You are here

Temperature excursions of biological medicines

22 December 2015

Biological medicines are often temperature sensitive, and susceptible to degradation if not stored (and transported) under controlled conditions.

Sponsors are responsible for ensuring the approved storage conditions (or, where applicable, the approved temperature excursion range(s)), are maintained while under their control, including during transport.

The approved shelf-life storage conditions and permitted temperature excursions are recorded in the Certified Product Details (CPD) and on the ARTG.

Why it's important that TGA is aware of temperature excursions

Many companies have strong procedures in place to deal with temperature excursions but, unless these have been documented and approved, we have no way of knowing:

  • what the procedures are
  • what limits have been set
  • whether they are appropriate for the product.

In addition, where the 'release for supply' step is not carried out in Australia, we are unable to ensure compliance with storage conditions during shipping to Australia. This is because it is:

  • not covered by GMP, and
  • not audited by the Manufacturing Quality Branch.

Deviations from approved storage conditions

If there is a deviation (excursion) from the approved storage conditions, the quality of the product may become unacceptable, and therefore the product may not be suitable for supply. This is because biological medicines:

  • are often temperature-sensitive
  • are usually stored refrigerated
  • may be unstable in a nonlinear or unpredictable fashion.

In these cases, you should contact Biochemistry.testing@tga.gov.au to confirm that the product quality is acceptable.

Supplying biological medicines exposed to a temperature excursion

This can only occur if we have evaluated (and approved) appropriate temperature stress/cycling stability data, covering both the temperature excursion range and its duration.

If such data is available, you should lodge an application to vary the products:

  • approved storage conditions, or
  • permitted temperature excursions.

Please note

Due to the complexity of biological medicines, it is not always possible to establish degradation pathways and identify decomposition products.

Since these degradation pathways are not simple, and may be interactive, the degradation of biological medicines can be non-linear and inconsistent.

Thus, the degradation of biological medicines is not usually amenable to kinetic analysis or extrapolation from accelerated testing.

Application to vary

This application (made under section 9D(3) of the Act) should clearly define the time and temperature ranges of any proposed permitted temperature excursions.

Ideally, to support this application, the sponsor/manufacturer will have conducted cycling stability studies, as stated in Guidance 14: Stability testing for prescription medicines.

Important

Any batches exposed to unapproved temperature excursions should be not be supplied, and should be quarantined until the application to vary has been determined.

If the application is approved

In this case, you will be required to submit an updated CPD with the new storage conditions and/or permitted temperature excursions.

We will also update the ARTG with these details.

If the application is rejected

In this case, the affected batches will be considered of unacceptable quality, and should be destroyed in a secure manner.

If the temperature excursion is within approved limits

You may release any product exposed to temperature excursions that fall within approved time and temperature limits noted in the CPD and/or the ARTG, without referring to TGA.

For older products

There are three other possible means of approval of scientifically justified temperature excursions for older products where they are rarely subject to variation applications, and it would be unreasonably expensive for a company to conduct a full stability study.

These were negotiated with the peak industry bodies, and are outlined below:
  1. Provide accelerated data which shows very little (or no) trends in degradation, with real time data showing complete stability for the full shelf life. An excursion of no more than 4% of the period of the accelerated study may be approved.
  2. Provide accelerated data which shows significant degradation trends that do not exceed specification, plus historical data showing at least ten years (or 100 consecutive batches) of product showing:
    1. the number of batches which exceeded storage temperature
    2. the maximum temperature
    3. the period of excursion
    4. a record of adverse events for that product for the same period.
  3. Submit a general procedure (applicable to multiple products using the most temperature sensitive product as the model) used to assess shipping temperature deviations, with details of:
    1. what temperature/duration conditions trigger a deviation investigation and report
    2. what measures are taken to quarantine the batch after a temperature deviation
    3. who makes the decision
    4. how is the decision made and communicated
    5. what data (and their quality) are considered in making the decision.
    You should also submit:
    • the Standard Operating Procedure for handling temperature excursions in shipping. These submissions are decided on a case-by-case basis.
    • an example deviation report to show the application of the process. These submissions are decided on a case-by-case basis, and the Manufacturing Quality Branch will be informed to ensure these procedures are satisfactorily followed at the next audit.

Please note

These three approaches for older products are:

  • not acceptable for the submission of new or recently registered products (within the last 3-5 years)
  • only intended for retrospective variation of approved products which have a substantial safety record.