The basis of expiry date in drug / vaccine label is based on the conducted stability study. There are guidances for the stability testing study. For the pharmaceutical product, the guidance by WHO is “Stability testing of active pharmaceutical ingredients and finished pharmaceutical products”, Annex 2 in the World Health Organization [WHO] Technical Report Series, No. 953, 2010,2018.
Purpose
The stability of vaccines has a major impact on the success of immunization programmes worldwide by providing the scientific basis and guiding principles for evaluation of vaccine stability for the purpose of clinical trial approval, licensing, and post- licensure monitoring. Vaccines consist of complex mixtures of proteins, carbohydrates, lipids, inactivated microorganisms, or indeed in some cases live attenuated microorganisms as active components, as well as stabilizers, adjuvants, preservatives and other substances which together contribute to overall vaccine efficacy and safety.
Factors
Among the environmental factors considered to influence pharmaceuticals, the only one that affects characteristics of all vaccines over time is temperature. The impact of humidity is not relevant for the vast majority of vaccines due to liquid formulation, and the protective nature of packaging, providing that the closure system of vial or ampoule is appropriate. In addition to temperature, other environmental factors [e.g., light] might be considered in the development of new vaccines. However, photo stability is not considered as a mandatory test in vaccine stability studies. For those vaccines that are susceptible to the light, such as BCG vaccine, the use of amber glass is part of the usual practice in packaging and shipment. This is however a measure to protect the vaccine from light, and does not require the exposure of vaccines already known as susceptible to light in routine stability studies.
Stress testing
Stress testing of extreme environmental conditions such as light or extreme temperatures is not a mandatory test in vaccine stability studies. However, it should be considered when a vaccine is intended for a market where exposure to extreme temperature or other environmental factors is a real possibility. Stress testing also helps to determine the intrinsic stability of a vaccine by establishing degradation pathways in order to identify the likely degradation products and to validate the stability indicating power of the analytical procedures used. These studies may include exposure of a vaccine to temperatures higher than those recommended for storage, light, and oxidizing agents, freeze thaw, as well as susceptibility to hydrolysis across a range of pH values.
A major problem in assessing vaccine stability is the fact that many vaccines possess a specific biological activity that cannot be fully characterized by physicochemical methods alone. Biological assays play an important role in the quality control of vaccines and are essential parameters of vaccine quality.
Stress testing may be carried out on a single batch. It should include the effect of temperature [In 10 °C increments (for example, at 50 °C, 60 °C) above the temperature used for accelerated testing], humidity 75% relative humidity [RH] or greater and, where appropriate oxidation and photolysis. The testing should also evaluate the susceptibility to hydrolysis across a justified range of pH values when in solution or suspension. The objective of stress testing is to identify primary degradation products and not to completely degrade. The conditions studied should cause degradation to occur to a small extent, typically 10–30% loss as determined by assay when compared with non-degraded. The target should be chosen so that some degradation occurs, but not enough to generate secondary products. In the total absence of degradation products after 10 days it is considered stable under the particular stress condition.
Selection of batches
Stability studies should be done on at least three primary batches. The batches should be manufactured at a minimum of pilot scale by the same synthesis route as production batches, and using a method of manufacture and a procedure that simulates the final process to be used for production batches. Stability studies should be performed on each individual strength, dosage form and container type and size unless bracketing or matrixing is applied.
Container-closure system
Same container- closure system that is packed for storage and distribution.
Specification
Stability indicating attributes are that likely to influence quality, safety and/or efficacy. The testing should cover, the physical, chemical, biological and microbiological attributes using validated analytical procedures. A single stability batch should be tested for effectiveness of the antimicrobial preservative [In addition to preservative content] at the proposed shelf life for verification purposes.
Testing Frequency
Long-term storage condition– every three months over the first year, every six months over the second year, and annually thereafter throughout the shelf life.
Accelerated storage condition– 0,3 and 6 months.
Intermediate storage condition is called for as a result of significant change at the accelerated storage condition and testing to be done at 0, 6, 9 and 12 months.
The initial date of storage should be considered t0 and stability time points should be defined as a date with respect to t0. For example, if t0 is 1 January 2021 then the one-month time point corresponds to either 1 February or 31 January 2021. For each time point, samples should be withdrawn and tested as per the protocol. Testing should be completed as soon as possible. Matrixing or bracketing, where the testing frequency is reduced or certain factor combinations are not tested at all, can be applied if justified.
Storage conditions
Storage conditions should be monitored and recorded. Short-term environmental changes due to opening the doors of the storage facility are accepted as unavoidable. The effect of excursions due to equipment failure should be assessed, addressed and reported if judged to affect stability results. Excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effects assessed.
Stability data must demonstrate stability of the product throughout its intended shelf life under the climatic conditions prevalent in the target countries. Zones are divided into I/II/III & IV based on climate.
The orientation of the product during storage, i.e., upright or inverted, as well as the rationale for the orientation, may need to be included.
For new product, the long-term testing should normally have taken place over a minimum of 12 months for the number of batches at the time of submission, and should be continued for a period of time sufficient to cover the proposed shelf life.
For existing products, data covering a minimum of six months may be submitted.
Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition, can be used to evaluate the effect of short-term excursions outside the label storage conditions [Such as might occur during shipping].
If long-term studies are conducted at 25± 2 °C / 60± 5% RH and “significant change” occurs at any time during six months testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. In this case, testing at the intermediate storage condition should include all long-term tests, unless otherwise justified, and the initial application should include a minimum of six months data from a 12-month study at the intermediate storage condition.
What is a “significant change”?
# A change from the initial content of 5% or more detected by assay, or failure to meet the acceptance criteria for potency when using biological or immunological procedures.
#Any degradation product exceeding its acceptance criterion.
For refrigerated conditions
If significant change occurs between 3 and 6 months testing at the accelerated storage condition, the proposed retest period should be based on the data available at the long-term storage condition. If significant change occurs within the first three months’ testing at the accelerated storage condition a discussion should be provided addressing the effect of short- term excursions outside the label storage condition, e.g., during shipping or handling. This discussion can be supported, if appropriate, by further testing on a single batch for a period shorter than three months but with more frequent testing than usual.
For freezer conditions
In the absence of an accelerated storage condition, testing on a single batch at an elevated temperature [e.g., 5± 3 °C or 25± 2°C or 30± 2°C] for an appropriate time period should be conducted to address the effect of short-term excursions outside the proposed label storage condition, e.g., during shipping or handling.
Ongoing stability study
At least one production batch per year should be added to the stability monitoring programme and generally should be tested at least every 6 months in the first year and then annually to confirm the stability. Stability study should be initiated after any significant change or significant deviation of the synthetic route, process or container-closure system.
In use and holding time stability
The purpose of in-use stability testing is to provide information for the labelling on the preparation, storage conditions and utilization period of multidose products after opening, reconstitution or dilution of a solution.
A minimum of two batches, at least pilot-scale, should be subjected to the test. At least one of these batches should be chosen towards the end of its shelf life. If such results are not available, one batch should be tested at the final point of the submitted stability studies. In general, this testing need not be repeated on commitment batches. Consideration should also be given to hold-time studies of bulk products. For example, when the bulk product may be stored for a period exceeding 30 days before being packaged and/or shipped from a manufacturing site to a packaging site, the stability of the bulk product in the intended bulk container should be evaluated and studied.
Note-The images given for representation in this blog are taken from Google Images. Many thanks for Google.