In 2020, the US Food and Drug Administration (FDA) issued a ‘Guidance for Industry’ recommending that sponsors include plans for developing age-appropriate formulations of drug products in instances where adult formulations may not be suitable for paediatric patients. In many cases, this guidance translates to a seemingly simple solution: for children, liquid formulations are often the preferred approach.
This strategy is essential not only for ensuring that the correct drug products are accessible to the appropriate patient populations at the right time but also serves as a strategic advantage for pharmaceutical companies aiming to sustain and drive growth. From a market perspective, the oral liquid segment is anticipated to grow at a compound annual growth rate (CAGR) of approximately 6.5% over the next decade, indicating both significant opportunity and critical importance within this space.
Increasingly, pharmaceutical companies are leveraging paediatric indications of approved adult dosage forms (ADFs) to support business growth. This shift is driven by two primary factors: firstly, the FDA’s concerted efforts to minimize off-label use in paediatric populations, aligning with the agency’s commitment to ensuring the safety and efficacy of treatments across all age groups; and secondly, the economic incentives linked to paediatric dosage forms (PDFs). Notably, the provision for paediatric exclusivity typically extends intellectual property protection by 180 days. This additional six months of market exclusivity can translate into significant revenue, offering pharmaceutical companies a lucrative opportunity to capitalize on branded drug sales during this extended period.
The High Potent Factor
Over a quarter of all drugs currently on the market are classified as highly potent, with approximately 60% of oncology treatments in development today incorporating highly potent active pharmaceutical ingredients (HPAPIs). As the prevalence of HPAPIs in adult dosage forms (ADFs) continues to rise, this trend is expected to extend into the development of paediatric dosage forms (PDFs), further increasing the high-potency ratio in this segment.
The handling of such potent molecules necessitates the implementation of rigorous controls to ensure both safety and efficacy. Best practices include the use of contained engineering solutions to safeguard drug product integrity and protect operators. Key measures involve purpose-built facilities, high-efficiency particulate air (HEPA) filtration systems, stringent cleaning validation protocols, and personnel who are comprehensively trained in managing and handling highly potent compounds.
Benefits of Oral Liquid Dosage Forms
Paediatric dosage forms (PDFs) provide considerable advantages over traditional oral solid dose (OSD) products, particularly in terms of improving patient compliance and ensuring therapeutic effectiveness. One of the most significant benefits of PDFs is their ease of administration. Liquid formulations are inherently more patient-friendly, as they are easier to swallow compared to tablets or capsules. This is especially important for children and elderly patients who may experience difficulties swallowing solid dosage forms (ADFs). By converting OSD products into formats that are more accessible to these populations, pharmaceutical companies help ensure patients can adhere to their prescribed treatments without unnecessary discomfort or difficulty.
Another key advantage of PDFs is the ability to incorporate sweetened or flavoured vehicles to mask the bitterness or unpleasant taste of active pharmaceutical ingredients (APIs). For paediatric patients, who are often particularly sensitive to taste, this feature plays a crucial role in promoting adherence to treatment regimens by making medications more palatable.
Liquid dosage forms also offer an additional benefit of enhanced drug absorption compared to OSDs such as tablets or capsules. Improved bioavailability can lead to a faster onset of therapeutic effects, which is especially valuable in conditions where prompt action is required.
Dosing flexibility is another prominent advantage provided by PDFs. A single bottle of liquid medication can accommodate different doses by adjusting the volume administered using a spoon, syringe, or dosing cup. This versatility eliminates the need to manufacture separate stock-keeping units (SKUs) for each dosage variation, streamlining inventory management and reducing production costs for pharmaceutical companies.
Development and Manufacturing Challenges
The development and manufacturing of oral liquid dosage forms, especially paediatric dosage forms (PDFs), come with distinct challenges that must be addressed to ensure safety, efficacy, and patient compliance. When these formulations involve highly potent active pharmaceutical ingredients (HPAPIs), additional processing considerations become critical to protect operators handling the product. Once the HPAPI is fully wetted, the risk to the operator diminishes significantly. However, the process of safely wetting the HPAPI presents a unique challenge.
One prominent issue is the inherent instability of liquid formulations compared to oral solid dose (OSD) products. Liquid forms are more prone to physical and chemical degradation, and the risk of microbial growth is substantially higher. These vulnerabilities necessitate robust preservation or sterilization measures to maintain product integrity throughout the shelf life.
Another critical challenge lies in selecting appropriate container closure systems for liquid formulations. These systems must prevent breakage and avoid interactions with the formulation. The consequences of a broken container can be severe, including total product loss and increased logistical and financial risks. This is particularly concerning for highly potent drug products, where evaporation of the vehicle could exacerbate safety hazards. While bottles are a common choice for liquid formulations, their bulkiness can make them inconvenient for patients. Single-use sachets offer a more portable alternative, but they come with their own set of challenges, including ensuring dose accuracy. Even small deviations in the dose removed from a sachet can impact therapeutic outcomes. That said, single-use sachets do provide an additional advantage: the option to include a nitrogen blanket, which can reduce oxidative degradation of the formulation.
Taste masking remains a crucial factor for paediatric formulations, as disagreeable flavors are often more pronounced in liquid forms than in OSD products. Without effective taste-masking techniques, achieving patient compliance becomes a significant hurdle. Reconstituted powder solutions, which are often used to mitigate stability issues, require cold storage to minimize degradation and microbial growth. This adds complexity to the supply chain, further compounding the challenges associated with liquid formulations.
In some cases, achieving a “good enough” outcome is the most realistic goal. Despite the best efforts of formulators, certain liquid drugs—particularly suspensions—are inherently difficult to mask in terms of taste or texture, which can adversely affect compliance. Addressing these challenges is essential to ensure that paediatric patients are willing and able to take their medication as prescribed.
Another significant technical hurdle is ensuring the solubility of poorly soluble active pharmaceutical ingredients (APIs) in liquid formulations. Advanced formulation techniques are often required to improve the solubility and bioavailability of these APIs. Moreover, liquid formulations are inherently bulkier to transport and store, especially when cold storage is required, leading to increased logistical costs and complexities.
How are CDMOs Managing This?
Given the significant and formulation-specific challenges inherent to paediatric dosage forms (PDFs), it is little surprise that a specialized “cottage industry” has emerged to assist pharmaceutical brand owners in expanding their portfolios into liquid formulations. Contract development and manufacturing organizations (CDMOs) operating in this space must demonstrate a combination of specialized expertise in liquid dosage formulation and manufacturing, alongside a deep understanding of the increasingly intricate regulatory landscape. Additionally, proven experience in handling drug products containing potent or highly potent active pharmaceutical ingredients (HPAPIs) is essential. Equally critical to success is access to advanced analytical testing capabilities and taste-testing tools such as electronic tongues (e-tongues), which play a pivotal role in developing palatable formulations that enhance patient compliance.
The growing demand for comprehensive, integrated, end-to-end solutions reflects pharma brand owners’ desire to de-risk and streamline their supply chains. These solutions span the entirety of the product lifecycle, from initial formulation development and detailed analytical testing to regulatory support and commercial-scale manufacturing. To meet these expectations, outsourcing partners must leverage state-of-the-art facilities, employ cutting-edge technologies, and utilize scalable equipment that offers the flexibility and efficiency required to support diverse project needs.
In conclusion, while oral liquid dosage forms offer distinct advantages, they also present complex challenges, particularly when dealing with potent drug products. However, with the right combination of expertise, advanced technology, and strategic processes, these challenges can be effectively managed to deliver high-quality, patient-centric therapies.
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