What current trends do you observe in the pediatric dosage form market, and how do they influence product development strategies?
Srinivasan Shanmugam, PhD., Executive Director of Pharmaceutical Sciences, Business Support, and New Technologies, Adare Pharma Solutions: The concept of “patient-centric dosage forms” for age-appropriate formulation development is a current trend in the pediatric dosage form market, focusing on enhanced acceptance and adherence of medications in pediatric populations.
Pediatric product development strategies are adapting to these trends by prioritizing dose flexibility and dose convenience. This product development strategy has favored technologies that offer dose flexibility and dose convenience to pediatric populations. These technologies include:
- Multi particulates, which can offer flexible dosing for various age groups
- Taste-masking solutions, which can improve the palatability of bitter or unpleasant drugs
- Easy-to-swallow formulation technologies such as orally disintegrating tablets
- Powder for suspension or reconstitution
- “Sprinkle on soft food” formulations
Overall, product development strategies are significantly influenced by the pediatric patient-centric formulation concept that leverages technologies for taste-masking, multi-particles, and easy-to-swallow formats.
Nazim Kanji, Executive Director, Pediatric Services, Quotient Sciences: Based on our experience working with sponsor companies, we see increased interest in developing a wide and full range of liquid and solid dose formats. This indicates the many drivers and preferences for the development of bespoke, age-appropriate dosage forms. There appears to be a preference for a single formulation that can be flexibly dosed to a wide age range of children and in dosage forms such as solutions, suspensions, powder for reconstitution, minitablets, and sprinkles.
One key factor in determining the product development strategy is to understand the taste attributes and palatability of the active pharmaceutical ingredient (API). We are seeing an increasing trend of taste characterization studies on APIs, with no prior taste data, in our Phase I clinics in the USA and UK before the commencement of formulation development activities. The data from these taste studies helps to inform the formulation and taste-masking strategies employed in the development of pediatric dosage forms.
Gus LaBella, Director of Formulation Development, Mikart: A patient-centric approach is preferred when developing dosage forms to meet the specific needs of pediatric patients. This trend emphasizes the importance of flexibility in dosing options, such as adjustable dosages based on weight or age, to ensure optimal efficacy and safety. Many drug products were developed only for the adult market leaving pediatric patients to suffer the poor taste of a ground-up tablet for many indications. We see many 505(b)(2) products now being converted to solutions and suspensions which are more amenable to the pediatric population. Another trend includes the diversification of dosage forms beyond traditional dosage forms like tablets suspensions and syrups. Dosage forms such as orally disintegrating tablets, chewable tablets, multi-particulate sprinkles, and minitablets provide additional options that are more suited for pediatric patients.
Can you provide insights into the key players dominating the pediatric dosage form market and their respective market shares?
LaBella: The key players dominating the market are large pharmaceutical companies that focus on pediatric dosage formulations. Some of these include Pfizer, Johnson and Johnson, GSK, Sanofi, and Novartis. These companies invest significantly in research and development to maintain market leadership in the pediatric form segment. In addition to these key players, it’s worth noting that there are smaller mid-sized Contract Development and Manufacturing Organizations (CDMOs) that offer specialized services for pediatric dosage forms. These CDMOs can provide biotech and pharmaceutical companies with tailored contract development and manufacturing solutions, including formulation development, scale-up, and commercial manufacturing of pediatric medications.
What are the major challenges faced by pharmaceutical companies in developing pediatric dosage forms, particularly concerning safety, efficacy, and palatability?
Shanmugam: Pharmaceutical companies are expected to address pediatric challenges such as dose flexibility, dose accuracy, and dose convenience while ensuring safety, efficacy, and regulatory compliance. This requires a significant investment of resources and time. Achieving a balance between need-based dosing solutions for pediatrics and economic feasibility is a predominant challenge faced by pharmaceutical companies.
Ensuring safety and navigating ethical considerations are important when conducting complex clinical trials, particularly when managing a limited patient population. Addressing potential long-term effects on developing systems is crucial. Achieving efficacy requires formulating precise and flexible dosages suitable for diverse age groups, from newborns to adolescents, considering their developmental phases and needs.
Palatability also poses a persistent challenge, requiring the development of acceptable formulations that mask the bitterness or unpleasant taste of the drug. Regulatory compliance, economic viability, and the limited patient population for pediatric studies further compound these challenges.
Addressing these multifaceted issues demands collaboration among pharmaceutical companies, regulatory bodies, healthcare professionals, and caregivers to deliver safe, effective, and acceptable pediatric dosage forms.
Kanji: There has been a consistent demand for more pediatric medications over the past two decades, especially ones that are appropriately optimized for young patients. The sponsor and its outsourcing partner(s) must consider numerous factors to develop an acceptable pediatric product that achieves clinical, regulatory, and commercial success.
The initial stage involves defining the target product profile for the intended pediatric patient population(s) and understanding the associated challenges and risks. The properties of the API (including taste and palatability), formulation factors including excipient selection for the target age group, and the administration method all must be factored in, along with any clinical and regulatory considerations, dose extrapolation from adult clinical data, and the target pharmacokinetic (PK) profile.
After formulation development, a clinical assessment of the proposed pediatric formulations in adult volunteer panels typically comes next to evaluate and optimize the taste and/or PK attributes before dosing in pediatric patient studies. Once the pediatric formulation has been optimized, the drug product can progress to patient studies to assess its efficacy in the target disease population. This can present new challenges that put a strain on traditional product manufacturing and supply logistics, something we see often in the development of therapies for rare diseases.
LaBella: Several factors impact these points. Dose is probably the most significant factor. A high dose of a drug will usually be more difficult to formulate into a palatable product. This may be driven by taste or mouthfeel. Solutions are a common basic platform used for many pediatric products but may offer the worst palatability for a bad-tasting drug. Formulation of a suspension product can help improve the taste of a solution. As you would expect, suspensions are more complex and require different manufacturing equipment. Other techniques such as using ion exchange resin encapsulation or taste masking coatings, create more challenges in manufacture including the use of organic solvents in some cases. Ingredients must be scrutinized for safety in the pediatric population as well, especially for medications taken for chronic conditions.
How do you address the issue of dose accuracy and variability in pediatric formulations, considering the diverse age groups and physiological differences among children?
Shanmugam: Addressing dose accuracy requires a precise and multi-faceted approach that considers the diverse age groups and physiological disparities among children. Dose accuracy can be achieved with the following strategies:
- Patient Characteristics (sp. population pharmacokinetics): This provides crucial insights into how drugs are metabolized in children and guides precise dosage adjustments based on factors like age, weight, and developmental milestones. Collaborating with pediatric clinical experts ensures the incorporation of their specialized knowledge into formulation design, contributing to safer and more effective medications for children.
- Formulation Strategies: This helps experts design dosage forms that are tailored to specific age groups, as well as formulations that can offer flexible dosing while taking into consideration factors like a child's ability to swallow, their preferences, and the need for age-appropriate formulation applicability (such as oral liquids, chewable tablets, or dispersible tablets.) Formulations for flexible dosing should be easily adjusted based on a child's age, weight, and specific medical needs.
- Patient-centric Dosing Tools: Accuracy can be achieved by developing tools for dose measurements and application, such as oral syringes for multi-particles, minitablet dispensers, etc. Any dosing tool with clear markings or the ability to dose precisely will enhance the accuracy.
Kanji: Dosing is generally done in bands that are based on age, weight, or body surface area, with oral liquid formulations and minitablets among the most popular choices for their acceptability and efficacy in younger patients. Modeling and simulation can also be used to aid dose extrapolation from adult data and predict the in-vivo performance of a dosage form in children.
LaBella: The easiest way to resolve this concern is the use of liquid platforms. The quantity of solution or suspension is easily modulated using a dosage syringe to offer the most appropriate dose of a drug to a patient based on their age or body mass.
How do you prioritize patient-centric approaches in pediatric dosage form development to ensure compliance and minimize treatment-related challenges for children and caregivers?
Shanmugam: A myriad of factors—including patient characteristics, product characteristics, clinical trials, and caregiver characteristics— reflect the diverse needs of pediatric populations. Unfortunately, addressing each single factor or need is impractical. Prioritizing essential factors with a significant impact on improving acceptance and adherence to medicines is a more practical approach. Dose convenience and dose flexibility are two key contributors that need to be prioritized for maximum benefits.
This typically involves optimizing palatability through taste-masking technologies and ensuring age-appropriate formulations that align with developmental stages. It also entails providing dosing and administration tools that are friendly to patients and caregivers and facilitate accurate dosing. Similarly, prioritizing flexible dosing options to accommodate varying dosing needs, such as weight[1]based or age-based dosing, is also crucial.
Additionally, caregivers’ input in pediatric-focused clinical trials is essential but often neglected. Engaging pediatric patients and caregivers in the development process allows for valuable input, ensuring formulations meet their preferences and needs. Similarly, conducting pediatric-specific clinical trials with a focus on patient-reported outcomes ensures that the experiences and preferences of children and their caregivers are considered.
Prioritizing these patient-centric aspects ensures acceptance/ adherence and minimizes treatment-related challenges.
Kanji: Many factors influence pediatric dosage form design and selection. To start, the inherent properties of the drug itself are influential, including taste/palatability and the physicochemical properties of the required dose form. The choice and levels of excipients must also be carefully considered to ensure safety and mitigate the risk of adverse effects, especially in young children.
Patient-related factors may include broader acceptability criteria, such as the swallowability of solid oral dosage forms, and the container packaging, to ensure ease and accuracy of administration by the parent or caregiver. If the dosage form is intended to be administered by an oral syringe and feeding tubes, then appropriate delivered dose and dose clearance studies should be performed to confirm dosing accuracy. Some formats need to be co-administered with foodstuffs, requiring sponsors to show diligence in performing representative food compatibility studies to inform the product labeling.
The sponsor must consider the host of clinical and regulatory factors, too. Typically, there will be a target PK profile to drive efficacy, and this can be challenging when it comes to extrapolating adult-to-child data for dose selection and the unique pediatric biopharmaceutical features affecting in vivo drug delivery and bioavailability. The intended posology should also be considered when justifying the levels of excipients to be included within the formulation.
LaBella: This is primarily achieved through creating a palatable product. With a good-tasting product, children are less likely to refuse to take or reject a dose of medicine. Color-free liquids and suspension may also be preferable if a child does reject a dose of medicine rather than causing a purple or red stain on their clothing or the carpet.
Could you share examples of innovative solutions or technologies adopted to meet the unique needs and preferences of pediatric patients?
Shanmugam: Several innovative solutions and technologies have been developed to address the unique needs and preferences of pediatric patients.
Adare Pharma Solutions, a pediatric product development expert, utilized taste-masking techniques to improve the acceptability of a very bitter-tasting antiretroviral drug for HIV in pediatrics, Tenofovir. This was accomplished using Microcaps®, one of Adare’s proprietary platform technologies. Additionally, these taste-masked Microcaps® were efficiently transformed into a powder that could be sprinkled on soft food and were packed into a multi-dose bulk HDPE bottle with a calibrated dosing spoon/scoop. This allowed for flexible dosing options based on body weight or age of the patient and offered convenience and ease of dosing.
In another example, Adare used MMTS minitabs to design and develop pancreatic enzyme formulations treating pancreatic insufficiency in pediatric patients who have difficulty swallowing multiple tablets. These minitabs with enzymes were protected via an enteric coating and converted into a formulation that can be sprinkled on soft foods. This product, Zenpep®, provides flexible dosing and an easy-to-swallow format for pediatric patients.
Additionally, Adare has taste-masked bitter-tasting drugs and successfully converted them into effective dosage forms like ODTs, chewable tablets, etc.
Kanji: For over 15 years, Quotient Sciences’ Translational Pharmaceutics® platform has been a turnkey solution we’ve leveraged to accelerate GMP manufacturing and clinical testing for clients. Drug products are made and dosed in a matter of days, with flexible CMC submissions and adaptive clinical protocols allowing formulation compositions to be optimized based on emerging clinical data.
We’ve applied Translational Pharmaceutics® to the assessment of pediatric formulations, for example, in the selection of flavor/ sweetener systems to overcome aversive drug properties and to understand the PK performance of age-appropriate medicines and use resulting data to inform dose selection. We’ve also addressed traditional product manufacturing and supply logistics challenges by using Translational Pharmaceutics® as a real-time manufacturing and supply model. This enables drug products to be tuned to individual patient needs and the design of the clinical trial. Customized products can be manufactured, released, and shipped for global patient studies within 1-3 weeks of subject eligibility and formulation requirements being confirmed, to get the right product to the right patient at the right time.
LaBella: Confectionary platforms like gummies are an innovation area in which there is a lot of interest. These platforms must be chewed by the patient and when broken down in the mount do not create a lot of surface area to the tongue which helps hide the bad drug taste. These types of platforms are not common in the Pharma space and finding an FDA-compliant confectionery shop will be very challenging. Additionally, it is unclear how the FDA will accept products that are confectionary-based as feasible drug platforms.
How crucial are partnerships with contract development and manufacturing organizations (CDMOs) in expediting the development and commercialization of pediatric dosage forms?
Shanmugam: Sponsors with limited or no in-house pediatric expertise benefit from collaboration with experienced CDMOs in the development and manufacture of pediatric dosage forms for commercialization.
CDMOs like Adare who have an in-depth pediatric product development and commercialization experience can offer sponsors their deep understanding of the unique requirements associated with pediatric products as well as their specialized expertise and proprietary cutting-edge technologies.
CDMO partners can leverage the latest advancements in technological and formulation science, enhancing the development of novel and effective pediatric dosage forms.
Partners experienced with pediatric regulatory compliance can help expedite the regulatory approval process and ensure that developed formulations align with stringent guidelines.
State-of-the-art CDMO facilities and streamlined processes will accelerate formulation development and result in shorter timelines.
The cost-effectiveness of working with a CDMO is particularly beneficial for sponsors who may lack in-house capabilities for pediatric formulation development. CDMOs offer sponsors efficient resource utilization and budget management. CDMOs can provide great flexibility in demand-based or need-based manufacturing capacities, which are essential given the variability in patient populations for pediatric drugs.
Overall, CDMO partners can function as efficient enablers of a sponsor’s commercialization strategies, streamlining the intricate process of bringing pediatric medications to market efficiently and effectively.
Kanji: To meet patient needs and regulatory expectations, the sponsor must consider the full development of a pediatric dosage form. This starts with defining the TPP and evaluating risks and challenges, progressing to formulation development and clinical assessment of the proposed pediatric formulation in adult panels to optimize and clinically validate dosage forms based on taste and/or PK attributes, and then into pediatric trials. Finally, the identification of a long-term manufacturing partner for what may be relatively low-volume commercial products must also be considered.
There is plenty to think about on this journey! The challenges present an opportunity for a strategic partnership between the sponsor company and its service provider. Strong partnerships are critical to ensure that the next generations of medicine can get to those in need, faster.
For the sponsor, the expertise of the service provider can make all the difference in the success of a program. For the service provider to truly be a strategic partner, they should not just act as a vendor that can efficiently and cost-effectively develop a pediatric formulation but be able to bring expertise forward to help their client anticipate and prevent challenges in clinical testing and regulatory milestones to go on to achieve market success.
LaBella: These partnerships can be critical to progressing a product to market at a rapid pace. Purchasing, installing, and qualifying new equipment to create some of these platforms can take away significant time to launch a new product. A CDMO with the capability and experience in developing and commercializing various technologies will allow a shorter time to market.
What criteria do you consider when selecting service providers for pediatric formulation development, and how do you ensure quality and regulatory compliance throughout the process?
Shanmugam: Regardless of the product or service type, the selection of a CDMO involves a meticulous assessment of multiple key criteria to ensure successful on-time development and commercialization within the constraints of budget, timeline, quality, and regulatory concerns.
When selecting a CDMO for pediatric product development, sponsors should prioritize potential partners with demonstrated expertise in pediatric formulation, who can provide facilities with state-of-the-art equipment and flexibility in manufacturing capacities, and who have experience successfully navigating regulatory requirements.
Reviewing and verifying a CDMO’s regulatory track record and quality management systems, including GMP practices and quality assurance systems, help ensure the reliability and consistency of pediatric formulations.
References and past pediatric product development project reviews can offer valuable insights into a CDMO’s capabilities and reliability.
But perhaps the most important criteria to look for in a CDMO partner is a collaborative approach and communication that is both transparent and frequent. This ensures a reliable and trustworthy partnership, which is vital for successful pediatric drug development.
Kanji: A CDMO services provider should have experience that goes across all areas of pediatric drug development, inclusive of the design, development, optimization, manufacturing, and supply of pediatric products. Additionally, the availability of integrated services from one provider can be invaluable when it comes to streamlining pediatric drug development. Leveraging the same partner that is both capable and willing to aid in drug substance and drug product development and manufacturing, even in situations where there are small patient populations, reduces hand-offs between multiple vendors, and improves knowledge-sharing and tech transfer.
At Quotient Sciences, we operate as both a CDMO and CRO, with capabilities to integrate the different modules of activity and support all stages of development, except conducting the pediatric patient studies themselves. For example, we have built our own internal pediatric excipients database with safety information on more than 60 excipients that we have readily available for reference. We also developed standalone protocols for in-vitro characterization studies, including food compatibility, dose delivery from oral syringes, and dose clearance from nasogastric and enteral feeding tubes. Finally, we’ve worked in collaboration with flavor manufacturers to identify and manufacture potential flavors that are more suitable for pediatric formulations.
LaBella: Understanding a company’s history of developing products of the desired platform, suspensions of example, is crucial. Quality audits are always suggested before making a final selection of a CDMO. FDA inspection history is another factor that should be evaluated before making a CDMO selection.
How do regulatory requirements, such as those outlined in the Pediatric Research Equity Act (PREA) and Pediatric Investigational Plans (PIPs), impact the development timeline and commercialization strategy for pediatric formulations?
Shanmugam: Regulatory requirements stipulated by mandates like PREA and PIPs are important components of drug safety, but they also introduce complexities and considerations that can impact the development timeline and commercialization strategy for pediatric formulations.
Due to the complexity of designing age-appropriate formulations, these mandates can impact a product’s development timeline and commercialization strategy significantly in several ways. Extended timelines are required for these more complex regulatory processes. Careful planning and execution are needed to overcome the unique challenges of comprehensive pediatric studies, resulting in additional time needed to complete these studies.
These regulatory requirements are essential for ensuring pediatric drug safety and their impact underscores the importance of strategic considerations in pediatric formulation development and commercialization. Regulations aim to ensure the safety and efficacy of drugs in pediatric populations, and sponsors must navigate these challenges strategically to successfully bring pediatric formulations to market.
Kanji: In the United States, the US FDA’s Pediatric Research Equity Act (PREA) requires mandatory studies of new drugs in pediatric populations unless a waiver is granted. A Pediatric Study Plan must be submitted within 60 days of the “End of Phase II” meeting for the adult product under development.
Similarly, in Europe, the EU Pediatric Regulation also mandates companies to perform pediatric studies and requires that a PIP should be submitted no later than upon completion of the Phase I PK studies in adults. The PIP is a binding document that includes information about the timings and studies proposed to demonstrate quality, safety, and efficacy. Following review by the Pediatric Committee (PDCO), amendments could be requested, which could impact the timeline for the development of a pediatric dosage form.
LaBella: Regulatory requirements such as PREA and PIPs significantly impact the development timelines and commercialization strategy for pediatric formulations within the pharmaceutical industry. Compliance with PREA mandates the conduct of pediatric studies for certain drugs, necessitating additional time and resources for study design, execution, and regulatory submission. Moreover, adherence to PIPs entails meticulous planning and execution of pediatric clinical trials according to predefined timelines and study objectives. Pharmaceutical companies must strategically incorporate these regulatory requirements into their development plans from inception to streamline processes and optimize timelines for pediatric formulation commercialization.
This is just proper science. Children and infants have very different physiologies than adults. Drugs may not be tolerated as well by pediatric patients, metabolism and elimination in children are very different from adults as well.
Looking ahead, what are your predictions for the future of the pediatric dosage form market, considering advancements in technology, the evolving regulatory landscape, and changing healthcare priorities?
Shanmugam: The future of the pediatric dosage form market is likely to encompass technological innovation, patient-centricity, regulatory refinement, and global collaboration. These are the trends that address current challenges, help optimize therapeutic outcomes, and are in line with evolving healthcare priorities focused on improving pediatric healthcare.
I anticipate a shift in the pediatric dosage form market towards more patient-centric formulations and personalized medication. Most importantly, child-friendly formulation design will be driven by children and caregivers.
Regarding technology advancements, I am confident that innovations such as 3D printing and nanotechnology will revolutionize pediatric formulations and enable personalized and precise drug delivery. Integration of digital health and dosing solutions like smart devices will help enhance medication adherence and monitoring in pediatric populations.
The regulatory environment for pediatric drug development is likely to evolve with a focus on refining guidelines and incentivizing research. I anticipate streamlined approval pathways, especially for rare pediatric diseases. Also, I predict that strategies will emerge that will expedite regulatory processes, including international collaboration and global harmonization of regulations and guidelines.
In terms of healthcare, the future will involve growth in telemedicine and remote monitoring technologies offering innovative ways to monitor pediatric patients.
LaBella: This area will continue to grow. Innovations will also continue to make more palatable platforms for children. Mikart has invested in the area of suspension manufacture to continue to grow with the trend. A new manufacturing suite was constructed at our facility in Atlanta, Georgia. The suite offers mix tanks from 50 L to 4000 L and various homogenizers and other capabilities.
Author Details
Srinivasan Shanmugam, PhD., Executive Director of Pharmaceutical Sciences, Business Support, and New Technologies- Adare Pharma Solutions; Nazim Kanji, Executive Director, Pediatric Services- Quotient Sciences; Gus LaBella, Director of Formulation Development- Mikart
Publication Details
This article appeared in Pharmaceutical Outsourcing: Vol. 25, No. 2Apr/May/Jun 2024Pages: 26-31