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End-user considerations are becoming increasingly important as they can provide a lot of value and help to ensure commercial success of a drug.
There are several factors that constitute an ideal dosage form, which should be considered in the development process. Not only must the dosage form perform optimally, so that the drug product is therapeutically effective and the formulation is manufacturable at scale, but also the end-user requirements must be taken into account.
“An ideal dosage form is designed by selecting the most appropriate route of administration to ensure adequate bioavailability and exposure to allow the drug to have the intended therapeutic effect in the body,” says Steven Winling, product development technical specialist, Catalent. “At the same time, the dosage form should be designed to facilitate patient adherence and ease of administration by offering the least invasive route possible, limiting the number of daily administrations, and allowing for a simple dosing regimen.”
The broad applicability and variety of characteristics that comprise an ideal dosage form have tended to lean toward oral routes of administration more readily. As Torkel Gren, science and technology officer, Recipharm, points out there are many things that are achievable with tablets, such as immediate release, modified release, orally disintegrating tablets, fixed-dose combinations, among others. “Consequently, there is a lot of opportunity to develop a product that can be adapted to varying needs,” he adds.
In agreement, Manuel Leal, business development director, Idifarma, states that an ideal dosage form would be one that can achieve the intended action, does not require special storage conditions, has the precise strength, minimizes side effects, is easy to dose, and capable of being manufactured affordably. “The oral route of administration is the one that meets most of those characteristics, compared with other routes,” he says.
“One key aspect that is receiving increased consideration, is the processability of the chosen API and drug product dosage form,” asserts Paul Kippax, pharmaceutical sector director, Malvern Panalytical/Amplify Analytics. “Recent studies have shown that out of those formulations which successfully pass the IND [investigational new drug] regulatory review phase, only 10% make it to market. This has a considerable impact on the return on investment achieved by innovator pharmaceutical companies, especially in the post-blockbuster era.”
Commonly, formulations fail regulatory review as a result of problems with achieving reproducible drug product performance during scale-up to commercial manufacture, Kippax further explains. “Addressing this issue required developers to consider how API and excipient selection impact not only bioavailability but also process robustness, which can directly affect dosage form selection,” he says. “As drug developers look to speed the development of new drug products and ensure a return on their development investment, we have seen a possible move away from more novel dosage forms, as these can be viewed as too high risk and/or labor-intensive to consider. Instead, developers are looking to align API and formulation selection with their existing manufacturing capability.”
“In most cases, the dosage form must successfully unlock the full potential of a drug by lifting or mitigating inherent biopharmaceutical limitations that could not be addressed at the lead optimization step,” continues Winling. “To be a truly ideal dosage form, all the required goals should be achieved with a robust manufacturing process where the critical process parameters are well characterized through a quality-by-design approach. Generally, a simple, easily manufacturable, and scalable formulation using established techniques is preferred to ensure reproducibility and consistency of the product. When more complex formulations and methods are required to create the product, it is important not to lose track of the industrial viability of the dosage form, which could ultimately delay a drug’s ability to reach patients.”
For Rob Lee, president, CDMO division, Lubrizol Life Science Health, it is critical to work backwards to attain the ideal dosage form. It is a good idea to routinely start with a target product profile (TPP) so that work can begin with the end goal in mind, he notes. “The TPP includes parameters such as the route of administration, how much API needs to be delivered over a specific time period, and other relevant critical quality attributes (CQA). Once this is established, the dosage form can be reverse engineered,” he confirms.
“In my view, the ideal dosage form should meet patient needs above all else,” asserts Frederique Bordes-Picard, manager business development for innovative products, Lonza Capsules and Health Ingredients. “Manufacturers should understand requirements and factors that include, but are not limited to, dose ranges, minimum intake per day, limitation of side-effects, swallowability, handling limitations, visual impairments and then develop dosage forms accordingly.”
According to Leal, user-friendliness can take different forms. “For instance, a common challenge in oral solutions or oral dispersible tablets is to improve the taste. Masking the bitter tastes of APIs without excessively increasing the weight of a tablet is a major development challenge,” he says. “Including more excipients to make a more user-friendly product can make the development of analytical techniques more complicated and can generate more interactions, leading to greater formulation instability. For these reasons, among others, user-friendliness should be considered as an additional CQA of the product from the beginning of development.”
There is a particular focus for user-friendly dosage forms when targeting pediatrics or geriatrics, notes Ralph Landau, head of development, Drug Product, Cambrex. “Taste and difficulty in swallowing can hinder patient compliance in pediatrics and geriatric populations,” he says. “Utilizing methods of drug delivery, such as multi-particulates, can help to address patient compliance while maintaining the target drug substance in-vivo absorption profile.”
“User-friendly formulations are intended to make patients’ lives easier and remove the barriers that interfere with proper administration and adherence,” notes Winling. Considering user-friendly oral solid dosage forms, the formulator may be required to reduce the pill burden, avoid food associated restrictions, or enable once daily dosing, Winling confirms. “Additional challenges may add-up when the dosage form also must suit specific patient needs such as improved palatability or decreased size of the dose units for pediatric populations,” he states.
For capsules, the greatest challenge in creating a user-friendly form relates to the characteristics of the API, adds Steve Rode, manager business development, Lonza Capsules and Health Ingredients. “The size of a molecule may make it impossible to deliver a substance orally—this is often the case with proteins. The solubility required will also require specific formulation approaches and we have to consider dose, stability, odor, and color during formulation,” he notes. “Manufacturers often need to think about final cost to ensure patient affordability, and it is rarely the case that one formulation or dosage form will fit all patient needs. As such, a number of options will be required.”
Driven by a continuous rise in patient expectation on therapeutic outcomes and an acknowledgement that considering the end user when developing a dosage form can help improve compliance, there is an increasing importance being attributed to user-friendly dosage forms, comments Jeremy Drummond, senior vice-president, business development, MedPharm. “Patients want dosage forms that suit their lifestyles as well as positively impacting their health,” he says.
Rode confirms that there is a strong incentive for companies to develop adapted dosage forms to support patient compliance, particularly in pediatrics and geriatrics and adds that manufacturers are becoming more aware of the criticality of patient compliance in trial and real-world outcomes. Ultimately, patient compliance has an impact on the commercial success of a drug, he asserts.
“The importance of user-friendliness is certainly increasing,” concludes Gren. “In short, this is because user-friendly dosage forms provide a lot of value. No medicine will give any effect if it is not taken, or taken correctly, and user-friendliness is increasing compliance with medication regimens.”
Supplement: APIs, Excipients, and Manufacturing
When referring to this article, please cite it as F. Thomas, “Making the Ideal Dosage Form,” APIs, Excipients, and Manufacturing Supplement (September 2020).