As requirements shift toward more complex, value-added solid formats and increased outsourced manufacturing, oral solid delivery (OSD) demand is expected to continue rising. In parallel, development hurdles persist, presenting biopharma companies with greater demands, more intricate pipelines, and a broader scope of technologies to assess than ever before.
Among these challenges is the predominance of poorly soluble molecules in development pipelines, which represents one of the most significant technical hurdles in OSD formulation. Compounds classified as Biopharmaceutical Classification System (BCS) Class II or IV require sophisticated approaches to achieve adequate bioavailability. Approximately 70% to 90% of new small-molecule drug candidates in development pipelines are classified as having poor aqueous solubility, with some compounds demonstrating solubility as low as 0.002 mg/mL.
Physicochemical degradation presents further ongoing hurdles throughout development and commercialisation. Amorphous forms may undergo crystallisation, moisture-sensitive compounds require specialised packaging configurations, and environmental factors during storage demand careful consideration of packaging solutions, including desiccants and specialised bottle designs. These stability considerations must be addressed early to prevent costly reformulation efforts during later development stages.
Scale-up complexities represent another critical challenge area. Laboratory-scale processes using 3-5 kg quantities must successfully transition to commercial production scales of 300-500 kg. This transition frequently reveals cascading complexities including inconsistent dissolution profiles, altered material flow properties, and variations in tablet hardness. Technologies like hot-melt extrusion and spray drying require extensive process optimisation to maintain quality target product profiles during scale-up operations.
To address each of these pain points, formulation scientists must employ various physical methods. However, the selection of appropriate technologies depends on multiple factors, including melting point, glass transition temperature, and thermal stability of the compound.
A strategic framework for early risk identification
With OSD demand expected to continue rising, a robust development framework grows more crucial. Below is a strategic framework for early risk identification, brought to you by the experts at Thermo Fisher Scientific’s Patheon pharma services.
- Comprehensive physicochemical profiling
The foundation of effective early risk identification lies in comprehensive physicochemical characterisation of drug substances. This assessment should encompass solubility evaluation across multiple pH conditions, hygroscopicity testing, polymorphism screening, and chemical stability assessment. BCS classification provides crucial guidance for formulation strategy, with class II and IV compounds requiring specialised solubility enhancement approaches.
Accelerated stability studies conducted under conditions such as 40°C/75% relative humidity or elevated temperatures of 50-60°C enable prediction of long-term degradation risks within compressed timeframes1. These studies inform excipient selection and formulation design while preventing downstream surprises that could necessitate reformulation efforts. Early detection of formulation hurdles related to bioavailability or degradation enables proactive mitigation strategies.
- Excipient compatibility and interaction assessment
Systematic excipient compatibility testing represents a critical component of early risk identification. Drug-excipient interactions, such as the well-documented interaction between tetracycline and calcium carbonate, can significantly impact product performance and must be identified early in development. Accelerated stability studies provide rapid assessment of potential incompatibilities, enabling informed excipient selection and formulation optimisation.
The selection of appropriate polymers for amorphous solid dispersions requires particular attention to molecular interactions. Advanced approaches utilising 3D quantum calculations enable analysis of hydrogen bonding, aromatic interactions, and hydrophobic interactions between APIs and potential polymers. This modelling-driven approach replaces traditional trial-and-error methods, dramatically reducing development time and material consumption.
- Quality by design integration
Quality by Design (QbD) principles provide a systematic framework for development that begins with predefined quality objectives. The establishment of Quality Target Product Profiles (QTPPs) and identification of Critical Quality Attributes (CQAs) create clear development targets from project initiation. Risk assessment tools such as Failure Mode Effects Analysis (FMEA) enable prioritisation of process parameters based on their potential impact on product quality.
For orally disintegrating tablets, FMEA analysis might identify super disintegrant concentration and compression force as critical parameters requiring careful control. This systematic approach delivers built-in quality rather than tested-in quality, providing greater regulatory flexibility and robust commercial processes. Design of Experiments (DoE) methodologies enable development of design spaces that facilitate process understanding and optimisation.
The crucial role of a CDMO
Successfully implementing a robust OSD development framework requires facilities, processes and controls designed for performance and safety. For many pharmaceutical teams, this makes CDMO selection a critical step in the development journey.
Today, the best biopharma partners don’t simply execute tasks; they actively reduce uncertainty across the programme. Large, experienced CDMOs, which have seen thousands of development journeys, across multiple modalities, stages, and regulatory pathways, can deliver value thanks to their ability to recognise patterns. Better able to anticipate hurdles, apply learning from broad datasets, and provide the technical depth and stability required for complex development pathways, a larger CDMO, such as Thermo Fisher Scientific’s Patheon, demonstrates how size can become a strategic advantage.
Patheon pharma services provides comprehensive end-to-end solutions, from early-phase formulation development to late-phase process optimisation and commercial manufacturing, specialising in late-phase development of OSD forms. With over 40 years of experience in developing a wide range of OSD forms, it has successfully supported the commercial launch of numerous projects for its clients, tailoring its solutions to meet a range of commercial production needs.
It offers a global network of facilities dedicated to the development and manufacturing of OSD products, with a global network of sites strategically located to meet the diverse needs of its local and global clients. All development equipment is aligned with commercial capabilities to ensure successful scale-up and commercial launch. To find out more about accelerating oral solid dosage drug development, a more in-depth framework for pharmaceutical innovation, and the technical expertise that Thermo Fisher Scientific’s Patheon pharma services can provide, download the in-depth white paper below.
