Journey of an API: Supporting quality by design in API development

Once a practice reserved for early adopters, quality by design (QbD) has evolved into a foundational concept in API development. This method not only drives consistency across the project lifecycle but also equips scientific teams to anticipate challenges and streamline manufacturing and regulatory processes. By fostering a deep, upfront understanding of each step, QbD allows pharmaceutical companies to maintain exacting standards and deliver reliable, high-quality products at scale. 

In this blog, we’ll dive into the key principles of quality by design, define how success is measured, and explore common challenges along with practical solutions to overcome them. 

As the name suggests, the primary goal of quality by design (QbD) is to ensure product quality. However, achieving and maintaining this quality goes beyond simply adhering to standards—it requires an unwavering focus on three key objectives: product consistency, deep process understanding, and operational efficiency. Success in QbD is not just about meeting specifications but doing so consistently and efficiently, throughout the entire API lifecycle. 

If quality by design were reduced to a single objective, it would be to ensure that both the process and product maintain consistent quality from the very beginning of a project. A fundamental aspect of this is the identification of critical quality attributes (CQAs) and their corresponding critical process parameters (CPPs). CQAs refer to the properties of an API that must remain within a specific range to meet desired quality specifications, while CPPs are the variables that directly impact these attributes. 

For example, if purity is identified as a CQA, factors like temperature and agitation rate might surface as CPPs that have an impact on purity if they fall outside of a specified range. Controlling them, therefore, is essential to producing a high-quality product.  

How it’s measured:  

The success of quality by design (QbD) is often assessed by measuring and controlling CPPs through development and manufacture to ensure they remain in range. Regular evaluations of product yield, purity, and other CQAs after each manufacturing run are essential to ensuring that specifications are consistently met. In real-world applications, implementing QbD has been shown to significantly reduce out-of-specification results, which cuts down on costly delays and accelerates time to market.

One of the primary advantages of quality by design is that it allows scientists a deeper understanding of a process, enabling them to proactively avoid potential issues before they arise during manufacture. By conducting well-considered experiments, which may include the use of one-factor-at-a-time (OFAT) and design of experiments (DoE) approaches where appropriate, chemists can gain valuable insights on how process parameters interact and influence the final product. 

Furthermore, engineers can use the data generated from these experiments to establish controls that ensure CPPs remain in range. For example, reactor jackets and heat exchanger design can be used to maintain stable temperature conditions, while sensors may be used to monitor pressure, pH, and other variables. 

How it’s measured:  

The success of process control is partially gauged by the stability of CPPs throughout development and manufacture. In addition, analytical advances and monitoring systems, such as process analytical technology (PAT) where appropriate, enable scientists and engineers to maintain a real-time view of these parameters. These tools enable scientific teams to ensure that all equipment and controls are working effectively and address any deviations in stride. 

With product consistency and process control in place, the next critical pillar of QbD is efficiency. QbD acknowledges the important and complex relationship between product quality and process efficiency, and considers efficiency a key measure of success. In pharmaceutical manufacture, efficiency encompasses speed, cost-effectiveness, and yield. Project team members must remain intently focused on maintaining high quality standards, while also adhering to customer demands for timely and cost-effective delivery. 

Furthermore, when adjustments are made to improve efficiency—whether by reducing costs, shortening timelines, or increasing yield—teams must ensure that these improvements do not negatively impact other factors.  

How it’s measured:  

Efficiency is tracked through key performance indicators (KPIs) such as cycle time, process yield, on-time delivery, and costs. Regular evaluations, including cost-benefit analyses, help ensure that any gains in efficiency do not lead to compromises in critical attributes like purity or consistency.

While quality by design is essential, it comes with its own set of challenges. Identifying the right CQAs and CPPs is the first challenge for scientists. Additionally, out-of-specification results or unexpected impurities can pose significant obstacles, especially as the process scales. Partnering with the right API development and manufacturing team can help you adeptly navigate these challenges and ensure success.

Defining CPPs can be particularly challenging due to the complex and interconnected nature of variables in some projects. For instance, a change in process temperature might not only affect the reaction rate but also influence impurity levels. This complexity makes it difficult to isolate the exact parameters that need to be controlled. 

The right partner will harness design of experiments (DoE) to help streamline this process by enabling scientists to gather comprehensive data from fewer trials. DoE facilitates the efficient identification of key parameters, ensuring that the impact of variable interactions is thoroughly understood and managed. 

Out-of-specification results are among the most common challenges scientists and engineers can encounter during scale-up, and addressing these deviations as efficiently as possible is crucial for keeping the project on track. 

The process understanding afforded by a QbD approach enables scientists to address deviations in an efficient and systematic way. When results fall out of specification, CPPs are the first things scientists should investigate. For example, if temperature is a critical process parameter and an impurity level is higher than expected, the team should first assess any temperature fluctuations that could have triggered unwanted side reactions. 

For more complex processes known to generate numerous impurities, quality by design can become more extensive and challenging. At the same time, however, it remains critical to providing scientists the process understanding needed to effectively manage and control those impurities, ensuring product quality and patient safety. 

Analytical techniques such as high-performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LCMS) are often deployed to detect and quantify impurities at low levels. Based on these results, scientists can specify appropriate process parameter ranges and define the controls needed to achieve them during manufacture. 

Quality by design extends beyond specific processes or metrics; it is a holistic approach that integrates quality into every phase of development and manufacture. By proactively understanding and controlling variables that impact quality, QbD ensures that consistency, compliance, and efficiency are maintained throughout the entire API lifecycle. This reduces the risk of costly deviations, facilitates smoother regulatory approvals, and enhances long-term project success. ... Read more

Quality by design is integral to developing a robust manufacturing process and a high-quality API. By aligning our expertise at Sterling with customers’ quality and efficiency goals, we support our customers in achieving excellence at every stage of the project lifecycle.

At Sterling, we tailor our approach to each customer’s unique needs, driving product consistency, deep process understanding, and efficiency gains at every stage of API development. Whether you’re facing scalability challenges or regulatory pressures, our QbD-driven solutions ensure your project runs smoothly from start to finish.  

To learn more about how Sterling can support your project with the utmost quality standards, speak to an expert or visit our Knowledge Hub to learn more.