The ICH guidelines for stability testing define what information must be provided when applying to register a new drug molecule. These guidelines were first adopted in 1993. After revision and updation, the current version in use, Q1A(R2), has been adopted since 2003. This guideline harmonizes the drug registration process for all drugs in the USA, Japan, and the EU. This means a drug registered in one of these regions will not require repeated stability testing when being sold in any of the other two regions.
Stability testing is important because drug products must be stable when administered to patients. If an unstable product degrades into toxic metabolites or if the drug's activity reduces below 85% of the label claim, serious therapy failures can occur, which may even result in death. Stability testing also provides data to choose the formulation parameters, excipients, and the right container-closure system to ensure safe and effective quality products that retain activity throughout shelf life.
The stability testing data must provide information about
how the drug molecule changes over time under different storage conditions.
This gives insight into how light, heat, and humidity will influence the
chemical nature of the product. Unstable drugs will need specific storage
conditions if they have to remain effective. Therefore, it is vital to perform
stress testing to study and document the conditions that lead to the degradation
of the drug molecule. This information is used to arrive at the shelf life of
the drug and what conditions will be optimal for the storage of the product.
Types of Stability Testing
1. Real-time testing: This involves testing drug products for a longer duration to determine the maximum product degradation when stored as recommended.
2. Accelerated stability testing: Here, the product
is subjected to stress in the form of higher temperatures, moisture, agitation,
light, pH, and packaging conditions to study its degradation profile.
3. Retained sample stability testing: This is the testing
of samples retained from each batch that has been sent into the market.
4. Cyclic temperature stress testing: Not routinely
used. It involves subjecting the products to temperature stresses in a way to
mimics likely market storage conditions.
Stability Testing Protocol
This is the written document that describes all major
requirements of a well-controlled stability study for a given drug substance or
drug product. The basic information to be included in a stability test protocol
includes:
• Batch selection – how many batches to be tested
• Containers and closures that must be used for the testing
• Different positions in which product containers must be
kept during testing
• Frequency of drawing samples for analysis
• Overall sampling plan – when and how much to sample and
from where
• Test storage conditions based on the climatic zone where the
drug will be used
• Parameters to be tested to evaluate product stability –
mainly the ones expected to change after storage
• Methods to be used for testing, and their validation
• Acceptance criteria for result values, and degradation
products
The data obtained by performing the stability studies is
used for expiration dating of the drug product and to determine its shelf life.
Overview of ICH Stability Guidelines Contents
Some of the areas covered by the ICH guidelines on stability
testing include:
• Stress testing: Study of degradation pathways, effects of
change in temperature, relative humidity, pH changes, and susceptibility to being
degraded by moisture (hydrolysis).
• Photostability testing: Study of the effect of light on
drug chemistry.
• Batch selection for stability testing: Not less than 3
primary batches of drug substance.
• Testing of container closure system: At least thrice; once
in 3 months in the first year, once in 6 months during the second year, and
then annually.
• Storage conditions for the drug substance and product.
• Storage instructions with respect to different regions and
climatic zones, and labeling requirements regarding storage region-wise.
Thanks to the harmonization process of ICH, there are now
more than 50 harmonized guidelines. This led to streamlining of the research
and development process and in turn, made it easier to develop and market new
medicines to patients all over the globe. There are certainly concerns that
non-ICH members are not consulted in the decision-making; however, the
educational material provided by ICH is largely beneficial for such countries
to streamline their own R&D and drug manufacturing efforts.
The membership of ICH has grown over the years of its
inception. For ICH to continue to grow and stay relevant, it is necessary to
have greater participation from more countries across the world. Future plans
must consider the involvement of non-ICH members, recognizing and finding ways
to overcome the challenges that developing nations face in using the ICH
guidelines.