(M1030-08-54) Benefits of the Structure-Data File (SD File) Format for Knowledge Aided Structured Assessment (KASA) and Cheminformatics in FDA

Purpose: Drug Master File (DMF) holders provide a hazard assessment for impurity classification¹ including the use of (quantitative) structure-activity relationship ((Q)SAR) models. Impurities consist of starting materials, intermediates, by-products, and degradants, and can total >15 for a single DMF. Currently, structures associated with these impurities are submitted through the Electronic Common Technical Document (eCTD) as unmanipulable PDF files. Further review of the impurities using cheminformatics tools—by application of (Q)SAR models and registration in the FDA Global Substance Registration System (GSRS)—or use in the Chemistry, Manufacturing and Controls (CMC) review document, requires structure conversion to a computer-readable format. Therefore, a new file format is proposed to accompany DMF and Abbreviated New Drug Application (ANDA) submissions to the FDA.

Methods: The Division of Lifecycle API (DLAPI) in FDA began requesting that DMF holders provide impurity structures as a single structure-data file (SD File) in Fall of 2021. The Agency also compiled a Quick Guide to assist industry in SD File creation.² The SD File provides an extensible, portable text file encoding computer-readable chemical structures linked to associated data fields. Under a collaboration between the Office of Pharmaceutical Quality (OPQ), the Office of Translational Science (OTS) and the Office of the Commissioner (OC), DMF holders may now provide SD Files through the eCTD, with standardized associated data fields meeting Agency cheminformatics and cross-functional regulatory review needs.

Results: Submission of structures as PDF files requires end users at the FDA to manually re-draw each structure for review and cheminformatics purposes. This is time-consuming, can unintentionally introduce errors, and is an inefficient use of resources. In contrast, submission of structures in the SD File format (Figure 1) allows them to be easily viewed in chemical drawing software, used in the DMF review, imported into (Q)SAR software, or used to create a record in GSRS. Furthermore, errors associated with redrawing structures are eliminated. In 2022, the Agency received 99 SD Files with a total of 2,850 chemicals from industry to support this effort.

Conclusion: The pharmaceutical industry may now submit structures to the Agency in the eCTD as a single SD File with standardized data fields that meet the FDA’s cheminformatics and review needs. SD Files are acceptable in all of Module 3 and their inclusion in all submissions to the FDA is strongly encouraged.

References: 1 ICH M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk
2 Please refer to the Quick Guide to Creating a Structure-Data File (SD File) for DMF Submissions for column definitions. This guide is located on the FDA's Drug Master File website.

Figure 1: Example SD File for Caffeine