P H A R M AC EU T I CAL S
Embedded Expertise for Clinical Manufacturing Lucile Vaysse-Ludot, Industrial Research Center Director (DS), Servier, explains that, while outsourcing clinical trial material production introduces risk to the development process, partnering with an embedded service provider (within a pharmaceutical company) may bring key benefits.
merging and small pharma companies serving as the innovation engine for much of the sector rely on contract development and manufacturing organizations (CDMOs). They provide the advanced technical capabilities and manufacturing capacity required for production of clinical trial materials, and ultimately the regulatory documentation, trial success and drug approvals critical to their enterprises. The complexity of active pharmaceutical ingredients (APIs) is increasing dramatically at a time when the industry is facing mounting pressure to reduce the costs of formulated products and accelerate the drug development process. CDMOs with ‘embedded expertise’ in process development and scale-up, analytical method development, regulatory compliance and manufacturing of preclinical to Phase III materials may provide certain advantages.
Collaborative synergies An integrated outsource partner may, for example, provide comprehensive support for the manufacture of APIs for clinical trials by assisting with both process development and the production of batches for preclinical through Phase III studies at a single site. With such organizations, there is no need for technology transfer, which adds to reliability and efficiency. Scale-up studies with expert outsourcing partners also include safety assessments and full analytical support. This approach can speed the development of processes that provide pharmaceutical intermediates of high quality, leading to accelerated production of the APIs needed for clinical trial material formulation. In addition, close collaboration occurs between technical project teams and regulatory experts, who act as advisors during process development and scale-up. Information needed for the elaboration of chemistry, manufacturing, and controls (CMC) chapters for the filing of regulatory documents, such as investigational files; investigational new drug (IND) in the US and investigational medicinal product dossier (IMPD) in the EU; and market authorizations (new drug approval [NDA] in the US and common technical document [CTD] in the EU) can be made rapidly available and accessible to the regulatory affairs department. As a result, these documents can be prepared simultaneously during process development, allowing for reduced time to filing for clinical trials. A truly embedded CDMO also has the capability to provide formulation development and final drug product manufacturing support. While there is often a need to transfer a project from an API production site to a different facility for final drug product manufacturing, these CDMOs have experience managing this type of technology transfer. Moreover, when chemical sites have process R&D centers and manufacturing workshops close one to Lucile Vaysse-Ludot, another, this can offer better flexibility Industrial Research Center in scale up, as there is a direct link Director (DS), Servier between efficient R&D and production.
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QbD Application of a quality-by-design (QbD) approach to lab-scale, research projects and well-developed processes enables the improvement of all types of processes. This type of approach, which has been adopted at Servier, can enhance the integrated services provided by CDMOs with embedded expertise.
Full analytical support CDMOs that offer true embedded expertise provide full analytical support through all pharmaceutical development stages from proof of concept through clinical and commercial API and drug product manufacturing. Full analytical support includes: Analytical process development and validation Microbiology assay development and validation Impurity tracking and characterization ICH stability testing. The analytical team comprises highly trained personnel with strong expertise in the advanced analytical techniques necessary for the characterization of the chemical and physical properties of APIs and drug products, the determination and monitoring of critical process parameters, product release testing and all other quality assurance and quality control activities required during drug development and manufacturing.
Industrial preparative chromatography A CDMO focused on providing embedded expertise should be able to implement tools and systems that enable rapid scale-up of processes from lab-scale to the production volumes required for Phase I-III studies. For example, one industrial tool that has proved useful to Servier’s clients is preparative chromatography, which the company has adopted in the laboratory and at production scales. With this purification tool, processes are not only readily scalable from the lab to the plant, it is possible to achieve the right quality immediately. Preparative chromatography has been a highly effective tool for reducing time to filing, time to initiation of clinical trials and, ultimately, time to commercialization of new drugs. These time savings can be used to develop efficient processes in parallel, such as crystallization for late clinical phases.
Optimized time-to-market organization When all embedded capabilities are properly aligned, the result is an optimized time-to-market organization. Client requests should be responded to rapidly. A batch should be produced quickly to demonstrate the CDMO’s capabilities, and the first preclinical or clinical batch is manufactured in minimal time due to the careful design of workflows, including safety assessments, regulatory dossier development and process development, optimization and scale-up. All of these activities should take place at the same site simultaneously, and close collaboration between all relevant departments ensures that the necessary experiments are completed and data generated.