Water activity, stability evidence and BUD assignment policy

Procedure

1. A period reported by a source, a study on a defined formulation and the BUD assigned to a compounded batch are recorded separately. Publishing a monograph does not certify stability of every local preparation. The responsible pharmacist records the batch BUD and label after reviewing evidence applicability, materials, packaging and use conditions.
2. Water activity testing is not required for every formulation or batch. Where classification is uncertain and aw <0.60 is not established, this local policy applies the more conservative aqueous category. This does not demonstrate chemical stability or justify refrigeration of an incompatible formulation. Classification as preserved requires documented suitability of the preservative system for the finished formulation.
3. A published stability period is adopted only after a signed applicability assessment covering API and salt, strength, complete composition, material grades, API source (substance or specific medicinal product), process, pH, container and closure, temperature, light and use after opening. A deviation receives a separate assessment; matching the API or branded vehicle alone is insufficient.
4. An extension is not assigned without applicable evidence. Water activity, microbial results or potency alone do not replace an overall stability assessment. Numerical results are published only with an identifiable report. USP rules are identified as a technical reference framework rather than Greek law. The applicable edition and national requirements are checked at approval. [S1–S5]
5. Before each application, identify the formulation and revision. Link the source or actual report to that formulation, package and use.
6. Select the decision pathway: existing applicable evidence, a conservative restriction or a targeted study. Record the rationale and responsible assessor.
7. For a study, approve the work order, methods, limits and samples in advance. The batch numbers and time points in this document are proposed local design choices.
8. During execution, preserve traceability of batches, conditions and raw data. Record every deviation and failure.
9. Complete review against all pre-approved criteria. Issue a final decision with explicit applicability, without substituting expectations for results.
10. Update the monograph, dependent formulations and evidence register together. Record the actual batch BUD after the required approval.
11. Proposed local protocol for approval before commissioning. The sample numbers, time points and decision rules below are design choices for this project, not claims of pharmacopoeial requirements.
12. Prioritise formulations for which an actual measurement would materially change classification or duration. Record formulation code and revision, salt, complete quantitative composition, material sources/CoAs, preparation method, yield, package, target BUD and critical specifications. Three independent batches are proposed to examine preparation variability. Three analytical replicates from one container do not constitute three batches.
13. For targeted initial aw characterisation, propose three separate test portions per batch from representative positions or containers, across three batches. Set 25 °C as the initial measurement condition; document actual tolerance, equilibration and temperature effects in the method. Include the end of the planned period when classification relies on maintenance of low aw. Do not dilute the formulation for measurement.
14. Require an appropriate measurement range, instrument/sensor identification, independent certified standards bracketing the decision threshold, verification before and after the series, repeatability data, representative sampling and reported uncertainty. For ethanol, isopropanol, propylene glycol or other potential interferents, request suitability testing on the actual matrix. Selective water-vapour measurement, such as appropriately verified TDL, is an available technical option; it is not automatically infallible. [S4, S5]
15. Proposed conservative rule: accept low aw for the assessed revision only if the highest result plus the appropriate expanded uncertainty remains strictly <0.600 for all representative test portions. The laboratory states coverage, coverage factor and how uncertainty is applied. A borderline or invalid result is not rounded towards compliance. Apply the conservative category or redesign the method.
16. For each batch and time point, propose a separate final container for physicochemical testing, another where required for microbiology, and a reserve. Before preparation, the laboratory finalises number and quantity from sample consumption and retesting needs. Do not repeatedly open stability containers instead of independent samples, except in a separate, deliberately designed in-use arm.
17. Target 14 days: days 0, 3, 7, 10, 14.
    Target 35 days: days 0, 7, 14, 21, 28, 35.
    Target 90 days: days 0, 7, 14, 30, 60, 90.
    Target 180 days: days 0, 14, 30, 60, 90, 120, 180.
    Use closer sampling for known rapid degradation. Examine actual storage conditions and, separately, expected excursions/in-use conditions. Accelerated data are supportive and do not automatically replace real-time duration.
18. Before starting, approve formulation-specific methods and numerical specifications: identity, stability-indicating determination of every API, relevant degradation products/impurities, pH where applicable, appearance, odour where appropriate, homogeneity, sedimentation and redispersibility, viscosity, crystallisation, mass/volume change and dosing-device function. Include microbial quality and preservative effectiveness according to dosage form, use and the selected framework. Do not adopt a universal “≥90%” criterion as the sole demonstration of suitability. [S2]
19. The microbiological method needs documented suitability, including neutralisation of antimicrobial activity where required. Propose microbial-quality testing initially and at the end, with intermediate testing according to risk. For the preservative system studied, propose AET on initial and aged formulation, using applicable criteria selected in advance. The in-use arm simulates the actual frequency of opening/dosing, device, temperature and handling, using separate samples. This proposes an assessment of system robustness, not AET for every batch.
20. Close laboratory substantiation only after an approved final report: all applicable criteria are met at every scheduled time point and batch through the claimed duration; deviations/OOS/OOT are evaluated; raw data and method suitability are available. Do not calculate a longer BUD from one good result. Failure requires investigation, a documented shorter period or redesign, without concealing failed batches.
21. Study a family by bracketing only after written justification of its boundaries and evidence. Examine genuinely adverse extremes of concentration, pH, preservation, package/fill. Do not extrapolate across different APIs or salts, a changed vehicle, a different tablet source or a material package change merely because names are similar. An intermediate formulation receives no longer period than the least favourable validly studied extreme. [S3]

Related forms

F-022, F-006, F-012, F-018