# Which Framework Governs

Research basis: **2026-07-27**. 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.

## The 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, 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. 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 FDA-cleared 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 sets no characteristic
list and no numeric criteria; 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.

## More 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.

## Do 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.

## Where 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.

## Related 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.