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Late Phase API Development and Clinical Manufacturing
The process that goes into the filing will run for the life of the product, and it is settled in late-phase development.
What changes after Phase II
Until Phase II, the process is only to make material; from Phase II onward, it has to be defensible. Every choice made quickly in early development is re-examined: where the regulatory starting material sits, whether the impurity profile is controlled or only observed, and whether the route gives the same result on a different scale with a different team.
We have taken more than 180 new chemical entities through process performance qualification since 2018, with a 100% success rate.
Regulatory starting material designation
Where the regulatory starting material is designated determines how much of the synthesis sits inside the filing and under GMP. A designation too late in the route carries unnecessary GMP cost for the life of the product, and one too early is likely to be challenged by the agency.
We assess the proposed designation against ICH guidance and FDA, EMA and NMPA expectations, and where a challenge is likely, we build the development data to defend it. If a challenge does come, the response takes about 12 weeks, including the quality-by-design study and the PPQ manufacturing behind it.
Process optimization
Step count, solvent volumes and cycle time are all worked on in late phase, because at commercial scale each determines cost of goods and process mass intensity for the life of the product.
Scale-up and clinical supply
Phase III needs substantially more API than Phase I, and the process has to arrive at that scale without a change to the impurity profile or the solid form. More than 700 process chemists and analytical scientists work exclusively on late-phase programs, and our GMP plants run batches up to metric-ton scale, so the scale-up happens inside one organization rather than across a technology transfer.
Where cost of goods is set
By late phase the question is what the process costs, and the answer usually sits in the three or four steps that have not been revisited since the first campaign.
Finding those steps is a matter of having optimized many similar processes before, which is why a process that already works is still worth putting in front of the late-phase team.