Journey of an API: Maintaining quality and compliance in API manufacturing

Every stage of an active pharmaceutical ingredient’s (API) journey is unified by a single, overarching objective: quality. While analytical method development, engineering, production,  hazard evaluation, and other aspects of API development and manufacturing each come with their own unique goals and success metrics, all components are ultimately focused on developing a product that is safe, effective, and high-quality. 

The API is responsible for producing the drug product’s intended effect in the body, meaning it also determines the final product’s safety and efficacy. As a result, maintaining high standards for quality and compliance throughout the entire API manufacturing process is imperative for ensuring consistent performance and improving patient outcomes. 

At Sterling, we’ve always been committed to quality and compliance, and our regulatory expertise is expansive. Read on as we examine quality control (QC) and quality assurance (QA) more closely, define key goals, success measures, obstacles, and strategies for success in API manufacturing, and provide an overview of our approach at Sterling.

Rigourous quality and compliance standards throughout the API manufacturing process are essential to protecting patient safety and ensuring product efficacy. Even slight deviations in purity, potency, or stability of an API can result in ineffective treatments, or worse, serious adverse effects. 

Frameworks like the International Council for Harmonisation’s (ICH) Q7 lay out comprehensive guidelines to help API manufacturers build quality into every stage of production. This framework outlines current good manufacturing practices (cGMP) from personnel training to equipment cleaning, raw material sourcing, process controls, and storage.  

If you imagine an API manufacturing process flow chart, quality and compliance span the entire process. For example, raw material testing occurs before manufacturing begins to ensure that any materials used meet the required specifications, in-process controls allow manufacturers to monitor and adjust key parameters in real-time, and final API release testing reviews purity, potency, and other specifications before the API is distributed. Building QC into every step, ensures manufacturers adhere to regulatory guidelines around the world and deliver a high-quality product.

QC and QA teams are inherently focused on ensuring product and project quality. However, there are several dimensions of quality, and some are far easier to measure than others. Here, we explore these elements in detail:

Quality is assessed against rigorous benchmarks that are critical for the safety and efficacy of APIs. These benchmarks often include specifications for purity, potency and stability, tailored to the API’s therapeutic use. For instance, quality teams might establish a specification of no less than 99.8% purity for the final API using advanced chromatographic techniques, like ultra-performance liquid chromatography (UPLC). 

Also, quality standards extend beyond purity, considering the API’s performance long after it leaves the facility. For example, stability testing under accelerated conditions ensures the API will maintain its quality attributes throughout its shelf life. No matter the project, skilled QA and QC teams will define the precise standards required by the API and the methodologies required to measure them, ensuring each product is carefully managed from a quality point of view as it moves through the lifecycle.

How it’s measured:

Quality standards are measured using advanced analytical techniques and statistical process control. 

• High-performance liquid chromatography (HPLC) or gas chromatography (GC) can be used to determine the purity and potency of compounds. In addition to evaluating these values at the batch level, quality teams should also consider the percentage of batches that meet exacting standards to affirm that the process is consistently generating high-quality results.
• In-process monitoring is a critical method for evaluating quality metrics continuously throughout the manufacturing process. Quality control teams employ in-process testing to monitor critical process parameters such as water content, pH and reaction completion, ensuring they remain within specified limits.

Regulatory compliance is achieved through meticulous adherence to standards such as ICH Q7 and current Good Manufacturing Practice (cGMP). This includes detailed control of the manufacturing process from raw material qualification to final API release. 

In many cases, regulatory standards inform and overlap with internal quality standards, creating synergy between the two functions. 

It is important to remember that regional regulatory standards can vary widely, and the QA and QC teams play an important role in navigating the variance between regional standards to shape and uphold a global quality standard.

By implementing a Quality by Design (QbD) framework, an organisation can carefully identify and control the variables that affect the API’s quality, ensuring consistent compliance with global regulatory expectations.

How it’s measured:

Regulatory compliance is assessed through detailed documentation reviews, validation of analytical methods, and regular audits. 

Compliance teams maintain comprehensive records of each manufacturing step to ensure alignment with guidelines from authorities like the FDA, EMA and ICH. Method validation reports are crucial as they demonstrate the analytical accuracy and reproducibility necessary for regulatory submissions. 

Additional measures include:

• Investigating and resolving all quality-related deviations
• Maintaining an effective change control system
• Conducting regular risk assessments to pre-emptively address potential compliance issues
• Training staff to ensure all personnel are updated on the latest regulatory standards and practices.

While customer satisfaction is a key objective for all teams involved in API development, it holds particular importance for QA and QC teams who often serve as a primary point of contact with customers. These teams play a crucial role in preparing for customer audits, ensuring that documentation and processes not only meet but exceed customer expectations. They are also instrumental in aligning documentation review methodologies and quality standards to cater specifically to the needs and requirements of each customer.

How it’s measured:

While customer satisfaction is often qualitatively assessed, it can also be quantitatively measured through several key indicators. These include:

• Audit frequency and timely resolution, to ensure the success of QA
• Customer audit results, to gather feedback on the adequacy and effectiveness of quality systems
• Post-market surveillance data, for insight into the API’s performance in the field and ability to meet therapeutic needs
• Regular customer feedback sessions, to understand evolving needs and refine processes accordingly

QC and QA teams can face a variety of roadblocks as they work towards their primary objectives, and these hurdles can vary based on the stage of development. Below, we summarise a few of the most common ones.

Processes can change quickly as an API makes its way through development, particularly early on when scalability issues are most likely to surface. A seasoned quality team plays a pivotal role in ensuring that any process changes are properly anticipated, adopted, documented, and reviewed by the customer, all while keeping the project on track. Having an experienced quality team available around the clock and maintaining tight communication loops with customers, enables the quality team to expedite review rounds and avoid significant impacts to project timelines.

The quality team must balance many moving pieces and coordinate across a multitude of stakeholders who contribute to a project’s success. This includes internal project teams, raw material suppliers, and regulatory agencies. For example, when onboarding raw material suppliers, the quality team must ensure that the supplier’s standards meet the project’s quality requirements and that all documentation, such as certificates of analysis, are obtained, reviewed, and vetted for accuracy. 

When dealing with regulatory agencies, the team must stay updated on the latest requirements and ensure compliance across different regions where the customer may want to market their product. Building strong working relationships with agencies and suppliers can help streamline the process, ensuring that the project maintains high quality and meets regulatory standards from procurement to final product.

Customer expectations and preferences can vary widely based on their size, background, and specific needs. 

Quality teams are responsible for providing guidance and understanding each customer’s preferred working style. For instance, some customers may prefer to be heavily involved in every step of the documentation review process, while others might only want to engage at key milestones. 

Adapting work styles to match customer preferences, keeping them informed of any potential changes, and ensuring projects remain on time are critical tasks. 

Establishing a direct line of communication from project inception and maintaining regular updates can help quality align with customer priorities and manage their expectations effectively.

Quality extends across all stages and components of an API’s manufacturing journey, making a proven and thorough approach to quality imperative. However, in addition to the role of QA and QC teams, it is important to note that quality must be considered from multiple perspectives and across multiple teams, from procurement and supply chain optimisation to analytical methods, to the setup of plant-scale manufacturing to equipment maintenance, process optimisation, and more. Through seeking a development and manufacturing partner that has not only demonstrated its commitment to quality through consistently exceptional delivery, but also continues to prioritise a culture of quality across every team, pharmaceutical organisations will maximise project efficiency and success.

At Sterling, our quality teams play an important role across the entire API lifecycle to affirm that the highest standards are consistently upheld. We believe that setting and upholding high quality standards is not just a regulatory requirement, but a responsibility to our customers to protect the integrity of their products and the well-being of patients.

Our approach to quality control begins with a proactive mindset, as quality standards are built into our systems, facilities, and culture. Comprehensive internal procedures and regular audits allow us to establish clear quality expectations, and continuously monitor and measure against them to maintain compliance. We leverage raw material testing, in-process monitoring, and thorough documentation to ensure a holistic approach to quality control at every stage of API manufacturing.

We operate under full compliance with regulatory authorities around the world, including the FDA, MHRA, and EMA, and adhere to cGMP manufacturing guidelines. Furthermore, regular customer audits affirm the strength of our quality systems and procedures.

With tightly integrated teams, strong relationships with regulatory agencies and raw material suppliers, and an outstanding track record bringing high-quality products to market, we ensure not only that every API meets the required specifications, but also the highest possible standards for safety, efficacy, and reliability.

If you’re interested in learning more about how we put quality first in our customers’ API manufacturing projects, contact us to speak to an expert or visit our Knowledge Hub to learn more.