Managing just the conjugation part of an antibody–drug conjugate (ADC) project can be a challenge. So when you consider all the component parts of an ADC, it is understandable why so many related activities are outsourced.
At Piramal Grangemouth, we provide conjugation development and manufacturing services. Together with our sister sites in the United States and United Kingdom, we offer payload manufacture and fill–finish capability. The Grangemouth (UK) site has been involved in ADC conjugation services now for over 13 years. Within that time frame, the company has delivered projects across all key chemistry platforms, worked with more than 100 monoclonal antibodies (MAbs), more than 50 drug linkers, and more than 30 products under good manufacturing practices (GMPs).
We have certainly seen that ADC manufacturers don’t have it easy. They have to consider production of antibody and drug (linker), ADC conjugation, and ADC fill–finish — as well as the toxicological and clinical aspects. Development activities (process and analytical) are associated with production of the above components, and with those come management of release and stability programs. Gaps in outsourcing needs can be diverse: Even if a sponsor has a number of relevant capabilities in-house, the capacity to develop and manufacture an ADC may still drive an outsourcing need.
Our initial ADC customer relationships started with large pharmaceutical and biotechnology companies that had reached a point in product development requiring external GMP capability. This was the pattern for a number of years, with our clients performing much of the process and analytical development in-house. Technology was for the most part transferred in, and methods were qualified on site after transfer, with our site supporting elements of development and validation.
But in 2011, following the Adcetris approval, the marketplace expanded. Many companies entered the field from either large- or small-molecule manufacturing but with no experience of the other. Some of those companies are almost virtual, which can make outsourcing essential and the choice of the right contract development and manufacturing organization (CDMO) critical.
Many decisions need to be taken when selecting a CDMO. They include the obvious quality considerations as well as GMP manufacturing experience and a proven track record. But some of the biggest decisions will be made about the development of a process and analytical methods that will ultimately define a product. Here are some questions you can ask.
Development Experience: Does a CDMO have the development experience to develop both a process and analytics that will provide the necessary process understanding, robustness, and control to ensure a safe and successful scale up? Process knowledge is only as good as the analytics used to generate the data, so analytical experience and resources available are critical.
Technological Understanding: Does a CDMO understand the technology and identify critical process steps and product quality attributes that will drive development? Will it consider not just product quality, but also process productivity? Selection of a very dilute process or low loading during a purification step can significantly increase manufacturing costs and may prevent scalability. Development by technology providers, research labs, or non-GMP CDMOs may not fully incorporate some of these aspects.
Integration of Key Groups: How integrated are the groups working to develop, test, and manufacture your process? Splitting those activities across different companies or sites can increase the risk of poor decisions that ultimately can increase your costs through technology transfer(s) or remediation.
Flexibility: How flexible is the CDMO? Can it adapt to issues arising during development or respond to delays with provision of raw materials?
Competitive Pricing: With an increasing number of companies offering conjugation and other ADC services comes the temptation to look at who can provide the service for the lowest cost. Our experience is that price is important, but it should not be a substitute for experience. A safe pair of hands is invaluable and can save much time in the lifespan of a development program.
When looking for a supplier, be sure that you are comparing apples with apples. One supplier might offer a better price on a development program, but when the project gets under way, clients could find the scope of work increasing. And in the long-run, the initial price saving is not as significant as it first appeared. For ADCs, price is a factor but should not be the key driver in decision-making.
These are just a some decisions that need to be made when outsourcing an ADC program with specific focus on conjugation activities. It continues to be a complex area, and it’s changing with developments of new linker technologies, new drugs, and advances in MAb production.
Allan Davidson is the analytical development manager for Piramal Pharma Solutions, ADC Services, Earls Road, Grangemouth, Stirlingshire, FK3 8XG, UK; 44 1324 494 561; allan.davidson@piramal.com.