This is a ready-to-use worksheet for the mechanical core of ICH Q12: walking every control-strategy element to a documented established-condition (EC) decision. It is the working paper behind the PLCM document’s EC table, not a replacement for it; keep this matrix as supporting evidence and transcribe the outcome into the PLCM document. Replace every <<FILL: ...>> placeholder with your own specifics and keep it under change control. A worked specimen follows. Verify each cited regulation against the current source before you rely on it.
Document control header
| Field | Entry |
|---|---|
| Matrix title | Established Conditions Identification and Classification, <<FILL: PRODUCT / DOSSIER>> |
| Document number | <<FILL: MTX-ID, e.g. RA-EC-004>> |
| Version | <<FILL: version>> |
| Effective date | <<FILL: date>> |
| Owner | <<FILL: regulatory CMC lead>> |
| Development approach | <<FILL: minimal / enhanced, and which elements have a registered design space>> |
1. Purpose
Provide a documented, auditable decision for every control-strategy element of <<FILL: PRODUCT>>: whether it is an ICH Q12 established condition, at what form, and what regulatory reporting category a future change to it would trigger. This worksheet is the evidence trail an assessor reads when the EC summary in the PLCM or the dossier is questioned.
2. Methodology
For each element pulled from the actual master batch record and registered specification (not from a development report), assess:
- CQA linkage. Does the element plausibly affect a critical quality attribute, per the development data and the ICH Q11 criticality assessment? No plausible linkage is a strong non-EC signal.
- Impact. If linked, how strong is the influence on the CQA.
- Evidence. How well is the impact relationship characterized (single-factor data, multivariate DOE, a registered design space, platform knowledge).
- EC form. Parameter-based (the value is binding), performance-based (the output is binding, inputs are free within the control strategy), or design-space-linked (the registered boundary is binding, movement inside it is free).
- Proposed reporting category. The regional category (for example prior approval / Type II, moderate / CBE-30 / Type IB, or notification / annual report / Type IA) a future change to this element would need, justified by impact and evidence, not by convenience.
Apply ICH Q9(R1) quality risk management to the impact and evidence ratings; do not assign a category without a documented rationale a reviewer who has never seen the product could follow.
3. Established conditions worksheet
One row per control-strategy element. Add rows as needed; do not omit an element because the answer seems obvious.
| Element | Dossier location | CQA(s) affected | Impact (H/M/L) | Evidence strength (H/M/L) | EC? (Y/N) | EC form | Proposed reporting category | Rationale summary |
|---|---|---|---|---|---|---|---|---|
<<FILL: e.g. drug substance final synthesis step>> | <<FILL: 3.2.S.2.2>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> |
<<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> |
<<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> | <<FILL>> |
4. Non-established-condition log
Elements explicitly considered and ruled non-EC, with the negative evidence, so a reviewer sees the decision was made, not skipped.
| Element | Why no CQA linkage / why non-binding | Supporting data reference |
|---|---|---|
<<FILL>> | <<FILL>> | <<FILL>> |
5. Acceptance criteria
- Every control-strategy element pulled from the current master batch record and specification has a row; none are missing because they seemed trivial.
- Every EC has a documented form (parameter-based, performance-based, or design-space-linked) matched to the strength of the supporting evidence, not to the flexibility the business wants.
- Every non-EC designation rests on data in section 4, not on an unsupported assertion.
- The proposed reporting category for each EC is justified by impact and evidence and is consistent with the dossier detail in the column “Dossier location.”
- The worksheet total reconciles line for line with the EC table transcribed into the PLCM document.
6. References
ICH Q12, Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, Annex I (established conditions examples). ICH Q9(R1), Quality Risk Management. ICH Q11, Development and Manufacture of Drug Substances (criticality assessment). ICH Q8(R2), Pharmaceutical Development (design space).
Confirm the current version and clause numbers of each reference before issue.
7. Revision history
| Version | Date | Author | Summary of change |
|---|---|---|---|
<<FILL: 1.0>> | <<FILL: date>> | <<FILL>> | Initial worksheet. |
8. Approvals
| Role | Name | Signature | Date |
|---|---|---|---|
| Process development / MSAT | <<FILL>> | ||
| Regulatory affairs (CMC) | <<FILL>> | ||
| Quality assurance | <<FILL>> |
Filled specimen
The following shows three illustrative rows for an immediate-release tablet product. Numbers and values are illustrative.
| Element | Dossier location | CQA(s) affected | Impact | Evidence | EC? | EC form | Proposed category | Rationale summary |
|---|---|---|---|---|---|---|---|---|
| Granulation end-point moisture (LOD) | 3.2.P.3.3 | Dissolution, content uniformity | High | Medium (single-factor development data, no registered design space) | Y | Parameter-based, 2.0% w/w point value | Moderate | Development batches at 1.6-2.4% LOD all met dissolution and CU specification, but the relationship was not characterized as a multivariate model, so the EC stays parameter-based pending a proven-acceptable-range study |
| Blend uniformity result | 3.2.P.3.4 | Content uniformity | High | High (platform method, validated RSD acceptance) | Y | Performance-based, RSD <= 5.0% | Moderate / CBE-30 | Output-based control; the mixing parameters that achieve it are managed internally under the process control strategy |
| Tablet press turret rotation speed | 3.2.P.3.3 | None identified at current speed range | Low | High (12 development and 3 validation batches across the operating range, all in specification) | N | N/A | N/A | No demonstrated CQA linkage across the studied range; managed under internal process control, logged in section 4 |
Common inspection findings this matrix prevents
- An EC table that lists conclusions (“not an established condition”) with no row showing the CQA-linkage data behind the call.
- A performance-based EC claimed without the input-output characterization to support it.
- Elements missing from the worksheet entirely because they were assumed too minor to document.
- A reporting category that does not track the stated impact and evidence rating.
- A worksheet that no longer matches the PLCM because one was updated and the other was not.
How to adapt this matrix
- Pull the full control-strategy element list from the current master batch record and registered specification, not from a development report or from memory.
- Score impact and evidence per element using your actual development data and the Q11 criticality assessment; do not default every element to “high impact” for safety, since that produces an unusable, overly rigid EC table.
- For every non-EC call, complete section 4 with the actual negative evidence.
- Transcribe the final EC list, form, and reporting category into the PLCM document and confirm the two documents agree line for line.
- Re-run the affected rows whenever new characterization data, a registered design space, or an ICH Q11 criticality update changes the evidence basis.