This is a ready-to-use checklist for reviewing the data integrity of the justification behind a comparability conclusion or a CMC flexibility position, not the scientific merit of the position itself. FDA’s CMC flexibilities framework for cell and gene therapy products allows phase appropriate CGMP expectations, risk based comparability scope, use of prior knowledge, a scientifically justified PPQ batch count, alternative analytical methods, and a lifecycle approach to specifications. None of that reduces what has to be true of the data behind the decision: it still has to be complete, attributable, and reconstructable, because when the dataset is smaller or the method is new, there is less redundant evidence to fall back on if the justification itself cannot be checked. Replace every <<FILL: ...>> placeholder, mark each item Pass / Fail / NA with evidence, and route the completed checklist through QA. A filled specimen follows. Verify each cited regulation and guidance against the current source before you rely on it.
Checklist header
| Field | Entry |
|---|---|
| Checklist number | <<FILL: ID>> |
| Program / product | <<FILL>> |
| Flexibility or comparability position under review | <<FILL: e.g. single representative PPQ lot, alternative potency method>> |
| Completed by / date | <<FILL>> |
| QA reviewed by / date | <<FILL>> |
How to score
Mark each item Pass (control in place and evidenced), Fail (gap), or NA (with a reason). Any Fail on a position that supports a BLA filing or an approved commercial specification is a finding to close before the position is relied on further.
Section A: Governing document
| # | Item | P/F/NA | Evidence / note | Reference |
|---|---|---|---|---|
| A1 | The flexibility position is supported by a named, approved, version controlled document, not an email thread, meeting minutes, or a briefing slide | <<FILL>> | <<FILL>> | FDA 2018 DI Q&A |
| A2 | The document was approved before, or independent of, seeing the data it was meant to justify (for a risk assessment or scope decision), not adjusted after the fact | <<FILL>> | <<FILL>> | ICH Q9 |
| A3 | Authorship and approval are attributable to named individuals with dates | <<FILL>> | <<FILL>> | ALCOA Attributable |
Section B: Reduced PPQ batch / representative lot justification
| # | Item | P/F/NA | Evidence / note | Reference |
|---|---|---|---|---|
| B1 | The rationale for the batch count, including any use of a single representative lot, is documented and traceable to process understanding, not asserted without support | <<FILL>> | <<FILL>> | FDA CMC Flexibilities guidance (final, May 2026) |
| B2 | Raw data behind every engineering run or development batch cited to support representativeness is retrievable, not summarized only | <<FILL>> | <<FILL>> | ALCOA Original |
| B3 | The representative lot’s own data (raw data, audit trail, disposition) is complete and was reviewed under the same rigor as a conventional PPQ batch | <<FILL>> | <<FILL>> | 21 CFR 211.192 |
Section C: Risk based comparability scope
| # | Item | P/F/NA | Evidence / note | Reference |
|---|---|---|---|---|
| C1 | An approved change to CQA risk assessment exists and set the comparability scope before testing began | <<FILL>> | <<FILL>> | ICH Q5E; ICH Q9 |
| C2 | Every lot in the comparability scope, including any that trended differently, is retained in the dataset and reported | <<FILL>> | <<FILL>> | FDA 2018 DI Q&A |
| C3 | Any lot excluded from the comparability dataset has a documented, approved scientific justification | <<FILL>> | <<FILL>> | FDA OOS guidance (Rev. 1, May 2022), by analogy |
Section D: Prior knowledge and platform data
| # | Item | P/F/NA | Evidence / note | Reference |
|---|---|---|---|---|
| D1 | Every prior knowledge or platform data citation has a traceable, attributable source, not a restated conclusion with no path back to raw data | <<FILL>> | <<FILL>> | ALCOA Original, Attributable |
| D2 | Where platform data comes from a different product or program, the basis for applying it here is documented, not assumed | <<FILL>> | <<FILL>> | FDA CMC Flexibilities guidance |
Section E: Alternative analytical methods
| # | Item | P/F/NA | Evidence / note | Reference |
|---|---|---|---|---|
| E1 | Method equivalence or bridging data exists comparing the alternative method to the method it replaces | <<FILL>> | <<FILL>> | ICH Q2(R2) |
| E2 | Bridging data was generated and reviewed under the same audit trail and second person review standard as a release test | <<FILL>> | <<FILL>> | FDA 2018 DI Q&A |
Section F: Stability and lifecycle specification setting
| # | Item | P/F/NA | Evidence / note | Reference |
|---|---|---|---|---|
| F1 | Stability data from clinical lots supporting a commercial expiration dating period is complete for every included lot, with any exclusion documented and justified | <<FILL>> | <<FILL>> | FDA CMC Flexibilities guidance |
| F2 | Every specification change has a dated rationale tied to the manufacturing data available at the time of the change | <<FILL>> | <<FILL>> | ICH Q12 |
References
FDA, Chemistry, Manufacturing, and Controls Flexibilities for Developing Human Cellular and Gene Therapy Products for a Biologics License Application (final Level 2 guidance, May 2026). 21 CFR Part 601 (licensing); 21 CFR 211.192, 211.194. ICH Q5E (comparability); ICH Q9 (quality risk management); ICH Q12 (lifecycle management); ICH Q2(R2) (analytical procedure validation). FDA Data Integrity and Compliance With Drug CGMP Q&A (final, Dec 2018).
Confirm each reference against the current source before issue.
Filled specimen
Illustrative extract for a single representative PPQ lot position supporting a defined release strategy.
| # | Item | P/F/NA | Evidence / note |
|---|---|---|---|
| A1 | Named, approved, version controlled document | Pass | Risk Assessment RA-2026-041, approved, version 2.0 |
| A2 | Approved before seeing the data it justifies | Pass | RA-2026-041 approved prior to PPQ execution per change control CC-2026-118 |
| B1 | Batch count rationale traceable to process understanding | Pass | RA-2026-041 section 4 cites platform history and two engineering runs (ENG-2026-004, ENG-2026-007) |
| B2 | Raw data behind cited runs retrievable | Fail | Engineering run raw data archived under a decommissioned system; retrieval pending IT request, logged as exception EX-2026-019 |
| C2 | All comparability lots retained, including outliers | Pass | Comparability report CR-2026-030 includes lot PUR-2026-0184, which trended low on one attribute, with a documented investigation |
| E1 | Bridging data for alternative method | Pass | Bridging report BRG-2026-012, 12 samples, both methods, statistically equivalent |
The Fail on B2 is exactly the kind of finding this checklist is built to surface before an inspector finds it: a scientifically sound representative lot position with a real gap in the retrievability of its own supporting raw data. It was logged as an exception and routed for remediation rather than left in the file.
Common inspection findings this checklist prevents
- A reduced testing or single lot position supported only by a narrative in a briefing document, with no underlying approved risk assessment.
- Prior knowledge cited by conclusion only, with no retrievable dataset behind the claim.
- A comparability or stability lot quietly excluded with no documented justification, caught only when someone reconciles the lot list against actual manufacturing records.
- An alternative method adopted for its efficiency without retained bridging data connecting it back to the method it replaced.
How to adapt this checklist
- Complete one checklist per flexibility position or comparability conclusion, not one checklist for an entire program; each position needs its own traceable evidence chain.
- Add or remove sections to match which flexibilities your program actually uses.
- Route any Fail through your deviation or CAPA process before the position is relied on in a filing or a release decision.
- Confirm every regulation and guidance reference against the current published version before issue.