ICH

PROCESS OF HARMONIZATION

The harmonization activities of ICH may fall into one of four

categories : Formal ICH Procedure, Q & A Procedure, Revision
Procedure and Maintenance Procedure.

First, a Concept Paper is prepared for the activity to be harmonized.

This is a brief summary of the concept being proposed. Sometimes, a
business plan may also be prepared to highlight the cost : benefit ratio
of the harmonizing activity.
The formal ICH procedure then begins, in the following steps:
Step 1: Building consensus:
Based on the objectives specified in the Concept Paper, a working
group prepares a consensus draft called the Technical Document. The
working group’s technical experts signoff on this, and the Step 1
Experts Technical Document is submitted to the ICH Assembly with a
request for adoption.

Step 2: (a) Based on the report:

Assembly confirms that the scientific consensus exists for the
technical issues, and the Technical Document may proceed further
for regulatory consultation. (b) This draft guideline is examined and
endorsed by regulatory members of the ICH Assembly
Step 3: This happens in three different stages:
 Consultation, discussion and finalization of the Expert Draft Guideline by
regulatory members at different levels.

Stage 1:
 The draft guideline goes to the different ICH regions for discussion in their
respective regulatory regions.
Stage 2:
 All comments obtained during stage 1 are addressed by the expert working
group and after discussion, consensus is reached to prepare the step 3 Experts
Draft Guideline.
Stage 3:
 This draft guideline is finalized and signed by the ICH regulatory member
experts. The document is sent to ICH Assembly regulatory members for
further proceeding to step 4.
Step 4:
 ICH Assembly regulatory members agree that sufficient scientific
consensus exists on the draft guideline, and it gets adopted as the ICH
Harmonized Guideline.

Step 5:
 ICH Harmonized Guideline is implemented in all the ICH regions
through their respective regulatory procedures. Information about when it
has become effective is sent to the ICH Assembly and published on
the ICH website.

Stability testing is the statistical analysis of how long a pharmaceutical

product can be stored without any change in its original chemical
composition.
 How Do You Perform a Stability Test?

Physical Changes: With the stability test, researchers monitor changes in the

physical attributes of the drug when stored for specified durations. Key changes
that are monitored include the change in color, water content level, change in
pH, change in viscosity, presence of crystalline substances, and its
difference in dissolution and disintegration properties from the day it was
packed.
Chemical Changes: The stability protocol for pharmaceutical products, when
analyzing chemical evidence, is to look for the presence of residual solvents,
related substances, and any degradation by-products along with assay.

Microbial Changes: Stability studies prove that pharmaceutical drugs, when

stored for long periods at room temperature and in temperature-controlled
conditions, can lead to a change in the microbial level. In microbial stability
studies of drugs, researchers look for the presence of pathogenic
microorganisms and the effectiveness of added microbial preservatives,
and any impact on the efficiency of the drug.
 ICH GUIDELINES FOR STABILITY

•Stability testing is important because drug products must be stable when

administered to the patients.
• If an unstable product degrades into toxic metabolites, or if activity of the drug
reduces below 85% of the label claim, there can be serious therapy failures that
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.
•Drugs which are unstable 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 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
storage of the product.
Based on the nature of the test and the estimated shelf life periods of certain
pharmaceutical drugs, various stability testing methods are used to arrive at
statistical data points that help manufacturers release safe and tested
products to the market for consumption.

 Types of Stability Testing

1. Real-time testing:

 This involves testing drug product for a longer duration to find out
what is the maximum product degradation when stored as
recommended.

•This form of stability testing is conducted on drugs for the same duration
as the recommended shelf life. In this, regular periodic tests are conducted
and conclusive analysis is done for its composition, efficiency, and
reaction to various conditions.
2. Accelerated stability testing:

•This is a form of shelf-life testing and is used to gain insights on the

predicted shelf life of the drug. In this, the drug is exposed to more than
ambient temperatures and the changes are noted.

• Earlier the drug used to be exposed to extreme conditions and higher

temperatures, moisture, agitation, light, pH, and packaging conditions to
study its degradation profile.  

•single accelerated condition storage usually at 40 degree Celsius and

75% Humidity is used as per ICH.

•This information was used to extrapolate the shelf life and relative
stability of the pharmaceutical product.
3. Retained sample stability testing:
 This is testing of samples retained from each batch that has been sent
into the market.
the stability of the drug is periodically inspected and is allowed a
degradation percentage of 2-5. For example, if a pharmaceutical drug has a
shelf life of 5 years, the drug is tested in its 3rd, 6th, 12th, 24th, 36th, 48th
and 60th month and the changes in its physical, chemical, and microbial
composition are noted and compared with the regulated permissible
levels.

4.Cyclic temperature stress testing:

 Not routinely used. It involves subjecting the products to temperature
stresses in a way to mimic likely market storage conditions.

In this, the minimum and maximum temperature conditions are mimicked

in a controlled environment and the drugs are exposed to these conditions
for 24 hours and the changes if any are noted.
Normally the drug undergoes 20 cycles of cyclic temperature stress
testing before any conclusive analysis on its stability is made.
 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
The batches selected for stability testing should be the same as the ones
that are reserved for distribution. The batches tested should be the same as
the ones used in clinical trials and post packaging. The batches used are to
be monitored for a period of 12 months and for those that were not
approved for mass consumption in its first evaluation should be monitored
for longer intervals.
• Containers and closures that must be used for the testing
The packaging used for testing pharmaceutical drugs should be the same as
the ones used during clinical trials and production.
• Frequency of drawing samples for analysis
•Overall sampling plan – when and how much to sample and from where
•Test storage conditions based on climatic zone where drug will be used
• Parameters to be tested to evaluate product stability – mainly the ones
expected to change after storage
The packaging material and the quality of the substance used while testing
the product should be the same as the one submitted to the regulatory bodies
in the clinical trials and production phase.
• Methods to be used for testing, and their validation
The test procedure should entail everything from efficiency, growth of
microbial by-products, the formation of degradation products, the formation
of crystalline by-products, the viscosity of the chemical, formation of
moisture/water, and the effectiveness of the drug.
• Acceptance criteria for result values, and for 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.
 Why should you go for the stability testing of your product?

1. Shelf-Life Determination: The quality of a pharmaceutical product

varies with time under temperature, humidity and light intensity. 
Stability testing studies; how long a pharmaceutical product can be
stored at normal and accelerated conditions without any degradation.
This study helps to determine the shelf-life of that product. As per the
report of the study, the expiry date of the product is fixed.

2. Storage Condition Recommendation: Different products require

different storage conditions. In the stability testing lab, storage
conditions and changes in the substances are recorded. As per the
stability study, the storage condition is recommended for a particular
product.
3. Elimination of Impurities: In stability testing, each ingredient has been
analyzed under various environmental factors. So, it becomes easy to
identify and eliminate any impurities that may be formed during the shelf
life of the product.

4. Product Development: Stability testing is a reliable way to study the

effectiveness of a new product. This testing helps to assess the physical,
chemical,  therapeutic stability of a product. As per the study, R&D
professionals redesign the existing product and develop a new product.

5. Ensures Quality: Quality assurance is an integral part of the

 pharmaceutical industry. The product is kept under the influence of high
stresses and the rate of decomposition is observed. Stability testing
assures the purity of ingredients and the quality of the final product. The
stability report ensures that the pharmaceutical product is fit for human
consumption. This gives the companies the confidence to launch new
products in the market. The chances of product recall may decrease.
6. Packaging Material Selection: During stability testing, the
pharmaceutical product is exposed to humidity and temperature. As
per the effect of water activity and temperature on the product,
packaging materials are chosen for the product. The ideal container
must tolerate the stresses. The packaging should maintain the quality
of the product during transportation and storage.

7. Legal Approvals: Stability testing of the pharmaceutical products is

required for regulatory approvals. If a product fails to meet the quality
standards prescribed by ICH and WHO, the product will not get
approval for commercialization.