Developing an active pharmaceutical ingredient (API) involves balancing quality and speed during the transition from candidate selection to first-in-human (FIH) clinical trials. Creating a safe, cost-efficient, and regulatory-compliant API production method is crucial to avoid costly repeat activities or bridging studies later in the development process.
Analytical techniques, including solid state analysis, is essential for understanding how changes in the synthetic process influence API properties, especially for small-molecule oral solid-dose drugs. In this article, we speak with Dr. Richard Castledine, Head of Drug Substance and Translational Pharmaceutics® Operations, about some of the main considerations that drug developers and their partners face in drug substance API synthesis.
Analytical techniques, including solid state analysis, is essential for understanding how changes in the synthetic process influence API properties, especially for small-molecule oral solid-dose drugs. In this article, we speak with Dr. Richard Castledine, Head of Drug Substance and Translational Pharmaceutics® Operations, about some of the main considerations that drug developers and their partners face in drug substance API synthesis.
What is an “API” in drug manufacturing?
An active pharmaceutical ingredient (API) is the substance which offers a therapeutic effect in a pharmaceutical product, and is responsible for the drug’s pharmacological activity within the body. It is combined with excipients which aid in the delivery of the API but do not themselves have any pharmacological activity.
What is process route design in API manufacturing? What challenges are typically encountered in process route design?
Process route design involves finding and selecting a synthetic pathway to the API which has favorable characteristics for scale-up and large scale current Good Manufacturing Practice (cGMP) production.
Modification or redesign of the process is often required to prepare larger batch sizes and ensure that enough material can be produced in a compliant and efficient manner. It is important to consider these potentially challenging factors earlier in the drug development process, including:
- Ensuring safety when working with hazardous materials and highly potent compounds
- Identifying and developing control strategies for process and degradation impurities which may otherwise remain in the API
- Avoiding the use niche or expensive starting materials or reagents for API synthesis which can result in supply chain sourcing difficulties and issues with cost-effective scaling
- Reducing costs and improving sustainability by using synthetic routes that have a high atom economy and process mass intensity
What factors must be considered in optimizing drug substance API?
A variety of methodologies can be employed to obtain a comprehensive understanding of an API. A targeted approach is best for obtaining insight into API properties and potential limitations that may occur when scaling up. Factors which should be considered include:
- Route scouting. An 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 assessment. Targeted work in the laboratory can 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.
- Solubility studies. Identifying the solubility of the API under varying conditions (e.g. pH, solvents, biorelevant media) is important to determine its developability classification system (DCS) score and 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 formulation technologies 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 environmental factors (e.g. storage, light, temperature.)
- Impurity identification. Identifying, isolating, and characterizing impurities is advantageous during API development. Once identified, drug development teams can deduce 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. To successfully de-risk a FIH program it is critical to choose a drug development partner with expertise in developing and analyzing API. Many of the activities listed above can be completed in parallel with interim outputs used to steer overall development decisions. When combined in this way, a holistic approach to process development is employed, avoiding delays and costs while facilitating efficient API scale-up.