As the medical cannabis industry matures, a question has started popping up more frequently regarding medicinal cannabis stability, namely: “What do I put down for shelf life/expiry for a new medicinal cannabis product?”
In this blog we provide a brief overview into stability, stability studies, and how to apply minimum shelf life requirements to medicinal cannabis products.
A quick background into stability and stability studies
Stability studies are performed on finished pharmaceutical products (including packaging and labelling components) to evaluate how the product may be affected by external environmental factors encountered during storage and transport, e.g. light, heat, humidity, temperature, etc.
When designing long term stability studies, time points should be chosen so that enough data on the stability profile of the active ingredient over the intended shelf life can be obtained. Luckily, these testing time points have already been defined in both internationally harmonized pharmaceutical guidelines (i.e. from the EMEA/CPMP/ICH), as well as local TGA notes and guidelines for specific product types and forms.
The two most common forms of stability tests are:
- Real-time tests, performed on products that are stored according to the recommended temperature conditions (in Australia we fall under climactic zone III and IV) and monitoring the product until it fails. Products are usually tested at 0, 3, 6, 9, and 12 months for the first year, 2 times a year for the second year, and once a year for each year thereafter.
- Accelerated tests, performed on products stored in environments where different environmental factors have been enhanced to forcibly cause an accelerated degradation of a product. For example, a product traditionally stored at 25°C or 30°C may have studies performed at 40°C / 75%RH for 6 months. A minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where results from accelerated studies indicate significant changes, additional testing may be performed defined timepoints to increase the data gathered.
While initial stability data may come from the testing of one pilot batch, the gold standard for stability testing is usually done on batches of 3, the results of which define the:
- retest period
- shelf life/expiry date
- storage conditions.
The degree of variability between individual batches can also provide confidence for future manufactured batches (i.e. they are also likely to conform with acceptance criteria throughout the stated retest period and shelf life). Thus, the initial stability testing performed is also considered applicable to all future batches manufactured, packed, and stored under similar conditions.
An aside: there are instances where differences between the shelf life and release acceptance criteria has been observed and accepted with appropriate justification. For example, a cream could fail an appearance test at the 9-month testing time point (going from opaque white to an opaque off-yellow) however the key active ingredients of concern are still stable up to the 24-month mark.
Stability and specifications
Another term that is thrown about a lot in pharma is “specification,” which refers to a list of tests required to verify that a product is, in fact, the product. Testing traditionally covers the physical, chemical, biological, microbiological attributes, and functionality tests (e.g. for a dose delivery system).
Specifications also contain references to validated analytical procedures for those tests and proposed acceptance criteria for the test results. Product qualities that are defined in specifications are usually also tested during stability, i.e. what attributes are required to maintain the quality, safety, and efficacy of the product in the long term?
Medicinal cannabis stability
TGA base their stability requirements on the EMEA’s Guideline On Stability Testing: Stability Testing Of Existing Active Substances And Related Finished Products.
Real-time data gleaned from production batches stored under the maximum recommended storage conditions for the duration of the proposed shelf life fall under 2 stability design options:
- ‘Option a’: For conventional dosage forms such as immediate-release solid dosage forms and solutions, when the active ingredient(s) are known to be stable, it is acceptable to provide a minimum of six months of long term, intermediate (if applicable) and accelerated stability data on a minimum of two batches of at least pilot scale.
- ‘Option b’: For products that are likely to be unstable, or for which stability failure would be critical, data for three batches are required in the submission. Two of the three batches should be of at least pilot scale (the third batch may be smaller). The data must include at least 12 months of long-term results, in addition to six months of accelerated data (and six months of intermediate data, if applicable).
However, this applies to registers or listed products. A lot of cannabis products aren’t registered or listed on the ARTG and are instead supplied through AP and SAS schemes. There is then this grey area of the product expiry needing to match the stated shelf life in the finished product specification (which is based on whatever data there is to support it).
In one client case during the early days of medicinal cannabis when there has been no previous stability data available, scientific studies were combined with risk mitigation and justification to alleviate TGA concerns about stability. In this scenario the regulator initially granted a preliminary 2-3 month shelf life for an “export-only” product, however, this also came with the requirement that the company continue to conduct ongoing stability studies so that a more accurate expiry date could be obtained.
This allowance is outlined in the ICH Harmonised Tripartite Guideline Stability Testing Of New Drug Substances And Products Q1a(R2), however, is more specific to products that are registered and not supplied through AP/SAS schemes:
“When available long term stability data on primary batches do not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the stability studies post-approval to firmly establish the shelf life.
Otherwise, one of the following commitments should be made:
- If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue the long-term studies through the proposed shelf life and the accelerated studies for 6 months.
- If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue the long-term studies through the proposed shelf life and the accelerated studies for 6 months and to place additional production batches, to a total of at least three, on long term stability studies through the proposed shelf life and on accelerated studies for 6 months.
- If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed shelf life and on accelerated studies for 6 months.”
If you want to find out more information about stability or medicinal cannabis, why not get in contact with one of our experienced consultants and have a chat?
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