FDA’s New Guidance on Essential Drug Delivery Outputs
SYNOPSIS
The FDA has recently released a draft guidance, “Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biological Products,” that redefines and expands upon what were previously known as “Essential Performance Requirements” (EPRs) for device constituent parts of combination products. This new guidance introduces the concept of “Essential Drug Delivery Outputs” (EDDOs) and provides a comprehensive framework for their definition, identification, verification, and control. Potential EDDOs are provided for various product types, including prefilled syringes, auto-injectors, on-body injectors, nasal sprays, inhalers, vaginal systems, infusion pumps, and subdermal implants.
Although the draft guidance is not enforceable and no guidance is legally binding, the FDA has been requiring that Sponsors verify and control EPRs for some time. The FDA may also require specific testing for a given program that aligns with the new EDDO definition.
Let’s dive into the key aspects and recommendations from this important development.
Of note, the FDA will accept comments on the draft guidance through 30 September 2024.
WHAT’S NEW IN THE EDDO GUIDANCE
- New Terminology: “Essential Drug Delivery Output” (EDDO) replaces the unofficial “Essential Performance Requirement” (EPR).
- New Definition: EDDOs ensure the delivery of the intended drug dose to the intended delivery site, including product preparation and the initiation, progression, and completion of dose delivery.
- Expanded Scope: The scope of EDDOs now includes product preparation specifications.
- Not Risk-based: The identification of EDDOs does not distinguish between emergency-use devices and non-emergency use.
- Not Aligned with Primary Functions: The new definition is not entirely aligned with the definition of “Primary Functions” from ISO 11608-1, which incorporates potential harm to the patient.
KEY DIFFERENCES OF EDDOs FROM EPRs & PRIMARY FUNCTIONS [1]
| EDDOs | EPRs | PRIMARY FUNCTIONS | |
|---|---|---|---|
| SCOPE | Encompasses all stages of delivery, including preparation, initiation, and completion | Performance at the point of dosing | Incorporates a potential for unacceptable harm to the patient in the definition in addition to potential to impact the delivery of the medicinal product |
| SELECTION PROCESS | EDDOs clarified to be System Level Outputs; selection process clarified in guidance | Selection needed to be justified per product through sponsor interactions with review division | Guided by risk analysis |
| STAGE OF DESIGN CONTROLS | Identified as Design Outputs | Not clearly defined; some industry interpreted to be Design Inputs, other as late-stage Design Outputs | Identified during the Design Inputs stage |
| APPLICATION TO VARIOUS PRODUCT TYPES | Does not distinguish between device types (non-emergency use vs. emergency use); Applies to a wide range of product types: Prefilled Syringes (PFS), Autoinjectors (AI), on-body injector, pen and jet injectors, nasal sprays, metered dose inhalers, Dry Powder Inhalers (DPI), nebulizers, and vaginal systems | While EPRs were generally not based on risk, different EPRs were often applied for emergency use vs. non-emergency use applications; Applied to a large range of combination product types | Focused primarily on Needle-based Injection Systems (NIS) for Subcutaneous (Sub-Q), intradermal, and/or intramuscular delivery; Excludes stand-alone PFS, continuous flow infusion pumps, NISs with refillable containers, and NISs intended for different routes of administration (e.g., Intravenous (IV), intrathecal, intraocular) |
EDDO IDENTIFICATION & PRESENTATION
The Guidance defines a new four-step process identifying EDDOs for a given product. This is the filtering steps involved to determine an EDDO.
STEP 01
Design Outputs
STEP 02
Drug Delivery Design Outputs
STEP 03
System Level Design Outputs
STEP 04
Device Dependent Design Outputs
[Image taken from “Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biological Products Guidance for Industry”]
- Filtering Method: The guidance presents a new four-step “filtering method” for identifying EDDOs. This method helps manufacturers systematically evaluate design outputs to determine which are essential for drug delivery. Appendix B of the guidance demonstrates how to implement this filtering method.
- Presentation of EEDO Information: The guidance provides example tabular formats for presenting EDDO information:
- A table showing how each EDDO relates to aspects of drug delivery (e.g., delivery of intended dose, product preparation.)
- A table presenting the EDDO Control Strategy
VERIFICATION, VALIDATION, & SHELF-LIFE CONSIDERATIONS
- Testing: EDDOs must be verified and validated across all conditions the device will be exposed to during production, shipping, storage, and preparation, as well as during intended use. Sampling plans for EDDO verification should be risk-based, with more robust sampling for higher-risk devices.
- Validation: Design validation should consider relevant studies and endpoints based on user needs, which may include clinical safety/efficacy studies, pharmacokinetic studies, and/or simulated-use studies.
- Shelf-life: If adequate justification is provided, EDDOs that can be demonstrated to not change over time may not need to be tested for shelf-life.
- Accelerated Aging: Accelerated aging data may be used to establish shelf-life, confirmed by real-time aging data with adequate justifications for the accelerated aging conditions.
- Post-Market Changes: Any modification to product design or manufacturing requires assessment of impact on EDDOs, including potential identification of new EDDOs and the need for additional verification/validation.
ONGOING CONTROL STRATEGY CONSIDERATIONS
- Control Strategy:
- Manufacturers should develop a risk-based EDDO control strategy that includes lot release, in-process controls, control of incoming materials, and purchasing controls.
- The control strategy should consider each step of the manufacturing process to determine appropriate controls related to each EDDO.
REGULATORY SUBMISSIONS & APPLICATIONS
- Regulatory Submissions:
- IND Requirements: The design verification provided should support the development stage of the combination product and ensure safety for the intended use of the clinical study.
- Marketing Applications: Marketing applications should follow specific submission requirements based on the regulatory pathway (PMA, 510(k), De Novo, NDA, ANDA, BLA) and include identification of EDDOs, justification of EDDO selection, and verification and validation data.
CONCLUSION
While this guidance is still in draft form and not yet enforceable, it represents a significant development in the regulation of combination products. While most of the information isn’t entirely different than the intent and scope of Essential Performance Requirements, it formalizes the Agency’s stance on definitions, testing requirements, and ongoing control strategies. Manufacturers should carefully consider these recommendations in their product development programs to mitigate regulatory risk.
The FDA encourages applicants to submit proposed EDDOs and control strategies for agency feedback, fostering a collaborative approach to ensuring the safety and efficacy of combination products. This key interaction is especially important during this transition period while the guidance is still in draft form.
As the industry adapts to this new framework, it will be crucial to stay informed about any updates or finalization of this guidance. Manufacturers should review their current practices against these new recommendations to ensure smooth regulatory processes in the future. Kymanox recommends discussing proposed EDDOs with the Agency, particularly those that may differ from previously-identified Essential Performance Requirements.
References
[1] As defined by ISO 11608-1:2022: Function or operation of the NIS which if it does not perform to specifications during use, would directly result in a failure to accurately deliver the medicinal product via the correct route and/or directly result in unacceptable harm to the patient
