For sponsors submitting a BLA or NDA for a drug product presented in a prefilled autoinjector, device-related information requests (IRs) from CDER—often reflecting input from CDRH—represent a critical and sometimes underestimated review hurdle. Understanding how FDA frames these requests, what types of data or justifications it expects in return, and how it formally records acceptance can materially inform a sponsor's IR response strategy and reduce the risk of review cycle delays.
The analysis below draws on FDA review memoranda and combination product assessments available in Drugs@FDA for decisions issued on or after January 1, 2022. It focuses specifically on autoinjector essential performance requirements (EPRs)—such as cap removal force, activation force, delivered volume, injection time, and needle extension—tracing the documented exchange from the original IR through the applicant's response to FDA's explicit disposition language.
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FDA information requests on prefilled autoinjector testing and performance: examples since 2022 where the applicant's response was found acceptable
During review of a BLA or NDA for a drug-device combination product, CDER's device reviewers (working with, or on consult from, CDRH) routinely issue information requests (IRs) when an autoinjector's essential performance requirements (EPRs), design verification, stability, or risk management documentation falls short of expectations. The applicant answers with additional data, a tightened specification, or a written justification, and the reviewer records an explicit disposition, typically "Response Adequate: Yes," "This is acceptable," or "The response is acceptable." This article walks through six documented examples from FDA review memos issued since 2022, quoting the request, the applicant's response, and FDA's acceptance language in each case.
Summary of examples
| Product (application) | What FDA requested | What the applicant provided | FDA acceptance language |
|---|---|---|---|
| IDACIO, adalimumab-aacf (BLA 761255) | Sharps-injury-protection testing per guidance: sample size of 500 with zero failures in a simulated-use study 47 | Declined the exact test; submitted HCP/lay-user trial data showing 1005 products used without a sharps injury (estimated true failure rate ≤0.62%) 47 | "This response was not what was requested but still fulfills the guidance ... Response Adequate: Yes" 47 |
| IDACIO (BLA 761255) | Provide an upper Delivered Volume spec; lower the autoinjector Injection Time upper spec (times over 10 s risk premature removal) 49 | Lowered injection-time spec with supporting data; declined an upper delivered-volume limit, citing syringe dimensions as a natural bound 49 | "The reduction in the injection time specification is acceptable ... Response Adequate: Yes" 49 |
| IDACIO (BLA 761255) | Perform release testing for all PFS and autoinjector EPRs; implement acceptance criteria for Break Loose/Glide and Extra Activation Force 17 | Committed to AI/PFS release testing; then implemented the existing design specifications as the release acceptance criteria 17 | "This approach is acceptable. Response Adequate: Yes" 17 |
| ENTYVIO Pen, vedolizumab (BLA 761133) | Data showing the autoinjector maintains functional performance (reliability limits) through the proposed shelf life; root cause for clogged samples 3 | Variables analysis of performance attributes plus 12-month real-time and 24-month accelerated data addressing reliability and clogging 3 | "Response Adequate: Yes" 3 |
| ENTYVIO Pen (BLA 761133) | Autoinjector Risk Management Summary lacked a clear risk/benefit analysis for "As Far As Possible / yellow" residual risks 40 | Updated the risk-management summary with a fuller risk-benefit assessment and added drug and device risk detail 40 | "Response Adequate: Yes" 40 |
| TYENNE, tocilizumab-aazg (BLA 761275) | Autoinjector cap-removal-force acceptance criterion was too high, especially for rheumatoid-arthritis patients; revise it downward 37 | Acknowledged the guidance and tightened the cap-removal-force acceptance criterion; updated the device section 37 | "Sponsor's response is adequate." 37 |
| BYNFEZIA PEN, octreotide (NDA 213224) | Revise the delivered-dose-accuracy spec to add upper/lower limits on the actual amount (mcg) delivered, using actual assay and dispensed volume 67 | Added delivered-dose accuracy in mcg; supplied one consolidated release/stability spec table plus batch and stability data 65 | "CDRH has no further information request from the sponsor." 6539 |
| TRYNGOLZA, olezarsen (NDA 218614) | Inadequate description of nonconforming-product handling (Subpart I) and post-manufacture labeling/packaging integrity (Subpart K) 41 | SOPs and controls using a hybrid quality-system approach addressing 21 CFR 820 subparts I and K 41 | "The provided information indicates adequacy ... The response is acceptable." 41 |
| ZURNAI, nalmefene (NDA 218590) | Questioned whether the autoinjector activation force was too high; requested justification / narrowing based on performance data 74 | Provided a written justification citing a CPSC-equivalent study for the activation-force and cap-removal-torque specifications 74 | "This justification is acceptable ... The device EPRs are acceptable." 741 |
Case detail
IDACIO (adalimumab-aacf), BLA 761255
IDACIO produced several textbook IR-to-resolution exchanges on the prefilled syringe and autoinjector presentations.
On the sharps-injury protection feature, FDA asked the sponsor to "provide testing of the sharps injury protection features as indicated by this guidance, including a sample size of 500 with zero failures in a simulated use study." 47 The sponsor "did not provide the requested test" and instead offered supporting evidence: trials with healthcare providers and lay users in which "1005 products were used without sharps injury," from which the sponsor estimated "a true failure rate of at most 0.62%." 47 FDA accepted the substitute: "This response was not what was requested but still fulfills the guidance and demonstrates adequate [s]harps injury prevention with the products. Response Adequate: Yes." 47 This is a useful precedent that a well-reasoned justification, backed by real-use data, can satisfy an IR even when it does not deliver the exact study FDA specified.
On EPR specifications, FDA flagged that "the Delivered Volume for both the prefilled syringe and the autoinjector is unbounded and the Injection Time for the autoinjector is high," warning that "injection times over 10 s can increase the risk that users will remove the product prematurely, resulting in an incomplete injection," and directed the sponsor to lower the injection-time upper specification. 49 The sponsor lowered the injection-time specification "and provided adequate data to support the change," while declining to add an upper delivered-volume limit on the grounds that the syringe dimensions form a natural bound. 49 FDA concluded: "The reduction in the injection time specification is acceptable ... The lack of upper limit for injection volume is acceptable as it is bounded by the dimensions of the product. Response Adequate: Yes." 49
On release testing, FDA expected release testing "for all essential performance requirements" across both presentations (PFS: break loose/glide force, cap removal force, delivered volume, extra activation force, needle safety activation/locking, override force; autoinjector: cap force, activation force, injection time, delivered volume, needle extension). 17 After a follow-up IR asking why acceptance criteria for Break Loose/Glide Force and Extra Activation Force could not be implemented immediately given that design specifications already existed, "the sponsor implemented the design specifications as the acceptance criteria for these EPRs," and FDA recorded: "This approach is acceptable. Response Adequate: Yes." 17 FDA later summarized that "the Sponsor provided adequate information to support the manufacturing control activities for the essential performance requirements of the combination product." 3371
ENTYVIO Pen (vedolizumab), BLA 761133
For the Entyvio Pen autoinjector, FDA challenged the shelf-life reliability evidence, noting the sponsor had "verified the functional performance ... of your autoinjector using a [redacted] confidence and reliability limit," but that the real-time (12-month) and accelerated (24-month) shelf-life testing "only tested the functional performance up to a[ redacted] reliability," so the sponsor had not shown the autoinjector "can maintain its performance up to the proposed shelf-life." 3 The sponsor supplied a variables analysis of the performance attributes and referenced the real-time and accelerated aging data, and FDA marked the response "Adequate: ... Yes." 3 FDA separately pressed on clogged autoinjector samples, stating that "invalidating test samples from analysis is not acceptable" and demanding a root cause; the sponsor's response was likewise accepted. 3
On risk management, FDA observed that "your autoinjector Risk Management Summary does not provide a clear risk/benefit analysis for risks in the As Far as Possible/yellow region," so labeling adequacy could not be judged. 40 The sponsor "updated their risk management summary to include a more thorough risk-benefit assessment" with added drug and device risk detail, and FDA recorded "Response Adequate: Yes." 40
TYENNE (tocilizumab-aazg), BLA 761275
FDA issued an IR that the autoinjector cap-removal-force acceptance criterion was set too high, noting that a tighter limit is typically expected "especially with Rheumatoid Arthritis patients," and asked the sponsor to revise it. 37 The company "acknowledge[d] FDA guidance and confirm[ed] implementation of the Cap Removal Force ... acceptance criteria" at the tighter value and updated the administration-device section of the application. 37 The reviewer concluded: "Sponsor's response is adequate." 37
BYNFEZIA PEN (octreotide), NDA 213224
On this pen-injector combination product, FDA (via a CDRH consult to CDER) asked the sponsor to strengthen the delivered-dose-accuracy specification by adding "an upper and lower limit for the actual amount (mcg) of the active ingredient present in the delivered dose," taking into account the actual assay value and dispensed volume. 67 The sponsor "added delivered dose accuracy in mcg in the specification" and provided a consolidated release-and-stability specification table plus batch and stability data. 65 FDA's resolution language was explicit: "The batch analysis and stability testing results showed that the delivered dose accuracy and average activation (injection) force met their specifications at release and during stability study up to 3 months. CDRH has no further information request from the sponsor." 65 The same conclusion is repeated in the CDRH consult record. 39
TRYNGOLZA (olezarsen), NDA 218614
For the olezarsen autoinjector, FDA cited a quality-system deficiency: the sponsor "has not provided adequate description of how non-conforming products are handled during manufacturing and assembly" (21 CFR 820 Subpart I) and "has not provided adequate information on the measures taken to ensure the integrity of labeling and packaging ... post manufacturing and storage" (Subpart K). 41 The sponsor's IR response summarized the SOPs and controls it uses "to achieve a hybrid approach for the drug product's management controls to address relevant elements of 21 CFR 820, including subparts I and K." 41 FDA concluded: "The provided information indicates adequacy of the sponsor's SOPs and management controls. The response is acceptable." 41
ZURNAI (nalmefene), NDA 218590
The Zurnai autoinjector is assembled around a prefilled syringe, and FDA noted that PFS attributes "such as Break Loose and Glide Force influence the delivery of Nalmefene and should be considered in your reliability and performance testing protocols." 74 FDA questioned the activation force as "appear[ing] to be high for activation of an autoinjector" and invited the sponsor to consider narrowing the specification. 74 The sponsor provided a written justification citing a CPSC-equivalent study supporting both the activation-force and cap-removal-torque specifications. 74 FDA accepted it: "This justification is acceptable and there are no indications that the activation force specification is too high for the product," 74 and, on the broader EPR set (needle-shield removal, safety-cap removal torque, trigger/activation force, exposed needle length, device triggers, delivered volume, injection time, viewing-window occlusion), "The device EPRs are acceptable." 1
What these examples show
Across these applications, three patterns recur for RA teams preparing autoinjector combination-product submissions. First, FDA device reviewers scrutinize the full EPR panel (break-loose/glide and cap-removal forces, activation/trigger force, injection time, delivered volume, needle extension, separation force) and expect release and stability testing plus acceptance criteria for each. Second, a persuasive written justification or alternative dataset can satisfy an IR even when it does not deliver the exact study or limit FDA named, as IDACIO's sharps-injury and delivered-volume exchanges and ZURNAI's activation-force justification demonstrate. Third, the fastest path to an "acceptable" disposition is often to adopt the existing design specification as the release acceptance criterion rather than deferring it, as IDACIO did for Break Loose/Glide and Extra Activation Force. Because the public review record redacts the numeric acceptance criteria, teams needing the exact thresholds or the full IR sequence for any one product should follow up on that specific application.