As I move through the development of a drug, I’m curious about what modifications can still be made—such as changes to the formulation, manufacturing process, or delivery method—without needing to repeat the preclinical toxicity studies
What changes are acceptable at the different stages of (clinical) development? What impact have changes (acceptable and non-acceptable) on clinical and regulatory approvals? Any insights into how to manage these changes efficiently would be greatly appreciated.
@Ronald @Youri @Mara you indicated that you have experience with drug development and/or CMC and/or (pre-)clinical development. Can you share your thoughts?
Sure Marlous, different from changes to the drug itself, it frequently occurs that the changes that Rosa mentions have to be made. Depending on “incidents” that may make a change unavoidable, it can also be a strategy decision to delay and push out costly elements of your overall program. For instance if your goal is to go for an exit after clinical proof of concept and knowing that a potential buyer will like to manufacture the final market formulation according to their own standards. But there are many other situations that all require their own particular approach, which is what continues to make our work so interesting.
Of course Marlous. From a CMC perspective, there is no one size fits all response to this question, it depends very much on time and budget constraints. My response in general terms:
With respect to the manufacturing process, changes are often inevitable. During the early (preclinical) stages of development, knowledge on the manufacturing process is often scarce since only a small number of batches are required and funding is limited. As one moves further through the development cycle, additional knowledge is gathered through characterization studies and from repeat processing. Furthermore, processes often require scaling up.
This additional knowledge and scale-up requirement often leads to changes in the process, for example changes to process parameters or the use of different equipment.
The impact of such change must be carefully assessed. No negative impact on the Critical Quality Attributes should be the result of the change. The change should always be subjected to a risk assessment, which can be sufficient in the case of minor changes to justify the change in the preclinical stages.
Examples of minor changes are modifications to a process to improve yields or purity, for example temperature settings of a (bio)reactor. Or changing a raw material/supplier, provided that the quality of the material is equal or superior.
A major change would be using a different intermediate for API synthesis, or using a different cell bank for production.
Generally, these changes can be made if one can demonstrate in vitro comparability of the drug substance/product, moving from preclinical to first in human clinical studies. The required data package needed to demonstrate comparability becomes larger and more costly when progressing further in the development.
After clinical PhII trials, manufacturing processes need to be validated. Range finding studies are required to identify safe operating ranges and critical process parameters for the process. Implementing major changes after such process validation studies is often too costly or time-consuming.
Therefore, it is important to design the manufacturing process with the end in mind. This means: in such a way that it is transferable between production facilities, delivers sufficient material to meet Cost of Goods targets, is robust and scalable.