Performing a deep dive on the data from the CRL list just published by the FDA, we have looked into the highest ranked reason for the FDA saying “No” to your filing. Here are the recurring themes we see in CMC-related CRLs:
- Incomplete or Inadequate Process Validation
FDA wants to see that your process is robust, reproducible, and controlled—especially for critical quality attributes (CQAs) and critical process parameters (CPPs).
What goes wrong:
- Sponsors submit validation protocols instead of completed reports
- PQ data is limited or missing across multiple lots
- Equipment is qualified, but processes are not proven to be in control
FDA’s View: If you haven’t shown the process performs as intended, you haven’t earned the right to commercialize.
- Poor Control of Raw Materials or Intermediates
CMC packages must clearly define how raw materials and intermediates are sourced, controlled, and tested — especially if sourced globally.
What goes wrong:
- No justification for acceptance criteria
- Lack of supplier qualification and testing verification
- Gaps in traceability or impurity profiles
FDA’s Message: Weak control of your inputs casts doubt on your outputs.
- Inadequate Container Closure System Information
You’re expected to demonstrate that the final packaging protects the product throughout its shelf life—particularly for injectables, biologics, and sterile products.
What goes wrong:
- Missing extractables/leachables data
- Incomplete compatibility testing
- No microbial integrity testing (e.g., for prefilled syringes or vials)
Impact: Even a perfect drug substance can be rejected if the container system isn’t fully qualified.
- Gaps in Stability Data and Shelf-Life Justification
FDA requires stability data across multiple batches, under ICH conditions, to justify your proposed expiration date.
What goes wrong:
- Not enough lots or insufficient real-time data
- Accelerated data used without clear modeling
- No justification for in-use stability or transportation stress conditions
Bottom line: If you can’t prove how long the product lasts, FDA won’t guess for you.
- Weak Justification of Specifications and Test Methods
Sponsors must define appropriate and meaningful specifications for release and stability—based on sound science and analytical validation.
What goes wrong:
- Broad, unjustified acceptance criteria
- Methods not fully validated or transferred
- No link between CQAs and test parameters
FDA will ask: How do you know what “good” looks like—and can you consistently measure it?
- Site or Facility Readiness Deficiencies
A well-prepared CMC submission can still fail if the manufacturing site isn’t audit ready. Often, CRLs cite 483s, inspection delays, or unaddressed remediation plans.
Common issues include:
- Incomplete CAPAs from prior inspections
- No QA oversight of validation activities
- Insufficient environmental monitoring or data integrity controls
What This Means for Sponsors
Too often, companies treat the CMC section of the submission like a formality—something to “wrap up” after clinical trials. But FDA sees it for what it is: proof that you can reliably, safely, and reproducibly deliver your product at scale.
If there’s any sign of weakness — FDA won’t move forward. It’s that simple.
How to Get It Right: Key CMC Readiness Strategies
- Start CMC work early. Don’t wait for Phase 3 to define your process, finalize test methods, or start stability testing.
- Treat validation as a performance demonstration. Show that your process works under real-world conditions, not just in theory.
- Engage QA and compliance leadership during development. Validation, testing, and document control must be QA-owned—not just tech ops functions.
- Conduct internal mock reviews of your Module 3. You’d be surprised what gaps are hiding in plain sight.
- Don’t underestimate the inspection. A well-written CMC section can still be undermined by a facility that isn’t inspection ready. Prepare accordingly.
Final Thought: CMC Isn’t “Back of the Book”—It’s the Whole Foundation
CMC isn’t the end of the story. It’s the part the FDA reads the closest.
If you’re preparing to submit, we can help you pressure-test your CMC package, inspect your inspection readiness, and ensure that your operations match your filing. Because when it comes to commercialization, you don’t get to make promises—you have to prove them.
Want a complimentary FDA CMC Readiness checklist?? Click here