Pharmacopoeial tests and acceptance criteria, microbiological quality of non-sterile products, pharmaceutical water, analytical method validation and OOS investigation — with the related laboratory SOPs.
This section is being expanded with new topics and tables.
Starting and packaging materials
In-process and finished product
Microbiology
Water and environment
Methods and instruments
Results and data
| Test | Chapter | Acceptance criteria |
|---|---|---|
| Uniformity of dosage units | USP <905> · Ph. Eur. 2.9.40 | 10 units: acceptance value AV ≤ L1 (15.0). If AV > 15.0, test 20 more: AV of 30 ≤ 15.0 and no unit outside (1 ± 0.25) × M. |
| Dissolution (immediate release) | USP <711> · Ph. Eur. 2.9.3 | S1 (6 units): each ≥ Q + 5%. S2 (12): mean ≥ Q, none < Q − 15%. S3 (24): mean ≥ Q, no more than 2 units < Q − 15%, none < Q − 25%. |
| Disintegration | USP <701> · Ph. Eur. 2.9.1 | 6 units disintegrate within the specified time; if 1 or 2 fail, test 12 more and at least 16 of 18 must pass. Ph. Eur. limits: uncoated tablets 15 min, film-coated tablets 30 min. |
| Friability | USP <1216> · Ph. Eur. 2.9.7 | 100 rotations (25 rpm, 4 min). Tablets ≤ 650 mg: whole tablets close to 6.5 g; > 650 mg: 10 tablets. Mean weight loss ≤ 1.0% and no cracked, cleaved or broken tablets. |
| Uniformity of mass | Ph. Eur. 2.9.5 | 20 tablets: no more than 2 deviate from the mean by more than 10% (≤ 80 mg), 7.5% (80–250 mg) or 5% (> 250 mg), and none by more than twice that. |
| Breaking force (hardness) | USP <1217> · Ph. Eur. 2.9.8 | No compendial limit; the in-house specification is set from development and validation data. |
| Water content | USP <921> · Ph. Eur. 2.5.12 | Karl Fischer titration (volumetric or coulometric) or loss on drying (USP <731>, Ph. Eur. 2.2.32), limit per monograph or specification. |
| Route of administration | TAMC (CFU/g or mL) | TYMC (CFU/g or mL) | Specified microorganisms (absent in 1 g or 1 mL) |
|---|---|---|---|
| Oral, non-aqueous | 10³ | 10² | Escherichia coli |
| Oral, aqueous | 10² | 10¹ | Escherichia coli |
| Rectal | 10³ | 10² | — |
| Oromucosal, gingival, cutaneous, nasal, auricular | 10² | 10¹ | Staphylococcus aureus, Pseudomonas aeruginosa |
| Vaginal | 10² | 10¹ | Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans |
| Inhalation | 10² | 10¹ | S. aureus, P. aeruginosa, bile-tolerant Gram-negative bacteria |
A limit of 10¹ CFU allows a maximum count of 20, 10² allows 200 and 10³ allows 2000. TAMC: total aerobic microbial count; TYMC: total combined yeasts and moulds count.
| Parameter | Purified water | Water for injections |
|---|---|---|
| Conductivity | ≤ 1.3 µS/cm at 25 °C (USP <645>, stage 1) · ≤ 5.1 µS/cm at 25 °C (Ph. Eur., bulk) | ≤ 1.3 µS/cm at 25 °C (USP <645>) · ≤ 1.1 µS/cm at 20 °C (Ph. Eur.) |
| Total organic carbon | ≤ 0.5 mg/L (500 ppb) | ≤ 0.5 mg/L (500 ppb) |
| Microbial action level | 100 CFU/mL | 10 CFU/100 mL |
| Bacterial endotoxins | — | < 0.25 EU/mL |
| Characteristic | Identification | Impurities, quantitative | Impurities, limit test | Assay |
|---|---|---|---|---|
| Specificity / selectivity | ||||
| Accuracy | ||||
| Repeatability | ||||
| Intermediate precision | ||||
| Detection limit | ||||
| Quantitation limit | ||||
| Response (linearity) | ||||
| Range |
Robustness is evaluated during development. For quantitative impurity tests the detection limit may also be needed.
Phase I — laboratory investigation
Analyst and supervisor check calculations, instrument and system suitability, standards, reagents and sample preparation, keeping the original solutions. A result is invalidated only for a documented, assignable laboratory error.
Phase II — full-scale investigation
If no laboratory error is found, production records and the process are reviewed and the impact on other batches is assessed. Retesting follows a predefined protocol by a second analyst; resampling needs justification.
Conclusion and batch disposition
QA decides the batch disposition and opens CAPA. Testing into compliance, averaging that hides an OOS result and outlier tests on chemical assays are not acceptable.
FDA Guidance: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production; MHRA OOS guidance.