Detailed Requirements concerning the DOE in the Regulatory Submission Dossier: EMA's and FDA's Recommendations

In our News dated 18 February we reported on a question & answer (Q&A) paper which was published by EMA and FDA together at the end of 2014. This document answers questions on detailed requirements in connection with the documents concerning regulatory submissions. It also answers a question on the topic design of experiments (DOE).

The document answers the question "What level of detail should be considered for design of experiments (DOEs) in a regulatory submission?" as follows:

The level of detail should be commensurate with the significance of the outcome of the DOE to the selection of the product design, commercial manufacturing process and control strategy. According to the document a DOE to define operating ranges for an important unit operation would normally be considered of high significance. The information provided to the authority in such cases could include: 

• Type of experimental design and parameter ranges studied. As a supplement it is pointed out that justification for choice of design could be useful. 
• Tables summarizing inputs and outputs, including batch size. 
• Summary of parameters that were kept constant during the DOE. 
• Delineation of factors as scale dependent or independent, with justification (for example experimental results, scientific rationale, prior knowledge). 
• Description of main effects and interactions on response variables, including statistical significance of parameters (p-value). 
• Discussion of regression model validation parameters (such as output from ANOVA regression analysis, residual plots, etc.) if applicable.

Please also see the "Questions and answers on level of detail in the regulatory submissions".