Stability And Release Testing For Delivery Devices: Waived Or Wanted?
By Doug Mead, CP Pathways LLC
In a previous article, I illustrated the results and benefits of using Gen AI search tools to uncover regulatory precedents around Human Factors. In this article, I am again reporting on insights gained from conducting precedent research into FDA policy. This time, I focused on a major source of regulatory uncertainty in pharmaceutical delivery device development. That is, the testing required for final product release and for “functional” stability to verify an applicant’s designated essential performance requirements (EPRs). I wanted to explore, in particular, regulatory risks and FDA flexibility in scenarios in which applicants have sought waivers on delivery device stability and release testing for delivery devices. For the exploration, I once again used AI tools to query the drugs@fda database for precedents related to functional stability programs and performance release testing for CDER-approved combination products.
Questions Arise On Performance Requirements And Delivery Outputs
In the FDA’s draft guidance, Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biological Products (2024), the FDA suggests 1) that “certain” EDDOs (analogous to EPRs) need not be tested in stability programs if they are not stability-indicating, and 2) that upstream controls may alleviate the need to test EPR functionality at release. A scientific justification for these waivers must be provided in the BLA or NDA, and such justifications would be subject to agency review. Sponsors can propose stability and release exceptions in Type B/C/D meetings and get feedback, which is certainly recommended. However, there remains the strategy question of what would likely be acceptable to FDA. This can come up early in the development plans for the products as teams develop a design verification traceability matrix.
Questions about what FDA might accept can result in uncertainty because of variation across existing scenarios. For instance, there are many examples of approved prefilled syringes with needle safety devices (PFS/NSD) and “platform” autoinjectors used for multiple drugs by the same company, or by different companies for highly similar drugs. Some companies routinely test all EPRs across all test programs, whereas others have considered justifying fewer EPRs for release testing, or excluding certain EPR tests from stability. Limited testing can significantly reduce sample sizes and testing effort, reports, and reviews.
Compounding any development strategy decisions is the FDA’s potential unpredictability when sponsors seek FDA feedback in meetings, which might instead depend on the strength of an applicant’s justifications.
My consulting clients, over the past several years, have struggled with these decisions. They ask, for instance, do we test all expected EPRs and maybe some other performance attributes? This strategy dilemma stems, in part, from the lack of clear or accepted regulatory definitions of EPRs (and now EDDOs), but more so from the regulatory risks applicants are willing to take in their device development plans. For example, some tests of a needle safety feature’s activation (e.g., post drug delivery) seem to have the same or stricter requirements than EPRs.
As the search results on FDA review precedents below will illustrate, there remains inherent uncertainty associated with any reduction in stability or release testing.
What Does FDA Say About Stability Testing?
What I’ve looked for are a) the EPRs that companies tested in stability programs or for release, b) whether testing waivers were sought and justified, and c) whether FDA agreed or disagreed with the applicant’s rationale.
First, finding specific examples of these instances is challenging when searching the drugs@FDA database. This NDA/BLA database includes CDRH review comments, and it can include examples of when an applicant successfully justified not testing certain EPRs. However, it’s likely not a complete record of these instances, as the database may not include the FDA’s comments (at CDRH’s discretion), or the content may be redacted. For those reasons, while common GenAI search tools, such as ChatGPT-5, Gemini Deep Research, Claude, etc., will find several examples, multiple search strategies will likely be needed, potentially including commercial search tools with additional capabilities.
Factors Behind Waiving Or Repeating Stability Testing
For my first foray into precedent research on stability testing, I employed a simple statement/query strategy, asking the following:
FDA has stated that some essential performance requirements (EPRs) for a drug delivery device may not need to be tested in functional stability programs for an NDA or BLA. Based on review memos and correspondence in the drugs@FDA database, provide all examples from the last five years where the FDA has agreed that an EPR for a prefilled autoinjector did not need to be tested in stability programs.
Of course, the search tools I tried could not claim to have found all examples, but each did return one or more, generally within the specified date range. Here are some results:
In BLA 761154, for a Mylan adalimumab autoinjector (now from Biocon Biologics Inc.), the FDA questioned EPR testing of injection depth in stability but, with the applicant’s information request response, FDA concluded, “Injection depth and needle retraction are not evaluated (in) stability because these EPRs are not changed during storage.”
One PFS/NSD applicant successfully listed needle length as being fixed and not a “subject of time.”
As I see it, it almost makes sense to exclude the parameter of needle length from stability (and release) testing. An autoinjector’s needle extension is a) controlled by the PFS-supplier’s needle length, and b) designed into the autoinjector with PFS transit stops that use dimensionally stable polymers. Moreover, the clinical specification is usually set at ± 2 mm, a very large criterion range unlikely to fail in stability testing. Nevertheless, this parameter is clearly an EPR (and expected per the draft EDDO guidance), and injection depth is an ISO 11608 Primary Function. So, it’s unlikely to be waived for stability testing.
Some review precedents included FDA expectations that companies extending shelf-life claims (including device stability) after approval should continue to test the same EPRs as for approval, or that annual stability batches should repeat functional stability tests to assess lot-to-lot variations. The latter point is questionable, in my view, because functional stability has already been proven for the NDA/BLA, and lot-to-lot test data differences may be tied to slight component variations unrelated to stability.
FDA Expectations For Prefilled Syringe Functional Stability
Following a CRL [Compete Response Letter] for an autoinjector under review in 2023, the FDA requested device performance testing (either real-time or accelerated aging testing) on a total of 3 batches of the prefilled syringe (PFS) with needle safety device (NSD) to include dose accuracy, peak force, injection force, and NSD activation force to demonstrate that the device will perform as intended to the end of its proposed shelf life of 36 months. Autoinjector requirements were also relayed.
The specific comment was:
“In an Information Request (IR) dated January 29, 2024, FDA requested device performance testing (either real time or accelerated aged testing) on a total of 3 batches of the subject prefilled syringe (PFS) with needle safety device (NSD) to include dose accuracy, peak force, injection force, and NSD activation force to demonstrate that the device will perform as intended to the end of its proposed shelf life of 36 months. The Agency also requested testing for a total of 3 batches of the subject autoinjector (AI) to include dose accuracy, injection time, activation force, extended needle length, and lockout force to demonstrate that the device will perform as intended to the end of its proposed shelf-life of 36-months. In the response dated February 5, 2024, it is noted that two additional batches of [drug ID/name] NSD and [drug ID/name] AI will be placed on stability and this data will be provided in an annual report. In your resubmission, please provide the results of the additional stability data rather than in an annual report. The FDA also requested testing for a total of 3 batches of the subject autoinjector (AI) to include dose accuracy, injection time, activation force, extended needle length, and lockout force to demonstrate that the device will perform as intended to the end of its proposed shelf-life of 36 months. In the response dated February 5, 2024, we note that two additional drug product batches of [drug ID/name] PFS assembled with NSD and [drug ID/name] and PFS assembled with AI will be placed on stability, and this data will be provided in an annual report. In your resubmission, provide the results of the additional stability data rather than in an annual report.”
One takeaway from this excerpt is that FDA is unlikely to defer stability results to a post-approval Annual Report commitment. In another example from an autoinjector [prefilled pen (PFP)] review, FDA provided the following expectations:
“We generally recommend providing 3 GMP lots of the drug/device product to be tested to account for lot-to-lot variability. Please provide summary data and test reports for a total of 3 PFP lots for stability testing (either real-time or accelerated aged testing). This testing should include cap removal torque, needle guard force (activation force), needle extension, time between clicks, delivery time and delivery volume that meet the acceptance criteria to demonstrate that the subject PFP can meet its performance specifications to the end of your proposed shelf life of X months.”
Note FDA’s consistent request for three GMP lots. Given that multiple autoinjector component lots and PFS barrel lots are rarely available, producing three assembly lots (by number) has met this requirement. Their recommendation for three lots seems to be a baseline, including their expectations for testing the EPRs. Beyond EPRs, the FDA may also want to know about safety shield override forces.
Takeaways From Precedent Research On Stability Testing
Overall, there were very few instances in the record in which an applicant either attempted to waive certain delivery device parameters in a functional stability program or received FDA acceptance of such waivers.
While the FDA states that certain EPRs (or EDDOs) can be excluded from functional stability programs with scientific justification, this position does not appear consistent with precedents in the FDA review database, as evidenced by a review of approved products from the last five years.
There is a need for certain stability testing, such as autoinjector injection time, which can be impacted by protein drug adherence to PFS barrel walls (increasing stopper friction) or the potential risk of PFS needle blockage, which needs to be confirmed. Other autoinjector functional stability parameters, such as cap removal torque, activation force, or safety sleeve overcome force, could be considered drug-agnostic and confirmed in accelerated stability testing. Dose volume accuracy or PFS glide force could be confirmed in drug product PFS stability testing, as these are not impacted by assembly processes.
What Does FDA Say About Release Testing?
On the specific question of lot release testing, the draft EDDO guidance, as well as FDA feedback in Type B/C meetings, suggests that certain EPRs for autoinjectors and PFSs may not need to be tested for final product release. This waiver would likely require a comprehensive and detailed discussion of the applicant’s control strategy in the NDA/BLA.
Typical controls can include incoming acceptance testing of components for assembly, PFS filling controls, design verification testing, assembly process validation (three lots) with defined in-process controls, stability testing, an implemented risk management plan and other activities. In some cases, PFSs are tested for extractable volume and glide forces for release to the final assembly process.
So, the question becomes, what is the purpose of final product release testing for every EPR, and has the FDA been flexible on lot release requirements?
Release Testing Remains A Consistent Expectation
I looked for FDA precedents from the last five years related to this topic for PFS/NSDs, using several GenAI search strategies, including the query below:
Release testing of a commercial prefilled syringe with a needle safety device may be performed after assembly of the product. However, upstream controls and the overall control strategy may justify that no release testing is needed. Has the FDA ever waived any release test of EPRs of a final prefilled syringe with a needle safety device in a BLA or NDA when upstream controls have been implemented?
The search results returned multiple drug reviews that included this topic in the review memos. After reviewing the source content, I concluded that examples where any EPRs for a PFS/NSD were waived were rare. In fact, FDA often stated explicitly that they were required and which tests should be conducted. Again, the unknown factor is the quality of any justifications the applicant provided.
In contrasting the results, the one example of a waiver in a review memo was for ERELZI (Etanercept-szzs), where FDA stated:
“Break loose and gliding forces testing is not considered needed for fully assembled GP2015 25 mg/0.5 mL and 50 mg/1.0 mL solution for the combination product since the NSD gets activated once the plunger rod has been fully pushed through; therefore, the NSD is not expected to impact the gliding or break loose force and the gliding or break force is not expected to impact the functionality of the NSD.”
However, the review is somewhat dated, and the applicant agreed per the review memo that the above release tests will be conducted in annual stability batches reported to FDA.
In several other reviews in the last five years, the FDA has not waived lot release tests for a final PFS/NSD, and FDA expected that dose accuracy, break loose glide force, and NSD activation force and override force testing (with the drug product) be tested. In a 2020 review, the FDA stated:
“The existing control strategy in the response is inadequate because it does not contain lot release testing for the needle safety activation force specification. Without an adequate control strategy, you cannot ensure that produced lots will conform to the specification for needle safety activation force. Without conformance to the needle safety activation force specification, users may experience issues deploying the safety feature. Include lot release testing for needle safety activation force as part of your Post Market Commitment.”
This example might be a reviewer-specific anomaly; NSD activation forces are apparent in the glide force graph, show consistency in design verification tests, and are often dependent on the choice of test velocity (an artificial construct given variability in manual injection techniques). Note that Appendix C of the EDDO draft guidance does suggest that NSD activation force might be an EDDO.
Other review memos reflected similar FDA policies. It does not appear that the FDA is inclined to waive lot-release testing for key EPRs in PFS/NSD products.
More Of The Same (Release Testing) For Autoinjectors
Asking the same questions about prefilled autoinjectors found similar results for lot release testing. Even with upstream controls, FDA has an expectation for the downstream controls, i.e., lot release testing. Activation force, needle extension, delivered volume, and injection time were commonly tested for autoinjector release in several products over the last several years. The only exception that came up in review memos was for cap removal force, as shown here:
“In the Dawnzera, NDA 219407, the autoinjector cap removal force was not tested for lot release. Activation force, needle extension, delivered volume, and injection time were release-tested.”
In the Alhemo / concizumab, BLA 761315 review of a pen injector (not an autoinjector), FDA objected when activation force, hold force, and injection time were not in DP release specifications and said this was needed to monitor device functionality at release. FDA stated:
“In section 3.2.P.5.1, dose accuracy is included in the concizumab drug product (DP) release specifications. However, the other essential performance requirements (i.e., activation force, hold force, and injection time) are not included in the DP release specifications. This is needed to ensure that the device functionality is monitored at release. Therefore, add the EPRs (i.e., activation force, hold force, and injection time) to the DP release specifications.”
The search routine eventually checked the review memos for Simlandi BLA 761299 / 761205, Yuflyma adalimumab-aaty, BLA 761219, Idacio / adalimumab-aacf, BLA 761255, Tyenne / tocilizumab-aazg, BLA 761275, Wezlana / ustekinumab-auub, BLA 761285 / 761331 S-001, Pyzchiva / ustekinumab-ttwe, BLA 761373 / 761425 S-001, Avtozma / tocilizumab-anoh, BLA 761420 / 761498, and Udenyca / pegfilgrastim-cbqv, BLA 761039 S-013. For these products, the control strategy included downstream controls that included final product release testing of EPRs.
Those Seeking Testing Waivers May Seek Them In Vain
Although the FDA has suggested that applicants can justify waivers for certain EPRs for common and platform PFS/NSD and autoinjectors in functional stability programs, and for lot release testing, using an overall control strategy, the precedent record in review memos does not indicate that such waivers are sought or granted by the FDA. There is also an emphasis on NSD performance testing of PFS/NSD at release, despite evidence from multiple approved products that NSDs function reliably. Basically, there is an overall FDA view that a final, assembled PSF/NSD or autoinjector should be tested against their EPR specifications for final product release.
Drug manufacturers with autoinjectors have largely accommodated this expectation by adopting automated lot-release testing equipment that can automatically and simultaneously test dose-volume accuracy, actuation force, injection time, and needle extension in production samples. They may find that the easiest pathway to approval is to perform these tests as efficiently as possible, regardless of their value or risk-based purpose. Not discounting the thousands of drug-filled PFS/NSD and autoinjector samples tested in design verification, process validation, and functional stability, the final product release for these combination products seems to be a critical downstream control strategy that the FDA likes to see.
Note that Appendix D of the EDDO draft guidance outlines a comprehensive “control strategy” for an autoinjector needle extension length. However, even with the multiple controls listed in this example, it remains a question whether justifications based on these controls could support a waiver of the final release test requirement for this parameter.
Regulatory Research: Definite Value Despite Non-Definitive Results
The precedent research I conducted in the drugs@FDA database was not particularly useful for identifying exceptions to stability and release waivers. However, deeper dives into this research may better prepare sponsors for considering strategies for going to FDA in Type B/C/D meetings to get additional policy-based expectations for these requirements.
While the underlying search results from FDA precedent research may be inconsistent or even unfavorable to a desired approach, it’s clear that these insights can help to inform the best regulatory strategies for regulatory success. Once again, my advice is to use GenAI search tools to assess regulatory risk and refine regulatory strategies.
About The Author
Doug Mead is Principal Consultant and President of CP Pathways LLC, a combination product consultancy. He helps combination product companies with their regulatory strategies and works closely with delivery device teams and regulatory staff to prepare submissions in line with the latest regulatory expectations.