# Official Source Ledger **Research date: 2026-07-27.** Every framework claim in this skill traces to an entry below. Re-check each source before operational use — guidelines are revised, editions change, and regional implementation dates differ from adoption dates. This ledger is a version baseline. It is not legal advice, an applicability determination, or a substitute for a controlled copy held under the laboratory's document control. ## Documents read directly These were downloaded and read as full text on the research date, so the requirements encoded in `scripts/_catalog.py` and summarised in `references/ich-q2r2.md` and `references/ich-m10-bioanalytical.md` come from the primary source rather than from secondary summaries. ### ICH Q2(R2) Validation of Analytical Procedures - Source read: - Verified metadata: Final Version, adopted by the ICH Assembly Regulatory Members under Step 4 on **1 November 2023**. Step 2 endorsement 24 March 2022. Supersedes Q2(R1) (November 2005). - Verified detail: an **error correction dated 30 November 2023** covers Table 5 (dissolution with HPLC, reportable range linearity formulae, page 25) and Tables 6–11 (pages 26–32). - Content taken: section structure; Table 1 (tests by measured attribute); Table 2 (reportable range examples); recommended data for specificity, response, lower range limits, accuracy, precision, and robustness; sections 2.1–2.5; Annex 1 and Annex 2 table inventory; the relative response factor 0.8–1.2 rule from Annex 2 Table 3. - Licence: ICH permits use, reproduction, adaptation and distribution under a public licence provided ICH's copyright is acknowledged. Acknowledged here and in `scripts/_catalog.py`. - Limitation: **adoption is not implementation.** Confirm the date from which your regional regulator expects Q2(R2) with that regulator. ### ICH M10 Bioanalytical Method Validation and Study Sample Analysis - Source read: - Verified metadata: Step 4, dated **24 May 2022**. - Content taken: chromatographic criteria (section 3) — calibration levels and tolerances, QC placement at four levels with the low/medium/high definitions, within-run and between-run accuracy and precision design and criteria, routine-run QC pass rules, carry-over, selectivity source count, dilution integrity, stability; ligand binding assay criteria (section 4) — calibration tolerances including anchor point exclusion, five QC levels, run and replicate structure, accuracy and precision criteria at LLOQ and ULOQ, and the total error criterion; incurred sample reanalysis (section 5) including the percent-difference basis and the pass fractions. - Verified distinction: the **total error criterion (≤30%, ≤40% at LLOQ and ULOQ) appears for ligand binding assays**. No equivalent criterion was found for chromatographic assays. - Licence: as for Q2(R2). - Limitation: regional implementation dates differ. Confirm with the regional regulator. ### ICH Q14 Analytical Procedure Development - Source read: - Content taken: section structure; the minimal versus enhanced approaches (section 2.1); the analytical target profile (section 3) and that its formal documentation and submission is **optional**; robustness and parameter ranges (section 5); established conditions (section 6.1); lifecycle management and post-approval change (section 7); multivariate procedures (section 8). - Adopted alongside Q2(R2) by the ICH Assembly in the same session. - Licence: as for Q2(R2). ## Documents identified but not read (paywalled) Designation, title, and scope only. **No requirement, threshold, or study design from any of these is reproduced anywhere in this skill.** Where a numeric criterion is needed, read it from an authorised copy. ### USP–NF general chapters - Official pages: `<1220>` ; `<1225>` ; `<1226>` - Verified metadata for `<1220>`: incorporated into USP–NF 2022 Issue 1 on **1 November 2021**, **official 1 May 2022**. It brings the concepts of `<1224>`, `<1225>` and `<1226>` into a single three-stage lifecycle. `<1225>` covers validation, particularly Stage 2 activities under `<1220>`; `<1226>` covers verification of compendial procedures. - Provenance limitation: this metadata came from **secondary sources** (publisher notices and trade press) rather than from the USP–NF text, which is behind subscription. Marked **[confirm in USP–NF]**. Confirm the current official text, revision, and any subsequent change. - Chapters referenced by designation only, not read: `<1224>`, `<1010>`, `<621>`, `<711>`, `<1092>`. ### CLSI EP series - Publisher: - Designations and subjects recorded in `references/compendial-and-clsi.md`: EP05, EP06, EP07, EP09, EP15, EP17, EP25, EP28 (formerly C28), plus the EP17IG and EP28IG implementation guides. - Provenance limitation: designations, titles and edition numbers were taken from **clsi.org product listings and secondary sources** on the research date, not read from the documents. Every edition number carries **[confirm edition]** in the reference file. Editions change; verify on clsi.org before designing a study. ### ISO standards - ISO/IEC 17025:2017 — . Edition 3; supersedes the 2005 edition. Relevant clauses: 7.2 (selection, verification and validation of methods), 7.6 (measurement uncertainty). Not read; identified by catalogue metadata. - ISO 15189, ISO 21748, ISO 5725 series — referenced by designation and scope only. - Provenance limitation: ISO catalogue pages have historically refused automated access. Confirm edition and status on iso.org or with a national member body. **[confirm on iso.org]** - See this repository's `iso-standards-readiness` skill and its own source ledger for the accreditation-level treatment of these standards. ## Statistical methods The statistical procedures in `references/statistics.md` and `scripts/_common.py` are standard published methods, not requirements of any framework: - Incomplete beta and gamma function implementations follow the standard continued-fraction and series algorithms; the t, chi-square and F distributions are derived from them. - Lack-of-fit F test against pure error: standard regression ANOVA. - Wald–Wolfowitz runs test: standard non-parametric test of randomness in a sequence of signs. - One-way random-effects variance components with the standard unbalanced expected-mean-square coefficient; Satterthwaite approximation for effective degrees of freedom of the total. - Deming regression with jackknife standard errors; Passing–Bablok with the rank-based slope interval. - Bland–Altman bias and limits of agreement. - Two one-sided tests (TOST) for equivalence. Implementations are verified against published quantiles and hand-checkable cases in `tests/analytical-method-validation/test_scripts.py`. Where a framework prescribes a specific statistical treatment, the framework governs — these are the general-purpose tools. ## What is deliberately absent - No numeric acceptance criteria are supplied for ICH Q2(R2) work. The guideline does not set them and neither does this skill; they come from the specification, the analytical target profile, or development data. - No text, table, threshold, or study design from any USP, CLSI, or ISO document. - No claim that a procedure is validated, a run acceptable, or an investigation closed.