The stability studies are one of the very important parameters of pharmaceutical products for prediction of shelf life, determine proper storage conditions, and suggest labeling instructions which are to be studied in accordance with International Conference on Harmonisation (ICH) Q1A(R2) and World Health Organization (WHO) for approval in Saudi Arabia SFDA and GCC.
In this article, we are going to detail the minimum requirements for SFDA drug registration. In the drug file, the requirements fall under the below three CTD sections:
- 3.2.P.8.1 Stability Summary and Conclusion (Overall Summary)
- 3.2.P.8.2 Post Approval Stability Protocol and Stability commitment
- 3.2.P.8.3 Stability Data
Stability Summary and Conclusion
The summary should clearly outline the number of batches manufactured, placed into stability study, and the time point at which the drug product analysis is done under the long term and accelerated conditions.
Stability batches containing information related to (Storage Conditions, Testing Frequency, and Type of tests) should be outlined, as indicated on the below table;
Stability result discussion for the batches studied at the time of submission should be mentioned for no significant change in the overall concentration of the batches.
The conclusion should be clear for no significant changes in any of the product parameters, either during the long-term or during the accelerated stability testing and accordingly, the shelf life and storage condition are proposed.
Post Approval Stability Protocol and Stability Commitment
A stability testing protocol is required to confirm the proposed shelf life. It should contain information on stability batches studied, test details, storage condition, and sampling plan. The stability commitments might be required by SFDA in cases such as:
- If the study does not cover the proposed shelf life.
- Post-approval long-term stability studies.
- Ongoing stability studies.
Selection of batches
Three primary stability studies batches are required. Two of the three batches should be at least pilot-scale batches (pilot-scale batch size is 10% of the proposed production size). The third one can be a lab-scale (lab-scale batch can be smaller than 10% of proposed production but NLT 25% of the pilot-scale)
The frequency of testing at the long-term storage condition should normally be every three months over the first year, every six months over the second year, and annually thereafter throughout the proposed shelf-life (e.g., 0, 3, 6, 9, 12, 18, 24, 36 months).
At the accelerated storage condition, a minimum of three-time points, including the initial and final time points (e.g. 0, 3, and 6 months), from a six-month study is recommended.
For Saudi Arabia, stability is required in Zone IVa for long term stability testing. Alternative storage conditions can be used if justiﬁed.
Long Term Testing Conditions:
|Climatic Zone||Temperature||Humidity||Minimum Duration required at submission|
|Zone I||21ºC ± 2ºC||45% rH ± 5% rH||12 Months|
|Zone II||25ºC ± 2ºC||60% rH ± 5% rH||12 Months|
|Zone III||30ºC ± 2ºC||35% rH ± 5% rH||12 Months|
|Zone IVa*||30ºC ± 2ºC||65% rH ± 5% rH||12 Months|
|Zone IVb||30ºC ± 2ºC||75% rH ± 5% rH||12 Months|
|Refrigerated||5ºC ± 3ºC||No Humidity||12 Months|
|Frozen||-15ºC ± 5ºC||No Humidity||12 Months|
Accelerated Testing Conditions:
|Climatic Zone||Temperature||Humidity||Minimum Duration|
|Accelerated Ambient||40ºC ± 2ºC||75% rH ± 5% rH||6 Months|
|Accelerated Refrigerated||25ºC ± 2ºC||60% rH ± 5% rH||6 Months|
|Accelerated Frozen||5ºC ± 3ºC||No Humidity||6 Months|
Stability data should include the type of batches used for the study (i.e production, pilot or lab), storage condition, stability entering date, and product manufacturing date. The data should be tested for stability-indicating parameters which should cover physical, chemical, and microbial parameters. In general appearance, assay and impurities should be evaluated for all dosage forms, as well as the preservative and antioxidant content and other parameters to be evaluated as per the dosage form.
In use stability data
In-use stability is performed to know that the product stored at °C/ % RH show acceptable quality throughout the in-use period. An in-use program is required for liquid multi-dose sterile products, multi-dose products with a protective outer package, and products that are constituted or diluted.
A minimum of two batches, at least pilot scale batches, should be subjected to the test. One batch should be tested at initially and the other one at the end of its shelf life. If the test result is not available at the end of the shelf life, then one batch should be tested at the final point of the submitted stability studies (with a commitment to submit the results at the end of shelf-life as soon as they become available).
In-use stability should be tested for physical, chemical, and microbial properties of the product which is susceptible to change during storage. Testing should be performed at the initial time point, intermediate time points, and at the end of the proposed in-use shelf-life on the final remaining amount of the product in the container.
Common SFDA Observaions on Stability Studies
- Unavailability of 03 pilot-scale batches or 02 pilot-scale and 01 small-scale batches with both accelerated and long-term data covering a period of minimum 12 months.
- Commitment letters to conduct ongoing stability studies (at least one batch per year).
- Commitment to place the first three production batches on long-term stability studies through the proposed shelf-life period.
- In-use stability studies should be conducted in accordance with the GCC Guidelines for Stability Testing on at least two batches.