The Pediatric Formulation Gap

Key Takeaways

• Pediatric medicines often require dedicated formulation development because age, size, physiological maturation, swallowing ability, and dose requirements can vary substantially across childhood.

• Palatability and acceptability extend beyond taste to factors including texture, mouthfeel, dose volume, swallowability, administration method, and the number of dosage units required.

• Liquid formulations can provide dosing flexibility but introduce challenges involving stability, excipients, preservation, taste, dose measurement, and administration devices, while minitablets and multiparticulates can offer viable alternatives.

• Pediatric product requirements can create distinct CMC and manufacturing challenges, including multiple strengths, low commercial volumes, small-batch production, specialized processes, and uncertain clinical-supply needs.

• Earlier coordination among clinical pharmacology, formulation, CMC, manufacturing, and external partners can help align the pediatric product with both patient needs and a practical route to commercial supply.

A drug can be well established for adult use and still require substantial additional development before it becomes an appropriate medicine for children. Pediatric pharmaceutical development can require reconsideration of the dose, dosage form, route of administration, strength, excipients, administration method, palatability, packaging, and delivery or measuring device. The appropriate solution may also change across pediatric age groups, making more than one dosage form or strength necessary for the same active ingredient.^1–3

That distinction creates a pediatric formulation gap between demonstrating that a drug can benefit children and having a product that children can actually receive safely, accurately, and acceptably. An adult tablet may deliver too large a unit dose or be difficult for a young child to swallow. An adult liquid may contain excipients that require additional consideration in younger patients. Even the form of the active substance selected for the pediatric formulation may differ from the one used in the adult product when that choice better supports an age-appropriate medicine.^3,4

The consequences reach beyond formulation science. Pediatric requirements can affect analytical development, clinical supply, chemistry, manufacturing, and controls (CMC), manufacturing scale, equipment, and packaging. Development guidance addresses analytical method considerations, while formulation experts have advocated integrating relevant analytical measurements early to assess risks related to bioavailability, compatibility, stability, and acceptability.^3,5

Children also do not constitute a single homogeneous patient group. An age-appropriate medicine has to reconcile pharmacology with physical capabilities, patient acceptance, caregiver administration, and manufacturability, and the balance among those requirements can shift considerably with age.^6,7

Children undergo continuous growth and physiological maturation. Anatomical and physiological changes throughout childhood can affect drug disposition, making pediatric pharmacokinetics different from adult pharmacokinetics and complicating the selection of appropriate dosing regimens. Age, size, and maturation can therefore matter alongside the exposure achieved in adults.⁸

Once an appropriate pediatric dose or dose range has been identified, formulation developers face a second problem: creating a product capable of delivering it. Required doses may vary substantially across pediatric ages and sizes, creating a need for multiple strengths, titratable formulations, or dosage forms that permit flexible administration. Pediatric development guidance accordingly treats dose flexibility as an important formulation attribute and recognizes that a single dosage form or strength may not serve the full intended population.^1,3,7

Identifying the appropriate pediatric dose is only part of the problem; the dosage form must also deliver it reliably. Liquids can offer graduated dosing, while multiparticulates, minitablets, and multiple fixed strengths provide other approaches to flexibility. The appropriate choice depends on the ages being treated, swallowing capabilities, required dose range, and characteristics of the drug itself.^3,9

Dose flexibility can also remain a moving target during development. Pediatric dose selection may still be evolving while CMC activities are advancing, creating the possibility that teams will develop or manufacture strengths or concentrations that ultimately fall outside the final target range. Closer coordination among clinical pharmacology, formulation, and CMC teams can allow emerging dose information to shape product design earlier.⁵

A pediatric formulation must do more than contain the correct amount of drug. Children and caregivers have to be able to use it as intended. Acceptability can depend on palatability, swallowability, dose volume, the number of units required for each dose, dosing frequency, the administration device, packaging, and discomfort associated with administration.³

Taste receives considerable attention, particularly when an active ingredient is bitter or otherwise unpleasant in the mouth. However, acceptability encompasses a wider range of physical and sensory properties. Depending on the dosage form, smell, mouthfeel, texture, particle size and shape, grittiness, viscosity, and the quantity that must be taken can all matter. The evidence is uneven across these attributes: taste and palatability have been studied much more extensively than many other characteristics that can influence whether children accept a medicine.⁹

Crizotinib illustrates how an apparently straightforward formulation solution can uncover a much deeper development problem. The drug was initially evaluated in pediatric patients as an oral solution for those unable to swallow the commercial capsules. The liquid included measures intended to mitigate bitterness and an unpleasant burning sensation, yet it showed poor palatability in pediatric patients, contributing to reduced tolerability and discontinuation in some cases.¹⁰

The subsequent effort required a different formulation architecture rather than continued adjustment of the original liquid. Taste-masked microspheres improved palatability, but an early version introduced a separate pharmacokinetic problem under elevated gastric pH conditions. Further reformulation using a different coating ultimately produced a multiparticulate product that combined acceptable palatability with consistent pharmacokinetic performance and bioequivalence to the adult capsule. Six clinical studies contributed to a development program extending over more than a decade.

Palatability in such a case is not a cosmetic attribute that can be optimized after the core product has been designed. Here, solving the taste problem altered the formulation architecture, drug release, and bioperformance, forcing those attributes to be optimized together.

Liquid medicines are often associated with pediatric use because they can accommodate patients who cannot swallow conventional tablets or capsules and can provide considerable dosing flexibility. Those advantages are real, but converting an adult solid product into a liquid changes the formulation problem rather than eliminating it.

Oral liquids can create challenges involving chemical and physical stability, microbial quality, preservation, solvents and other excipients, taste, storage, transport, dose volume, and accurate measurement. The volume a child must consume can also affect acceptability and practical administration. A liquid product must additionally be paired with a dosing device capable of measuring its intended dose range accurately.¹

Solid formulations therefore remain relevant even for relatively young children. Flexible approaches can include multiparticulates and very small tablets, potentially combining dose flexibility with advantages associated with solid dosage forms. Their suitability still depends on the particular product and patient population, and assumptions about what young children can or cannot accept require evidence rather than convention.^1,9

A randomized crossover study of 306 children from six months to five years of age provides a useful example. The study compared 2-mm coated and uncoated minitablets with 3 mL of syrup. Across the study population, uncoated minitablets showed higher acceptability than the syrup, as well as greater measured capability to swallow. The result does not establish that minitablets are preferable to liquids for every drug or child, but it demonstrates that very small solid dosage forms can be viable even in age groups for which liquids might otherwise be assumed to be the default.¹¹

Formulation selection therefore depends on matching product characteristics to the requirements of its intended users. A liquid, multiparticulate, minitablet, dispersible product, or another format may be appropriate, but each carries its own development requirements.

The suitability of a pediatric medicine also depends on components that can receive less attention when an adult product already exists. Excipients are one example. An excipient used successfully in an adult formulation cannot automatically be assumed to be appropriate for children across different ages. Pediatric development therefore requires consideration of both the function of an excipient and the exposure that the intended patient population will receive.^1,4

The objective is not simply to remove excipients. A formulation may need them to achieve stability, microbial control, manufacturability, palatability, or dose uniformity. Developers instead have to select the type and quantity required to achieve necessary product performance while considering pediatric safety and tolerability. That assessment can make the composition of a pediatric formulation meaningfully different from its adult counterpart.¹

Administration devices add another layer. A well-formulated liquid does not guarantee an accurately delivered dose if the measuring device is poorly matched to the product. In a randomized experiment involving 2,110 parents of children eight years old or younger, each participant measured multiple liquid doses using cups and syringes. Overall, 84.4% made at least one error exceeding 20% of the intended dose, and cups were associated with substantially more errors than syringes. These results belong to the specific experimental setting rather than representing a population-wide medication-error rate, but they demonstrate how strongly the device can affect dose delivery.¹²

Packaging and container-closure design connect to pediatric use as well. Development guidance considers compatibility with dosing and administration devices, preservation of product quality and stability, and protection against unintended access or ingestion as part of designing an age-appropriate medicine.^1,3

The development target is therefore the complete product presentation: the drug, excipients, dosage form, device, and package must function together under realistic conditions of use.

The consequences of a formulation gap become most visible when clinicians or caregivers have to modify an available medicine to produce a usable pediatric dose. Manipulation can include splitting tablets, dispersing them in liquid, diluting products, or otherwise altering the supplied dosage form. Such practices can provide a practical route to administration when an age-appropriate commercial product is unavailable, but they move part of pharmaceutical preparation away from the conditions under which the original product was developed.^1,13

A three-site observational study of pediatric practice identified 310 drug manipulations. Tablets accounted for 62% of those manipulations, intravenous drugs for 21%, and sachets for 10%. Among 54 manipulations directly observed, 40 involved tablets; most of those tablets were either cut or dispersed to obtain a smaller dose. Survey respondents also expressed concern about dose accuracy and the lack of guidance supporting these practices.¹³

The study did not establish the clinical consequences of the observed manipulations, and its results should not be extrapolated into a general prevalence estimate. Regulatory guidance nevertheless identifies risks associated with altering dosage forms, including uncertainty around the amount of drug actually administered, product stability, and bioavailability. The significance depends on the individual product and manipulation.^1,2

Developing another strength, a dispersible format, a multiparticulate, or an appropriate liquid can remove manipulation steps that would otherwise fall to healthcare professionals or caregivers at the point of administration.

Once pediatric requirements call for a new dosage form, multiple strengths, or a specialized delivery system, the challenge extends directly into CMC and manufacturing. A pediatric product may require fundamental formulation and process development rather than straightforward transfer of the adult manufacturing process.⁵

Clinical development itself can complicate supply planning. Pediatric enrollment may proceed over extended periods, while dose selection can remain uncertain as CMC work advances. Development teams may consequently need to extend product shelf life, manufacture additional clinical batches, or prepare strengths, concentrations, or fill volumes before the final pediatric dose range is fully resolved.

Commercial manufacturing presents a different mismatch. Pediatric product volumes may be relatively low, and total demand can be divided among several strengths or concentrations. That profile may fit poorly with manufacturing models optimized for larger batches. Pediatric formulation literature has specifically identified small-batch manufacturing capability and viable manufacturing economics as areas of need, while low projected volumes may sometimes make pilot-scale facilities suitable for commercial pediatric supply.^5,7

Small-volume pediatric products can involve substantial process complexity. A pediatric solid product may require careful control of product, material, and process variables while accommodating requirements such as dose accuracy, stability, palatability, and age appropriateness. A review of pediatric solid formulations mapped critical quality attributes, critical material attributes, and critical process parameters across technologies including tablets, minitablets, multiparticulates, and films.¹⁴

For pharmaceutical companies evaluating internal and external manufacturing strategies, the relevant capabilities extend beyond the ability to run a smaller batch. Formulation expertise, flexible equipment, process-development capacity, and the ability to translate patient-facing product requirements into a reproducible manufacturing process can be equally important.

The crizotinib program shows how those formulation requirements can translate into manufacturing engineering. The final pediatric presentation uses taste-masked multiparticulates packaged in three capsule strengths. The capsules are opened, and the multiparticulate contents can be combined across strengths as needed to deliver the required dose.¹⁵

Producing that presentation required blending, extrusion and melt spray congealing, screening, fluid-bed coating, and encapsulation. The process also incorporated customized equipment, including a custom rotary atomizer and a modified encapsulation system.

The program had to establish this process with limited material. Because the target pediatric population was small, the developers pursued a material-sparing strategy and used a limited number of development batches produced on commercial-scale equipment to design, understand, and verify the manufacturing process space. Quality-by-design (QbD) principles and design-of-experiments approaches reduced the number of batches and amount of material needed for process characterization.

External manufacturing expertise was integral to that work. Pfizer and Lonza collaborated on manufacturing-process design, and Lonza designed and built equipment required for good manufacturing practice (GMP) manufacture of the product. The relationship therefore extended beyond receiving and executing a mature process to include process design and equipment engineering.

That example should not be treated as a universal model for pediatric outsourcing. Many products will require less extensive redevelopment. Its value lies in showing how far development may have to progress from an established adult dosage form to a commercially viable pediatric presentation. In this case, challenges involving palatability, formulation architecture, bioperformance, dose flexibility, process design, and manufacturing execution had to be resolved within the same product-development program.^10,15

For a drug developer selecting external manufacturing support while the pediatric dosage form is still being defined, development capabilities may matter as much as technology-transfer capabilities. Manufacturing constraints identified early can influence which formulation concepts offer a practical route to commercial production.

A pediatric quality target product profile (pQTPP) provides one framework for bringing these decisions together earlier. It can support discussion between clinical pharmacology and CMC teams while the age range, route of administration, dosing regimen, formulation, and commercial presentation are still being defined. The pQTPP can also evolve as clinical information narrows the eventual product requirements.⁵

That approach is valuable because uncertainty cannot always be eliminated at the beginning of a pediatric program. Final doses may still be evolving, enrollment may be difficult to predict, and the formulation may have to serve patients with substantially different physical capabilities. Earlier coordination allows those uncertainties to inform formulation and supply strategy rather than emerging after key product decisions have already been made.

For companies working with contract development and manufacturing organizations (CDMOs), the same logic applies to partner selection. Evaluating a provider solely against the established adult process can overlook capabilities that the pediatric presentation may ultimately require, including formulation development, smaller-scale manufacture, specialized processing, devices, or packaging. Where the pediatric product remains under development, bringing relevant manufacturing expertise into those decisions can expose process constraints while alternatives are still available.

The central development question is what product will deliver the required pediatric dose in a form children can use, with a composition, presentation, and manufacturing process capable of supporting reliable supply. Addressing that question early can turn pediatric development from a sequence of late adaptations into a product strategy designed around the patients it is intended to serve.

1. “TRS 1067 - Annex 8: Development of paediatric medicines: points to consider in formulation.” World Health Organization. 9 Jun. 2026.

2. E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population: Guidance for Industry. U.S. Food and Drug Administration. 11 Apr. 2018.

3. Guideline on pharmaceutical development of medicines for paediatric use. European Medicines Agency. EMA/CHMP/QWP/805880/2012 Rev. 2. 31 Jul. 2013.

4. Salunke, Smita, et al. “The STEP (Safety and Toxicity of Excipients for Paediatrics) database: Part 2 – The pilot version.” International Journal of Pharmaceutics. 457: 310–322 (2013).

5. Walsh, Jennifer, et al. “Path towards efficient paediatric formulation development based on partnering with clinical pharmacologists and clinicians, a conect4children expert group white paper.” British Journal of Clinical Pharmacology. 88: 5034–5051 (2022).

6. Ivanovska, Verica, et al. “Pediatric drug formulations: a review of challenges and progress.” Pediatrics. 134: 361–372 (2014).

7. Zajicek, Anne, et al. “A Report from the Pediatric Formulations Task Force: Perspectives on the State of Child-Friendly Oral Dosage Forms.” The AAPS Journal. 15: 1072–1081 (2013).

8. Batchelor, Hannah K, and John F Marriott. “Paediatric pharmacokinetics: key considerations.” British Journal of Clinical Pharmacology. 79: 395–404 (2015).

9. Mistry, Punam, Hannah Batchelor, and SPaeDD-UK Project. “Evidence of acceptability of oral paediatric medicines: a review.” Journal of Pharmacy and Pharmacology. 69: 361–376 (2017).

10. Bartlett, Jeremy A, et al. “Development of a Taste-Masked, Dose-Flexible, Multiparticulate Pediatric Dosage Form: Case Study of Crizotinib, a Challenging Pediatric Formulation.” Pharmaceutical Medicine. 40: 193–207 (2026).

11. Klingmann, Viviane, et al. “Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children.” The Journal of Pediatrics. 163: 1728–1732.e1 (2013).

12. Yin, H Shonna, et al. “Liquid Medication Errors and Dosing Tools: A Randomized Controlled Experiment.” Pediatrics. 138: e20160357 (2016).

13. Richey, Roberta H, et al. “Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence.” BMC Pediatrics. 13: 81 (2013).

14. Gurski, Carla Suelen, et al. “Quality by Design applied to pediatric-friendly formulations: a scoping review-based manufacturing process mapping for solid dosage forms.” Journal of Drug Delivery Science and Technology. 108: 106915 (2025).

15. Bartlett, Jeremy, et al. “Commercialization of the Xalkori Pediatric Multiparticulate Product Using Quality-by-Design Principles.” Pharmaceutics. 16: 1027 (2024).