framework-selection.md
87 lines · skills/analytical-method-validation/references/framework-selection.md at 5f2bc03
Most marks come from matching words in the file, so treat them as pointers.
Which Framework Governs
Research basis: 2026-09-30. Confirm every date and edition against the official source before relying on it; see source-ledger.md.
Framework selection is the first decision and the one most often skipped. Getting it wrong invalidates the protocol regardless of how well the studies are executed, because each framework requires a different set of characteristics, a different study layout, and a different treatment of acceptance criteria.
Raw lines 1 to 10The deciding questions, in order
1. Is the measurand a drug concentration in a biological matrix, supporting a nonclinical or clinical study? → ICH M10. This covers pharmacokinetics, toxicokinetics, and bioequivalence. M10 supplies explicit numeric criteria, and they differ between chromatographic assays and ligand binding assays. Q2(R2) does not govern here.
2. Is it a quality attribute of a drug substance or drug product — assay, potency, impurity, identity, dissolution, content uniformity? → ICH Q2(R2) for validation, with ICH Q14 for development, robustness, the analytical target profile (formal documentation optional), and lifecycle change management. If the procedure is compendial and being used as written, see question 3 first.
3. Is the procedure a compendial (pharmacopoeial) procedure? → USP <1226> verification if it is used as written and within its stated scope. Verification assesses selected characteristics to show the procedure works under actual conditions of use; it is not revalidation and does not repeat the full study. → USP <1225> validation if the procedure is non-compendial, or compendial but used outside its scope. Confirm the effective edition: the linked 2025 <1225> preview is a proposal. Both sit inside the USP <1220> three-stage lifecycle. Regional pharmacopoeias (Ph. Eur., JP) have their own general chapters — check which pharmacopoeia the specification cites.
4. Is it a clinical laboratory measurement procedure reporting patient results? → CLSI EP series, inside a CLIA/CAP or ISO 15189 quality system. The vocabulary differs from pharmaceutical work: verification of a manufacturer's claims for an unmodified FDA-cleared or approved nonwaived assay is a much smaller exercise than establishment of performance for a laboratory-developed test, and the distinction is regulatory, not stylistic.
5. Is the laboratory accredited to ISO/IEC 17025 and the method non-standard, laboratory-developed, or a modified standard method? → ISO/IEC 17025 clause 7.2.2 requires validation as extensive as necessary to meet the needs of the intended application, plus measurement uncertainty under clause 7.6. It does not prescribe one universal characteristic checklist or numeric acceptance limits; the laboratory justifies both.
6. Is it an environmental, food, or forensic method under a prescribed method system? → The method system governs (for example a published EPA method, an AOAC Official Method, or a regulator's prescribed procedure), usually with its own validation and QC requirements written into the method itself. Do not substitute a pharmaceutical framework.
Raw lines 11 to 49More than one can apply
Common and legitimate. A contract laboratory accredited to ISO/IEC 17025 running a compendial assay for a pharmaceutical client satisfies <1226> for the procedure and 17025 clause 7.2 for the accreditation scope, with the client's specification supplying the criteria. Record which framework each requirement traces to, so a later change can be assessed against the right one.
Raw lines 50 to 56Do not blend them
The failure mode is a protocol that mixes Q2(R1)-era characteristic names, an M10 numeric tolerance imported because it was memorable, and a CLSI study layout. It satisfies none of the three and is hard to defend because no single source can be cited for any of it. If a requirement is in the protocol, name the framework and section it comes from.
Raw lines 57 to 63Where the numbers come from
| Framework | Numeric acceptance criteria |
|---|---|
| ICH Q2(R2) | Almost none. Derive from the specification, the ATP, or development data, and justify. |
| ICH Q14 | None. It supplies the ATP concept and the development/robustness framework. |
| ICH M10 | Explicit, and modality-dependent. Use them as written. |
| USP <1225>/<1226>/<1220> | Consult the authorised text. |
| CLSI EP | Consult the authorised text; many EP documents supply study designs rather than limits. |
| ISO/IEC 17025 | None. The laboratory sets and justifies them. |
Q2(R2)'s reticence is deliberate: a criterion that is not tied to what the result is used for is arbitrary. An assay releasing product against a 95.0–105.0% specification needs different precision than one supporting a 70–130% content-uniformity limit. Deriving the criterion from the decision the result supports is the substance of the exercise, not paperwork around it.
Raw lines 64 to 79Related skills in this repository
iso-standards-readiness— the surrounding quality system (ISO/IEC 17025, ISO 15189 accreditation readiness, quality manual, CAPA). That skill operates at the laboratory level; this one operates at the level of a single procedure.statistical-analysis,statistical-power— general inference and study sizing.uncertainty-and-units— unit handling and measurement uncertainty propagation, which ISO/IEC 17025 clause 7.6 requires alongside validation.