Below is a summary of questions CDER has asked in BLA reviews since 2023 related to design verification testing, shipping testing, PPQ/process validation, and essential performance requirements (EPRs) for autoinjectors and prefilled pens. Human factors, IFU, and prefilled syringe/vial topics are excluded.

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1. Design Verification Testing

• Request for Design Verification Reports and Data

  • CDER has asked sponsors to provide design verification reports for autoinjectors and prefilled pens, including summary test results and full test reports for verification and validation testing. For example:
    • "Please provide your design verification reports for the AI [autoinjector]."
      "Please provide your risk analysis assessment used for the design of your final drug product with respect to the device design." ²⁸
    • "Design Verification Data included in the NDA / BLA or adequately cross-referenced to a master file." ⁷³⁴⁷⁴
    • "You did not verify the separation force of your AI in your design verification real time/accelerated aging or shipping testing. You should verify your design inputs after conditioning that is representative of intended use. Provide data verifying the separation force of your AI after aging (real-time or accelerated) and simulated shipping. Alternatively, provide rationale why separation force would not be impacted by aging or shipping." ³⁹
    • "The sponsor did not provide verification testing of your auto-injector including 'Audible Click... Deficiency will be issued to the firm." ¹⁹
    • "Please provide design verification testing data verifying the ... dose delivered specification is consistently achieved by your device per your quality control strategy." ⁴⁷

• Sample Size and Reliability

  • CDER has questioned the adequacy of sample size and statistical assurance in design verification:
    • "Your sample size should be based on your risk assessment and should provide an adequate level of statistical assurance of 95% confidence with 95% reliability that your device will perform as intended to the end of its proposed shelf-life." ¹³

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2. Shipping Testing

• Requirement for Shipping Validation Studies

  • CDER has asked for shipping validation studies to demonstrate that device performance and product quality are maintained after shipping:
    • "Conduct one shipping validation run in summer 2024 for final packaged autoinjector (AI) to validate the shipping from (r) to the US distribution sites from a temperature control perspective. Provide the report and summary validation data." ²²
    • "To perform commercial shipping studies to qualify the actual shipping conditions for the drug product (prefilled pen). The commercial shipping studies will include: ... Device functionality tests to demonstrate that the shipping conditions do not adversely impact the integrity and functionality of the device." ⁶⁰
    • "Provide testing after simulated shipping per ASTM 4169-16, Standard Practice for Performance Testing of Shipping Containers and Systems on your final finished device in the final packaging." ^5101116
    • "CCIT [Container Closure Integrity Testing] testing is always performed after shipping due to the different locations of the AVT02 manufacturing and assembly facilities and the CCIT testing facility." ⁷³³⁵

• Specific EPR Testing After Shipping

  • "In order to ensure proper functioning of the ... lockout force, provide testing after simulated shipping ... on your final finished device in the final packaging." ^51011167027

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3. PPQ/Process Validation

• Submission Timing and Content

  • CDER has asked for PPQ reports for assembly of autoinjectors/prefilled pens to be submitted at the time of BLA submission, not as a post-submission update:
    • "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." ⁸

• Process Validation Data

  • "The Sponsor also described process validation of the device functionalities -- AI ... This is reviewed within the table below." ³³

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4. Essential Performance Requirements (EPRs)

• Identification and Verification of EPRs

  • CDER has asked sponsors to:
    • Identify EPRs for autoinjectors/prefilled pens (e.g., dose accuracy, injection force, injection time, needle extension).
    • Provide verification and validation data for each EPR, including after aging and shipping.
    • "For each identified essential performance requirement, your marketing application should include verification and validation information of EPR specifications. The final set of essential performance requirements should be based on your design control process." ^14215517
    • "You should evaluate all your essential performance requirements (EPRs) at batch release." ⁴⁸
    • "The Sponsor provided the following control strategy information regarding the EPRs of the device constituents for the AI ... The Sponsor also described process validation of the device functionalities -- AI ..." ^33515667
    • "Essential Performance Verification ... Delivered Volume ... Delivery Time ... Needle Extension ... Cap Removal Torque ... Needle Guard Force ... Activation force ... Time between clicks ... Needle Guard Override Deflection ..." ⁵²

• Control Strategy for EPRs

  • CDER has asked for a control strategy that ensures EPRs are maintained through incoming acceptance, in-process, and release testing:
    • "Provide a control strategy that ensures that the final finished combination product maintains its essential performance requirements. The control strategy may consist of, but is not limited to, lot release, in-process, control of incoming materials, purchasing controls, etc." ^4956673351

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5. Other Related Questions

• Batch Records and Testing Across Configurations

  • "It is unclear if you mean you only intend to provide functional data to support the lower concentration and strength prefilled pen configuration ... Please note that we will expect you to provide data to support both prefilled pens ... as the concentration can impact the functional performance testing." ⁹

• Stability Testing for Device Functionality

  • "Your stability program should include endpoints to verify that device essential performance is maintained at expiry." ^14485253

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Summary Table of Example Questions

Topic	Example CDER Question/Request	Source(s)
Design Verification	Provide design verification reports for the AI (autoinjector).	287347419471339
Shipping Testing	Provide testing after simulated shipping on your final finished device in the final packaging.	5101116226070277335
PPQ/Process Validation	Submit all PPQ results for assembly of AI at the time of BLA submission.	833
EPRs	Identify and verify EPRs for the device; provide verification data for each EPR at batch release and after aging/shipping.	1421551748335156675249
Control Strategy for EPRs	Provide a control strategy ensuring EPRs are maintained through acceptance, in-process, and release testing.	4956673351
Batch Records/Multiple Configs	Provide data to support all prefilled pen configurations as concentration can impact functional performance.	9
Stability Testing	Include endpoints in stability program to verify device essential performance at expiry.	14485253

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Note: Some sources contain redactions or missing data, which may limit the specificity of certain questions.