Strategies for the Development of Safe and Effective Pediatric Formulations

Unique Requirements for Pediatric Drug Development

Medicines developed for infants and children present unique formulation challenges compared to those intended for adults. In deciding on the appropriateness of the pharmaceutical design, the relevant developmental physiology and the age specifics should be considered. In addition, selecting a child-friendly dosage form and optimizing a set of characteristics related to palatability and ease of administration are essential.

Drugs for infants and children should also be designed for convenient and accurate dose administration with a minimal dosing frequency. To further increase the likelihood that the child will accept the medication and adhere to the dosing schedule, the actual size of the dosage form, as well as its palatability – which includes taste, smell, and texture¹ – should be optimized. Masking the bitter taste of an active pharmaceutical ingredient (API), for example, may be critical. While adults are more likely to tolerate an unpleasant taste, children may not be able to swallow a bitter pill or a bitter syrup. Without the development of a dosage form tailored to pediatric needs, patient acceptance and, as a result, the therapeutic effect could be affected. It is essential, however, that the taste is not too attractive to children and that the appearance of the dosage form is readily distinguishable from candy to minimize what would otherwise present a high safety risk.

The ability to precisely administer a dose is also essential as children exhibit significant variability in drug absorption, distribution, metabolism, and excretion as compared to adults, and as the required dosage typically varies by age and/or weight. Especially for therapies targeting neonates, the small volumes needed for parenteral formulations can be challenging. In addition, formulators must also account for potential dosage form modification by the caregiver, such as crushing tablets and mixing with food done with the aim to aid in administration, potentially impacting formulation performance. 

Preferred Pediatric Dosage Forms

Several dosage forms are preferred for pediatric populations including topical and rectal preparations, oral liquids such as syrups, suspensions or drops, and orally dispersible or chewable tablets. Oral powders or granules are also commonly used in pediatric formulations due to their dosing flexibility.

While these dosage forms have all proven their effectiveness throughout the years, challenges remain such as: dose flexibility and high need for good taste and palatability. Combined with the need for high safety, these challenges necessitate the development of optimized, age-appropriate medicines, including tailored dosage forms and excipients specifically targeting the described challenges.

Dosage form innovations include mini tablets and oral thin films which can overcome the difficult swallowing of standard-sized tablets. Additional advantages of orally dispersible films (ODFs) are that they disintegrate rapidly and do not require water for administration. 3D printing is another future strategy for tailoring dosage forms as it enables manufacturing of age-appropriate solutions and even personalized medicine. 

Regulatory Requirements for Pediatric Patient Safety

Regulators in the United States and Europe have established age-specific requirements for pediatric formulations. For example, representatives of the Food and Drug Administration (FDA) have highlighted that oral solid dosage forms for pediatric use should be:²

• Easy to swallow
• Palatable
• Stable
• Possible to be dosed accurately in small volumes
• Including safe excipients

The requirements for liquid dosage forms also include the need for a proper measuring device and secure container closure.

According to the EU Guideline on pharmaceutical development of medicines for pediatric use, developers of new drug products must include a Pediatric Investigation Plan in the development program which includes the availability of a formulation that is suitable for pediatric use.¹

As highlighted in these regulations, a careful excipient selection is very important. While the selection criteria are generally similar for adult and pediatric applications, some excipients that are well-tolerated and widely used in adult formulations can cause adverse effects in pediatric populations. Given the risk that accompanies the choice of excipients, the European Medicines Agency recommends that the following aspects be taken into account for a pediatric medicinal product: ³

• Excipient function in the formulation and possible alternatives
• Safety profile of the excipient for children in target age groups, based on a single and daily exposure
• Expected duration of treatment, whether short-term (a single dose for a few days) or long-term (weeks and/or months)
• Severity of the condition to be treated and therapeutic alternatives
• Patient acceptability, including palatability
• Allergies and sensitization

Excipient Quality and Supply Chain Security Are Essential

Quality issues in pharmaceutical products can have severe implications on patient safety which is why excipient quality, selection of the excipient supplier, and supply chain security are key considerations in formulation development, especially for pediatric formulations. Incidents observed over the years underscore the urgent necessity for appropriate formulation, quality control, and risk mitigation and resulted in actions taken by regulatory authorities:

• In 2022, the World Health Organization (WHO) issued a medical product alert about cough syrups which failed to meet either quality standards or specifications.⁴ Laboratory analysis confirmed the presence of unacceptable amounts of diethylene glycol (DEG) and ethylene glycol (EG) as contaminants. This was only the most recent case of a recurring issue with these contaminants, which dates back to 1937, and has led to many fatalities.⁵ 
• In 2023, the FDA made pharmaceutical manufacturers, compounders, repackers, and suppliers aware of the potential public health hazard of glycerin and other high-risk drug components contaminated with DEG or EG.⁵ The agency also provided guidance on how to prevent the use of DEG- and EG-contaminated components including proper testing, supply chain transparency, and training.

A Toolbox of Excipients for Pediatric Applications 

Choosing the right excipients for a new pediatric drug formulation is one of the most important aspects of development and requires special safety considerations. As noted above, it is essential to address the unique requirements of this vulnerable population while avoiding excipients that are potentially toxic or unsuitable for children. 

Given the need to balance many factors during pediatric drug formulation, success relies on access to an extensive set of high-quality excipients that includes the following:

Excipients for Oral Solid Dosage Forms

• Fillers: Directly compressible functional excipients of our Parteck^® range that have a good flow and mouthfeel are ideal for pediatric oral solid dosage forms. Directly compressible Parteck^® M mannitol for example provides a pleasant, cool taste and is well suitable for mini-tablets. The directly compressible Parteck^® ODT excipient system is ideal for orally disintegrating tablets because it makes robust, rapidly disintegrating tablets with a good mouthfeel.
• Coatings: Functional film coatings prevent direct contact of the drug substance with taste bud cells, thus masking an unpleasant taste. The pigment titanium dioxide is widely used as a colorant in tablet coatings. Toxicological concerns about nanoparticulate titanium dioxide and its ban from use in foods and nutritional supplements in the European Union⁶ have led to an interest in suitable alternatives for use in drug products. As a titanium dioxide alternative, we offer the particle-engineered Parteck^® TA calcium carbonate which can provide uniform tablet finishing and good opacity due to its unique morphology and designed particle size distribution. It is well compatible with the film coating agent Parteck^® COAT polymer, a PVA-based excipient that is able to achieve increased opacity in comparison to standard HPMC-containing formulations. 
• Sweeteners: High-intensity sweeteners such as neotame and sucralose are safe, sugar-free, non-carcinogenic, cost-effective due to their high sweetness potency, and can be used in both liquid and solid formulations.

Excipients for Oral Liquid Formulations

Liquid formulations like solutions, suspensions, or syrups are very common in pediatric use due to their easy swallowability, flexible dosing and potential for taste improvement. Our excipient portfolio covers all functionalities to address these formulation challenges. However, some products are considered as high-risk products regarding a potential EG/DEG contamination by the US FDA, including the following products:⁵

• Glycerol and propylene glycol: widely used solvents and vehicles for liquid formulations
• Sorbitol solutions: commonly used non-cariogenic, sugar-free sweetener
• Polysorbates: surfactants to increase API solubility

All the above products are tested for DEG and EG contents according to their specifications.

DEG and EG risk assessment of entire Emprove^® excipients and API portfolio in execution

In addition to high-risk products regarding DEG and EG contamination, a risk assessment of the complete Emprove^® excipients and API portfolio is performed resulting in product-specific DEG and EG impurity declaration.

APIs and Vitamins for Pediatric Applications

Active pharmaceutical ingredients (APIs) and vitamins used in pediatric drugs must meet international quality standards and have a secure supply chain. Suppliers should provide high quality products with extensive documentation to ensure product safety and regulatory compliance.

•  Mineral salts and vitamins: Our portfolio of life-impacting APIs and vitamins consists of high-quality and multi-compendial Emprove^® products. For APIs, regulatory e-submissions are offered to efficiently support drug product marketing authorization.
• Folates: Metafolin^® and Arcofolin^® are very stable salts of L-5-methyl-tetrahydrofolate and highly bioavailable active forms of the B9 vitamin folate which is an essential nutrient needed for optimal cell division, tissue growth and cognitive development.

Metafolin^® and Arcofolin^® are the nature-identical solution for infant and follow-on formula and are the preferred form taken up by the fetus and breast-fed child that is delivered into all folate-sensitive organs like the brain.

Full Excipient Documentation and Supply Chain Transparency

The extensive documentation provided via the Emprove^® Program facilitates qualification of raw materials, risk assessment, and process optimization. The program includes excipients that are stringently qualified according to industry-leading standards and supported by comprehensive information packages. Dossiers for each product include comprehensive, up-to-date documentation, regulatory risk assessments, navigating regulatory challenges, managing risks, and improving manufacturing processes. Supply chain transparency is provided by our electronic Original Manufacturer Tracking (eOMT).

Conclusion

Pediatric drugs have unique formulation requirements designed to help ensure patient safety while facilitating compliance and adherence to the prescribed medication schedule. Use of well-established and safe excipients with the required quality and supporting documentation is essential for successful development and manufacturing of these drugs and to minimize risk for highly vulnerable patients. 

As a trusted supplier of excipients, we ensure the quality of these essential materials for drug formulation, backed by regulatory expertise, and supported by comprehensive documentation. Our extensive and expert application services are available to help formulators as they optimize the palatability of pediatric medications and address other requirements for this patient population.