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14.2 General guidance

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14.2.1 The purpose of stability testing

The purpose of stability testing is to determine how an active substance and a drug product vary with time under a variety of environmental conditions, including:

  • high temperature
  • high humidity
  • exposure to light.

Stability testing is used to:

  • establish the retest period for an active substance
  • determine the appropriate storage conditions for a medicine
  • establish the shelf life for a medicine.

Note

A medicine may be tested at any time during its period of use by either:

  • the methods of the pharmacopoeia

    OR
     
  • in the absence of a pharmacopoeial method, a suitable or alternative method that has been reviewed and approved by the TGA.

Advise manufacturers that they may need to apply more stringent test limits at the time of release of a batch of the medicine in order to ensure compliance throughout its shelf life.

14.2.2 Active substance stability testing

Stability testing of active substances is required to establish:

  • the inherent stability characteristics of the molecule, particularly the degradation pathways
  • the identity of degradation products formed
  • the suitability of proposed analytical procedures for quantification of both the active substance and degradation products.

14.2.3 Drug product stability testing

The design of the formal stability study for a drug product should be based on the known properties and stability of the active substance(s) at the intended storage conditions of the prescription medicine.

Australian climate: specific stability requirements

Major population centres in Australia experience a combination of high humidity and high temperature during the summer. These areas are classified as Zone IV regions.

  • Ensure stability studies for medicines to be registered in Australia are performed under conditions representative of Zone IV regions.

Photostability studies

  • Provide evidence to demonstrate that light exposure does not result in unacceptable changes to the medicine.

14.2.4 In-use stability testing on medicines for multi-dose use

For medicines intended for multi-dose use:

  • provide evidence that repeated access (i.e. opening and closing) does not affect the physical, chemical or microbiological quality of the medicine.

For bottles containing solid dosage units (e.g. capsules) that are to be refrigerated provide information or a justification that addresses:

  • the possibility of moisture condensation after repeated openings and closings of the bottle
  • effects of condensation on the medicine.

14.2.5 Reconstituted and/or diluted prescription medicines

For medicines that may be diluted or reconstituted with a range of solutions, for example a parenteral medicine that is diluted for intravenous infusion:

  • provide stability data that establishes compatibility with each recommended diluent at the extremes of the recommended dilution ratios for the permitted duration of storage. Testing of reconstituted and /or diluted solutions include:
    • pH
    • clarity/particulate matter
    • assay and (if assay sensitivity allows)
    • degradation products.

Where storage at 2-8oC is not possible because of adverse effects on the medicine:

  • specify and justify the maximum time for storage at room temperature (not more than 6 hours).

If the reconstituted and/or diluted medicine may be kept for longer than 24 hours at 2-8oC (or 6 hours at >8oC):

  • provide data to show that when the medicine is presented with a microbial challenge (similar to a preservative efficacy test), ideally there is evidence of microbial death. However the minimum requirement is demonstrating stasis (i.e. not more than 0.5 log10 units higher than the initial value of the inoculum) over the proposed storage period.

The Product Information (PI) for injections that are intended to be reconstituted or diluted should include the direction:

'To reduce microbiological hazard, use as soon as practicable after reconstitution/preparation. If storage is necessary, hold at 2-8oC for not more than 24 hours'

or words to that effect.

14.2.6 Container, container closure and delivery device effects on liquids

The stability of liquid medicines may be affected by the components of the storage containers, container closures and delivery devices.

For parenteral, ophthalmic, inhalation medicines, and medicines used with a delivery device (such as infusion pump) provide data on investigations relating to the possibility of substances leaching from the container or device into the medicine.

Pay particular attention to:

  • extractable substances leaching from outside the primary container, if manufactured from semi permeable materials, into the medicine (e.g. adhesives used to affix labels to the bottle)
  • additives in plastics and elastomers, and their possible degradation products that may form during the manufacturing steps, especially during filling and sterilisation steps and storage
  • plastic components of metered-dose aerosols
  • injectables and opthalmics supplied in non-glass containers, with a plastic or rubber stopper.

To determine whether contact with the container closure affects the container integrity and/or the stability of liquid medicines in containers (other than ampoules):

  • provide the stability data conducted with the liquid medicine stored in the inverted position to maximise contact with all parts of the container, the container closure (e.g. rubber stopper) and/or delivery device.

14.2.7 Preservative efficacy

Stability testing for a preserved medicine includes testing of the physical, chemical, biological and microbiological attributes and preservative content of the medicine that are susceptible to change during storage are likely to influence quality, safety or efficacy.

For guidance on the stability testing for a preserved medicine:

For guidance on preservatives in liquid and semisolid formulations that are not self-preserving, refer to the European Union guideline:

For guidance on:

  • the requirements of the PI for a sterile medicine to include information on how long the medicine may be used after opening
  • the requirements for a microbiological simulated in-use study to justify the open shelf life for certain dosage forms, such as injectables and eyedrops. The chemical stability of the preservative over the open shelf life should also be demonstrated

Refer to:

Specific guidance related to Biotechnological products:

14.2.8 Presenting data in a registration application

  • Include, where possible, quantitative results rather than a statement that the medicine complies with a particular specification.
  • Discuss all results.
  • Give explanations where necessary, for example:
    • for anomalous or unusual results
    • for change in analytical methods
    • change in appearance
    • whether mass balance has (or has not) been achieved with respect to assay and degradation products.

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