@pikaa-ai/pikaa 0.2.4 → 0.3.0

package/skills/analytical-method-validation/references/framework-selection.md

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+# 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.

package/skills/analytical-method-validation/references/ich-m10-bioanalytical.md

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+# ICH M10 — Bioanalytical Criteria, by Modality
+
+Research basis: **2026-07-27**, read from the ICH Harmonised Guideline *Bioanalytical Method
+Validation and Study Sample Analysis M10*, Step 4 dated 24 May 2022. ICH licenses its documents for
+reuse with acknowledgement. Confirm the current text and your region's implementation at
+<https://database.ich.org/sites/default/files/M10_Guideline_Step4_2022_0524.pdf>.
+
+M10 harmonised what had been separate FDA and EMA bioanalytical guidance for studies in its scope:
+methods quantifying drug and metabolite concentrations in biological matrices supporting nonclinical
+and clinical studies, plus the analysis of study samples.
+
+## The distinction that matters most
+
+**Chromatographic assays (section 3) and ligand binding assays (section 4) have different numeric
+criteria throughout.** They are not stylistic variants of one set. Applying chromatographic
+tolerances to an LBA is the most common error in this area, and importing the LBA total-error
+criterion into a chromatographic method is its mirror image.
+
+| | Chromatographic | Ligand binding assay |
+| --- | --- | --- |
+| Calibration levels (minimum) | 6, including LLOQ | 6, including LLOQ |
+| Calibration standard tolerance | ±15% | ±20% |
+| … at LLOQ | ±20% | ±25% |
+| … at ULOQ | ±15% | ±25% |
+| Calibration standards that must pass | ≥75% | ≥75%, excluding anchor points |
+| Accuracy | ±15% | ±20% |
+| … at limits | ±20% at LLOQ | ±25% at LLOQ **and** ULOQ |
+| Precision (%CV) | ≤15% | ≤20% |
+| … at limits | ≤20% at LLOQ | ≤25% at LLOQ **and** ULOQ |
+| A&P QC levels | minimum 4 | 5 (LLOQ, low, medium, high, ULOQ) |
+| A&P replicates per level per run | ≥5 (within-run) | ≥3 |
+| A&P runs | ≥3 runs over ≥2 days | ≥6 runs over ≥2 days |
+| **Total error** | **no such criterion** | **≤30%; ≤40% at LLOQ and ULOQ** |
+| Routine run QC tolerance | ±15% | ±20% |
+| Routine run QC pass rule | ≥2/3 of all QCs **and** ≥50% at each level | same rule, ±20% |
+| Dilution integrity | mean within ±15% | mean within ±20% |
+| Stability | mean at each QC level within ±15% | mean within ±20% |
+| ISR agreement | within ±20% for ≥2/3 of repeats | within ±30% for ≥2/3 of repeats |
+| Selectivity sources/lots | ≥6 individual sources | ≥6 individual sources |
+| Carry-over in blank | ≤20% of LLOQ analyte response and ≤5% of IS response | per guideline |
+
+Verify any figure against the guideline before using it in a protocol; regional implementation and
+subsequent revisions can change the picture.
+
+## Chromatographic QC placement (section 3)
+
+Accuracy and precision validation QCs at a minimum of **four** concentration levels:
+
+- the **LLOQ**
+- **low QC** — within three times the LLOQ
+- **medium QC** — around 30–50% of the calibration curve range
+- **high QC** — at least 75% of the ULOQ
+
+For runs that are not accuracy-and-precision runs, low, medium and high QCs may be analysed in
+duplicate; these plus the calibration standards form the basis for accepting or rejecting the run.
+
+Calibration standards and QCs should be prepared from **separate stock solutions**, to avoid a bias
+that is not a property of the analytical performance. If a single stock must serve both, verify the
+accuracy and stability of that stock. A single source of blank matrix may be used if it is free of
+interference and matrix effects.
+
+Calibration curves for accuracy and precision assessment should use freshly spiked standards in at
+least one run; if other runs use frozen standards, demonstrate their stability.
+
+## Reporting obligations that catch people out
+
+**Report everything.** Validation data and the determination of accuracy and precision must include
+*all* results obtained, including individual QCs outside the acceptance criteria — except cases where
+errors are obvious and documented. Silently dropping an out-of-criteria QC is a data integrity
+problem, not a rounding decision.
+
+**Within-run accuracy and precision are reported per run.** If the within-run criteria are not met in
+every run, calculate an overall estimate of within-run accuracy and precision for each QC level.
+Between-run (intermediate) accuracy and precision combine data from all runs.
+
+**Trend within a run.** It is recommended to demonstrate accuracy and precision over at least one run
+sized like a prospective study-sample run, so time-dependent drift is visible.
+
+## Incurred sample reanalysis (section 5)
+
+ISR repeats the analysis of a subset of study samples in separate runs, to verify that measured
+concentrations in real samples are reproducible. It is not a substitute for QCs — QCs are spiked,
+incurred samples are not, and only incurred samples can reveal metabolite back-conversion, protein
+binding effects, or matrix instability.
+
+- The extent depends on the analyte and the samples and should be justified.
+- Objective criteria for choosing the subset should be **predefined**; selecting samples around
+  Cmax and the elimination phase is recommended.
+- **Do not pool samples** — pooling masks anomalous findings.
+- ISR samples and QCs are processed and analysed in the same manner as the original analysis.
+- Percent difference is `(repeat value - initial value) / mean value x 100` -- assessed
+  against the **mean of the two**, not against the initial value.
+- Repeats are performed within the analyte's stability window, but **not on the same day**
+  as the original analysis.
+- Acceptance: within ±20% for at least 2/3 of repeats (chromatographic), or within ±30% for at least
+  2/3 (LBA).
+
+For nonclinical studies in scope, ISR should in general be performed; the guideline notes incurred
+samples need only be included if available, so inclusion was not felt to be mandatory in every case.
+Confirm the situations requiring ISR against the guideline text for your study type.
+
+## Study sample reanalysis is a separate thing
+
+ISR is a method-reliability check. *Reanalysis of study samples* for a reportable-value decision is
+different, and the reasons for reanalysis, the number of replicates, and the criteria for selecting
+the value to report must be **predefined in the protocol, study plan, or SOP before study sample
+analysis begins.** Deciding after the fact which of two values to report is the classic finding.
+
+## Partial and cross validation
+
+M10 addresses partial validation (a change to a validated method — matrix, anticoagulant, species,
+instrument, or a range change) and cross validation (comparing data from two methods or two
+laboratories contributing to the same study). Both are scoped by the change and the risk; consult
+the guideline for what each requires. For a cross validation between sites or methods, the
+statistics in `compare_methods.py` — equivalence testing against a pre-stated margin, and a
+regression that allows error in both measurements — are the appropriate treatment.
+
+## Biomarkers and other contexts
+
+M10's scope centres on drug and metabolite concentration measurement. Biomarker assays, immunogenicity
+assays, and diagnostic measurements are addressed differently or fall outside scope; do not assume the
+concentration-assay criteria transfer. Where a biomarker assay supports a regulatory decision, the
+fit-for-purpose framework and the applicable regional guidance govern the extent of validation.

package/skills/analytical-method-validation/references/ich-q2r2.md

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+# ICH Q2(R2) — Structure and Recommended Data
+
+Research basis: **2026-07-27**, read from the ICH Harmonised Guideline *Validation of Analytical
+Procedures Q2(R2)*, Final Version adopted 1 November 2023, with the error correction dated
+30 November 2023. ICH licenses its documents for reuse with acknowledgement, so requirements are
+summarised here directly. Confirm the current text and your region's implementation date at
+<https://database.ich.org/sites/default/files/ICH_Q2%28R2%29_Guideline_2023_1130.pdf>.
+
+## Document history that matters
+
+| Version | Date | Note |
+| --- | --- | --- |
+| Q2A | Oct 1994 | Text |
+| Q2B | Nov 1996 | Methodology |
+| Q2(R1) | Nov 2005 | Q2B merged into the parent guideline |
+| Q2(R2) | 1 Nov 2023 | Complete revision, aligned with the new Q14 |
+| Q2(R2) correction | 30 Nov 2023 | Table 5 reportable-range linearity formulae; Tables 6–11 |
+
+If a protocol cites "ICH Q2(R1)" or lists characteristics in the R1 order, it is working from the
+superseded structure. The error correction is easy to miss and applies to the dissolution example
+and to Annex 2 Tables 6–11.
+
+## The restructure
+
+Q2(R1) presented a flat list. Q2(R2) groups methodology under section 3 by performance
+characteristic:
+
+```
+3.1  Specificity/Selectivity
+       3.1.1 General considerations (absence of interference, orthogonal comparison,
+             technology-inherent justification)
+3.2  Range                                    <-- parent characteristic
+       3.2.2 Response
+               3.2.2.1 Linear response        <-- what R1 called "linearity"
+               3.2.2.2 Non-linear response
+               3.2.2.3 Multivariate calibration
+       3.2.3 Validation of lower range limits <-- what R1 called LOD and LOQ
+3.3  Accuracy and Precision
+       3.3.1 Accuracy
+       3.3.2 Precision (repeatability, intermediate precision, reproducibility)
+       3.3.3 Combined approaches for accuracy and precision   <-- new
+3.4  Robustness  --> largely a development activity, see ICH Q14
+```
+
+Section 2 carries the general considerations, including two concepts absent from R1: **reportable
+range** (2.3) and **considerations for multivariate analytical procedures** (2.5).
+
+## Table 1 — which tests for which measured attribute
+
+Required tests follow the *measured quality attribute*, not the instrument.
+
+| Characteristic | Identity | Impurity: quantitative | Impurity: limit test | Assay (content/potency) |
+| --- | --- | --- | --- | --- |
+| Specificity test | yes | yes | yes | yes |
+| Response (calibration model) | no | yes | no | yes |
+| Lower range limit | no | QL† | DL | no |
+| Accuracy test | no | yes | no | yes |
+| Repeatability test | no | yes | no | yes |
+| Intermediate precision test | no | yes‡ | no | yes‡ |
+
+† In some complex cases DL may also be evaluated.
+‡ Not required independently where reproducibility has been performed and intermediate precision
+can be derived from that dataset.
+
+Further notes from Table 1: other quantitative measurements follow the impurity scheme when the
+range limit is close to DL/QL, and the assay scheme when it is not. Some characteristics may be
+substituted by technology-inherent justification for physicochemical properties. Lack of specificity
+in one procedure should be compensated by one or more supporting procedures unless justified.
+
+## Table 2 — reportable range examples
+
+The reportable range derives from the specification and must include the upper and lower
+specification or reporting limits. Other ranges are acceptable if justified; at low amounts a wider
+upper range may be more practical.
+
+| Use | Low end | High end |
+| --- | --- | --- |
+| Assay of a product | 80% of declared content, or 80% of the lower specification limit | 120% of declared content, or 120% of the upper specification limit |
+| Potency | lowest specification limit −20% | highest specification limit +20% |
+| Content uniformity | 70% of declared content | 130% of declared content |
+| Dissolution, IR, one point | Q − 45% of the lowest strength specification | per specification |
+| Dissolution, IR, multi-point | lower limit as justified, or QL | 130% of declared content of the highest strength |
+| Dissolution, modified release | lower limit as justified, or QL | per specification |
+| Impurity | reporting threshold | 120% of the specification limit |
+| Purity (area %) | 80% of the lower specification limit | upper specification limit, or 100% |
+
+Where assay and impurity run as a single test with one standard, linearity must be shown both at the
+impurity reporting level and up to 120% of the assay specification limit.
+
+**Reportable range vs working range.** The reportable range is the interval of *reported results*.
+A working range is what is presented to the instrument, and may differ because of dilution or other
+sample preparation. They can be identical. Mathematical calculation normally links the two.
+
+## Recommended data, by characteristic
+
+**Specificity (3.1).** Demonstrate absence of relevant interference, or compare against an
+orthogonal procedure, or justify from the technology. For a stability-indicating claim (2.4),
+include samples containing relevant degradation products: spiked with target analytes and known
+interferences, stressed physically and chemically, and aged or stress-stored product samples.
+
+**Response — linear (3.2.2.1).** Evaluate across the range. **A minimum of five concentrations,
+appropriately distributed, is recommended.** Report the plot, the correlation coefficient or
+coefficient of determination, the y-intercept, the slope, and *an analysis of the deviation of the
+actual data points from the regression line* — for a linear response, assess the impact of any
+non-random pattern in the residual plot. Data may be transformed (for example logarithmically) if
+necessary. Other approaches require justification.
+
+**Response — non-linear (3.2.2.2).** Some procedures are legitimately non-linear; immunoassays and
+cell-based assays commonly give an S-shaped curve, typically modelled with four- or five-parameter
+logistic functions. For these, **linearity of the concentration–response relationship is not
+required.** Assess the model by non-linear regression, and evaluate whether results are proportional
+to the true values across the range.
+
+**Response — multivariate (3.2.2.3).** Algorithms may be linear or non-linear. Accuracy depends on
+the distribution of calibration samples across the range and on the reference procedure's error.
+Assess how the residuals change across the calibration range, graphically.
+
+**Lower range limits (3.2.3).** Four approaches:
+
+| Approach | DL | QL |
+| --- | --- | --- |
+| Visual evaluation (3.2.3.1) | lowest reliably detected | lowest reliably quantitated |
+| Signal-to-noise (3.2.3.2) | S/N 3:1 generally acceptable | S/N at least 10:1 |
+| SD of response and slope (3.2.3.3) | 3.3σ / S | 10σ / S |
+| Accuracy and precision at the limit (3.2.3.4) | — | validated directly, not estimated |
+
+σ may come from the SD of blank responses, the residual SD of the regression line, or the SD of
+y-intercepts of regression lines. S is the calibration slope. Signal-to-noise applies only where
+there is baseline noise, and the noise region should sit around where the peak would appear.
+
+Reporting (3.2.3.5): give the limit **and the approach used**. An estimated limit should then be
+validated by analysing a suitable number of samples at or near it. **For impurity tests the QL must
+be at or below the reporting threshold.** Where the QL is well below the reporting limit — roughly
+ten times lower — the confirmatory validation may be omitted with justification.
+
+**Accuracy (3.3.1).** Establish across the reportable range under regular test conditions, including
+the sample matrix and the described preparation steps. Three routes: comparison against a reference
+material of known purity, a spiking study into matrix, or comparison against an orthogonal
+procedure. Accuracy can be inferred once precision, response within the range, and specificity are
+established.
+
+Recommended data (3.3.1.4): an appropriate number of determinations and levels across the reportable
+range — **for example 3 concentrations × 3 replicates of the full procedure.** Report as mean percent
+recovery of a known added amount, or as the difference between the mean and the accepted true value,
+**together with an appropriate 100(1−α)% confidence interval** or justified alternative interval. The
+observed interval should be compatible with the accuracy criterion. For impurities, state whether
+the determination is weight/weight or area percent. For quantitative multivariate procedures use
+RMSEP, compared against an acceptable RMSEC.
+
+**Precision (3.3.2).** Use authentic homogeneous samples, or artificially prepared ones if
+unavailable.
+
+- *Repeatability (3.3.2.1)*: **a minimum of 9 determinations covering the reportable range** (for
+  example 3 concentrations × 3 replicates), **or a minimum of 6 determinations at 100% of the test
+  concentration.**
+- *Intermediate precision (3.3.2.2)*: establish the effects of random events — typically different
+  days, environmental conditions, analysts, and equipment. **Studying these effects individually is
+  not necessary**, and design of experiments is encouraged. The extent should be justified from
+  development understanding and risk assessment (ICH Q14).
+- *Reproducibility (3.3.2.3)*: an inter-laboratory trial. **Usually not required for a regulatory
+  submission**, but consider it for pharmacopoeial standardisation or multi-site procedures.
+
+Recommended data (3.3.2.4): report the standard deviation, the relative standard deviation, and an
+appropriate 100(1−α)% confidence interval.
+
+**Combined accuracy and precision (3.3.3).** Instead of separate criteria, assess total impact
+against a single combined criterion, using a prediction interval, a tolerance interval, or a
+confidence interval. Report the combined value, describe the approach, and supply the individual
+results as supplemental information where they help justify suitability.
+
+**Robustness (3.4).** Deliberate variation of procedure parameters, plus stability of sample
+preparations and reagents over the duration of the procedure. Considered during development; may be
+submitted as development data case-by-case or made available on request. See ICH Q14 section 5.
+
+## Lifecycle, transfer, and prior knowledge
+
+Section 2.1 permits suitable development data (ICH Q14) to form part of the validation data, and
+allows abbreviated validation testing for an established platform procedure used for a new purpose,
+with scientific justification. A validation protocol must exist before the study, stating the
+intended purpose, the characteristics to be validated, and the associated criteria; where prior
+knowledge is used, justify it. Results are summarised in a validation report.
+
+The experimental design should reflect the number of replicates used in routine analysis to generate
+a reportable result, unless a different number is justified.
+
+Section 2.2 covers change: partial or full revalidation may be needed, decided on science and risk,
+and scoped to the characteristics the change affects. **Transfer** to another laboratory calls for
+partial or full revalidation and/or comparative analysis of representative samples; not performing
+transfer experiments requires justification. **Co-validation** across multiple sites can demonstrate
+the criteria are met and can simultaneously satisfy transfer at the participating sites.
+
+## Annex 2 — illustrative technique examples
+
+Non-mandatory worked examples, useful as a starting point for the robustness parameter list:
+
+| Table | Technique |
+| --- | --- |
+| 3 | Quantitative separation techniques (HPLC, GC, CE) for impurities or assay, and relative-area quantitation |
+| 4 | Elemental impurities by ICP-OES or ICP-MS |
+| 5 | Dissolution with HPLC as product performance test (corrected 30 Nov 2023) |
+| 6 | Quantitative ¹H-NMR for assay of a drug substance |
+| 7 | Biological assays |
+| 8 | Quantitative PCR |
+| 9 | Particle size measurement |
+| 10 | NIR analytical procedure |
+| 11 | Quantitative LC/MS |
+
+From Table 3, a detail worth carrying forward: **relative response factors.** Where the analyte
+responds differently from the reference material, calculate the RRF from the appropriate ratio of
+responses under final procedure conditions and document it. **If the RRF falls outside 0.8–1.2,
+apply a correction factor.** Where an impurity is overestimated, omitting the correction may be
+acceptable.
+
+## Multivariate procedures (2.5)
+
+Results come from a model relating many input variables to the property of interest. Validate in two
+phases:
+
+1. **Model development** — calibration plus internal testing. Test data may be a separate set or
+   part of the calibration set used rotationally, and are used to estimate performance and tune
+   parameters such as the number of PLS latent variables. See ICH Q14.
+2. **Model validation** — an independent validation set. For identification libraries, analyse
+   challenge samples *not* represented in the library to demonstrate discriminative ability.
+
+Samples need reference values or categories, normally from a validated or pharmacopoeial reference
+procedure whose performance **equals or exceeds** the expected performance of the multivariate
+procedure. Reference measurement and multivariate data collection should be on the same samples
+within a period short enough to assure sample and measurement stability. Describe any correlation or
+unit conversion, and any assumptions.

package/skills/analytical-method-validation/references/source-ledger.md

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+# 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: <https://database.ich.org/sites/default/files/ICH_Q2%28R2%29_Guideline_2023_1130.pdf>
+- 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: <https://database.ich.org/sites/default/files/M10_Guideline_Step4_2022_0524.pdf>
+- 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: <https://database.ich.org/sites/default/files/ICH_Q14_Guideline_2023_1116.pdf>
+- 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>` <https://doi.usp.org/USPNF/USPNF_M10975_02_01.html>;
+  `<1225>` <https://doi.usp.org/USPNF/USPNF_M99945_40101_01.html>;
+  `<1226>` <https://doi.usp.org/USPNF/USPNF_M870_03_01.html>
+- 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: <https://clsi.org/standards/products/method-evaluation/>
+- 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 — <https://www.iso.org/standard/66912.html>. 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.