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, are 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 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 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 API can be produced in a compliant and efficient manner. The following factors should be considered early in the drug development process:
- Ensuring safety when working with hazardous materials
- 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 difficulties and issues with cost-effective scale-up
- 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 targeted approach is best for obtaining insight into an APIs physical and chemical properties, as well as the potential limitations that may occur in the manufacturing phase. 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.
- Robustness. Understanding of the edges of failure of any given reaction conditions.
- 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 and can also lead to optimized isolation conditions.
- 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. temperature and humidity).
- 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 program can mitigate downstream development risks. It is therefore critical to choose a drug development partner with extensive 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.