Journey of an API: Pharmaceutical engineering and production

Once an API reaches the manufacturing stage of its journey, scientific priorities converge with good manufacturing practices as the production team works to ensure optimal product quality, safety and yield while adhering to the project objectives set in earlier stages. Pressures intensify as the project scales to adhere to increasingly stringent regulatory, safety, and quality implications. Addressing the heightened scrutiny requires close collaboration between scientists and engineers.

In this blog, we’ll explore key focus areas for engineering and production teams as an API reaches the plant scale, define how success is measured, and discuss how pharmaceutical manufacturers can proactively address as many challenges as possible while remaining flexible and agile in the wake of any new challenges.

Measuring success: Key objectives for engineering and production

Pharmaceutical manufacturers have a number of key considerations when a project reaches larger scale production, from compliance, to safety, quality, cost and more. Below, we take a closer look at three of the most important objectives:

Health, safety and environmental considerations are crucial in pharmaceutical manufacturing to ensure ongoing adherence to GMP and other regulatory standards while protecting people and the planet. This requires engineers to ensure that all equipment is well-maintained and regularly monitored, and that emissions and waste limits are closely followed. In addition, the process safety team must affirm that a product is safe to manufacture with a given equipment configuration and that appropriate containment measures are taken. By coupling these best practices with thorough training and a plant-wide focus on EHS, organisations can maintain safety in manufacturing whilst mitigating environmental impact.

How it’s measured: Engineering teams can monitor and measure equipment performance on an ongoing basis using several key metrics, such as overall equipment effectiveness (OEE), which assesses equipment performance, availability and quality, and mean time between failures (MTBF), which evaluates the average amount of time equipment operates without experiencing a failure. In addition, each piece of equipment should be closely monitored using vibration analysis and other techniques to predict a breakdown before it occurs while ensuring optimal safety and performance.

Furthermore, tests like minimum ignition energy (MIE) identification and reaction calorimetry should be performed before the project moves to the plant to understand the extent of any hazards involved. With regard to environmental objectives, engineering teams should perform regular assessments to ensure the process remains within predefined emissions and waste limits.

High product quality and sufficient yield remain critical priorities across a project’s entire lifecycle, but their importance is further amplified once a project reaches the plant scale. Maximising yield has a trickle-down effect, as it enables project teams to produce more of their desired product while using the same amount of raw materials and internal resources, ultimately containing costs.

Quality is equally important across each stage of development, but with regulatory requirements becoming more stringent as a product reaches phase III and commercial manufacturing, there is no room for compromise when it comes to quality and consistency.

How it’s measured:Scientists leverage a range of techniques to analyse product quality and purity, including high-performance liquid chromatography (UPLC/HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and more. All of these play an important role in identifying any impurities, residual solvents, or other components of a product mixture that could impact either quality or product yield. Scientists can monitor this on an ongoing basis by comparing the volume of API produced to the expected yield.

As with any stage of the API’s journey, the project team is focused on remaining on track to meet the timing and budget objectives that the project manager and customer aligned on from the start. This requires scientists and project teams to closely track timing and spend, maintain consistent communication with the customer and carefully navigate any challenges that arise. Proactive equipment maintenance is a key contributor to meeting this objective as well to avoid unplanned downtime and delays.

How it’s measured: Everyone involved in the project must remain conscious of the specifications in the original proposal, and track progress against established benchmarks. When it comes to meeting project management objectives, customer satisfaction is the most important measure of success, so regular meetings between project teams and with the customer are a key focus at any stage of the API’s journey.

Overcoming obstacles: Addressing challenges in API manufacturing

While earlier stages of API development focus on ensuring a smooth and seamless transition to the plant scale, the potential for unexpected obstacles that can arise during manufacturing still exists. Let’s explore some of these challenges and discuss how engineering and production teams can adapt to overcome them.

As a product is manufactured on a larger scale, the potential impact of a safety incident increases. While any project should undergo thorough hazard evaluation prior to progressing to the plant scale, manufacturing teams should always adopt ongoing strategies to mitigate risk, such as using appropriate personal protective equipment, monitoring containment measures, ensuring all equipment is regularly checked, and having a well-defined incident response plan in place. From an environmental standpoint, manufacturers should also aim to mitigate waste, and ensure that any waste produced is properly treated. Equipment maintenance is another crucial part of adhering to safety and environmental objectives, as engineers can pre-emptively avoid equipment leaks and other issues that have the potential to increase emissions and risk.

As a project moves to plant scale, certain inefficiencies related to the larger scale and introduction of new equipment can surface. These might include things like inadequate stirring, dense metals sitting at the bottom of a reaction vessel, issues with distillation, and other hurdles that prevent the manufactured product from achieving pre-defined specifications. In these scenarios, manufacturing teams may look to modify the equipment for a particular purpose. For example, when reactions are not stirring properly, engineers may change the agitator in the vessel to avoid products settling at the bottom of the reactor and improve stirring speed. Or when challenges with heat transfer arise, scientists can change out the fluid in the jacket around the vessel in an effort improve it.

When it comes to engineering, proactivity is crucial to avoid delays; no matter how robust scientific methods are, any manufacturing process is only as strong as the equipment it involves. Before the project reaches the plant scale, project teams should carefully assess the manufacturing streams that are available and select the one that is best suited to the project’s requirements.  Leveraging total productive maintenance (TPM) enables engineers to minimise downtime and extend equipment life by incorporating data-driven analysis, applying preventative maintenance, and more.

Back to the big picture: Combining proactivity with reactivity

During manufacturing, project teams must juggle a variety of priorities—including quality, safety, compliance, environmental sustainability, and more. However, these considerations do not start once a project reaches manufacture. Instead, they must be considered across the entire lifecycle. Since challenges on the plant scale have a much greater impact than at the lab scale, project teams must pre-emptively address any challenges they can early on. An expert project team is best equipped to navigate these challenges, as they can leverage previous experience to overcome similar challenges and support a culture of continuous learning and improvement.

However, not all of these challenges can be foreseen. While proactivity is key, engineering teams must also have the agility and adaptability to respond to new challenges rapidly. By anticipating as many potential hurdles as possible while still being prepared to flexibly adapt to change, project teams can maximise manufacturing success.

Engineering and production at Sterling

With more than 50 years of expertise in API manufacturing, at Sterling we have the experience and equipment to address a wide range of pharmaceutical production priorities for our customers. We specialise in complex and hazardous chemistry, enabling us to support a variety of requirements with stringent standards for quality, safety, and sustainability. Our approach to engineering and production is marked by preventative maintenance and close collaboration across teams to maximise quality and efficiency.

If you’re interested in discovering how we can apply proactivity and flexibility in your API manufacturing programme, contact us to speak to an expert or visit our Knowledge Hub to explore more insightful content.