Leveraging Experimental Design in Regulatory Applications

Tips from FDA – Put Design of Experiments to Use in Drug Applications

BY Philp Crooker, J.D. Vice President, Technical –Regulatory - 11.11.19 -

One of the benefits to having worked at FDA was the opportunity to gain exposure to how a wide variety of manufacturers perform product development and manufacturing and how they present that information to the FDA.  But if you’re not part of FDA then you don’t have access to that proprietary information.

A scant amount of information can be gleamed from redacted drug approval packages that are posted on the FDA website, but even those have become more streamlined with the implementation of the initial phases of the integrated review process.  However, every so often the FDA will publish some information that gives a glimpse into how they are analyzing information in their databases that gives the regulated industry insights that can improve their regulatory submissions and review outcomes.

In July 2019, the FDA published an article in the Journal of Pharmaceutical Innovation titled “Assessment of Applications of Design of Experiments in Pharmaceutical Development for Oral Solid Dosage Forms.”  The article can be found here.  The FDA will also post the article on its website here.

The FDA examined 131 randomly selected new drug application (NDA) submissions and 606 abbreviated new drug application (ANDA) submissions that were reviewed between 2012-2016 based on the biopharmaceutics classification system (BCS) class of the active pharmaceutical ingredient (API).  The paper includes four cases studies – two focus on dissolution behavior and two on specific manufacturing process unit operations. The FDA reached several conclusions:

  • Design of experiments (DOE) has not yet become a routine common practice to assist development of oral solid dosage forms.
  • The percentage of BCS Class II NDA (80%) and ANDA (40%) submissions using DOE was much higher than those of the submissions in other three BCS classes – likely due to the inherent low solubility of BCS Class II API and pointing out the critical role of the API properties for determining how best to implement DOE studies.
  • The information provided in most of the NDA submissions is not as detailed as ANDA submissions.
  • DOE studies provide valuable information that can help applicants identify and mitigate formulation and process related risks and helps gain smooth regulatory approvals for marketing applications and post-approval changes.

Particularly helpful to applicants who are submitting applications to the FDA for both immediate release and extended release oral solid dosage forms, the FDA authors included some common problems that occurred during the review of the DOE information in the application.  These included:

  • Study design does not support the intended purpose of the DOE.
  • The studied range of selected input factors is too narrow.
  • Response factor is not properly chosen.
  • The DOE study is conducted with a non-CGMP release dissolution method.
  • The DOE study conclusions were made without a detailed protocol in place.
  • Statistical analysis was not properly conducted.
  • The DOE data analysis is not reproducible.

Leaving aside for a moment the debates regarding how the information in the development pharmaceutics section (3.2.P.2) of the NDA or ANDA should be reviewed, what fraction is “safe harbor” information and whether or not the above points remain valid for all DOE in every development program, these points are gleamed from the review of detailed information in hundreds of applications drawn from a vast database of marketing applications. 

Applicants are well advised to consider them in designing, evaluating and defending the information intended to be included in NDA or ANDA submissions. Applicants can also take advantage of a wide array of pre-submission meetings and correspondence to raise and prepare resolution of issues related to DOE prior to submission of an application.

Immediate and extended release oral solid dosage forms are nearly ubiquitous and remain an extremely convenient and popular regimen for ease of use and compliance.  Applicants are well advised to consider how best to deploy DOE in their submissions for these products to improve product and process design, scale-up and commercial manufacturing and mitigating risk.

In the future, it will be interesting to learn whether FDA chooses to perform further research to determine if appropriate DOE studies reduce the number of information request letters, reduce the number of review questions related to areas in the development program where DOE has been applied, improve the performance and outcome of CGMP facility inspections (in particular pre-approval and post-approval audit inspections), and reduce the number of review cycles prior to approval of marketing applications and supplements.

We are always available for a conversation.