Economic, competitive and healthcare pressures are driving continued change in pharmaceutical drug development as companies strive to improve returns on investment and accelerate times to market. Taking the right active pharmaceutical ingredient (API) forward is crucial for the success of any project, making early and comprehensive characterization an absolute requirement.
Detailed physicochemical characterization of the API helps manage and mitigate the uncertainty and risks inherent in early-stage drug development. ‘Win quick, fail fast’ approaches are critical to longer-term success, enabling the rapid identification of developable APIs that meet safety, bioavailability and likely processability requirements.
Malvern Panalytical combines expertise in API development, discovery, and manufacturing, with a deep understanding of how to apply physicochemical analysis in drug development. Our systems, which are used throughout the pharmaceutical development workflow, help answer questions about API bioavailability, stability, processability and quality, to support:
- Selection of viable candidates
- Gaining an understanding of critical material attributes (CMAs)
- Implementation of scale-up for quality in API manufacturing
- Application of Quality by Design (QbD) by helping define the physicochemical design space
API Bioavailability
The poor solubility of the majority of today’s APIs adds to the complexity of ensuring that a molecule has adequate bioavailability for effective use. Approaches such as the Developability Classification System (DCS) and Manufacturing Classification System (MCS) help identify those candidate molecules that are likely to meet bioavailability requirements and which will then also be successful in scale-up and manufacturing. These systems rely on appropriate physicochemical analyses to provide the data needed to link decisions made during lead optimization and API salt and polymorph selection to the critical material attributes (CMAs) required to meet both product and process requirements.
Common strategies employed in API design to improve solubility include particle size reduction, the identification and selection of different polymorphs, and, increasingly, the use of amorphous forms of the molecule.
Malvern Panalytical systems help answer questions including:
- What solid forms are available?
- Are there multiple polymorphs?
- What is the impact of particle size reduction on particle and polymorph stability?
- How much amorphous content is present, and how can amorphous structures be defined and characterized?
Analysis tools that support bioavailability strategies
Empyrean range
Morphologi 4-ID
Mastersizer range
API Stability
Understanding the stability of the solid form API is an essential part of lead optimization, salt screening and process development. Polymorphic transitions may result in changes such as altered dissolution rates, reduced drug efficacy and possible adverse reactions, and their presence can raise patent issues.
Polymorph selection, and confirmation of polymorphic stability over time, is therefore crucial. This becomes even more important when an amorphous form of the API is selected to improve solubility, as unexpected crystallization of an insoluble form can be fatal.
Ensuring that all polymorphic forms are known, and their behavior is understood, helps in managing API stability and reducing the risk of late breakthrough polymorphs that might jeopardize downstream development.
Malvern Panalytical systems help answer questions including:
- What polymorphic forms of the API are possible?
- How will these polymorphic forms behave?
Analysis tools that enable stability studies
Empyrean range
Crystallinity determination - Quantification of low amounts of amorphous material in a crystalline matrix and vice versa
Advance your XRD research with in-situ and amorphous testing
API Processability
Monitoring the impact of processing on the size and shape of API particles
Many APIs fail on scale-up, often because of issues connected with stability or processability. With the advent of continuous processing and moves towards novel manufacturing methods, it is increasingly important that the API easily fits developability, processing and scale-up requirements.
Malvern Panalytical systems provide the insight that enables a QbD approach to API development, supporting robust design space definition, process optimization and the maintenance of process performance within that space.
Malvern Panalytical systems help answer questions including:
- What is the stability of the API during processing?
- How can critical material attributes (CMAs) relating to bioavailability be controlled?
- What is the safety profile of my product or ingredients with respect to elemental impurities?
Analytical approaches to improve processability and aid scale-up
Empyrean range
Morphologi 4-ID
Insitec range
Epsilon 4
API Quality
The handover to manufacturing requires the definition of a robust Chemical Manufacturing and Controls (CMC) package. This package must ensure that CMAs are monitored in order to maintain API product quality and safety. Microstructure and solid form analysis are often key characterizations, in line with ICH guidance (ICH Q3D, ICH Q6A and ICH Q1A).
Malvern Panalytical systems help answer requirements including:
- Quality control of raw materials and intermediates for APIs and excipients, and stability testing for batch release
- Root cause analysis for batch release
- Physicochemical insight to assist process optimization
- In vitro bioequivalence assessment to aid the transfer of processes or products between sites and/or from old to new processing methods