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.

Considerations	One batch for both SD and MD studies		One batch for SD and another for MD
	Pros	Cons	Pros	Cons
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.