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Volume 43, Issue 10
As the development pipeline becomes more saturated with complex molecules and patient experience becomes more important, developers are looking to outsourcing partners to provide more specialized expertise and solutions.
Oral-solid dosage forms remain the most common drug formulation used within the pharmaceutical industry and, according to market research (1), should continue to experience market growth in the near future. However, a range of factors, such as an amassing focus on biologics, higher proportion of poorly soluble molecules in the development pipeline, and regulatory development pathways, are potentially set to shift the balance and raise the profile of newer, innovative dosage forms, increasing the requirement for expert skills.
“Pharma’s development pipeline is being filled with more sophisticated, harder to make compounds that require complex delivery strategies to administer doses correctly,” notes Louis Weber, managing director, Bora Pharmaceuticals. “Demand for specialist expertise has soared, and drug developers are increasingly seeking outsourced solutions to commercialize products.”
A major challenge currently impacting drug development is overcoming bioavailability issues, which is becoming more difficult as a result of the increasing number of complex and poorly soluble molecules entering the development pipeline. “Around 40% of all new chemical entities (NCEs) have low water solubility, meaning a strategy for improving poor bioavailability becomes mandatory,” emphasizes Manuel Leal, business development director, Idifarma.
“The ‘put it in a tablet’ dosage form approach that may have worked in the past is no longer effective as molecules require more complex and advanced drug delivery technologies that address insoluble compounds,” explains Robert Lee, president, Particle Sciences. “There are a range of technologies to increase bioavailability but for them to be viable, expertise and experience on how to apply them is required so formulations stand a better chance of being effective.”
Using solvents, such as isopropyl alcohol, ethanol, and acetone, is a practical way in which developers can improve solubility of most drug substances, notes Weber. “In addition, solvent methods for dispersing drug substances can also be useful to deal with poorly soluble compounds prevalent in today’s therapeutic compounds,” he says.
For Leal, there is a need for innovative processes to advance the galenic formulation of finished products as the discovery of new drugs that improve existing therapies has slowed. “Using innovative technologies helps improve the therapeutic arsenal and reduces the reliance on finding new active molecules for the industry,” he says. Constant adoption of a variety of strategies that enable enhancement of a drug’s absorption is vital for formulation scientists, in Leal’s opinion.
Adoption of an orthogonal approach and being open to a variety of methods, particularly during early development was also advised by Lee. “Good development practice starts with the client providing a clear target product profile (TPP), which describes an idealized drug product image, including route of administration, dose, form factor, pH, particle size distribution, and so on,” he continues. “Once there is an understanding of the TPP and the physicochemical characteristics of the active, it is possible to assemble potential drug delivery technologies that may achieve the TPP.”
“The key to success,” stresses Jeremy Drummond, senior vice-president business development, MedPharm, “is to use a holistic approach considering the overall requirements of any formulation; from the properties of the API (the only ingredient that cannot theoretically be left out) to the end-use market, patient requirement, and target indication.”
Speeding up the development pathway has obvious benefits for drug developers. Not only can these accelerated routes help shorten the development timeline but can also offer significant cost reductions.
Using the US FDA’s 505(b)(2) pathway as an example, Lee highlights that innovative drug dosage forms are being realized thanks to the opportunities afforded by the accelerated development route. “A key advantage of the pathway is the 505(b)(2) sponsor can use clinical data produced by other companies to seek FDA approval without performing all the work required with a traditional new drug application,” he says. “This pathway is being used to improve existing drug products with new dosage forms, indications, dosing regimens, and new routes of administration.”
In agreement, Weber adds that through accelerated pathways, such as 505(b)(2), developers are managing to breathe new life into existing products in an economical way. “According to FDA, the pathway allows drug developers a faster route to improve existing drugs, including new dosage forms that are faster acting or that combine two active ingredients in a new way,” he comments. “This includes creating new administration routes that enhance therapeutic performance or dose adherence.”
On a global scale, other regulatory bodies also offer accelerated route options, for example in Europe the European Medicines Agency (EMA) allows developers to submit applications via the hybrid procedure, which is considered to be roughly equivalent to 505(b)(2). “The appeal of accelerated pathways is leading drug innovators to rethink existing market medicines and reformulate them in ways that place a greater emphasis on patient centricity,” confirms Lee. “This is leading to innovations such as long-acting injectables that require a lower dosing regimen than before or improving the bioavailability of a drug so that it can be delivered via an alternative, more convenient route of administration.”
“The patient or consumer must always be at the forefront of any development strategy,” stresses Drummond. “It should always be remembered that it is not a drug (i.e., an API) that you give to a patient, but a drug product. For a formulation to achieve a positive clinical outcome and be a commercial success for the developer, the patient must be happy to use it.”
In fact, a patient-centric approach to dosage form can be particularly vital when considering specific patient populations. “Traditional dosage forms, particularly tablets, may not always be taken by a patient as prescribed, which can lead to a negative therapeutic outcome and render a course of treatment much less effective,” says Lee. “Pediatric and geriatric patient populations are particularly averse to swallowing large tablets and in these cases powders or liquids formation can provide a much more convenient method of administering a therapeutic.”
Another way of improving the patient experience and ultimately medication adherence in pediatric patients is through the use of modified-release formulations as they have a narrow therapeutic index and can support dose compliance strategies, confirms Weber. “Most patient groups respond well to taking medications that require fewer doses to be effective (and for longer periods) and reduced side effects from dose fluctuation for example,” he notes. “In addition, fixed-dose combination products with multiple APIs and different modified-release profiles can deliver more therapeutic value and better outcomes for both pediatric and geriatric patients.”
Adherence issues are also found within patient groups suffering from chronic conditions, specifies Leal. “One answer for chronic disease therapies is to improve the solubility and bioavailability to allow for oral administration, which can improve comfort for the patients and allow them to take the drugs at home,” he adds. “A further way of supporting patient-centric approaches to drug dosage forms is through taste masking. Overcoming this issue can also directly impact the comfort of the patient taking the product and improve therapeutic compliance.”
According to Weber, patient-centric principles are being applied in a variety of ways in pharmaceutical development. “Genetic profiling and advanced analytical techniques for example are assisting the personalized/precision medicine approach by providing deep insight into different patient populations and the pharmacokinetic and pharmacodynamic effects of drugs,” he says. “Therefore, patients can be more selective in their choice of pharmaceutical products, taking into consideration their efficacy in certain subsets of the populations.”
As a result of cost-efficiency and patient compliance being major considerations for primary healthcare providers and payors, solid-dosage forms are still a preferred option for many pharmaceutical products, Leal specifies. “Demand for contract manufacturing of solid forms is, therefore, still strong,” he says. “However, there have been vast therapeutic improvements witnessed in smaller patient populations with unmet medical needs, such as in the field of oncology.”
Oncology treatments tend to require smaller manufacturing volumes and require a higher degree of expertise, such as containment capabilities and agile manufacturing methods, Leal continues. “For traditional contract development and manufacturing organizations (CDMOs), who manage large volumes, these specialist products are very complicated to handle,” he emphasizes. “Hence, made-to-measure services can be better provided by smaller independent CDMOs.”
In agreement, Lee adds that working with an outsourcing partner for formulation and development can be particularly relevant for non-conventional dose forms. “Dosage forms, such as nasal and ophthalmic, as well as implantable devices and depots, can have additional complexity and regulatory issues for developers to consider,” he notes. “Through an outsourcing partner, developers can access expertise and technologies that they do not possess in-house.”
A further benefit for Lee is that an outsourcing partner can also provide an extension to a developer’s available resources. “If there is a backlog or lack of available resources with the client, they can use an outsourcing partner as an extension of their internal development teams,” he says.
Flexibility and being able to adapt to any changes that may occur during formulation development is critical to drug development success, stresses Weber. “By partnering with organizations that have experience in commercialization and technical expertise in complex dosage forms such as modified release or fixed-dose combinations, companies will be able to overcome project challenges in an agile and efficient way,” he confirms.
“Specialism is key in the pharma industry. If our clients were to make the investment into their own manufacturing facilities, they would have to dedicate huge amounts of resource and capital,” states Leal. “Outsourcing gives a drug developer access to unique skills and support within the supply chain, which means other benefits such an increased speed to market and reduced cost in the long run can be achieved.”
In Lee’s opinion, routes of drug administration that have been previously overlooked, such as nasal dosage forms, will experience growth in the near future. “Nasal delivery can offer an ideal route and increased bioavailability for several drug types, particularly those indicated to treat the central nervous system,” he explains. “This route of administration may also be suitable for non-conventional APIs, such as biologics.”
For Leal, the increasing prevalence of high-potency ingredients being developed is leading to more growth in demand for outsourcing partners that can effectively manage the associated containment issues. “High potency facilities are capital intensive and containment requirements are stringent,” he says. “Therefore, it will be more economical and practical for pharmaceutical companies to work alongside outsourcing partners to develop and manufacture their products in a more efficient manner.”
A further trend that Leal believes will be important in the near future is that of value-added medicines that are based on well-known molecules with new applications, indications, finished-dosage forms, or strengths. “These drugs are an improvement on the traditional generics, which means more cost, but they remain more economical to develop than medicines based on new chemical entities,” he adds.
Currently, there is a trend happening in the industry to use artificial intelligence to mine for APIs to hit relevant newly discovered biochemical pathways, according to Drummond. “A major trend going forward will be the alignment of formulation with information technology and any relevant devices with a focus on making it simple and easy, and even attractive, for the patient to be compliant,” he comments.
Ultimately, however, keeping the patient in mind when looking at drug development is and will remain to be of critical importance, emphasizes Lee. “If a patient does not like the dosage form then they are unlikely to take the drug, leading to negative therapeutic outcomes,” he concludes. “Dosage forms should appeal, not repel, the target audience.”
1. Future Market Insights, “Oral solid Dosage Pharmaceutical Formulation Market: Emerging Markets of Latin America, APEJ, and MEA to Collectively Hold Over 45% Market Value Share: Global Industry Analysis 2012–2016 and Opportunity Assessment 2017–2027,” futuremarketinsights.com, market report, July 18, 2017.
Vol. 43, No. 10
When referring to this article, please cite it as F. Thomas, “The Demands of the Perfect Dose,” Pharmaceutical Technology 43 (10) 2019.