The importance of a seasoned commercial partner: Successfully scaling your product

[Lynda Harrison:] Welcome to our webinar, “The importance of a seasoned commercial partner: Successfully scaling your product.” Thank you all for joining us today.

Today we are joined by Ian Lisle, VP of Global Quality, and Jamie Wolstenhulme, NPI Manager.

Today, we’ll take a closer look at the importance of an experienced outsourced partner for late phase API manufacturing projects. We’ll begin with an overview of late phase projects, followed by some of the key considerations and challenges organisations face as their project scales.

We’ll then discuss our approach to late phase projects here at Sterling, and our ability to help customers overcome common challenges.

Finally, we will end with a case study that explores one of the many late phase projects our team has worked on. With that, I’ll hand it over to Ian.

[Ian Lisle]: Thank you. Let’s begin with an overview of late phase, and some of the things that are top-of-mind for pharmaceutical and biotechnology organisations as they begin to prepare for commercialisation.

As organisations near the end of clinical trials and start looking ahead to commercialisation, high costs and risk of failure are both top concerns. Success rates drop as products progress deeper into clinical trials, with only around 1 in 4 products that enter phase III trials moving on to the next phase. In addition, later stages of the drug development lifecycle represent some of the greatest expenses for an organization. In fact, once a product is approved for commercial sale, post-approval research and development costs alone can reach $312 million.

In order to overcome some of the challenges associated with late phase and set their projects up for success, many organisations work with outsourced partners. Around two-thirds of pharmaceutical organisations outsource portions of manufacturing.

On top of cost concerns and low success rates, there are a lot of additional key considerations for late phase projects, some of which are consistent with early phase considerations and others of which are highly unique to the development lifecycle’s latter phases. Quality, compliance, efficiency, and cost-effectiveness are all top priorities for organisations throughout the entire duration of their projects.

As a project scales, though, additional process and safety considerations come into play. That makes it critical for processes to be designed with scalability and flexibility in mind early on, proactively overcoming these challenges to increase the product’s chance of success.

In addition, the complexity of molecules in the pipeline continues to rise. This has resulted in higher demand for specialised technologies in late phase projects, such as continuous manufacturing. Factors like novel technologies, complex molecules, and high costs associated with implementing specialised capabilities in-house have led to significant growth in the pharmaceutical manufacturing market. In fact, it is expected to grow at a CAGR of 11.34% over the next six years.

[Ian Lisle]: So what do organisations most prioritise when engaging an outsourced partner? When asked how they evaluate their outsourced partners on an ongoing basis, pharmaceutical professionals’ top responses included going above and beyond project requirements, safety audits, communication and transparency, timely delivery, and quality compliance. All of these are critical from a project’s onset, but they are especially important for maintaining a close, lasting, and successful partnership with an outsourced partner as a product approaches commercialisation.

[Ian Lisle]: In order to secure approval and ultimately maximise success once a product reaches the market, quality is a critical focal point for late phase projects. Quality by design, or QbD, is a major buzzword in the industry today, and it is something that carries throughout a project’s entire duration. We can’t talk about late phase without touching on early phase—a project’s late phases are when organisations realise the implications of all the decisions they made early on. By proactively building quality into the product and processes, organisations can avoid roadblocks in their project’s later stages.

Critical process parameters, or CPPs, are a key aspect of quality by design. These parameters have a direct impact on product quality, so they should be carefully identified and closely monitored during process design and throughout manufacturing. After establishing CPPs, the ranges should be adhered to throughout manufacturing and, later, specified in the new drug application.

ICH guidance sets the standard for quality in pharmaceutical development and manufacturing projects. Guidelines include ICH Q7, which details good manufacturing practices, ICH Q8, which discusses pharmaceutical development, including CPPs, ICH Q9, which examines quality risk management, and the list goes on. It’s important to adhere to these guidelines in any late phase project to ensure ongoing quality of the product and processes.

Now that we have a strong overview of some of the main factors at play during late phase projects, I’ll pass it over to Jamie.

[Jamie Wolstenhulme]: Thank you, Ian. Let’s take a more in-depth look at five top considerations for late stage manufacturing.

There are a plethora of important considerations in any late phase project, but here we’ve surfaced five of the most important. These are risk management, scale-up and production planning, quality and compliance, specialised technologies, and looking ahead to commercialisation.

[Jamie Wolstenhulme]: We’ll begin with risk management. Risk is top-of-mind for organisations during their projects’ late phases, with 70% of pharmaceutical professionals citing risk management as a top characteristic they search for in an outsourced partner. When we talk about risk management, there are several different sources of risk that are important for us to address. There’s the safety of the actual processes and the people handling them. Then, we have security and consistency of the supply chain. Both of these are critical in late phase projects.

The supply chain can be very unpredictable and difficult to control, which we’ve seen to be especially true given the recent climate. In order to mitigate risk in the supply chain as much as possible, it’s important to work with reliable, consistent providers to obtain raw materials and other critical project components.

In addition, it’s imperative to protect people and processes in any manufacturing project by implementing the proper safety measures. This is especially true for projects that involve hazardous chemistries like diazomethane and fluorination. It’s important to thoroughly evaluate hazards and implement strict controls to minimise the potential for heat release, explosion, ignition, and other hazards during manufacturing. Finally, it’s important to protect our planet by ensuring that any hazardous project waste is properly treated and disposed of.

[Jamie Wolstenhulme]: Next, we have scale-up and production planning. As we touched on earlier, scaling up a project can necessitate significant process changes and added safety considerations. Take powders, for example—it’s important to implement strict controls as processes are carried out at a larger scale to avoid contamination.

Production planning also becomes a key consideration as a project scales. It can be quite difficult to accurately plan for demand as a product nears commercialisation, with 63% of supply chain leaders stating that they struggle with demand forecasting. This makes it all the more important to work with a reliable partner who delivers the flexibility and scalability needed to quickly adapt to changing demand.

On top of these process considerations, organisations also remain focused on scaling their projects as quickly, efficiently, and cost-effectively as possible. As a result, ongoing process optimisation is important in every project to ensure the most efficient route. Whenever processes are changed, however, process validation and documentation are necessary to affirm continued quality and satisfy regulatory authorities.

[Jamie Wolstenhulme]: That brings us to quality and compliance. We talked a bit about quality by design and critical process parameters earlier. During late phase, it’s important to continually monitor and control the CPPs defined earlier on to uphold high quality standards. Quality is the single most important focus for organisations working with outsourced partners, with industry professionals citing quality concerns as the top factor that would prompt them to work with a different outsourced partner.

Impurity screenings are another key aspect of quality. Organisations must take care to identify and eliminate or minimise any known or potential impurities, such as potentially genotoxic impurities, that may compromise the product’s quality and safety.

In addition, towards the end of clinical trials, organisations begin thinking about the new drug application required by regulatory authorities for approval. This application requires detailed data and documentation, including manufacturing information, safety details, CPPs, clinical trial results, and more. The right partner can streamline the new drug application process by offering guidance, providing the necessary data, and drafting relevant portions of the document.

[Jamie Wolstenhulme]: With rising molecule complexity and an emphasis on process improvement, more and more specialised technologies are being utilised in pharmaceutical manufacturing. Things like high potency APIs and controlled substances are becoming more common for their ability to treat a range of indications. Also, capabilities like continuous processing and hazardous chemistries can bring about significant efficiency gains and other project advantages.

While these technologies differ, they share one thing in common. They all require substantial time and cost investments to implement in-house—as a result, many organisations turn to outsourcing for projects involving capabilities like these. It’s become a key priority for organisations in their CDMO search, with 80% of pharmaceutical organisations preferring to select an outsourced partner who keeps customers informed about its new technologies, capabilities, and equipment.

[Jamie Wolstenhulme]: Finally, commercialisation is our last key consideration. As organisations progress later into clinical trials, they begin more actively planning for their product’s official entry to the market. With only 12% of products that enter clinical trials ultimately being approved for sale, gaining commercial approval is an exciting accomplishment for pharmaceutical and biotechnology organisations. However, the project doesn’t end there, as commercialisation brings on a whole new set of considerations.

To successfully launch their products, organisations require an experienced, flexible, and collaborative manufacturing partner. Your partner should possess deep expertise in manufacturing a wide variety of commercialised products, close relationships with raw material suppliers, a strong track record of process optimisation, and the flexibility needed to meet changing supply requirements. Most importantly, they should maintain close alignment and partnership, working closely with you to overcome challenges, seek opportunities for process improvement, and ensure ongoing success. All of these are critical attributes in an outsourced partner as you prepare to manufacture your product at a commercial scale.

Now that we’ve taken a closer look at these five attributes, Ian will touch on how we address each of these at Sterling.

[Ian Lisle]: Thank you, Jamie. Let’s explore how we help maximise our customers’ late phase success here at Sterling.

As an overview, Sterling is an end-to-end PDMO^®, or partnership development and manufacturing organisation. This underscores our commitment to serving as true scientific partners to our customers in every project. We deliver services ranging from discovery through to commercialisation, and our more than 50 years of API manufacturing expertise enables us to support our customers in overcoming a wide range of late phase project challenges.

For late phase projects in particular, there are five key ways we help to maximise our customers’ chances of success. These are risk mitigation, flexibility and scalability, high quality standards and CMC support, a commitment to technology and innovation, and API manufacturing expertise.

First, let’s discuss risk mitigation. We help our customers mitigate risk both in terms of process safety and in terms of supply chain security. We apply more than 50 years of expertise in hazardous chemistry to conduct thorough hazard evaluation for every project, mitigate or eliminate hazardous processes, implement stringent safety controls, and safely handle processes involving fluorination or diazomethane. In addition, we ensure that all of our team members are fully aligned, from hazard evaluation, to chemistry, to engineering, in order to adhere to the necessary safety considerations throughout a project’s entirety. We also have an on-site biological treatment plant, and we take care to properly treat and dispose of any hazardous waste that may result from a project, prioritising safety and sustainability.

We also work to ensure supply chain consistency and reliability for our customers by working closely with trustworthy suppliers. We carefully vet raw materials suppliers to assess stability, and, like with our customers, we maintain close partnerships with them. Many of our preferred suppliers are organisations we’ve worked with for many years.

Our dedicated Technology and Innovation Programme supports our work in many of these areas, like continuous manufacturing and biocatalysis, in particular. Through this programme, we work closely with a variety of academic and technical institutions who specialise in areas such as these. In turn, we are able to expand our capabilities in these technologies and offer our customers direct access to leading experts. One example is our partnership with Durham University’s BAXENDALE Research Group, which supports our work in flow chemistry.

By vetting new technologies and maintaining close partnerships through the Technology and Innovation Programme, we can support a broad range of innovative technologies in our customers’ projects.

In line with our PDMO^® model, we also deliver a high level of flexibility and adaptability in the way we work with our customers, enabling us to seamlessly overcome challenges and adapt to evolving requirements as a project scales.

One way we do this is by assigning a dedicated Partnership Manager for projects. The Partnership Manager consistently communicates with the customer to understand project requirements, help identify areas for improvement, keep the customer informed, and more. By maintaining close alignment, we work flexibly with customers to meet their project requirements.

In addition, our asset flexibility enables us to right-size equipment configurations to each unique project in order to generate the best results. We understand that no two projects are alike and that needs can change along the way, so we pride ourselves on taking a tailored, flexible, and scalable approach.

We highlighted quality as perhaps the most important thing for customers in their late phase projects, and we believe strongly in upholding the highest quality standards here at Sterling. We work to design processes with quality built in, and we identify and adhere to relevant critical process parameters to ensure continued quality and compliance.

We also perform extensive impurity investigations, enabling us to identify impurities early on, assess their potential risk, and take measures to control or eliminate them. In addition, we take care to adhere to the latest ICH quality guidance. All of this gives our customers confidence in the quality of their products as they near commercial launch.

Finally, our years of industry experience, UK and US presence, and global customer base, have given us a deep understanding of the regulatory landscape. We support our customers in adhering to regulatory requirements in their projects. In addition, as customers prepare to submit their new drug application, we can help to draft portions as needed and deliver the robust supporting data needed to maximise their chances of approval.

Finally, we have our API manufacturing expertise. For more than 50 years, we have delivered comprehensive API manufacturing services with capabilities spanning a wide range of project requirements, including highly complex and hazardous chemistry. We have a right-first-time mentality, and our facilities, team members, equipment, and expertise enable us to deliver world-class manufacturing services to our customers.

This, coupled with our flexible and adaptable approach, gives us the ability to successfully support customers and overcome challenges through late phase manufacturing, and continuing into commercialisation. We prioritise ongoing process improvement, regularly seeking areas to improve efficiency and cost-effectiveness in each customer’s projects while still accounting for their requirements. Through all of this, we put the customer first and serve as their true partners.

Now that we’ve gone through our late phase capabilities, let’s see what they look like in action.

Jamie, would you like to bring us through the case study?

[Jamie Wolstenhulme]: I’d be happy to. Thanks, Ian. In this case study, we’ll look at a late phase project that involved chiral chemistry, hazard evaluation, and continual process optimisation.

This particular customer required assistance in sourcing a key intermediate for one of its products at a commercial scale. This intermediate involved hazardous production processes, so the customer needed a partner who could safely produce the material at scale. In addition, they were focused on containing costs, enhancing efficiency, and ensuring environmental sustainability. Above all, they required a partner who would maintain a high level of communication and collaboration as the project scaled, which is why the customer ultimately chose Sterling.

Let’s take a look at how we applied the principles of Service, Passion, and Science to maximise this project’s success.

As I mentioned, process optimisation played an important role in this project, and our team worked closely with the customer to seek opportunities for improvement on an ongoing basis. Our main goal was to improve catalytic activity to enhance efficiency and cut down waste. We applied our chiral chemistry expertise to do so, and these efforts have ultimately led to a 40% increase in throughput and a 92% decrease in production costs.

In addition, the customer had concerns about the product’s packaging, as the original packaging did not work effectively with the automated manufacturing process. We worked to adapt the packaging to meet the customer’s requirements by using smaller drums than usual, as well as setting a weight specification and engineering a customised handling procedure.

We aimed to uphold the highest safety and sustainability standards throughout this project. Specifically, we identified a warming issue with the large exotherm early on that could prove to be hazardous. Applying our hazardous chemistry expertise, our team increased dilution and optimised our choice of base to manufacture the product as safely as possible. We also improved the project from an environmental standpoint by cutting down waste, and we continue to pursue a solvent recycling and treatment programme to continually improve sustainability.

Chiral chemistry was critical to the late stage efficiency gains that were so integral to this project. We developed a dimeric version of the catalyst in order to improve quality and efficiency—producing both a diol and an epoxide from a single process. This enabled the substantial increase in throughput, and it has eliminated the customer’s need to work with a third-party supplier to source the raw material.

Today, we continue to work with this customer and seek additional opportunities to improve efficiency, quality, and cost-effectiveness at scale. Each year, we produce up to 100 tons of the intermediate.

[Lynda Harrison]: So now let’s jump into some questions. Jamie, this one’s for you.

How have you seen late phase projects and customer requirements evolve in recent years?

[Jamie Wolstenhulme]: We’ve seen more complex chemistry with multi-stage processes coming through in earlier GMP starting points. Customers are more eager to learn about how alternative technologies can be used to improve processes and this is where our technology and innovation program really comes into play. We collaborate with a range of academic institutions and industry partners to investigate and embrace new technologies in our customers projects to enhance processes and the value we deliver as a CDMO. But overall there is still a strong requirement for small molecule development and manufacturing.

[Lynda Harrison]: Next one’s for you, Ian.

What are some of the examples of specific safety controls you put in place for late stage or commercial manufacturing projects that may be hazardous?

[Ian Lisle]: We adopt a comprehensive approach to hazard evaluation, leveraging over 50 years experience in development scale up and manufacture of hazardous chemistry. Hazard evaluation as an integral part of our new product introduction process and we’re always seeking ways to mitigate risk and maximise safety when hazardous processes are required. We have many years of experience in handling hazardous chemistry at laboratory pilot and commercial plant scale. We have a dedicated internal hazard evaluation group to identify risk on scale up and mitigate that risk at every stage. All processes will go through this assessment, regardless of scale or value, providing a unique offering within the contract space.

[Lynda Harrison]: Second question for you, Jamie.

What does Sterling’s customer base look like for late phase projects?

[Jamie Wolstenhulme]: Our customers are located around the globe from North America, to Japan and Europe. These include big pharma, mid-sized pharma, and smaller biotechnology organisations who have limited resources and require our technical support throughout their project.

[Lynda Harrison]: Last but not least, Jamie, do you have any examples of specific process improvement steps you’ve taken in a project’s later stages to improve efficiency or cost effectiveness?

[Jamie Wolstenhulme]: We have a few but the first one that comes to mind is our introduction of holding vessels on our plan to speed up process velocity. Identifying the process critical path and the rate limiting parts of the process, including any bottlenecks, are essential in improving and continuing to improve the efficiency of a process. We have on-site a dedicated process improvement team that look to continually implement process improvements to increase efficiency. We also conduct continual raw material sourcing reviews for our procurement team and look at options for solvent recovery.

[Lynda Harrison]: That’s all we have time for today. Thank you for tuning in to our late phase webinar, we appreciate your time and we hope you found it interesting. Enjoy the rest of your week.