FDA Releases Draft Guidance on Essential Drug Delivery Outputs

For several years, FDA has requested that sponsors of drug or biologic led combination products identify essential performance requirements (EPRs) related to the device constituent in their applications.  EPRs were usually requested in the context of design controls, although 21 C.F.R. § 820.30 does not use this term.  In various meetings with the Agency and at conferences, FDA was often asked to clarify this term.  Are EPRs the same as “Essential Performance” as defined in IEC 60601-1 Medical electrical equipment – Part 1: General requirements for basic safety and essential performance?  Are EPRs design outputs that are essential for the proper functioning of the device that are required to be identified per 21 C.F.R. § 820.30(d)?  Are EPRs a new term to describe a subset of design input requirements and specific to combination products?

FDA recently released a much-anticipated draft guidance to address these frequent questions:  Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biological Products.  We were thankful to see that the term, EPR, has been replaced with Essential Drug Delivery Outputs (EDDO), which better aligns with terminology and requirements of the Quality System Regulation.

The draft guidance (June 2024) defines an EDDO as the “design outputs necessary to ensure delivery of the intended drug dose to the intended delivery site.  Drug delivery includes successful product preparation and the initiation, progression, and completion of dose delivery.  EDDOs are system level outputs for which device drug-delivery function is dependent on the device design.”   There is a lot to unpack in this definition and the draft guidance includes sections to help sponsors identify and differentiate which design outputs should be considered EDDOs, and includes appendices with examples demonstrating the process of identifying EDDOs as well as an appendix providing examples of potential EDDOs based on product type that includes prefilled syringes, auto-injectors, on body injectors, pen injectors, jet injectors, nasal sprays, metered dose inhalers, dry powder inhalers, nebulizers, vaginal systems, infusion pumps, and subdermal implants.

While the scope of the guidance indicates that it is intended to address information about EDDOs submitted for drug- or biologic-led combination products, the guidance also covers applicability to 510(k)s, PMAs, and IDEs suggesting that the draft guidance may also apply to the device constituent of cross-labeled combination products, or drug delivery devices not associated with a combination product.

With respect to verification and validation of EDDOs, the draft guidance recommends demonstration that the EDDO is met after preconditioning that includes conditions of storage and shipping.  Design verification testing should include risk-based sampling plans and include evaluation over the shelf-life for EDDOs that may change over time or have age-related failure modes.  Design validation may be covered by clinical studies, pharmacokinetic/pharmacodynamic or bioequivalence/bioavailability studies, literature, simulated bench testing, and/or anthropometric data and should include endpoints that have the capability of validating device performance.

A control strategy should be established to ensure that each lot of the final finished product is manufactured to conform to the design outputs.  A risk-based approach can be used for each EDDO to determine the appropriate control strategy.

Information to include in IND, IDE, and marketing applications is also described within the draft guidance.  Common across application types are a description of the device constituent and performance data.  For marketing applications, a summary of the EDDO information is recommended in the device description with reference to performance data and other supportive information.

Although there are some inconsistencies in the scope of the guidance, it overall should be a valuable resource for developers of drug delivery devices when final.  Comments may be submitted by September 30, 2024.