Threshold analyses
The guidance outlines three types of threshold analyses that manufacturers should perform to compare the proposed generic and RLD products thoroughly. These analyses are recommended for all generic combination products:
- Labeling comparison – Side-by-side, line-by-line comparison between the proposed generic and RLD products’ labeling, including (but not limited to) the complete prescribing information, instructions for use, product labeling and packaging
- Comparative task analysis – A systematic “deconstruction” of the user-product workflow. This involves “analyzing and comparing the sequential and simultaneous, manual and intellectual, activities for end-users” interacting with each product
- Physical comparison – A thorough visual and tactile examination of each product’s physical features and characteristics (e.g., delivery device constituent part(s) and/or container closure).
For instance, consider an RLD inhaler fitted with a “black-text-on-white-background” dose counter. The dose counter window is rectangular and measures 0.5 centimeters by 0.8 centimeters, and the dose numbers are printed using a point 10 font size. The generic inhaler is fitted with an oval-shaped dose counter window, and the dose numbers are printed using a point 12 font size. These physical differences may impact users’ ability to correctly determine the number of remaining doses when switching from the RLD to the generic inhaler.
Therefore, companies developing using an off-the-shelf device design should conduct thorough threshold analyses, noting that such analyses may serve as a primary reference for the FDA to consider the suitability and interchangeability of the proposed generic inhaler compared to the RLD inhaler. That said, using an off-the-shelf device identical to the RLD product will be impossible. Therefore, the FDA expects that the differences shall not affect someone’s ability to use the proposed generic inhaler if substituted for the RLD inhaler without additional instructions or intervention. As such, substantial differences in the user interface, including the product’s use steps, physical form, on-product labels and other labeling (e.g., instructions for use) might be considered unacceptable by the agency.
Categorizing the identified differences and justifying difference categorizations
According to the 2017 guidance, each threshold analysis finding should be categorized based on whether or not a design difference impacts an external critical design attribute; i.e., features that directly affect how users perform a combination product critical task necessary to use or administer the drug product.
