2. •Ensuring quality, safety, and efficacy of drugs.
•Harmonization of drug technical requirements.
•Avoid duplication of human clinical trials.
•Reduce use of animal testing but without a compromise on evaluating efficacy and safety of drugs.
The purpose of ICH may be summarized as follows:
3. ICH comprises 16 Members and 32 Observers.
Member countries: United States, Japan, and European Union
Regulatory Representatives:
1. European Commission (EC) and European Medicines Agency (EMA).
2. United States Food and Drug Administration (USFDA).
3. Japan’s Ministry of Health, Labour and Welfare (MHLW).
Industrial Representatives:
1. EU’s European Federation of Pharmaceutical Industries and Associations (EFPIA).
2. USA’s Pharmaceutical Research and Manufacturers of America (PhRMA).
3. Japan’s Pharmaceutical Manufacturers Association (JPMA).
4. The harmonization activities of ICH may fall into one of four categories:
Formal ICH Procedure, Q & A Procedure, Revision Procedure, and
Maintenance Procedure.
Process of Harmonization
ICH Procedures
5. 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 sign off 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, a
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.
6. The ICH guidelines are covered under four headings under the acronym QSEM – Quality, Safety, Efficacy, and
Multidisciplinary.
(a) Quality guidelines: These guidelines cover the areas of quality of drug products such as impurity testing
and stability studies and a flexible approach to quality based on GMP risk management.
(b) Safety guidelines: They help to detect potential risks such as genotoxicity, carcinogenicity, and
nephrotoxicity. For example, the ICH came up with a non-clinical test methodology to evaluate QT interval
prolongation which is probably the most significant reason why drugs have been withdrawn in recent times.
(c) Efficacy guidelines: These guidelines guide designing, conducting, safety aspects, and reporting of clinical
trials for pharmaceutical products. Novel drug products derived from biotechnology and
genomic/pharmacogenetic techniques for targeted drug delivery are also covered.
(d) Multidisciplinary guidelines: Topics in the pharmaceutical field that do not fit into any of the above
categories are covered under this area. This guideline also includes details of (MedDRA), CTD, and standards
such as Electronic Standards for the Transfer of Regulatory Information (ESTRI)
ICH Guidelines
Quality, Safety, Efficacy, Multidisciplinary (QSEM)
7. Quality Guidelines
The areas covered under this are labeled
from Q1 to Q11 and deal with different
aspects of Quality Assurance (QA)
relating to pharmaceuticals. Stability
testing, analytical validation, impurities,
quality systems, risk management, and
GMP are some of the most important
areas covered.
8.
9. 1. The ICH guidelines for stability testing define what information must be provided at the time of applying to
register a new drug molecule.
2. These guidelines were first adopted in 1993. After revision and updation, the current version in use called
Q1A(R2) has been adopted since 2003.
3. This guideline harmonizes the drug registration process for all drugs in the USA, Japan, and the EU.
4. This means a drug registered in one of these regions will not require repeated stability testing when to be
sold in any of the other two regions.
5. Stability testing is important because drug products must be stable when administered to the patients.
6. If an unstable product degrades into toxic metabolites, or if the activity of the drug reduces below 85% of the
label claim, there can be serious therapy failures that may even result in death.
7. 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 the shelf life.
8. The stability testing data must provide information about how the drug molecule changes over time under
different storage conditions.
9. 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.
10.Therefore, it is vital to perform stress testing to study and document the conditions that lead to the
degradation of the drug molecule.
11.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.
ICH Guidelines for Stability
10. Types of Stability Testing
1. Real-time testing: This involves testing drug products for a longer duration to find out what is 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 mimic 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:
1. Batch selection – how many batches are to be tested
2. Containers and closures that must be used for the testing
3. Different positions in which product containers must be kept during testing
4. Frequency of drawing samples for analysis
5. Overall sampling plan – when and how much to sample and from where
6. Test storage conditions based on climatic zone where the drug will be used
7. Parameters to be tested to evaluate product stability – mainly the ones expected to change after storage
8. Methods to be used for testing, and their validation
9. Acceptance criteria for result values, and degradation products
11. 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, 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 the 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 for different regions and climatic zones, and labeling requirements regarding storage
region-wise.
Overview of ICH Stability Guidelines Contents
