INTERNATIONAL CONFERENCE ON HARMONIZATION ( ICH) || QSEM || ICH guideline || ICH guidelines for stability

 

INTERNATIONAL CONFERENCE ON HARMONIZATION (ICH)

Ø ICH and its purpose

Ø Process of harmonization

Ø ICH Guidelines: QSEM

Ø Quality guidelines

Ø ICH Guidelines for stability

ICH AND ITS PURPOSE

The full form of ICH is "International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use."

This body was set up to bring together representatives of pharmaceutical industry and regulatory bodies to discuss technical and scientific aspects of registration of drugs.

As the pharmaceutical industry grew more international, the differences in technical requirements across countries meant that drug makers had to spend lot of time and money to duplicate test procedures if they wanted to market their products at an international level.

It started becoming important to make safe and effective drugs available to patients all over the world without the delays caused by regulations not matching across regulatory bodies of the different countries.

Thus, a need was felt to rationalize and harmonize drug regulations, and this resulted in the inception of ICH in 1990.

Purpose of ICH may be summarized as follows:

• 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.

PARTICIPANTS:

• ICH assembly
• ICH management committee
• MedDRA management committee
• ICH secretariat

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.

ICH Procedures

Type of procedure	Deals with
Formal ICH Procedure	New topic for harmonization
Q & A Procedure	Clarification for an existing ICH Guideline
Revision procedure	Adding new information to an existing ICH Guideline
Maintenance procedure	Changes to be made to maintain a guideline

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 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, 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.

ICH GUIDELINES: QUALITY, SAFETY, EFFICACY, MULTIDISCIPLINARY (QSEM)

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 on the basis of GMP risk management. ( Q1 to Q11)

(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. (S1 to S11)

(c)   Efficacy guidelines: These guidelines provide guidance about 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.(E1 to E19)

(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). (M1 to M11)

QUALITY GUIDELINES

Out of all these guidelines, the one most relevant to us is the 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.

Guideline	Subpart	Area covered
Q1 Stability	Q1 A	Stability testing of new drug substances and products.
	Q1B	Photostability testing of new drug substances and products.
	Q1C	Stability testing for new dosage forms.
	Q1D	Bracketing and matrixing designs for stability testing of new drug substances and products.
	Q1E	Evaluation of stability data.
	Q1F	Stability data package for registration applications in climatic zones III and VI
Q2		Validation of analytical procedures.
Q3 Impurities	Q3A	Impurities in new drug substances.
	Q3B	Impurities in new drug products.
	Q3C	Guidelines for residual solvents.
	Q3D	Guidelines for elemental impurities.
Q4 Pharmacopeias	Q4A	pharmacopeial harmonization
	Q4B	Evaluation and recommendation of pharmacopeial texts for use in ICH regions.
Q5 Quality of biotechnology products	Q5 A	Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin.
	Q5 B	Analysis of expression construct in cells used for production of r-DNA derived protein products.
	Q5C	Stability testing of biotechnological/ biological products.
	Q5D	Derivation and characterization of cell substrates used for production of biotechnological/biological products.
	Q5E	Comparability of biotechnological/biological products subject to changes in their manufacturing process.
Q6 Specifications	Q6 A	Test procedures and acceptance criteria for new drug substances and new drug products: chemical substances.
	Q6 B	Test procedures and acceptance criteria for biotechnological/biological products.
Q7		Good manufacturing practices for API
Q8		Pharmaceutical development
Q9		Quality risk management
Q10		Pharmaceutical quality system.
Q11		Development and manufacture of drug substances (chemical and biological entities).

 

ICH GUIDELINES FOR STABILITY

• The ICH guidelines for stability testing define what information must be provided at the time of applying to register a new drug molecule.
• These guidelines were first adopted in 1993.
• After revision and updating, the current version in use called 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 to be sold in any of the other two regions.
• 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.

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.

2. Accelerated stability testing: Here, 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 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:

• 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 climatic zone where 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 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.

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, susceptibility to be degraded by moisture (hydrolysis).

Photostability testing: Study of 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 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.

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