Comprehensive Answer:

Based on a review of multiple FDA review documents and regulatory submissions, the FDA does not universally or explicitly require that autoinjectors or prefilled pens undergo all prefilled syringe performance tests specified in ISO 11040, such as leakage beyond the plunger or flange break resistance, as part of the final device testing. However, the FDA does expect that the relevant performance characteristics of the prefilled syringe component—often referenced in ISO 11040—are addressed and justified within the combination product submission. There are some nuanced and occasionally conflicting interpretations in the regulatory landscape, summarized below.

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1. FDA’s General Approach

• Component vs. Final Device Testing:
  The FDA typically distinguishes between:

  • Testing of the prefilled syringe component (prior to assembly into the autoinjector or pen), and
  • Device-level testing (after assembly into the autoinjector or pen).

  The FDA expects that the prefilled syringe component meets relevant performance requirements (which may include ISO 11040 tests) before it is assembled into the final device. The final autoinjector or pen is then tested for its own functional performance, not necessarily for all prefilled syringe-specific tests such as leakage beyond the plunger or flange break resistance ²⁰²¹²².

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2. Leakage Beyond the Plunger

• Expectation for Demonstration:
  The FDA expects demonstration of container closure integrity and leakage testing for the prefilled syringe component. This is sometimes referenced to ISO 11040-8, which includes tests for leakage beyond the plunger ⁷⁹. For example, in the SKYRIZI (risankizumab) review, the sponsor demonstrated compliance with ISO 11040-8 for leakage beyond the plunger ⁷.

• Not Always Explicitly Required:
  While leakage testing is expected, the FDA does not always mandate that it be performed exactly as specified in ISO 11040, nor is it always required at the device (autoinjector/pen) level. Instead, the FDA may accept alternative standards (e.g., ISO 11608-3, ISO 13926-2) or sponsor-justified methods that demonstrate equivalent integrity ¹³⁷⁹.

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3. Flange Break Resistance

• Not Universally Required:
  There is no consistent evidence that the FDA requires explicit testing for flange break resistance (as specified in ISO 11040) for autoinjectors or prefilled pens. Some reviews discuss the need to address risks related to device breakage and may request justification if ISO 11040 requirements (such as annealing or flange strength) are not met, but do not mandate the specific test ²⁴.

• Risk-Based Justification:
  If a sponsor deviates from ISO 11040 (e.g., does not perform flange break resistance testing), the FDA expects a risk-based justification and may request data or rationale for how the risk of breakage is mitigated ²⁴²⁵²⁶.

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4. FDA’s Focus on Essential Performance Requirements

• Device-Level Testing:
  For the assembled autoinjector or pen, the FDA focuses on essential performance requirements such as:

  • Dose accuracy
  • Activation force
  • Injection time
  • Breakloose force
  • Glide force
  • Tip cap removal force

  These are often referenced in FDA review comments, but leakage beyond the plunger and flange break resistance are not universally listed as required tests for the final device ^{1420212227282931}.

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5. Reference to ISO Standards

• ISO 11040 as a Benchmark:
  The FDA frequently references ISO 11040 as a benchmark for prefilled syringe performance, especially for the syringe component of a combination product. However, full compliance with all ISO 11040 tests is not always required, and sponsors may reference alternative standards or justify their testing strategy ^5679111214.

• Case-by-Case Flexibility:
  The FDA may accept alternative test methods or rationales if full ISO 11040 compliance is not feasible, provided that safety and effectiveness are demonstrated ⁶⁷⁹²⁴.

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6. Conflicting Interpretations

• Some FDA reviews and sponsor submissions indicate that compliance with ISO 11040 (including leakage beyond the plunger) is expected for the prefilled syringe component, even if not for the final device ⁷⁹⁵⁶.
• Other reviews show that the FDA does not explicitly require all ISO 11040 tests for autoinjectors or prefilled pens, and instead focuses on risk-based justification and essential performance requirements ^{14202122242526}.

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Summary Table

Performance Test	FDA Requirement for Autoinjector/Pen	Notes
Leakage beyond the plunger	Expected for syringe component; not always at device level	Often referenced to ISO 11040-8; alternative standards/methods may be accepted 7913
Flange break resistance	Not universally required; risk-based	FDA may request justification if not performed; not a blanket requirement 242526
Other ISO 11040 tests	Not universally required	FDA focuses on essential performance for device; ISO 11040 used as benchmark 14202122

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Conclusion

The FDA does not categorically require that autoinjectors or prefilled pens be tested for all prefilled syringe performance characteristics specified in ISO 11040, such as leakage beyond the plunger or flange break resistance. Instead, the FDA expects that the prefilled syringe component demonstrates relevant performance (often referencing ISO 11040), and that any deviations from ISO 11040 are justified with a risk-based rationale. For the final device, the FDA’s focus is on device-level functional testing and essential performance requirements, not on repeating all prefilled syringe-specific tests ^{1356791112141516171820212224252627282931}.

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References:
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(Note: Reference numbers correspond to those in the original provided answers.)