These common issues may lead to requests for further information and delays in approval of a shelf life for medicines.
14.5.1 Batch information issues
Did not:
- specify the formulations used in the trial, and which batches are identical to the formulation that will be registered in Australia
- state the size or scale of the batches used in the trial
- identify the active substance batches used to manufacture the batches of medicines used in the trial
- describe the packaging used in the trial and to confirm whether it is identical to the pack that will be used in Australia.
14.5.2 Stability trial conditions and/or design issues
Did not:
- accumulate stability data on more than one batch of each strength of the medicine
- accurately define the temperature, lighting and humidity conditions applied during the trial
- reconstitute radiopharmaceuticals at the activities and radioactive concentrations that would be used in a clinical situation
- include stability studies under conditions of high humidity for medicines that are to be registered in moisture-permeable containers, and especially for those that are potentially sensitive to moisture
- investigate the possibility of leaching of substances from the container/closure system into the medicine
- store liquid medicines in an inverted orientation.
For biological medicines
- Did not include temperature excursions or temperature cycling in the stability study when these temperature excursions will be inevitable under the intended conditions of transport.
- Included only pilot-scale batches in the stability study and not batches made by the commercial process.
14.5.3 Analytical methodology/testing issues
- Did not fully describe test methods and sample sizes.
- Did not provide validation of analytical methods.
- Used an HPLC assay procedure to detect impurities without validating the procedure for this purpose.
Note
HPLC assay procedures used to measure the active ingredient are often unsuitable for separation and detection of impurities because they use too short a run time; however, such a procedure would be acceptable if it is validated for impurity detection.
Longer run times do not in themselves ensure good separation.
14.5.4 Data reporting and evaluation issues
- Provided Qualitative expression of results ('passes test' or similar) when a quantitative figure was available.
- Did not include quantitative or semi-quantitative determinations of the content of degradation products, or provided only total content rather than values for individual impurities.
- Did not comment on or conduct additional tests when there is a lack of mass balance between the formation of degradation products and the loss of the active substance. For example:
- Failure to investigate whether the assay procedures are sufficiently specific, whether the active substance is volatile, or whether the active substance is adsorbed onto the container wall.
- Did not conduct additional tests to investigate the significance of obvious alterations in the characteristics of the medicine. For example, a distinct change in the colour of the medicine may require additional investigation for degradation.
- Did not include information on the physical characteristics of the medicine during storage, such as dissolution characteristics, homogeneity and particle size.
- Did not provide results from intermediate time points to help assess trends in the parameters measured.
- Did not provide results for individual dosage units where these are available (e.g. dissolution profiles).
- Attempts to extrapolate data obtained in the trial beyond reasonable limits.
- Did not take into account the worst-case scenario in predicting a shelf life from regression analysis of the data.