The Increasing Importance of Manufacturability in API Development

Incorporating optimized active pharmaceutical ingredient (API) design and synthesis early on within the drug development process allows drug developers to raise formulation compatibility, lower downstream risk processes and accelerate drug candidate validation. Together, these factors efficiently advance therapies through development and into the market

Integrating Manufacturability Across the Drug Development Lifecycle

Manufacturability in API development represents far more than just the ability to produce a compound. It encompasses the entire journey of optimising chemistry processes to ensure efficiency, consistency and reliability throughout the clinical lifecycle and into commercial production. In essence, this process revolves around the ability to build a scalable, reliable and economical drug development process that can be applied to real-world production, rather than just a process that looks feasible on paper.

When implemented successfully, manufacturability directly impacts several critical factors throughout the manufacturing and commercialisation processes. First, it reduces the overall cost of goods throughout drug discovery and development. When manufacturers have efficient and well-established processes in place, they can lessen the waste that comes from low yields and failed batches, avoiding additional material and disposal costs that less optimised processes may require. Not only does it translate to lower production costs, but it ultimately affects accessibility and affordability for patients.

Product robustness is another important component of manufacturability, as well-developed processes enable the delivery of consistent results batch after batch. This reduces variability in factors like yield, purity and cycle time within drug development and ensures product quality meets stringent regulatory standards every time a new batch is developed. When drug development and formulation scientists can decrease these irregularities, they also lessen the risk of unexpected and unintended outcomes. Ultimately, this helps minimise the risk of drug shortages, while also ensuring a steady supply chain.

The importance of manufacturability increases throughout the drug development journey. While early-phase programs may prioritise simply producing enough material for clinical trials, the focus intensifies as products advance. By Phase II and certainly into Phase III development, having an optimised, efficient process becomes crucial for successful commercialisation.

Diverse Needs Require Customised Approaches

Is it worth calling out how there is no one-size-fits-all approach to API drug development. This means that manufacturability can often look different for the individual molecules being developed. Each chemistry process can lead to unique obstacles, as pharmaceutical organisations often prioritise different factors of manufacturability, depending on their specific needs.

The more complicated the process, the more opportunity there is for optimisation, and the more critical manufacturability becomes. For example, in chemistry, the term “unit operation” represents a single step or action within a process. Ideally, chemists are looking for processes with fewer unit operations, which are therefore easier to control.

Different volume requirements are also a factor that could potentially uncover the need for different manufacturing approaches. For example, when it comes to determining how much of a drug to bring to market, a highly potent product requiring only 20 kilograms every three to four years demands a fundamentally different strategy than a blockbuster drug requiring multi-metric ton production annually. For the former, the focus centers on achieving perfect quality in limited runs. For the latter, efficiency and speed also become paramount while maintaining quality standards.

Manufacturability extends beyond technical considerations. While some companies focus its impact on the environment or secure supply chains, others prioritize reducing costs to increase access.

The ability to tailor manufacturing strategies to these various needs demonstrates a critical differentiator for CDMOs in today’s competitive landscape.

Safety: The Foundation of Every Process

Safety throughout the manufacturing process shapes almost every decision. This is especially true as modern API synthesis often involves hazardous reagents and conditions. To ensure manufacturability, pharmaceutical companies must consider all safety concerns.

First and foremost, safety considerations influence the actual design of the drug development process. Oftentimes, processes require working with dangerous materials that can cause chemical reactions. This means that manufacturers must take alternative synthetic routes or technologies to minimise risk as much as possible.

The progress from medicinal chemistry routes, which could easily involve 20-30 moves designed solely to make small amounts for early studies, to commercial processes, demonstrates how safety drives innovation.

Development teams are often looking for alternative routes to avoid dangerous chemistry, taking options like flow technology or biocatalysis to replace dangerous batch reactions into consideration. These continuous tweaks not only advance safety, but they also often improve efficiency and sustainability simultaneously.

Sustainability: Meeting Today’s Environmental Imperatives

The idea of environmental responsibility is becoming a more critical component for the pharmaceutical industry as it continues to work through API manufacturing processes. Today’s manufacturability assessments are more often emphasising sustainability metrics alongside traditional efficiency measurements.

One of the most impactful areas of improvement is solvent management. Reducing solvent volumes delivers immediate environmental benefits, like reduced carbon footprint and lower waste generation. Equally important is simplifying solvent systems. To illustrate this, processes using six or seven different solvents in one individual stage can lead to waste management challenges. However, streamlining processes to use around two or three solvents, or maintaining consistent solvents across multiple stages, significantly lessens the impact on the environment.

Energy consumption offers an additional critical lever, as sustainability efforts are improved when processes are simplified. Shortening what is typically a week or two long manufacturing procedure to two or three days significantly decreases the energy required for activities like heating, cooling, stirring and maintaining controlled environments. These improvements cascade through the entire production system, reducing utility demands and carbon footprint.

Yield improvements, while traditionally viewed through an economic lens, also deliver substantial sustainability benefits. Each percentage point of yield improvement means less raw material input for the same output, reducing upstream environmental impacts from raw material production and transportation. CDMOs can assist with this as well by implementing continuous manufacturing platforms, developing strong optimization strategies to minimise waste and outlining advanced process analytics.

The growing prioritisation of supply chain sustainability demonstrates increasing corporate responsibility commitments, especially among large pharmaceutical organisations. The expectation now extends past direct manufacturing to include the entire value chain, creating more opportunities for collaborative improvement while guaranteeing a stable supply chain.

The Path Forward

The modern pharmaceutical industry is currently at a crossroads where traditional API manufacturing approaches no longer suffice. Growing intricacies of drug molecules, increasing quality requirements, stricter sustainability demands and more pressure to lower costs while maintaining supply security, all converge to make manufacturability a critical, and even required, factor of API development.

Throughout my career, I have learned that while pharmaceutical companies have a general understanding of this process, it requires a combination of technical expertise and willingness to solve the unique challenges each drug presents.  Whether dealing with complex multi-stage syntheses, highly potent compounds, or high-volume production, safety, efficiency and sustainability are top priorities.  The journey from discovery within a laboratory to commercial medicine has never been more complex than it is right now, but with the right partner, it’s a journey that can be both thoughtfully and successfully navigated.

Ultimately, understanding the role these technical aspects play translates directly to patient benefit. Efficient, reliable manufacturing processes ensure medications reach patients consistently and safely. In an era where drug shortages can have life-threatening consequences, excellence in manufacturability becomes not just a business advantage but one that can also have life-changing benefits for patients around the world.

--PFAm Issue 07--