14.4 Biological medicines: specific requirements

14.4.1 Biological medicine stability testing

We evaluate stability data for biological medicines on a case-by-case basis, with regard to:

• the nature of the medicine
• the methods of analysis (physical, chemical, biological) that are appropriate for that medicine:
  • it may not always be possible to establish degradation pathways and identify decomposition products formed in significant amounts
  • the use of only compendial methods is not acceptable unless it has been demonstrated that the methods used are able to detect critical degradation pathways for that product
  • use of only physicochemical assay techniques, such as chromatographic methods for decomposition products, may not always be appropriate for biological medicines.

14.4.2 Predicting shelf life of biological medicines from stability data

The maximum shelf life permitted by the TGA for biological medicines is normally three years, but longer may be justified by supportive data.

The degradation of biological medicines is not usually amenable to kinetic analysis and extrapolation from accelerated testing. All biological medicines require real-time stability data. All approved shelf lives will be no longer than the real-time data submitted to support them.

Trend analysis (either linear or exponential nonlinear regression) may be done by the TGA on consolidated real time datasets, and the overall trend is regarded as more important than the individual data points.

Example

For example, consider a medicine that loses a mean of 6 per cent potency each year and whose label claims a lower expiry specification of 90 per cent. All batches in the stability study have an initial potency of 105 per cent (without an approved overage), therefore all batches appear to comply over the proposed shelf life of 24 months. However, the approved shelf life will be 18 months because, if the medicine is filled to target (100 per cent) potency and loses 6 per cent potency each year, it is likely to reach its expiry specification after only 19.2 months.

14.4.3 Stability data for biological medicine applications

For biological medicines:

• Provide stability data generated from at least three batches manufactured using the commercial process or earlier processes unchanged in scale and method from the commercial scale.
• A content assay (e.g. HPLC, ELISA) is not sufficient unless the content assay is a pharmacopoeial activity assay (e.g. insulin or somatropin).
• For medicines with two storage temperatures (e.g. 1 month at <25 &deg;C and 23 months at 2-8&deg;C), provide a study using both temperatures in a worst-case scenario (e.g. high temperature first, then low temperature).
• For time out of refrigeration (TOR), sponsors should define and justify the time the medicines are out of recommended storage conditions during manufacture, up to the point of return to the recommended storage conditions. Justification should include real-time data to support the TOR worst case scenario.

14.4.4 Shipping and stability data

Stability data are required to indicate acceptable duration and magnitude of temperature excursions during shipping.

Real time data should be provided to support the proposed shipping method.

• Include a justification of how the proposed shipping conditions represent the worst case shipping scenario (based on both time and likely external temperature exposure) for product being imported into Australia.
• Validation of shipping containers should also cover the worst case shipping scenario.
• Ensure the data for justifying any temperature excursions during shipping includes real time studies of the proposed excursion, followed by return to the normal storage conditions for the remainder of the shelf life.

Deviations to storage conditions

A biological medicine that has undergone a deviation to the recommended storage conditions may only be supplied if the TGA has assessed the data to support the release. This data may be submitted:

• as part of an initial application for registration under s25 of the Act or
• as a variation under s9D of the Act to permanently allow ongoing release within defined conditions (e.g. Store at 2-8&deg;C with no more than 72h at <30&deg;C and 6h at -5&deg;C).

In either case, the approved excursions will be recorded in the ARTG and in the Certified Product Details.

Where possible, include a temperature cycling study. Structure cycling stability studies as follows:

• Preferably, include three batches of commercial scale product.
• Include at least one cycle above (and if desired, below) the storage conditions of sufficient magnitude as to cover the majority of projected excursion likely to occur (e.g. -5&deg;C and +30&deg;C). Multiple cycles may be included if desired.
• The duration of the cycle should mimic or exceed the maximum likely duration of a shipping excursion (e.g. 3 days or 72 h for air freight or 3-6 weeks for sea freight)
• Conduct the cycles at the beginning of shelf life and store the samples at the approved or proposed long-term storage conditions for the remainder of the shelf life. Carry out a stability assessment at the end of the shelf life, because biological medicines (particularly those that are complex mixtures extracted from human or animal sources) are sometimes subject to multiphasic and non-linear degradation.
• Apply appropriate stability testing techniques, specifications and intervals.
• For already-registered products, you may incorporate this type of stability study into the design of the annual stability study required under GMP.

Where a cycling study is not available, the sponsor will need to provide a justification, with sufficient supporting evidence, why the product quality has not be impacted.

Reason for approach

We take this approach because most biological medicines are temperature-sensitive and are required to be shipped at the approved storage temperature, which usually means the maintenance of a cold chain. Biological medicines manufactured in Europe and the USA are shipped to Australia after release for supply.

• Shipping is always lengthy due to the distances involved and crosses the equatorial region (Zone IV¹) of the globe.
• It is not uncommon that during shipping, excursions from approved storage conditions of extensive duration occur that reach temperatures capable of denaturing proteins.
• Deviations from approved storage conditions may cause a biological medicine to be of unacceptable quality and therefore not suitable for supply.

14.4.5 Manufacturing variations and stability data

Any change in the manufacturing process has the potential to impact the quality of the active substance and/or drug product. Therefore, the impact of the change on quality characteristics and stability has to be assessed, because these are integral to the overall assessment of comparability of biological medicines before and after changes are made in the manufacturing process.

In addition to other comparability or characterisation studies of quality aspects, for manufacturing changes that might lead to changes in the protein structure, purity, impurities profiles and potency:

• Conduct a real-time stability study on the active substance or the drug product, depending on the point at which the change in the manufacturing process takes place.
• Justify the number of batches included in the stability study.
• Design the stability studies to cover the entire duration of the approved shelf life.

Example

For example, a change in the manufacturing process during production of the active substance will require that a stability study be conducted, at the minimum, on the active substance. Where the change occurs after the manufacture of the active substance, that is during the manufacture of the drug product, stability study on the final drug product will be required. Additional stability studies, on the active substance or drug product in each of the cases above, may be conducted to provide further support for the proposed change, if you consider this necessary.

Recommended batch number and study duration

Data submitted to support major manufacturing changes (e.g., establishment of a new host cell line, change to a critical raw material, change of a critical step etc.) should include stability data using at least three batches of the drug product and conducted for the length of the approved shelf life. Comparability of the pre- and post-change stability data should be provided.

The stability study may be conducted with reduced number of batches when the sponsor can demonstrate all of the following:

• that there is a history of the active substance or drug product stability
• that the manufacturing changes are deemed minor
  
  AND
   
• with appropriate validation and specifications data that the active substance or product are unaffected by the change.

The applicant may submit an available stability study that does not cover the entire duration of the shelf life for evaluation provided that robust comparability data that permits trend analyses is submitted. This should be accompanied by a commitment to complete the ongoing stability study and report any confirmed out of specification results to the TGA. Acceptability of these abridged stability studies will be considered on a case-by-case basis.