What are active pharmaceutical ingredients (APIs)?
A core part of drug development is the identification of APIs that retain their quality and efficiency when produced at scale. However, APIs that show promise during development can lose their efficiency when scaled-up. This happens for a variety of reasons, including chemical contaminants introduced during processing and the formation of alternate API polymorphs.
Detecting and quantifying these substances is vital to ‘win quick, fail fast’ approaches, enabling the rapid identification of developable APIs that meet safety, bioavailability, and processability requirements.
Malvern Panalytical has developed tried and tested methods and instruments that provide significant time and cost savings to our partners in the pharmaceutical sector. These instruments ensure that you have the insights needed to make informed decisions, improve processability, and aid scale-up.
Physicochemical analysis in API manufacturing
Malvern Panalytical has a deep understanding of how to apply physicochemical analysis throughout the lifecycle of your API, from discovery, through scale-up and all the way to manufacturing. Our systems can help you answer questions about API bioavailability, stability, processability, and quality. They support:
- Selection of viable candidates
- Understanding of critical material attributes (CMAs)
- Optimizing scale-up processes in API manufacturing
- Application of Quality by Design (QbD) by helping define the physicochemical design space
Mastersizer range
Analyze wet and dry API particle dispersions with ease at various points in the API development workflow with the world’s leading laser diffraction system
Morphologi range
Determine how processing impacts API bioavailability with statistically significant particle size and shape data with automated image analysis and more
Aeris
Understand how crystallinity and solid-form stability are affected during API processing with this easy-to-use X-ray diffractometer
Empyrean range
Access polymorph stability during processing and accelerated stability studies with this powerful and flexible X-ray diffractometer
Epsilon 4
Apply simple and robust screening for elemental impurities during process development and scale-up with easy-to-use and intuitive X-ray fluorescence
Revontium
Perform fast, non-destructive, and robust quantification for elemental purity process development and scale-up according to ICH-Q3D
Insitec range
Control API milling process and stability using online particle size analysis
API Processability
Monitoring the impact of processing on the size and shape of API particles
Many APIs fail on scale-up due to issues with stability and/or processability. Malvern Panalytical systems provide insights that enable a QbD approach to API development, supporting robust design space definition, process optimization, and the maintenance of process performance within that space.
Malvern Panalytical’s systems help answer questions including:
- How stable is my API during processing?
- Will my API pack together with excipients?
- Will my API flow and how will it react to industrial processes?
- How can I control critical material attributes (CMAs)?
- What is the safety profile of ingredients with respect to elemental impurities?
Analytical approaches to improve processability and aid scale-up
Mastersizer range
Control API particle size with precision to hit your scale-up and processes goals faster.
Aeris
Generate a full pattern to fingerprint your API in minutes with high sensitivity for low detection limits.
Morphologi 4
Determine how processing impact drug bioavailability due to changes in particle size and shape
Morphologi 4-ID
Produce statistically significant particle shape information, determine polymorphic forms and link particle shape to polymorphic form
Revontium
Apply simple, robust screening for elemental impurities in support of process development and scale-up
API bioavailability enhancement
Focus on Pharma - XRD Masterclass 1 - Characterization of Amorphous API
The poor solubility of many APIs adds to the complexity of ensuring that a molecule has adequate bioavailability. Approaches such as the Developability Classification System (DCS) and Manufacturing Classification System (MCS) help identify molecules likely to meet bioavailability and scale-up requirements. These systems depend on physicochemical data to connect lead optimization and API salt & polymorph selection to the Critical Material Attributes (CMAs) necessary for meeting production needs.
Common strategies to enhance solubility in API design include reducing particle size, selecting different polymorphs, and using amorphous forms of the molecule. Malvern Panalytical’s 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
Mastersizer range
Set specifications for drug substance particle size to control API bioavailability during scale-up and manufacturing
Morphologi 4-ID
Investigate the relationship between polymorphs and their morphological properties as part of bioavailability and processability assessments
Empyrean range
Differentiate API polymorphs or find and define amorphous forms during drug substance development and stability studies
Revontium
Apply robust screening for a wide range of applications such as measuring salts and inorganic compounds
API stability testing
Understanding the stability of solid-form APIs is crucial in lead optimization, salt screening, and process development. Polymorphic transitions can alter dissolution rates, reduce efficacy, and cause adverse reactions, potentially complicating patenting processes. It is therefore vital to select and confirm polymorphic stability, especially when using amorphous forms to enhance solubility, as unexpected crystallization can be detrimental. Knowing and understanding polymorphic behavior ensures API stability and mitigates risks associated with late-emerging polymorphs that could hinder downstream development.
Malvern Panalytical’s solutions help answer questions such as:
- What polymorphic forms of the API are possible?
- How will these polymorphic forms behave as a function of time or upon changes in temperature or humidity?
Analysis tools that enable stability studies
Empyrean range
Detect polymorphs and assess polymorph stability during lead optimization and salt screening
Aeris
Verify polymorph structure under the effect of time or environmental changes and assess shelf-life failure
Crystallinity determination - Quantification of low amounts of amorphous material in a crystalline matrix and vice versa
Application note
API purity
Eliminating elemental impurities in pharmaceutical products is essential for patient safety. Impurities introduced during processing must be removed throughout development, scale-up, and manufacturing. Access to precise elemental analysis methods is crucial for rapid process development and control.
Introducing X-ray fluorescence and morphological imaging into your workflow can help to accelerate your development processes and shorten your route to market significantly. Fast and non-destructive, these technologies provide robust screening solutions for the elemental purity of your API.
Malvern Panalytical’s solutions help answer questions such as:
- Has my chemical synthesis process been successful?
- Did my purification routine work as intended?
- What by-products are affecting my API?
Revontium
Perform robust elemental screening with simple sample preparation, delivering results in as little as 30 minutes
Empyrean range
Reveal the crystal structure of your API for vital information on phase and chemical purity
Morphologi 4-ID
Detect and identify contaminants on a particle level using Morphologically-Directed Raman Spectroscopy.
XRD Masterclass 2: In situ Stability Studies
Learn from examples of successfully performed In situ stability studies
API quality control
Handover to manufacturing requires the definition of a robust Chemistry, Manufacturing, and Controls (CMC) package. This package must ensure that CMAs are monitored 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 provides comprehensive solutions for instrument qualification and application in a validated (GxP) environment that can help support:
- 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
Supporting robust API manufacturing and quality control
Mastersizer range
Conduct robust, reliable particle size analysis for raw materials and intermediates to ensure manufacturing robustness.
Morphologi 4-ID
Understand the changes in particle size and shape which may account for batch failures or processability issues.
Revontium
Reduce expensive material loss and sample preparation when fulfilling impurity reporting requirements
Aeris XRD for pharma
Verify polymorph structure and detect potential contaminations upon scale-up activities
Insitec range
Control API milling process start-up and stability using online particle size measurements