Over view of Stability Testing of Pharmaceutical Products
What is Stability?
Stability of a pharmaceutical product may be defined as the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, toxicological, and protective specifications.
In other words, it is the extent to which a product retains, within the specified limits, throughout its period of storage and use, the same properties and characteristics possessed at the time of its packaging.
What is Stability Testing?
Stability testing is perform to evaluates the effect of environmental factors on the quality of the a drug substance or a formulated product which is utilized for prediction of its shelf life, establish proper storage conditions and to suggest labelling information.
What are the factors affects the product stability?
There are varieties of factors influencing the stability of a pharmaceutical product. These factors include stability of the active ingredient(s); interaction between active ingredients and excipients, manufacturing process followed, type of dosage form, container/closure system used for packaging and light, heat and moisture conditions encountered during shipment, storage and handling. In addition, degradation reactions like oxidation, reduction, hydrolysis or racemization, which can play vital role in stability of a pharmaceutical product, also depend on such conditions like concentration of reactants, pH, radiation, catalysts etc., as well as the raw materials used and the length of time between manufacture and usage of the product.
A pharmaceutical product may undergo change in appearance, consistency, content uniformity, clarity (solution), moisture contents, particle size and shape, pH, package integrity thereby affecting its stability. Such physical changes may be because of impact, vibration, abrasion, and temperature fluctuations such as freezing, thawing or shearing etc. The chemical reactions like solvolysis, oxidation, reduction, racemisation etc. that occur in the pharmaceutical products may lead to the formation of degradation product, loss of potency of active pharmaceutical ingredient (API), loss of excipient activity like antimicrobial preservative action and antioxidants etc. (Carstensen et al., 2000). Stability of a pharmaceutical product can also be affected because of microbiological changes like growth of microorganisms in non sterile products and changes in preservative efficacy.
Why Stability Testing is required?
The major aim of pharmaceutical stability testing is to provide reasonable assurance that the products will remain at an acceptable level of fitness/quality throughout the period during which they are in market place available for supply to the patients and will be fit for their consumption until the patient uses the last unit of the product.
Furthermore, the data generated during the stability testing is an important requirement for regulatory approval of any drug or formulation.
Other benefits of stability studies at the developmental stage or of the marketed products are to provide a database to determine shelf life and storage conditions for development of a new product, preparation of registration dossier, to prove the claimed shelf life for the registration dossier.
When Stability Testing is required?
Stability testing is a routine procedure performed on drug substances and products and is in use at various stages from the product development stage to commercialization.
What kinds of studies used in the industries to test the stability of drug products?
Depending upon the aim and steps followed, stability testing procedures have been categorized into the following types:
Accelerated stability testing
In early stages, accelerated stability testing (at relatively high temperatures and/or humidity) is used in order to determine the type of degradation products which may be found after long-term storage.
In accelerated stability testing, a product is stressed at several high (warmer than ambient) temperatures and the amount of heat input required to cause product failure is determined. This is done to subject the product to a condition that accelerates degradation.
This information is then projected to predict shelf life or used to compare the relative stability of alternative formulations.
This usually provides an early indication of the product shelf life and thus shortening the development schedule. In addition to temperature, stress conditions applied during accelerated stability testing are moisture, light, agitation, gravity, pH and package.
Because the duration of the analysis is short, the likelihood of instability in the measurement system is reduced in comparison to the real-time stability testing.
Further, in accelerated stability testing, comparison of the unstressed product with stressed material is made within the same assay and the stressed sample recovery is expressed as percent of unstressed sample recovery.
The concept of accelerated stability testing is based upon the Arrhenius equation (1) and modified Arrhenius equation
These equations describe the relationship between storage temperatures and degradation rate. Using Arrhenius equation, projection of stability from the degradation rates observed at high temperatures for some degradation processes can be determined.
Retained sample stability testing:
This is a usual practice for every marketed product for which stability data are required. In this study, stability samples, for retained storage for at least one batch a year are selected. At the time of first introduction of the product in the market, the stability samples of every batch may be taken, In this study, the stability samples are tested at predetermined intervals i.e. if a product has shelf life of 5 years, it is conventional to test samples at 3, 6, 9, 12, 18, 24, 36, 48, and 60 months.
Cyclic temperature stress testing:
This is not a routine testing method for marketed products. In this method, cyclic temperature stress tests are designed on knowledge of the product so as to mimic likely conditions in market place storage. The period of cycle mostly considered is 24 hours since the diurnal rhythm on earth is 24 hour, which the marketed pharmaceuticals are most likely to experience during storage. The minimum and maximum temperatures for the cyclic stress testing is recommended to be selected on a product- by-product basis and considering factors like recommended storage temperatures for the product and specific chemical and physical degradation properties of the products.
What are the various Regulatory guidelines for stability testing?
The regulatory authorities in several countries have made provisions in the drug regulations for the submission of stability data by the manufacturers. Its basic purpose was to bring in uniformity in testing from manufacturer to manufacturer. These guidelines include basic issues related to stability, the stability data requirements for application dossier and the steps for their execution.