFS technology can be used to produce a wide range of products in various shapes and sizes, and pre-molded, pre-sterilized inserts, such as sterile tipand- caps, rubber stoppers, or multi-entry inserts, can be added once the container is filled, providing flexibility and increasing the number of options for drug delivery combined with enhanced sterility.
In fact, BFS is ideally suited for the production of sterile, single-unit dose liquid products, including ophthalmic treatments (eye drops), inhalation solutions, topically applied gels, creams and ointments, and oral liquids. Its use for the packaging and delivery of biologic drugs, such as monoclonal antibodies, is also being investigated.18
Consequently, dosing regimens, delivery methods, and product packaging are now being considered much earlier in the drug development cycle.
The Convenience of Stick Packs
Stick packs are a new delivery technology that offers all of the benefits of single-dose packaging with the added advantage of excellent barrier properties and versatility with respect to volume and filling options. In addition, they can be used for both powders and liquids (solutions and suspensions), and gels for oral and topical administration. They are also appropriate for drugs that require sterile processing.
Importantly for patients, no special device is required for delivery. Stick packs are also highly portable and easy to carry, particularly when compared to conventional bottles of liquids with separate cup dispensers. They are also easy to open and inconspicuous—all features that can help improve patient adherence.
There are benefits for the sponsor company as well. Security of the supply chain, another major topic of discussion in the pharmaceutical industry today, is ensured due to the toughness and durability of the material used to manufacture the stick-packs. As with BFS products, the single-use design of stick packs can potentially eliminate the need for the use of preservatives.
Buccal Transmucosal Delivery Systems for Lipophilic APIS
Buccal transmucosal delivery is a noninvasive route for the administration of drugs that would typically be administered via intravenous injection. There is much interest in developing technologies for transmucosal drug delivery.19-21 In recent years, significant progress has been made in the development of advanced technologies for oral delivery through the buccal and sublingual transmucosal membranes. This path of administration is attractive because it is relatively painless and is easier for self-administration and in many clinical settings.
The buccal mucosa has a lipophilic epithelial membrane that is highly vascular. As a result, lipophilic molecules are very rapidly absorbed through the buccal mucosa and then rapidly distributed throughout the entire body via systemic circulation. This behavior is very important for several reasons. Rapid absorption and systemic delivery through the mouth avoids exposure of the drug to harsh stomach acids and the undesired metabolism of the drug in the liver, known as the “first pass effect.” As a result, it is often possible to achieve pharmacodynamic performance comparable to that obtained with delivery via standard injection at a much lower dose. In addition, increasing numbers of drug candidates and new chemical entities (NCEs) are lipophilic and thus poorly water soluble, which means that delivery by conventional means is not possible. Buccal transmucosal delivery is a very promising new drug delivery technology that can address this significant issue while helping to improve patient adherence and increase the value that pharmaceutical manufacturers provide to their patients, payers, and investors.
References
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