The contract development and manufacturing organization (CDMO) sector is having to quickly respond to challenges within the pharmaceutical industry, particularly as drug substances become increasingly complex. There is now a greater need for rapid innovation and the production of more effective process solutions to quickly deliver outstanding drug development. To fulfil this goal, modern CDMOs must be agile and flexible, bringing together professionals from multiple disciplines to find solutions that increase efficiency.

Change in the CDMO sector
Over the past two decades, the CDMO sector has greatly advanced and is now considered an integral source of drug development and delivery. Big Pharma companies are embracing outsourcing as a strategic way of accelerating their drug development timelines. For biotechnology companies, CDMOs are increasingly being seen as extensions of their development and manufacturing departments, providing capabilities that are fully integrated with their own pre-existing services.

Overall, this greater reliance on outsourcing partners has amplified the need for locating experts at particular stages of drug development. CDMOs are adapting to this demand by specializing in a number of services to provide greater agility. This approach is being used to deliver effective solutions for drug substances to quickly progress, from the preclinical phase through to full-scale commercial launch.

The importance of integration and collaboration for accelerated delivery
Increasing drug substance complexity has created greater challenges for identifying process routes that ensure swift progress through clinical development phases. Speed is of the essence and innovative approaches are needed to find solutions that enable complex drugs to quickly reach the market. One way of increasing delivery velocity is by creating a culture of collaboration and providing an environment that facilitates communication between teams.

By integrating all services at one site, modern CDMOs can encourage close relationships between multidisciplinary experts, creating a more agile approach to pharmaceutical development. Talented drug substance process chemists are routinely supported by experienced analytical chemists to ensure rapid development and optimization of drug substance. Guidance on formulation and solid-state parameters, from integrated solid state teams, provide drug substance chemists with clear and unambiguous data for optimizing drug substance form, leading to rapid drug substance and drug product delivery. The close working relationships between departments can be more easily fostered in one location, in comparison to some CDMOs with geographically diverse assets and service units. An advantage of this approach is that issues can be resolved quickly and the depth of knowledge available from multiple experts ensure the provision of efficient solutions for complex small molecule projects. When full, on-site integration is not possible, CDMOs often collaborate with alliance partners to jointly serve the needs of the client. It is important that partners share the same ethos and project management discipline for efficient delivery of project objectives.

Collaboration, project management and strong communication are also vital for successful new product introduction (NPI) and technology transfer—the processes required to progress from drug discovery all the way through to commercialization. CDMOs must provide the capability, discipline and experience in NPI and technology transfer, both within their organization and externally. It is important that NPI and technology transfer teams are formed with experts in a wide range of areas, including project management, development, quality assurance and regulatory affairs. Plans are vital for ensuring the clear definition of project deliverables, along with swift communication and feedback of information to all stakeholders. The combination of a well-defined new product introduction system and strong project governance capability will also ensure a smooth exchange of information to achieve the efficient development and manufacture of high-quality drug substance and drug product.

The importance of flexibility and agility for more efficient drug development
Flexibility is key to the fast delivery of drug substances and drug products. CDMOs must be adaptable to each new project, by either providing a fully integrated package of services or a bespoke offering to meet a client’s particular requirements. Having the ability to take on both small and large-scale projects is especially important in a competitive market. This agility must be combined with strong project management capabilities to enable fast refinement of deliverables and timelines where necessary. The introduction of coherent project metrics and IT systems for accurate measurement of delivery can also provide an advantage when applying a more flexible approach to drug development.

Successful CDMOs have a client-centered ethos at the heart of their work. Client requirements frequently evolve and it is common for objectives to expand after initial preclinical or phase I projects. Rapid adaptation to changing or additional requirements involves altering key project deliverables and metrics. Employee training in the provision of rapid client response is also vital for achieving greater agility in this area.

Advantages of technological innovation
Newer CDMOs have the advantage of greater flexibility in the technological assets they invest in. If a client requires the implementation of new technology as part of the delivery process, companies that have not significantly invested in older technology will be able to respond more quickly. For example, continuous flow can enable a more flexible, timely and controlled approach to drug substance development, but many companies approach drug synthesis through legacy batch reactors and may be unwilling or unable to invest in a new technology. CDMOs that have invested in flow technology from the beginning are benefiting hugely from this innovative technology. They now have the ability to deliver pharmaceutical products more efficiently to their clients when compared with older companies who are locked in to existing assets.

Flow chemistry is an important innovation that has the power to transform the pharmaceutical industry. This technology is already being used to compress reaction stages and take months out of delivery programs, while significantly improving process safety, economics and scalability. CDMOs are further enhancing their capabilities in this area through large scale investment in flexible modular manufacturing technology. This system enables the quick configuration of batch, flow and CSTR reactor modules for drug substance manufacture before rapid reassembly for the next project.

Speed and efficiency are also being increased through the employment of synthetic biology for drug substance development. The interdisciplinary branch of biology and engineering is being used to significantly shorten the number of process stages, with the prospect of eliminating some stages entirely. By harnessing the metabolic pathways found in nature, drug substance manufacture can be simplified with the potential to produce drug compounds more efficiently from different starting points. These innovations are being driven by the current influx of PhD and post-doc students with expertise in novel technologies and methodologies. By utilizing the skills of the next-generation of scientists, CDMOs can confidently enhance their capabilities to supply more efficient routes for drug development.

There have also been significant advances in the application of automation for improving drug development and manufacturing. Data analytics are important for understanding reaction processes and to quickly find optimum process parameters, which help improve both scalability and efficiency. A key group of CDMOs are investing in real-time and controlled system analysis to enable the automatic adjustment of reaction parameters to optimize processes. This includes the use of FT-IR (Fourier-transform infrared) spectroscopy probes to provide real-time analytical data, which is then used to identify optimal temperature, pressure and solvent flow rate. The integration of analytical and process chemistries within a closed loop manufacturing process creates a scalable solution quickly, without requiring multiple screening reactions.

Adapting to a changing industry
The industry is moving towards small molecule drugs that are becoming increasingly complex and potent, while being manufactured in smaller volumes. The greater complexity is being driven by the advent of personalized medicines, where a highly targeted and patient-centric approach is applied to the development of drugs. This is producing a greater need for small production volume that traditional chemical and drug manufacturers are struggling to fulfil. Large, commercial manufacturing systems are based on economies of scale and are designed to fabricate hundreds of thousands to millions of units. The development of novel drugs for small patient populations requires a new approach, one that will increase the global capacity to handle high potency medicines.

CDMOs are developing digital manufacturing platforms for short bespoke runs of drug products at an affordable cost. One project involves the development of novel production equipment that uses robotic capsule filling systems for greater speed and dosage accuracy. Big Pharma and biotechnology companies can be reassured that the industry is ready to take on these challenges and modern CDMOs have the technologies in place to provide a secure source of delivery for technically complex projects.

The recent high-profile recall of drug products due to contamination has highlighted the importance of strong analytical discipline during pharmaceutical development. It is vital that modern CDMOs put in place the technologies and methodologies to generate high purity drug substances for clinical trials. CDMOs must have expertise in material and process control, along with product testing, to ensure low levels of impurities. There is a significant advantage to employing on-site analytical teams with extensive experience in the provision and interpretation of high quality analytical, microbiological and materials science-based data. Combining state-of-the-art technologies with innovative site capability and analytical discipline ensures that the client is always supplied with high quality products.

Conclusion
To be successful, today’s modern CDMO must understand the importance of flexibility, collaboration and innovation, which requires continuously developing the capabilities that will ensure the secure delivery of drug substance and drug product. Greater agility and flexibility can save clients valuable time, helping them to quickly bring life-changing medicines to the market. Whether clients want a fully integrated service or individual offerings, it is essential that CDMOs are ready to take on new challenges rapidly and have the expertise to offer added value.

This requires teams work in close contact with each other to deliver an integrated approach to pharmaceutical development. At Arcinova, for example, this is enabled by our all-in-one facility. Clients benefit from having the brightest minds working together and CDMOs with widespread facilities must work hard to ensure the same level of collaboration can be fostered. Supplying a unified delivery system also enables an increased ability to seamlessly overcome challenges in development processes, for rapid delivery of high-quality products.

Technological innovation is also fundamental for the CDMO sector and is core to the Arcinova approach. The introduction of continuous flow systems and the use of synthetic biology are now regularly enhancing the drug substance development process. CDMOs with the capacity to invest in new technologies and hire skilled scientists with expertise in these novel areas will have a significant advantage in a rapidly changing industry.

The past two decades have seen significant change, with outsourcing now considered an important source of drug substance and drug product development and delivery. Some service providers have responded to this environment by focusing on either drug substance or drug product offerings. A new approach to outsourcing provision is enabling the development of technological expertise in a number of areas, while applying a flexible and integrated approach to services. As the industry moves towards personalized medicines, innovative approaches to contract service provision are fundamental. Some CDMOs already have the capabilities and leading-edge technologies to rapidly adapt to this changing environment.

---

Paul Quigley is Head of Drug Substance at Arcinova. He has a PhD in Organic Chemistry from the University of Dublin and an MBA from Warwick Business School. Paul has a wealth of experience in the provision of small molecule process development and project management. His work at Arcinova involves building and coaching technical teams for the commercial application of technology within the pharmaceutical industry.