Active pharmaceutical ingredient (API) development can be a complicated undertaking with competing priorities. Consider, for example, balancing the need for quality versus speed during the transition from candidate selection to first-in-human (FIH) clinical trials. Considering that the availability of a small molecule API is on the critical path for initiating a wide range of activities, defining a safe, cost-efficient, regulatory-compliant, and sustainable route for the API saves costly repeat activities or bridging studies in later phases of development.
Analytical techniques play an essential role in this process, providing insight into the API's characteristics while monitoring how changes in the synthetic process influence API properties. Running a comprehensive analytical strategy in parallel with synthetic route optimization helps identify any impact on the API's critical quality attributes (CQA). For example, when developing a drug for oral solid dose administration, a critical component is understanding the potential impact of API solid-state properties on the drug’s bioavailability and how best to optimize these properties.
Making the most of early insight
Only gram-scale quantities of API are synthesized at the candidate selection phase, often using a medicinal chemistry approach that favors late-stage structural variation to prepare arrays of compounds for screening. The API's solid-state properties are unlikely to be well understood, and the reagents and solvents used at this point may be unsuitable for GMP synthesis, containing impurities or other potential degradants that may lead to batch-to-batch variability.
Through the increased control of solid-state properties and using a “process route design” targeted toward the specific candidate compound, characteristics favoring easier, more scalable development of the API can be selected. A comprehensive account of these early batches and the differences in analysis can be vital for predicting and mitigating potential issues further down the development pipeline. To prepare larger batch sizes, modification or redesign of the process is often required to ensure that enough material is produced efficiently. Some of the challenges include:
- Ensuring safety. Reagents, intermediates, and even the API may possess thermal liabilities, friction/shock or dust explosion properties, and reactions may be exothermic. Commonly used chemical moieties, such as nitro groups, often increase the likelihood of these properties.
- Hazardous materials. Trace quantities of solvents and reagents used in the synthesis may remain in the API. Therefore, careful selection of materials used in the process is important. Selecting a route that avoids the formation of any potentially mutagenic impurities should also be a key consideration.
- Promoting sustainability. Developing synthetic routes that have a high atom economy and process mass intensity significantly reduces manufacturing costs and improves process sustainability.
- Costly starting materials. Using niche or expensive starting materials or reagents for API synthesis can result in sourcing difficulties and issues with cost-effective manufacture as scale increases.
Identifying the right purification strategy. The best control strategy for managing process impurities is to minimize their formation in the first place. A high level of process understanding and analytical capability is required to achieve this. Establishing key control points in the synthesis with stable, crystalline intermediates is also highly advantageous.
Credit: Adobestock.com
Optimizing the API further
A variety of methodologies can be employed to obtain a comprehensive understanding of an API. A targeted approach is best to obtain insight into API properties and potential limitations that may occur when scaling up, considering the following factors:
- Route scouting. Initial desk-based screening of potential synthetic routes can highlight specific challenges or concerns in a proposed sequence, including raw material and waste considerations.
- Feasibility. Targeted work in the laboratory can then quickly establish the viability of a given approach and identify any potential issues for scale-up.
- Salt screen. If ionizable groups are present in the compound, developing novel salt forms can advantageously alter API properties, including solubility, crystallinity, and stability. Alternate salt forms may also give an intellectual property advantage.
- Crystallization screen. Initial API isolation is often of amorphous or thermodynamically less stable polymorphic forms. Obtaining a stable crystalline form imparts several advantages in early development for purity and form consistency. Early crystallization screening allows the researcher to gauge polymorphic tendency and identify the conditions promoting crystallinity.
- Solubility studies. Identifying the solubility of the API under varying conditions (for example, pH, solvents, and biorelevant media) is vital to determine its developability classification system score and the likely impact on the drug’s clinical bioavailability. This information also informs the formulation strategy; if poor solubility is observed, for example, the API’s particle size may be modified, or alternate salt or polymorphic forms may be made to increase solubility. Furthermore, specific formulation technologies may be utilized to overcome solubility limitations.
- Stability studies. Stability issues can significantly delay any drug development program. Conducting stability studies with early technical batches provides essential data on how the quality of an API varies with time and under the influence of environmental factors, including storage, light, and temperature.
- Impurity identification. Identifying, isolating, and characterizing impurities is advantageous during API development. Once identified, drug developers can determine the mechanism of their formation and optimize manufacturing processes accordingly. Additionally, insights into control strategies and purge points can be gained through this process.
Deploying data-driven API development strategies early in a drug program can mitigate downstream development risks. Many of these assessments can be completed in parallel with interim outputs to steer overall development decisions. When combined in this way, a holistic approach to process development is used, avoiding delays and costs while facilitating efficient product scale-up.
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