A new global study from the International Pharmaceutical Federation (FIP)’s Pediatric Formulations Focus Group is the first to report current and global paediatric oral extemporaneous compounding practices. Here, lead author and focus group chair Hala Fadda discusses the reasons for widespread off-label prescribing, the FIP study’s rationale and main findings, compounding challenges and considerations for improving clinical practice.
Prevalent off-label prescribing in paediatrics stems from historical constraints that restricted clinical trial participation to individuals capable of providing informed consent. It is now well recognised that off-label prescribing in paediatrics is associated with compromised therapeutic efficacy and increased risks of adverse effects, which has led to regulatory initiatives to require evidence-based data of medications used in children.
Other reasons for widespread off-label prescribing include the high development cost and complexity in paediatric drug development. Challenges may also present in developing age-appropriate formulations that are acceptable across the heterogenous paediatric population, which ranges from neonates to adolescents.
Furthermore, there is a predominance of off-patent drug use in the paediatric setting and a lack of incentives to the pharmaceutical industry to conduct paediatric clinical trials on off-patent medicines.
Synchronisation of activities between global regulatory authorities, pharmaceutical industry and research bodies can overcome some of these challenges. Translational research can have a significant impact with a team-based approach to enhance collaborations between clinicians, pharmacists, epidemiologists and scientists who have expertise in formulation, pharmacometrics and pharmacogenomics.
Clinical trials in the paediatric population are more complex and therefore enhancing the capacity and expertise of paediatric hospitals and academic centres to engage in paediatric research is important.
The FIP global study rationale
Despite the widespread use of paediatric oral extemporaneous preparations, there is limited knowledge about the practice of extemporaneous compounding for children on a global scale. Studies in the USA and Europe have shown that there is considerable variability in compounding practices and regulations, both nationally and regionally. Poor availability of essential medicines for children has been identified in low resource settings.
The FIP study aimed to identify current global paediatric oral extemporaneous compounding practices, challenges and needs. The survey was distributed to all WHO regions: Africa, the Americas, the Eastern Mediterranean, Europe, South-East Asia and the Western Pacific. It acknowledged that through an understanding of current practices and the challenges to effective and safe oral extemporaneous compounding, the global pharmaceutical community can work together to overcome the barriers and harmonise paediatric oral extemporaneous practices.
Key findings
Our research identified the active pharmaceutical ingredients (APIs) most frequently compounded as paediatric oral extemporaneous preparations, both on a global and regional scale. Omeprazole, captopril, spironolactone, propranolol and furosemide were the top five most compounded globally. All the above listed APIs, with the exception of captopril, are on the World Health Organization (WHO) Model List of Essential Medicines for Children.
The FIP global survey also showed that commercial vehicles are utilised in all world regions by almost 60% of pharmacy professionals. Commercial vehicles are most used in North America by 97% of pharmacy staff, in contrast to 50% usage in the regions of Africa and South America. Our survey also showed that in-house developed vehicles were utilised by almost 50% of pharmacists in all world regions, with simple syrup the most frequently used in-house vehicle.
A need identified in the practice of extemporaneous compounding for children was the use of simple vehicles that can be prepared in-house, as opposed to expensive commercial vehicles that may not be accessible in all regions.
Additionally, pharmacy professionals highlighted the challenge of finding validated formulations for children. A crucial requirement was the availability of an open-access formulary containing validated formulations with details on preparation methods, stability, pH, and organoleptic properties. Furthermore, these formulations should rely on straightforward methods and readily available excipients. Concerns were also raised about formulations that use excipients with safety issues, such as ethanol, propylene glycol and parabens.
Furthermore, it is imperative to raise physician awareness of the practice of compounding and ensure communication between physicians and pharmacists to achieve accurate paediatric prescribing. Our survey also highlighted other challenges in some regions, such as workforce capacity constraints, the need for up-to-date training for pharmacy professionals, and the availability of adequately resourced compounding laboratories.
Additional compounded oral formulation challenges
Our study showed that liquids, including suspensions, solutions and syrups, were the most compounded oral dosage forms for children. The most frequently compounded classes per WHO Anatomic Therapeutics Classification include: diuretics, drugs for acid-related disorders, beta-blockers, agents acting on the renin-angiotensin system and psycholeptics.
Compounding liquids that are stable and acceptable to paediatric patients present some of the greatest challenges. For example, omeprazole is hygroscopic and rapidly degrades below pH 7.8. It is therefore compounded at a high pH using sodium bicarbonate solution to maintain stability.
APIs typically have an unpleasant taste, which can compromise the acceptability of medicines to children. Taste masking of APIs in oral liquids is often utilised to improve patient adherence, however preferred flavours is subjective.
In addition, some drugs, such as oncology drugs, need to be prepared in biologic safety cabinets, which are not available in community pharmacies or in all hospitals, especially in low- and middle-income countries.
Addressing compounding variability
Our study showed that there is variability in the source of APIs. When available, APIs may be obtained as bulk powders from compounding suppliers. Alternatively, APIs from commercial medicines – commonly tablets and capsules – may be used directly in extemporaneous preparations.
Globally, the sources of APIs for compounding paediatric oral extemporaneous preparations were similar. However, on a regional level, there were notable differences. The use of bulk API powders was the lowest in Africa, the Eastern Mediterranean, North America and the Western Pacific.
There is limited information available on how interchanging tablets and capsules with different excipients affects the physical-chemical properties and stability of compounded formulations. Some APIs are only available as coated or modified release dosage forms, adding to the complexity of compounding. The source of the API can impact dose accuracy, particularly for low-dose drugs, as well as the dissolution process during compounding, the formulation of homogeneous suspensions and drug pharmacokinetics.
Improved stability data and compounding management
Enhanced stability data can extend the shelf-life of compounded preparations, improving accessibility and reducing financial burdens on healthcare facilities and individuals. It’s also essential to have stability data for different storage conditions, as cold storage may not always be feasible. Additionally, stability data under high humidity and temperature conditions, common in certain regions, is necessary.
National formularies offer valuable validated formulations, but they are not globally accessible. Improved data sharing is needed to ensure healthcare facilities worldwide can access this information.
An open-access platform with simple, robust and validated formulations with stability data would help minimise compounding risks, such as using incorrect ingredients and quantities, and the formulation of unstable products.
Improving clinical practice
Regulatory initiatives have come into place that require clinical studies for new drugs in all relevant paediatric subpopulations. Some of these initiatives include the United States Food and Drug Administration Pediatric Research Equity Act of 2003, as well as the European Union’s Regulation on medicinal products for paediatric use, implemented in 2007.
While regulatory initiatives have made significant strides in increasing the number of new medicines available for children, as well as providing new paediatric indications for already approved medicines, there continues to be a lack of attention dedicated to furthering the development of older, off-patent medicines commonly used in paediatric populations.
Despite several initiatives happening worldwide to accelerate the development of age-appropriate medicines for children, these efforts can become synergistic through global coordination. Regulatory bodies can incentivise the development of affordable formulations for off-patent medicines. Formulations need to be affordable, so they don’t put a financial burden on individuals or healthcare organisations.
Research is needed on the safety and dose limits of excipients. Recent studies have demonstrated that minitablets are acceptable for children as young as six months, offering enhanced stability, dose flexibility, and safer excipients compared to liquid forms.
Pharmacists are at the forefront of healthcare and have the best understanding of which age-appropriate formulations are the most acceptable for paediatric subpopulations and can therefore inform the research.
Author
Hala Fadda PhD
Pediatric formulations chair, International Pharmaceutical Federation (FIP)
Professor of pharmaceutics, Butler University, Indianapolis, US
Honorary professor at University College London, UK
Reference
H. M. Fadda, H. R. Weiler, M. Carvalho, et al. Global pediatric oral extemporaneous preparations, practices and challenges. Eur. J. Pharm. Biopharm., 24, 114483 doi.org/10.1016/j.ejpb.2024.114483.
