Understanding Essential Drug Delivery Outputs: Things To Know About EDDOs
By Fran DeGrazio, executive editor, Drug Delivery Leader
The recent FDA draft guidance Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biological Products was one of the most highly awaited documents for biopharma professionals involved in developing and bringing drug- or biologic-led combination products to market. Frankly, the first thing that jumps out of the document, especially to those, like me, with significant history within the industry, is the change in terminology from Essential Performance Requirements (EPRs) to Essential Drug Delivery Outputs (EDDOs). The FDA guidance defines EDDOs as “design outputs necessary to ensure delivery of the intended drug dose to the intended delivery site.”
Why the change from EPRs to EDDOs? As my observations below will illuminate, the change not only clarifies nomenclature, but also clarifies fundamental concepts related to device and product design.
As for nomenclature, many in the industry believe that the changes were made to avoid confusion with other standards that employ similar terminology. For example, IEC 60601 uses the term essential performance in addressing safety and performance for medical electrical equipment. As for concepts, many in industry viewed EPRs as correlating with design inputs. The new guidance clarifies that EDDOs are, rather, a subset of design outputs and are, therefore, inherent to design features. That clarification in terminology now better aligns with standard design control terminology, including the term design outputs.
Questions Abound about EDDOs
To help industry understand the new guidance, Drug Delivery Leader coordinated a DDL Live! virtual event, The FDA Guidance on EDDO: What To Know, What to Do. I moderated the panel discussion featuring two well-known industry experts: Alan Stevens, former director at CDRH and currently in a regulatory leadership role at AbbVie, and Susan Neadle, formerly of J&J and currently president of her own consulting firm, Combination Products Consulting Services LLC.
At the outset of the session, we polled the webinar attendees about the degree to which the new EDDO guidance answers critical questions industry had about EPRs and clarifies understanding. The audience response indicated that, although the guidance is generally considered to be helpful, many areas for added clarity remain. In fact, less than 2% of the respondents feel fully confident in their understanding of EDDOs. The questions they submitted during the session further illustrated these acknowledged gaps in understanding.
Among the topics we addressed during the session were the following:
- How EDDOs compare to primary functions
- The difference between dependent and independent outputs
- Verification and validation of EDDOs
Are EDDOs the Same as Primary Functions?
Primary function is a term associated with ISO 11608-1:2022 Needle-Based injection systems for medical use. That standard includes this definition of a primary function: “a function or operation of the needle-based injection system, 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.”
As underscored by the definition’s emphasis on the avoidance of patient harm, aligning with the ISO standard means that the identification of a primary function is guided by risk analysis. To further clarify, primary functions, as outlined in the ISO standard, apply only to needle-based injection systems. By contrast, the FDA guidance on EDDOs applies to all drug- or biologic led combination products, not just those leveraging needle-based injection. (You can view Drug Delivery Leader Live! event panelist Alan Stevens commenting on the difference between EDDOs and primary functions here.)
Moreover, developing or identifying EDDOs is not formally part of risk analysis, as it is in the ISO-driven identification of primary functions. Nevertheless, once EDDOs have been identified, the risk process is, in fact, used to develop plans and strategies associated with the EDDOs. These risk-based activities include developing the design verification sampling plan or the EDDO control strategies. And, yes, each EDDO must have a clearly defined control strategy. By contrast, a control strategy is not a formal requirement of the ISO standard when identifying a primary function. (You can view Drug Delivery Leader Live! event panelist Susan Neadle commenting on EDDO-based control strategies here.)
What Makes an EDDO Independent of the User?
Regarding the difference between dependent outputs (i.e., those that may be affected by the user’s interaction with the device) and independent outputs, EDDOs are clearly and only in the latter category. Put simply, EDDOs are independent of the user. If the output is influenced by a person using the device, then it is not an EDDO. For example, the deliverable volume of a syringe in an autoinjector is an EDDO because autoinjection, by definition, precludes alteration of the amount of delivered drug product.
Another example of the device-dependence of an EDDO is cap removal force of a prefilled syringe system (PFS) that employs a Luer lock needle hub. Because the force to remove the cap is dependent on the design and manufacture of the cap and its interface to the PFS tip, the ability to remove the cap, which is a product preparation step, is considered to be an EDDO. (View Susan Neadle commenting on device-dependence here.)
How Do Verification and Preconditioning Apply to EDDOs?
One of the most interesting aspects prompting discussion and clarification during the Drug Delivery Leader Live! event was testing for design verification versus testing for design validation. Because EDDOs are to be based on device design and, therefore, are closely aligned with design verification testing, a key challenge is understanding the relationship of EDDOs to design validation, which is tied to users/patients. The panel discussed how verification proves the performance range of a specific output, while validation proves that the range is appropriate for the user group. That tie-in of user-focused design validation to device-focused design verification underscores how human factors considerations are always critical to device development, even when focusing on EDDOs.
As noted in the FDA guidance, a key activity related to design verification testing is pre-conditioning. Preconditioning exposes the product to conditions that are representative of the stresses it will most likely see throughout the supply chain and use. Examples of preconditioning include storage conditions, such as temperature and humidity, along with shipping considerations such as vibration, shock, and pressure changes, to name a few. Prior to any clinical studies, applicants must verify the performance of the combination product and complete preconditioning prior to design verification testing. (View Alan Stevens commenting on device preconditioning here.)
As an audience survey at the end of the Drug Delivery Leader Live! event on the FDA’s EDDO guidance confirmed, there remains a desire for even further clarity around such activities as design verification, design validation, and release testing. Anticipate further coverage of the EDDO guidance as we monitor the industry’s response to it.