Shelf life evaluation and extrapolation

How do you set a retest period for a drug substance or shelf life for a drug product? How can extrapolation be applied to propose a retest period or shelf life for a drug product that extends beyond the period covered by real-time stability data? In this article, we outline how we can assist you with your shelf life evaluation studies.

In a recent Q1 Scientific webinar, Dr. Mark Powell covers all the above in addition to regulatory guidance, poolability of stability data and appropriate statistical models for shelf-life evaluation.

Stability studies are a critical component in drug and regulated product development. They help determine whether any physical, chemical or microbiological changes affect the functionality, efficiency and integrity of a product over a period of time. Data can be used to either establish an expiry date for a new product, or to support an already existing expiry date for a commercial product.

A good stability study programme gives both regulators and consumers’ confidence that the product will perform ‘as expected’ from the date of manufacture through to the end of the product’s shelf life. Ultimately shelf-life evaluation studies ensure that a pharmaceutical or regulated product is safe and effective, irrespective of where in the world it will be supplied.

ICH Q1E – Evaluation for stability data

ICH Q1E describes in detail when and how extrapolation can be considered when proposing a retest period for a drug substance or a shelf life for a drug product that extends beyond the period covered by available data from the stability study under the long-term storage condition.

Some extrapolation is allowed beyond real-time data in certain situations. When using stability data to evaluate when and how much extrapolation can be considered for a proposed retest period or shelf life there are a few key considerations as highlighted by Dr. Mark Powell during a recent Q1 Scientific webinar on ‘Shelf life evaluation and extrapolation’:

Data variability (within / between batch)
Degree / significance of change under real-time, intermediate and accelerated conditions
Whether data are amenable to statistical analysis

An extrapolation of stability data assumes that the same change pattern will continue to apply beyond the period covered by long-term data. Whether extrapolation of stability data is appropriate depends on the extent of knowledge about the change pattern, the goodness of fit of any mathematical model, and the existence of relevant supporting data.

Statistical analysis can be useful in supporting the extrapolation of retest periods or shelf lives. See our recent webinar with Dr. Mark Powell for an overview of appropriate statistical models for shelf-life evaluation and extrapolation.

Common stability storage conditions used for shelf life evaluation

The shelf life of a drug or regulated product is commonly estimated using long term, accelerated and intermediate stability testing. At Q1 Scientific, we work with our customers to store samples at their specified conditions for the length of their shelf life evaluation studies.

Long Term Stability Storage

Q1 Scientific provide long-term stability storage performed for a longer duration of the test period to allow significant product degradation under recommended storage conditions.

The ICH defines this as:

Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labelling

Long-term stability testing is also referred to as room temperature stability storage condition testing. The most common storage condition is 25°C +/- 2 degrees and Relative Humidity (RH) of 60% +/- 5%.

Long term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life.

At your specified time points for testing e.g. 0, 3, 6, 9, 12, 18, 24, 36 months, etc., Q1 Scientific will remove your samples from their set temperature/humidity storage condition and deliver them back to you for testing. Typically, our customers put samples into long-term stability storage with us to collect data that will help establish an expiry date of a new product or confirm a shelf life of an existing product.

Accelerated Stability Storage

The ICH defines this as:

Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies

Most commonly, it is storage at 40°C +/- 2 degrees and RH of 75% +/- 5% for up to 6 months when the long-term stability storage condition for the product is 25°C +/- 2 degrees and RH of 60% +/- 5%. It is referred as “accelerated” because the high temperature/humidity exposure to the product over a short period of time accelerates product degradation.

Customers storing samples at Q1 Scientific under accelerated conditions typically test under this condition at the 0, 3, and 6 month time points. In some cases, our customers will assess the stability of their product at the 1 and 2 month time points to produce more stability data. Real-time studies are also started at the same time for confirmation purposes.

Accelerated stability tests provide a means of comparing alternative formula-dons, packaging materials, and/or manufacturing processes prior to making significant changes that may affect the shelf life of the product. From this, a products shelf-life and storage conditions can be determined.

Intermediate Stability Storage

Intermediate conditions are generally 30°C / 65% RH. It is designed to moderately increase the rate of degradation compared to the accelerated study. This condition is usually referred to as a “back-up” storage condition in the event that an out-of-specification result or significant stability change is identified during testing at the accelerated level.

When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g. 0, 6, 9 and 12 months etc.) is often used by our clients to evaluate product shelf life.

Many of our customers set down their stability study samples into all storage conditions at the same time and only test the intermediate samples if or when a significant change occurs at the accelerated condition.

Reference / Retain sample storage

In addition to the above studies, our customers also store long-term samples of existing drug products with us and place a minimum of one lot per year of marketed product into long-term stability for each dosage strength, size, and from each type of container/closure, to support an existing products expiry date.

Reference samples are retained to fulfil two purposes; firstly, to provide a sample for analytical testing and secondly to provide a specimen of the fully finished product. They serve as a record of the batch of finished product or starting material and can be assessed in the event of, for example, a dosage form quality complaint, a query relating to compliance with the marketing authorisation, a labelling/packaging query or a pharmacovigilance report.

Samples may therefore fall into two categories:

Reference sample: a sample of a batch of starting material, packaging material or finished product which is stored for the purpose of being analysed should the need arise during the shelf life of the batch concerned. Where stability permits, reference samples from critical intermediate stages (e.g. those requiring analytical testing and release) or intermediates, that are transported outside of the manufacturer’s control, should be kept.
Retention sample: a sample of a fully packaged unit from a batch of finished product. It is stored for identification purposes. For example, presentation, packaging, labelling, patient information leaflet, batch number, expiry date should the need arise during the shelf life of the batch concerned.

For finished products, in many instances the reference and retention samples are presented identically, i.e. as fully packaged units. In such circumstances, reference and retention samples may be regarded as interchangeable.

See our recent post on Reference and Retain Samples to find out more about the storage requirements.

How can Q1 Scientific help with shelf life evaluation?

At Q1 Scientific, we offer state of the art environmentally controlled and monitored stability storage facilities to meet all ICH requirements and non-ICH requirements.

To challenge the lifespan of either your new or existing commercial drug product, Q1 Scientific can work with you to expose your samples to various extremes of regulated temperature and humidity conditions for specified lengths of time inside our stability chambers.

At designated time points throughout your study, Q1 Scientific will remove your samples from their storage conditions and deliver them back to your site or testing laboratory for evaluation.