Today’s posting stems from a client question. The client’s product candidate is an oral product that requires both single- and multiple dose pharmacokinetic studies.
Question: Do companies ever use one pivotal batch for single-dose (SD) study and another batch for the multi-dose (MD) study? What are the pros and cons of doing this?
See the table below for detailed pros and cons considering one batch for both SD and MD studies or one batch for SD study and one batch for MD study. The two primary drivers of the decision process will be the risk of failure due to the increased number of runs and secondarily the cost incurred which will vary depending on the materials and process involved. Also included in the decision process should be the examination of the strength of the pharmaceutical development program and documentation. Below the table, four cases are presented and recommendations made on how to proceed.
One batch for both SD and MD studies
One batch for SD and another for MD
|Cost||Minimum upfront||May have to spend more later to understand critical processing issue||Potential to get experience with different batches of API||More cost upfront, mfg, API, testing and documentation|
|API and excipients||One batch of API and excipients in humans, all data consistent||Less experience with suppliers||Use of multiple lots of API and excipients||Risk of batch failure is higher|
|Potential to qualify a range of impurities|
|Additional experience with supplier|
|Additional testing and review|
|Stability||One lot to support application||No back-up for failure on long-term stability||Multiple stability lots||More testing and drug handling|
|Back-up if failure occurs to support root-cause investigation|
|More robust support for application overall|
|More experience handling drug product|
|Manufacturing||>One manufacturing run prior to approval (in 1:10 ratio compared to the commercial scale)||Risk of problems due to inexperience||More hands-on experience prior to approval||Opportunities for failures increased|
|Supports the expertise in the development of this product|
|Allows insight into batch variability (a little or a lot)|
|FDA View||Acceptable||If there is not enough pharmaceutical development documentation, they may ask for more supportive information.||Acceptable||None|
|Provides more information from a pharmaceutical development perspective. FDA is looking for depth here.|
Selected cases with recommendations:
Case 1: A research and development program which demonstrates depth of experience at various scales with no apparent issues with the API or excipients. In this case one batch for both studies would be sufficient (there would be no problem submitting two).
Case 2: A research and development program which demonstrates poor reproducibility during the production of small scale batches, with little or no experience at one tenth commercial scale would be a case where multiple batches would be recommended to demonstrate control, safety and quality adequate for commercial scale.
Case 3: A research and development program for a new variation on an already marketed drug product, where there is full documentation at various scales and stability is well demonstrated. Upon evaluation of the pharmaceutical development documentation no issues were found, this program could be supported with only one batch (again there would be no problem with two different batches).
Case 4: An abbreviated research and development program for a new variation on an already marketed product, where there are few controls in place and multiple variations in historical lots. In order to build a case for a well controlled, quality process multiple batches would be recommended.
Lynn Gold, Camargo VP of CMC provided this post.