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Stability testing for prescription medicines

6 March 2017

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14.3 Chemically derived medicines: specific requirements

14.3.1 Predicting shelf life from stability data

The maximum shelf life for chemically derived medicines is normally five years.

  • Provide the stability data to support the proposed retest period for active substances and shelf life for a medicine.
  • Justify any extrapolation beyond the period covered by available data.
  • Take into account the worst-case situation at batch release. For example:
    • For medicine that has a lower assay release limit of 95 per cent and a lower assay expiry limit of 90 per cent, the maximum decrease in assay allowed over the shelf-life is 5 per cent.
    • Similarly, for a medicine that has a release limit for an individual impurity of 0.2 per cent and an expiry limit of 0.5 per cent, the maximum increase in the impurity allowed over the shelf life is 0.3 per cent.
    • For the same medicine, if the actual release assay result is 101 per cent, then the shelf life should be determined at the time the medicine (or confidence interval of the regression line) decreases by 5 per cent and reaches 96 per cent, rather than the expiry limit (90 per cent). This takes into account the possibility of batches being released at the lower release limit (i.e. 95 per cent) and ensures they will comply with the expiry limit throughout the shelf life.
    • Similarly, if the actual impurity content is 0.1 per cent at batch release, the shelf life should be determined as the time the 95 per cent confidence interval reaches 0.4 per cent (i.e. increases by 0.3 per cent).

Maximum extrapolated shelf life for a medicine

The maximum extrapolated shelf life is normally three years.

For a shelf life longer than three years:

  • include real-time data on production batches stored under the maximum recommended storage conditions for the duration of the proposed shelf life.

14.3.2 Extending the shelf life of individual batches of chemically derived medicines

The TGA may approve a limited extension of shelf life for individual batches of chemically derived medicines that are approaching their expiry date.

The prerequisites for this approval include:

  • the existing shelf life should be at least two years
  • real-time stability data that either
    • validate the existing shelf life and show no significant deterioration of the medicine during this period
    • extrapolation of stability data shows that the medicine will comply with the expiry specification after storage at the maximum recommended storage temperature for the duration of the proposed extension period
  • a certificate of analysis that is less than two months old at the time of application showing compliance with specifications for the batch near its expiry date, together with the results obtained at batch release
  • an assurance that a stability study to validate a permanent extension of the shelf life has or will commence, if relevant.

Note

Prospective extensions of more than six months or extensions that result in a shelf life of more than five years are not normally acceptable. If there are extenuating circumstances include a justification for consideration.

14.3.3 Self-assessable request for shelf-life extensions

This relates to variations for a registered prescription medicine.

The shelf-life of a medicine may be extended through the self-assessable request (SAR) process. Amongst other requirements for a shelf-life extension, ensure that the supporting stability has been generated using a stability testing protocol explicitly approved for this purpose by the TGA.

Approval of such a protocol may be applied for at the time of product registration or subsequent to registration. For the proposed protocol include all of the following:

  • included in the stability trial at least three production batches of the registered product in the marketing container/closure system
  • state the storage conditions and duration of tests
  • state details of the tests to be performed and the test methods to be used
  • state acceptance criteria for the tests performed. This should generally be tighter than the approved expiry limits, particularly for quantifiable test parameters such as assay, degradation products, dissolution, disintegration etc. (this is to provide a safety margin for sponsor self-assessment of the test results)
  • provide a matrix indicating the time stations at which testing will be conducted.

Note

The stability data generated according to such a protocol may be self-assessed against the acceptance criteria stated in the protocol. If all test results are within the limits, the product shelf-life may be extended using the SAR process stated in Minor variations to registered prescription medicines: Chemical entities.

If some of the test results are outside the approved protocol limits but within the registered expiry limits, the stability data may be submitted as a minor variation application to the TGA.

  • Include a justification as to why the shelf-life should be extended.

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