CDER Review Questions on Autoinjectors and Prefilled Pens

CDER review questions on autoinjectors and prefilled pens: design verification, shipping, PPQ, and essential performance requirements (BLA reviews since 2023)

Scope and question

This article summarizes the questions, information requests (IRs), and review deficiencies that CDER raised in biologics license application (BLA) reviews from 2023 onward concerning the device constituent of autoinjector and prefilled pen combination products. It is limited to four subject areas:

• Design verification testing
• Shipping / distribution / transportation testing
• Process performance qualification (PPQ) and process validation
• Essential performance requirements (EPRs)

Human factors and instructions-for-use (IFU) questions are excluded by design, as are questions specific to prefilled syringe or vial presentations. Where a review discusses a combined prefilled syringe plus autoinjector platform, only the autoinjector/pen-relevant asks are carried forward.

Products reviewed

Twelve BLA products approved since 2023 with an autoinjector or prefilled pen device constituent were in scope: Entyvio (BLA 761133), Tyenne (761275), Omvoh (761279), Andembry (761367), Ebglyss (761306), Bimzelx (761151), Simlandi (761299), Alhemo (761315), Zymfentra (761358), Ngenla (761184), Hympavzi (761369), and Merilog SoloStar (761325).

What CDER asked, by theme

1. Identify and justify the essential performance requirements (EPRs)

The most consistent CDER ask across programs was for a clearly defined, product-specific EPR set derived from the sponsor's design-control process, not a generic list. For autoinjectors, reviewers repeatedly stated the expected minimum EPR set:

• For Entyvio, CDER's device IR asked the sponsor to "identify the essential performance requirements" and specified that for auto-injectors the EPRs should include, at minimum, dose accuracy, activation force, injection time, and extended needle length ³¹.
• For Omvoh, CDER used the same minimum-EPR language and added a leakage dimension: "provide information to verify that the risk of leakage is sufficiently controlled," noting that injection time as an EPR "should be included as an important factor in mitigating the risk of device leakage and/or the user failing to complete the injection" ³². Reviewers also asked that design inputs/outputs carry "objective acceptance criteria" per 21 CFR 820.30 and be framed in the context of intended use ³².
• For pen injectors, CDER gave analogous example EPRs. For Ngenla, the review pointed to "Delivered Volume Accuracy," "Injection Force," and "Injection Time (if applicable)" ²⁰⁷, and for Simlandi CDER stressed that the example EPRs are "not an exhaustive list" and that "product specific factors should influence your EPR selection" ¹⁷⁷.
• For Merilog SoloStar, CDER asked for a "separate document (signed and dated) of the essential performance requirements of the Insulin Lispro pen-injector" ²³⁴ and, in an earlier cycle, flagged that the EPR table "did not give the actual values" for dose accuracy and requested the dose-accuracy specifications ²¹⁸.

2. Provide traceability from EPRs to verification, validation, shelf life, shipping, and lot release

CDER routinely asked for a traceability matrix mapping each EPR across the full evidence chain. Entyvio's review gave the canonical column structure: essential specification against verification, validation, shelf life, shipping / lot release performance / stability, and transportation ⁴⁴. Omvoh received the same recommendation (design input, design output, design verification, validation, shelf life, shipping, and lot release) with EPRs highlighted for ease of review ¹¹³. Merilog SoloStar was asked for "a traceability matrix for all the essential performance requirements, which should include the location of the verification and/or validation testing documents" ²³⁴, an IR the review notes was first sent in an earlier cycle ²²³²²⁸.

3. Design verification testing: reports, not summaries, and testing on the to-be-marketed configuration

Several reviews escalated from a request for documentation to a specific deficiency when only summaries were provided:

• For Entyvio, CDER stated the sponsor "did not provide the actual design verification reports" and requested the reports including real-time and accelerated aging testing, with underlying data such as force traces and statistical summaries ¹⁰². CDER also required that verification testing be "directly traced to the design requirements" using test methods and preconditioning that simulate intended use ³³.
• CDER repeatedly required verification on the final configuration. For Omvoh: "As part of design verification, you should verify the EPRs with the to-be-marketed version of the device constituent and the intended biologic/drug product," with a scientific rationale required for any surrogate ¹¹¹. Zymfentra's CDRH review stated that "design verification testing to support the final finished device EPRs should be completed on the to-be-marketed combination product" ¹⁴¹.
• For Simlandi, CDER asked the application to include the "Design Verification Plan/Summary Report, supporting data and traceability" and, for each EPR, "verification and validation information of EPR specifications" ¹⁷⁷. Ngenla received the same design-verification-plan and EPR verification/validation recommendation ²⁰⁷.

4. Shelf-life and stability-linked verification: demonstrate EPRs are maintained to expiry at defined reliability

A recurring and often product-limiting theme was whether verification and stability data demonstrated the device would still meet its EPRs at the end of the proposed shelf life, at an adequate statistical confidence/reliability level:

• Entyvio drew several midcycle deficiencies. CDER found the autoinjector's functional performance (dose accuracy, injection time, activation stroke, activation force, needle extension, needle cover override force, cap removal force) verified only to a limited reliability level, with real-time and accelerated data not supporting performance through shelf life; CDER asked for data showing the device could "maintain the initial reliability limits" through the proposed shelf life ¹⁰³. CDER also noted the shelf-life testing used a lower reliability limit than required at time zero ¹⁰⁸ and that testing did not extend to the proposed shelf life or demonstrate performance after a claimed 25°C excursion ¹⁰⁵.
• Hympavzi (prefilled pen) generated a cluster of stability-driven verification IRs. CDER noted only 2 lots were submitted and that "accelerated aged testing did not meet the acceptance criteria for delivery time and delivery volume" ²¹¹, asked for data on 3 lots covering "cap removal torque, needle guard force (activation force), needle extension, time between clicks, delivery time and delivery volume" to end of shelf life ²¹³, and required the sample size to give "95% confidence with 95% reliability" ²¹⁶. CDER also requested the protocol for any shelf-life extension beyond 24 months, specifying attributes, acceptance criteria, and number of lots ²¹⁷.
• Simlandi's review asked that "your stability program should include endpoints to verify that device essential performance is maintained at expiry," allowing exclusion of an EPR only with scientific rationale that it is unlikely to change over time ¹⁷⁷. Andembry had a design-verification deficiency for not providing EPR stability testing on 3 device lots; the review records it was resolved after the sponsor provided 3 lots aged to the 36-month shelf life ¹⁹³.

5. Product-specific device performance deficiencies

Beyond the systematic asks, reviewers raised concrete engineering deficiencies:

• Entyvio: the autoinjector cap removal force specification remained too high, and the sponsor "did not provide adequate evidence to validate the specification"; CDER asked for an updated specification and updated verification reports ¹⁰⁴¹⁰¹. CDER also flagged that separation force was not verified in aging or shipping testing and requested aging/simulated-shipping data or a rationale ¹⁰³, and asked for the root cause of autoinjector clogging (which could affect dose accuracy and injection time) and why it would not appear after real-time aging ¹⁰³.
• Tyenne: CDER sent an IR on the autoinjector cap removal force acceptance criterion, stating it "typically want[s] this specification to be < N especially with Rheumatoid Arthritis patients" and asking the sponsor to tighten it ²⁰⁵. CDER separately concluded the EPR testing (including aged and post-shipping devices) was adequate ²⁰⁵.
• Bimzelx: CDER stated the sponsor "should support the adequacy of a 12 second injection with design validation testing," tying the injection-time specification to validation evidence ¹¹⁸¹¹⁹.
• Merilog SoloStar: during bench review of the final design verification, the reviewer noticed the device "appeared to not meet one functional requirement" but concluded the deviation was acceptable given labeling and retained function ²²⁴; CDER also expected ISO 11608-2 needle-threading/compatibility verification ²³⁰.

6. Shipping, distribution, and transportation testing

CDER's shipping asks were most often framed as a requirement to show EPRs are maintained after actual or simulated shipping, and to fold that into the traceability matrix:

• Entyvio: "provide documentation that ensures that the final finished combination product maintains its essential performance requirements after actual or simulated shipping" ⁴⁴. Omvoh received the parallel ask to show the to-be-marketed combination product maintains EPRs "after actual and/or simulated shipping," and noted these studies may be incorporated into design verification testing ¹¹³.
• Simlandi produced the most specific transportation-testing record: the sponsor committed to provide data for 3 device and 3 assembled-device batches "post transport validation (real world and simulated shipping) using the validated spectrophotometric dye ingress method," with container closure integrity testing (CCIT) performed after shipping because manufacturing, assembly, and CCIT occur at different sites ⁹⁶⁹⁷.
• Simlandi, Alhemo, and Merilog SoloStar were each asked, in near-identical language, to "provide documentation for the final finished product to demonstrate that the device EPRs are met after shipping" ^177204234. Alhemo was additionally asked for a control strategy ensuring the final finished combination product maintains its EPRs (lot release, in-process, incoming-material, and purchasing controls) ²⁰⁴.

7. PPQ and process validation

PPQ and process-validation questions were less frequent than EPR/verification questions, and where present often addressed the combination-product final assembly or the drug-product filling process:

• Simlandi drew the clearest device-assembly PPQ position: CDER stated "We do not agree with your proposed approach to submit process performance qualification (PPQ) reports for assembly of AI during BLA review cycle (as part of 120-day update). All PPQ results should be submitted at the time of BLA submission" ⁹⁹, and referenced bioburden and endotoxin data from three PPQ lots ⁹⁸.
• Alhemo was asked for "bioburden and endotoxin data obtained during manufacture of three process qualification (PPQ) lots" ²⁰⁴.
• Andembry received a process-validation deficiency: a PPQ protocol and first-batch results were provided, but "additional process validation and other supporting data are needed," and CDER asked for complete process-validation data for the drug-product filling process, noting the PPQ batch data came from limited samples and sampling points ²⁹⁹.
• Ebglyss was asked to "provide additional process validation data, using a scientifically justified number of ... process run(s)" to fully support validation of the drug-product process, after CDER found a re-evaluation of existing data "alone is not sufficient to fully support" validation ²⁴⁵.

Cross-product summary

Patterns worth noting for submission planning

• EPRs are the organizing concept. CDER's device-constituent questions almost always trace back to a defined EPR set. For autoinjectors, expect the minimum set of dose accuracy, activation force, injection time, and extended needle length ³¹³²; for pens, delivered-volume accuracy, injection force, and injection time ²⁰⁷. Reviewers expect product-specific EPRs from the design-control process, not the example list ¹⁷⁷.
• Summaries do not satisfy design verification. Multiple programs were told to provide the actual verification reports and underlying data (including force/injection traces and statistical summaries), traced to design requirements ¹⁰²³³.
• Shelf life is where verification most often failed. The recurring deficiency was failing to demonstrate EPR performance to the end of shelf life at a stated reliability (commonly 95% confidence / 95% reliability), including after temperature excursions ^{103108105216211213}.
• Shipping is treated as an EPR-maintenance question. The standard ask is documentation that the final finished combination product maintains its EPRs after actual or simulated shipping, captured in the traceability matrix; container closure integrity after shipping appears where sites are geographically split ^{441131772049697}.
• PPQ timing can be a filing risk. At least one program was told that device-assembly PPQ results must be in the original BLA rather than a 120-day update ⁹⁹, and drug-product process-validation adequacy (sampling, number of runs) was a distinct line of questioning ²⁹⁹²⁴⁵.

Limitations and suggested follow-ups

This review reflects what CDER asked as recorded in published Drugs@FDA review documents for 12 autoinjector/pen BLAs decided since 2023; it does not capture sponsor IR responses in full, pre-submission (Type B/C) meeting feedback, or applications still pending. "None found" in the table means no qualifying question was located in the available review text for that product and theme, not a guarantee that none was raised. Readers who need to go deeper can ask Rhizome for the full quoted IR text and review-discipline attribution for a specific product (for example, the complete Entyvio midcycle device deficiencies or the Hympavzi stability IRs), a side-by-side of cap-removal-force expectations across autoinjector programs, or an equivalent scan of prefilled-syringe or vial device questions that were deliberately excluded here.