Journey of an API: Chemical process development

One of our key differentiators at Sterling is our cross-lifecycle perspective, and the depth of knowledge and continuity it brings to our customers as their active pharmaceutical ingredients (APIs) make their way to the market. In our Journey of an API blog series, we’ll follow an API’s journey as it progresses from the preclinical stage to scale-up and full commercialisation.

In this blog, we cover a vital part of API manufacturing: chemical process development. While quality, scalability, safety and efficiency matter throughout the entire development and manufacturing lifecycle of an API, it is during process development that these factors come into sharper focus. In many ways, chemical process development creates a foundational blueprint that guides the API’s entire journey to market.

During process development, the intended chemistry is put into practice as the CDMO aims to optimise process parameters early for the most efficient scale-up and manufacture. Below, we’ll take a closer look at chemical process development, discussing key objectives, common challenges, and implications for other stages in the journey of an API.

Breaking it down: Building process understanding from the very start of API chemical process development

At its core, API process development aims to design an efficient, scalable process that will maintain stringent quality and safety standards and contain costs during the resource-constrained development phase, while maximising the probability of success in commercialisation.

Process development requirements vary not only depending on the chemistry complexity and the stage of the molecule’s lifecycle, but also on how much development work a customer has previously completed. Is it a robust process that is being transferred to an outsourced partner? Or is it an earlier stage project that requires more significant development work? In any case, a thorough process understanding is the bedrock of a scalable and viable API manufacturing process. The initial phase of process development always entails a comprehensive process familiarisation effort, which is fundamental to understanding customer objectives and evaluating developmental requirements.

The best process development efforts embrace cross-team collaboration wholeheartedly. While chemistry teams spearhead chemical process development, close alignment and communication is vital between multiple technical disciplines. Analytical chemistry collaboration is needed to understand the chemistry and establish robust methods for process controls and specifications. Close cooperation with process engineers is required to design and utilise the manufacturing equipment efficiently. Safe scale-up of a process is only achieved together with hazard evaluation groups. cGMP compliance of the process is directed by operational quality.

Measuring success: Key objectives for API process development

While process development requirements vary widely, this stage of the API lifecycle is focused on the following key indicators of success:

Reaction conversion captures the degree to which reactants have been transformed into the intended products, while yield captures the efficiency of a given process in producing the intended product. Both of these indicators are vital to ensuring a process’s operational and financial viability, optimising resource utilisation, maximising consistency and quality, and even minimising purity challenges. Process optimisation can be achieved with the aid of methodologies such as Design of Experiments (DoE).

How it’s measured: By analysing samples at different points in the reaction using techniques like high-performance liquid chromatography (HPLC), gas chromatography (GC) and others, research and development (R&D) teams effectively build a picture of the reaction profile and impurity/side-product generation. Reaction kinetic modelling can also be used to plot the relationship between reaction rate and process parameters. To maximise yield outputs, mass balance analysis is conducted to understand yield losses to waste streams and side-products.

Impurity generation and the potential for unwanted side reactions are also important to consider, as both of these can impact product quality and yield. API quality is critical to patient safety, so understanding impurity generation, fate and acceptable levels is crucial to ensuring final product quality.

How it’s measured: Some of the techniques utilised to evaluate reaction conversion and yield are also instrumental in evaluating chemical purity. HPLC and GC are used to assess purity profiles by examining components by retention time and peak area. These techniques can also be used to track impurities through the process to determine their fate and extent of removal to waste streams. Structural characterisation of impurities can be obtained from mass spectrometry (MS) and nuclear magnetic resonance (NMR). Knowing the structure of an impurity is important to target its origin in the synthesis and therefore minimise its impact, further improving process understanding.

Process safety considerations are critical to ensure the project can be effectively risk assessed and safely supported on plant. During development, scientists should assess safety considerations such as reaction heat and gas output, material dust explosivity, thermal decomposition of products and the toxicity of materials being handled. If hazards surface at this stage, then a more thorough hazard evaluation study and collaboration with plant process engineers is important to mitigate and control any safety issues.

How it’s measured: A variety of tests can be harnessed to evaluate the many facets of process safety. For example, differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) can both provide valuable insight into a compound’s behaviour under temperature changes. Reaction profiles can be evaluated for exothermic activity and gas evolution. Vent sizing and all-on-board reactions can be assessed with Accelerating Rate Calorimeters (ARC). Materials can be assessed based on their exposure limits, flash point and material compatibility. In addition, more straightforward tests, like pressure tests and pH monitoring, are regularly applied to ensure safe operational limits are upheld.

Overcoming obstacles: Navigating common process development challenges

What happens if we’re not achieving the results we need during process development? Some challenges can be addressed with chemistry alone through optimisation of process parameters or developing an alternative synthetic strategy. Some may require collaboration with other departments, including hazard evaluation, analytical and engineering teams, or a combination of the three. The following is a recap of some of the most common hurdles during process development, and how we work to address them. Note that each obstacle corresponds to one of the key indicators discussed above.

• Low yield: When yield is lower than needed or anticipated, an investigation into the root cause of the low yield is the first course of action. If the reaction is leading to side-products or incomplete conversion, process parameters can be adjusted to minimise this loss. Most common is the loss of product to a waste stream during an isolation/purification operation, such as crystallisation. With input from an experienced solid state team, scientists can work to develop a crystallisation process that maximises quality and yield through solubility understanding, optimised temperature profiles and mixing control.
• Impurity management: If a problematic unknown impurity surfaces during process development, that impurity must be accurately characterised and potentially removed. Chemists often work backwards to understand how the process came together and identify which step resulted in the impurity formation. They can then target that specific area of the process to prevent the impurity from forming altogether. Chromatography techniques can help to isolate and quantify the impurity. In addition, fate and purge experiments may also be necessary to determine whether the impurity will carry through to the final product, or be released as waste during one of the process steps. Purge studies allow chemists to track impurities downstream and quantify the level of rejection to waste. This also requires robust and effective analytical methods.
• Safety concerns: Hazard increases along with scale, so it’s important to mitigate hazards early to ensure a project’s ongoing safety compliance. If a reaction is exothermic, for example, adjusting batch temperature, reagent addition rates, and other factors can aid in minimising heat generation. Once the process reaches the plant scale, cooling mechanisms and other measures may be necessary to support the reaction safely, so it’s important to consider whether these measures can realistically be implemented on plant early in the development process. This requires close collaboration with the hazard evaluation team, as well as the process engineering team.

In addition to those listed above, other hurdles can arise related to stability, sustainability, cost, reproducibility and even conflict with patented processes or methods. These are multifaceted challenges that can only be navigated through the combined contributions of a multidisciplinary team; one that balances scientific understanding, engineering expertise, economic perspective and regulatory knowledge.

Back to the big picture: Proactive API process development

Proactivity is a central element of successful process development, and an ineffective process often only becomes apparent in the later stages of the pharmaceutical lifecycle. All of this underscores the importance of a full-lifecycle understanding during the process development phase in creating an optimal process that will remain viable throughout an API’s journey to market.

By collaborating across teams, considering the impact of increased scale, and using equipment in the lab that mimics that on the plant scale as closely as possible, such as jacketed lab vessels rather than standard glassware, scientists can better account for hurdles that might surface and prevent process-related bottlenecks down the line. For example, a good understanding of batch stability and safe hold-points can prove invaluable should unexpected events occur during manufacturing.

API process development at Sterling

At Sterling, our extensive experience and multidisciplinary approach enable us to account for the full scope of considerations that can impact quality, yield, efficiency and safety at every stage of the API lifecycle. With expertise across a broad range of complex chemistry and comprehensive services from preclinical discovery to full commercial manufacture, we understand the many challenges that can arise on an API’s journey to market, and possess the scientific rigour needed to mitigate them with confidence.

If you’d like to learn more about how we can support your molecule through process development and beyond, speak to an expert. Visit our Knowledge Hub to explore more useful resources.