Release testing strategies for oral granules (mini-tablets) enabling safe and efficient supply of pediatric drugs

Abstract

The enactment of Regulation No 1901/2006 on medicinal products for pediatric patients, Pediatric Research Equity and Best Pharmaceuticals for Children Acts (PREA and BPCA), encouraged many pharmaceutical companies to consider development of pediatric formulation platforms for solid oral dosage forms. Mini-tablets have gained considerable interest for proven acceptability among children of almost all age groups, dose flexibility and superior stability compared to liquids. The demand for most pediatric drugs is generally low compared to adult products, resulting in a significantly higher proportion of the produced batch being allocated for release testing relative to the total available quantity.

Given 1) the generally unfavorable economics of pediatric drug development, and 2) the need to ensure access to high quality medicines to all patients, including children, members of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ consortium) were motivated to develop flexible and efficient release testing strategies spanning dose strengths. Critical quality attributes and data to justify rational release strategies for mini-tablet dosage form are discussed.

Introduction

Prior to implementation of regulations such as the Pediatric Research Equity Act (PREA, 2003)1 and the Best Pharmaceuticals for Children Acts (BPCA, 2007)2,3 by the US Food and Drug Administration (FDA), and of Regulation (EC) No 1901/20064,5 by the European Medicines Agency (EMA), the branded pharmaceutical industry focused new product development efforts mainly on medicines with high medical demand. New pediatric formulation development was often not pursued due to low medical need and a variety of other reasons.6,7 These considerations challenged development of pediatric drugs in a highly competitive, fast-paced, and growth-oriented industry. Some active pharmaceutical ingredients in medicines approved for adults can be safe and effective in the treatment of the same indications in pediatric patients when dose adjusted. However, in the absence of age-appropriate pediatric products, the approved adult drugs are frequently modified and used “off-label”, which can be a major safety concern in pediatric patients where no clinically controlled efficacy and safety data are available.8 Thus, the above-mentioned regulatory mandates by EMA and FDA address the needs of the underserved pediatric patient population and the pharmaceutical industry has adjusted Research and Development efforts accordingly.

To accommodate unique needs of pediatric patients, diverse dosage forms are developed. Pediatric populations benefiting from new treatment options may include a single age group (e.g., only adolescent patients) or span the entire age range, from premature born babies to young adults. Therefore, different formulations (mini-tablets, powder for oral use and suspension, etc.) and an increased number of doses are typically required to treat pediatric patients compared to adult patients.

Adult patients typically prefer solid oral dosage forms, hence the prevalence of capsules and tablets compared to oral liquids or parenteral drugs. Additionally, solid oral dosage forms offer greater stability compared to oral liquid formulations. Similarly, pediatric patients and caregivers prefer oral drug administration over any other route of administration.9, 10, 11, 12 The design of oral dosage forms smaller than those for adults is influenced by a child’s ability to safely swallow solids without the risk of choking. Over the last two decades, the pharmaceutical industry began to focus their pediatric age-appropriate oral formulation development efforts on mini-tablets. Mini-tablets are small, compressed tablets typically 2-4 mm in diameter as illustrated in Figure 1.

They provide a versatile dosage form suitable for all pediatric age groups, as they can be taken directly or mixed with soft foods or liquids, improving ease of swallowing and dosing accuracy. Regulatory terminology for mini-tablets is not harmonized across authorities. According to EMA product information and guidance, formulations commonly described by developers as mini-tablets are typically treated and labeled for patients as oral granules, reflecting their multiparticulate administration (e.g., sprinkling or dispersion).13,14 By contrast, the FDA does not provide a distinct, formal dosage-form definition for “mini-tablets”; instead, it addresses such products within the broader framework of multiparticulate systems (including pellets, beads, and granules) and applies comparable CMC and bioequivalence expectations.15, 16, 17 These classifications emphasize practical administration and handling characteristics and do not imply equivalence in manufacturing method or physical properties. Existing precedent, combined with ongoing development, suggests several new mini-tablet products will be available in the future.18,19

The scope (i.e., indication, age groups, dosing regimen, route of administration), which are part of the Target Product Profile and the clinical development plan20 of new drugs intended for use in pediatric patients is typically discussed with the EMA and FDA prior to initiation of Phase 3 clinical trials in adults. Once a Pediatric Investigation Plan (PIP) and/or a Pediatric Study Plan (PSP) are accepted by the EMA (PIP) and FDA (PSP), development of age-appropriate formulations is initiated.

Appropriate doses to be used in clinical trials in each pediatric age group, as defined in the PIP and PSP, are usually derived from pharmacokinetic results, safety, and efficacy assessments in adults. A harmonized definition of pediatric age groups by health authorities is currently not available. However, the National Institute of Child Health and Human Development suggests as many as eight age groups reflecting different physical pediatric development stages.21 An internet search of proposed pediatric age groups by FDA and EMA suggests four and five groups (https://www.qvigilance.com/blog/summary-of-gvp-paediatric-population).22 One can easily rationalize why children of different age groups likely require different doses and potentially different drug preparations prior to administration. However, estimating pediatric doses is complex and is usually based on pharmacokinetic allometric scaling and modeling.23.

Since the selection of age-appropriate formulations for clinical trials is influenced by expected doses, companies aim to develop mini-tablets at a strength that achieves multiple doses by adjusting mini-tablet count. The FDA and EMA may require that companies develop age-appropriate doses for pre-term new-born neonates, term and post-term neonates, infants, children, and adolescents. Further dose differentiation may be required given large differences in the children group (2-11 years).

Based on apparent differences in physiology, adolescents are likely to require the highest dose, whereas pre-term neonates and neonates are likely to require the lowest dose.24. As such, appropriate doses may need to be offered in individual packaging units and/or configurations to ensure the correct dose can be accurately administered.

To ensure the consistent production of high-quality mini-tablet drug products, release testing—defined as the set of quality control tests performed on each batch at the time of release to confirm compliance with all required specifications—is conducted according to country-specific criteria.25. Evaluating critical quality attributes (CQAs) at product release can be a resource-intensive effort because several doses in different packaging configurations must be tested. For example, a single bulk mini-tablet batch can be used to deliver multiple dosage strengths in capsule or sachet (differing in mini-tablet count). Alternatively, a single packaging presentation could be used, accompanied by clear instructions for caregivers to administer the correct number of mini-tablets. However, this approach risks dosing errors unless a dosing aid is provided, which would add cost and increase regulatory complexity. A strategy to streamline release testing for several doses in different packaging configurations without compromising product quality is presented in this paper.