Quality by Design applied to pediatric-friendly formulations: a scoping review-based manufacturing process mapping for solid dosage forms

Abstract

There is a significant deficiency of suitable pediatric medications, attributed to limited market, trial complexities, and strict regulatory requirements. Ensuring appropriate dosing and medication acceptance in this population requires careful consideration of age, weight, and administration route. Quality by Design (QbD), a systematic approach to product development, relies on quality principles that can enable manufacturers to address medications’ safety, efficacy, and palatability concerns while increasing product reliability and process efficiency. This study aims to map the critical parameters and quality standards for the development of pediatric solid formulations using QbD tools. A scoping review with systematic searches in Pubmed, Scopus, and Web of Science (last updated in February/2024) was conducted. After removing duplicates, two independent reviewers evaluated the manuscript’s title and abstract, and those selected were read in full. The studies that met the eligibility criteria had the data extracted and discussed. In addition, the Critical Quality Attributes, Critical Material Attributes, and Critical Process Parameters of each formulation were mapped. Overall, 37 studies, published between 2008 and 2023, mostly by India and evaluating solid pediatric formulations such as tablets and mini-tablets, multi-particulate forms, and films, were selected for synthesis. The most mentioned classes of drugs included antibiotics (25 %), antihistamines (10 %), and anticonvulsants (7.5 %). Thirty-one studies (84.6 %) did not apply specific risk analysis methods during the QbD approach. Yet, Ishikawa diagrams (7.7 %), Failure Mode and Effects Analysis (5.1 %), and Hazard Analysis (2.6 %) were the most used methodologies. The statistical models used to conduct the Design of Experiments were Factorial Design (43.6 %), Central Composite Design (17.9 %), and D-Optimal Design (15.4 %). With this review, we identified the main manufacturing factors to ensure the development of child-friendly medications that meet their unique needs and preferences, are palatable, accurately dosed, and stable.

Introduction

The lack of suitable medications for pediatric populations represents a significant challenge in clinical practice, mainly due to market limitations, ethical and logistical difficulties in conducting clinical trials with children, and stringent regulatory requirements [1,2]. Consequently, healthcare professionals often rely on medications developed for adults, disregarding the physiological and therapeutic differences in children, which can lead to suboptimal dosing and an increased risk of adverse effects [2,3].

Additionally, the World Health Organization (WHO) recommends the use of oral solid formulations for pediatric patients over liquids, citing their superior stability, dosing precision, logistical convenience, and customization potential (e.g., flavor and color adjustments to improve palatability and acceptability) [2,4]. However, the implementation of this recommendation is hindered by the scarcity of pediatric-appropriate formulations that are safe, effective, and acceptable for children [1,2]. The development of such formulations is further complicated by the need to minimize the number and concentrations of excipients, thereby reducing the exposure of pediatric patients to substances that may cause adverse effects. This restriction often necessitates the search for alternative excipients or a combination of them compatible with the targeted age group, adding complexity to the formulation process. Thus, it is not always easy to obtain dosage forms with appropriate characteristics that meet the specific needs of pediatric patients.

In this context, Quality by Design (QbD) emerges as a systematic and promising approach to developing medications with greater predictability in quality, addressing critical attributes such as safety, efficacy, and acceptability [1,[5], [6], [7], [8]]. Despite its potential, few studies have explored the application of QbD in pediatric contexts, particularly in developing solid dosage forms like orodispersible tablets, films, and multiparticulate systems, which meet the unique needs of pediatric patients.

This study addresses the critical gap in the literature regarding the systematic development of pediatric solid formulations. Specifically, our review aims to map the key quality attributes and critical process and materials parameters that have been investigated for this type of formulation. By identifying the attributes and parameters essential for ensuring compatibility with the target pediatric age group, as well as safety and efficacy, we provide a comprehensive overview of the current state of research. Furthermore, our analysis highlights areas that require further study, such as selecting excipients and process optimizations tailored to pediatric needs. Ultimately, this study seeks to serve as a practical guide for formulation developers, offering a structured framework to inform future research and promote the development of safer and more effective treatments for this vulnerable population.

Quality by Design applied to pediatric-friendly formulations: a scoping review-based manufacturing process mapping for solid dosage forms

Abstract

Introduction

Read more on Quality by Design (QbD) here: