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Shelf life test (medicinal products)

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The shelf life test (also: stability test) of a medicinal product is used to experimentally determine its shelf life. It is tested whether the medicinal product complies with the defined specifications with regard to microbiological, physical and chemical properties over the storage period. For example, the content of the drug (in the case of combination drugs: the drugs) must not fall below a certain value (usually: 90 %). Also, decomposition products may only be formed in very small quantities within defined limits. It is also particularly important that the release of the drug from the dosage form does not change adversely during storage. The expiry date by which a medicinal product must be used up at the latest is derived from the results of the shelf life tests.

For the storage of the medicinal products for stability testing, the storage conditions, i.e. Temperature and relative humidity, are selected depending on the requirements specified by the climate zone(s).

The procedure for conducting shelf-life tests is precisely prescribed for drug manufacturers by the guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

Implementation

A prerequisite for the performance and interpretation of the stability tests is the establishment of a drug specification. It defines the quality characteristics of a medicinal product in qualitative and quantitative terms. This includes a minimum value for the drug content as well as the designation of possibly occurring decomposition products with upper limits. Likewise, stability-relevant physical characteristics such as the release of the drug and, if necessary, other variables such as pH value (for solutions), water content (for example, for solid dosage forms) or discoloration are limited.

The medicinal product manufacturer must demonstrate that the analytical methods he uses are valid, i.e. specific and accurate.

With regard to storage, a distinction is made between long-term tests and accelerated shelf-life tests.

Long-term tests

The finished medicinal products are stored in the final packaging under climatic conditions in climatic cabinets or rooms, depending on the consumer region[1] in climatic cabinets or climatic rooms and regularly tested at prescribed intervals. The test lasts a maximum of 5 years.

Climate zone Description Storage condition[2]
I Moderate 21 °C / 45 % r.h.
II Subtropical and Mediterranean 25 °C / 60 % r.h.
III Hot and dry 30 °C / 35 % r.h.
IVa Hot and humid 30 °C / 65 % r.h.
IVb Hot and very humid 30 °C / 75 % r.h.

r.H. = relative humidity

Accelerated durability testing

These are used for rapid preliminary characterization of stability by storage at elevated temperatures.

The finished medicinal products shall be stored in the final packaging at 40 °C and 75 % relative humidity in climatic cabinets and regularly inspected at prescribed intervals, for a maximum of six months.

In early pharmaceutical development, the performance of kinetic studies can already provide indications of the course of stability. A distinction is made between:

  • isothermal tests: storage of the drug at, for example, 40, 50, 60 and 70 °C. Determination of the respective reaction rate constant of the drug decomposition by analyzing the decrease in content. Subsequently, the measurement results are converted to 21 °C via the Arrhenius equation.
  • allothermic test: linear or logarithmic heating of the drug, regular periodic analysis of the decrease in content due to the (partial) decay of the drug and calculation of the reaction kinetic data via complex mathematical equations.

Requirements of the pharmaceutical authorities

In the marketing authorisation application, manufacturers of medicinal products must specify a shelf life from which the expiry date to be given for the medicinal product is determined. The shelf life indicates how long the medicinal product specification will be adhered to. Stability data must be collected in accordance with ICH quality guidelines. Typically, data from three batches over at least 12 months of storage at long-term conditions must be submitted, which may be supplemented by data from short-term tests (= accelerated stability test). Data from accelerated stability tests alone are not sufficient.

Literature

Web links

  • Quality guidelines of the ICH, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (English)

Individual references

  1. WHO Technical Report Series, No. 953 (2009). Annex 2: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. Appendix 1: Long-term stability testing conditions, Table 2.(PDF)
  2. WHO Technical Report Series, No. 953 (2009). Annex 2: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. Appendix 1: Long-term stability testing conditions, Table 1