Formulation Design / Quality
5. Formulation Design:
When designing paediatric medicines, the route of administration, dosage form and dose of the API are decided on the basis of the disease state, API properties such as taste, aqueous solubility, pharmacokinetic and pharmacodynamic properties and stability during manufacture, storage and use of the chosen dosage form (10). The age, size and condition of the child (e.g. critical illness, concomitant medication, or inability to swallow a dose), and the expected duration of the therapy must be taken into account. Selection of the most appropriate dosage form is, therefore, based on case-by-case considerations.
Most medicines are formulated as single compounds. FDCs are chosen only when the combination has a proven advantage over single compounds administered separately, for example, to achieve compliance in multidrug regimens for treating human immunodeficiency virus (HIV) and/or tuberculosis (TB). The development of FDCs may be more complex than for single compounds; guidance is provided in WHO guidelines (11).
5.1 Quality:
In the pharmaceutical development of paediatric medicines attention should be paid to current quality guidelines, especially those provided by WHO (1).
The acceptable level of impurities in APIs and degradation products in finished dosage forms should be qualified and controlled according to regulatory guidelines, e.g. ICH guidelines (12–14). Safety margins established during toxicological studies on an API and finished dosage form usually apply to a
worst-case level in adults. Such limits typically apply to both adults and children; although a child would receive a smaller dose, the exposure per kilogram is likely to be similar. Term and preterm neonates have to be considered specifically, and establishment of safety limits may require safety studies in juvenile animals. Additional guidance may be found on the EMA web site (15–17).
The final product should comply with the requirements in relevant pharmacopoeial monographs, preferably those in The International Pharmacopoeia. With regard to dissolution testing, dissolution media should be carefully reconsidered in view of the different gastric pH of children from that of adults. Testing at other pHs should be considered in relevant cases. For dissolution testing of special dosage forms, such as chewable tablets, suspensions and patches, see the International Pharmaceutical Federation/American Association of Pharmaceutical Scientists (FIP/AAPS) guidelines for dissolution testing of special dosage forms (18).
Development of Paediatric Medicines: points to consider in formulation,
(Annex 5, WHO Technical Report Series 970, 2012)
