FIH-PMF-FMF Manufacturing

First-in-human (FIH) formulation development is done for phase I-IIa CTM Manufacturing to advance FIH clinical trial and obtain proof of concept (POC) of the safety and efficacy of the molecule under investigation. Usually, extensive development is not required at this stage, however, dosing over a wide range with desired in vivo exposure should be achieved by scientific product design. The main activities of this stage include: 

• Pre-formulation study

• Prototype formulation development

• Probe batch manufacturing, characterization and stability study

• IND batch manufacturing, release testing and stability study

• IND filing

• Phase I-IIa CTM batch manufacturing and release testing

After successfully passing the POC, a seamless drug product supply for subsequent clinical study is required. The formulation and process usually need to be optimized or even re-developed to avoid major changes after the initiation of pivotal clinical study, and to be more adaptive to large-scale production, especially when PIB or PIC were used for phase I-IIa clinical study. The main activities at this stage include:

• Composition justification and process feasibility DOE study

• PMF candidate development

• CTM manufacturing for human biocomparison (BC) study

• Pilot scale study

• Phase IIb CTM batch manufacturing and release testing

• Stability study

Phase III trials are performed on larger groups (300–3000), and the manufacturing process must be scalable and robust to ensure CTM supply. The requirements for FMF are consistent with those for commercial products. If the product is inconsistent, BE study will be required and will affect the new drug’s launch time. The transition from POC to NDA needs to be fast and cost-effective. The main activities of this stage include:

• Technology transfer

• Process scale-up and process optimization

• Analytical method validation

• Phase III CTM batch manufacturing and release testing

• Stability study