Title: The Challenges and Opportunities of Pediatric Dosage Form Development: Part 1- Program Design and Formulation Development
The number of licensed pediatric drug treatments on the market for children continues to remain substantially less than those for adults. Over the last 15-20 years, global regulatory bodies have placed a greater priority on the development of age-appropriate pediatric dosage forms to improve and protect children’s healtha,b,c. A combination of unmet patient needs, regulatory incentives and potential penalties has now driven a significant upturn in industrial research to develop new pediatric medicines.
There are many important factors to keep in mind when developing a pediatric dosage form and the requirements can differ greatly from drug products designed for adult used,e. Development scientists must consider the route of administration, the safety profile, overall taste and palatability, the child’s age, weight, physiological condition and the overall treatment plan. All of these key points must be balanced appropriately in order to successfully develop an acceptable pediatric product that achieves clinical, regulatory and commercial success. Arguably however, the greatest industry challenge remains a lack of clarity and guidance on how these development objectives can be successfully met.
In Part 1 of this two-part blog piece, Quotient’s Executive Director of Pediatric Services, Nazim Kanji, will cover key considerations in pediatric program design and formulation development strategies that sponsors should take into account if they want to successfully bridge from initial concept into later stages of development and through to commercialization.
Program design and target product profile (TPP)
The initial stage is to understand the TPP for the intended pediatric population(s) and the associated challenges and risks. The following factors should be considered:
· Drug-related factors such as dose, solubility, particle size, taste and palatability
· Formulation-related factors including stability/shelf-life requirements, preservative systems, pH and excipient selection for the target age group
· Patient-related factors such as age range, delivery route, administration methods, co-administration with foodstuffs and container closure systems
· Clinical and Regulatory factors including dose extrapolation from adult clinical data, posology and target pharmacokinetic (PK) profile
The next stage is to conduct formulation studies to develop dosage forms in line with the TPP. Liquid dosage forms (solutions or suspensions) can offer flexibility of dosing across the target age groups from neonates through to adolescents by adjusting the volume delivered. A liquid dosage form can be manufactured as a ready-to-use, bulk formulation or as powder for reconstitution with a shorter in-use shelf life.
Mini tablets also offer dose flexibility and are suitable across a wide age range. As interest in mini tablets has grown, their acceptability in younger patients, including neonates, has been demonstrated when co-administered with soft foods or a beveragef.
Other common formats for pediatric patients include powder-based systems such as granules and multiparticulates, often co-administered with food, and portable dose formats such as chewable tablets and orodispersible tablets/mini tablets which can be administered without water.
Excipients used in pediatric formulations must be carefully selected and quantities justified as some excipients may cause adverse effects in children due to differing physiology to adults. For example, the preservative benzoic acid and its sodium salt may increase neonatal jaundice. The aim of the formulation scientist should be to minimize the quantity and levels of such components in a pediatric formulation.
In order to mask any adverse taste properties which could impact upon patient palatability and compliance, the formulator may have to consider alternative taste-masking strategies such as flavor or sweetener combinations, complexation or barrier coatings.
Understanding the risks and challenges that your molecule poses in the initial stage of program design plays a key role in developing a formulation that meets the needs of your pediatric patients and global regulatory agencies and that will ensure downstream success.
In part 2 of this blog piece, Nazim Kanji will discuss the challenges and opportunities that sponsors face when dealing with clinical taste/acceptability assessments, clinical supply chains for patient trials and commercial scale manufacturing.
a. Best Pharmaceuticals for Children Act; 2002
b. Pediatric Research Equity Act; 2003
c. Regulation (EC) No 1901/2006 on medicinal products for paediatric use (“Paediatric Regulation”); 2007
d. European Medicines Agency (EMA) CHMP. Reflection Paper: Formulations of choice for the paediatric population. EMEA/CHMP/PEG/194810/2005; 2006
e. European Medicines Agency (EMA) CHMP. Guideline on pharmaceutical development of medicines for paediatric use. EMA/CHMP/QWP/805880/2012 Rev. 2; 2014
f. Klingmann V, Acceptability of mini-tablets in young children: results from three prospective cross-over studies. AAPS PharmSciTech 2017; 18(2): 263-266