ICH GUIDELINES OF STABILITY DATA: A REVIEW
Final Year Graduate Student
Sri Lakshmi Narasimha College of Pharmacy,
Palluru, Chittoor-517132, Andhra Pradesh, India.
The International Conference on Harmonization of technical requirements of pharmaceuticals for human use was established in 1990 as a tripartite venture representing regulatory bodies and research based industry. The major aim of ICH is to provide a forum for constructive discussion on the real and perceived differences in technical requirements for the registration of new chemical entities. Other objectives are: To achieve greater harmonization in the interpretation and application of technical guidelines for the registration of new active substances or products obtained by biotechnology by its members; to improve the efficiency of global drug development; to reduce redundant studies; and to improve pharmacovigilance activities and quality assurance.
REFERENCE ID: PHARMATUTOR-ART-1644
The co-sponsors of ICH are : The European Commission and the European federation of Pharmaceutical Industries Associations [EFPIA]; The Japanese Ministry of Health, Labour and Welfare [JMHLW] and the Japan Pharmaceutical Manufacturers Association [JPMA], and the United States Food and Drug Administration [FDA] and the Pharmaceutical Research and Manufacturers of America [PhRMA]. These six cosponsors are the voting members of the ICH Steering Committee. ICH thus represents 17 countries comprising 15% of the world’s population and accounting for 90% of the US $ 320 billion global pharmaceutical sales of the year 2000. ICH regulatory authorities are among the first to evaluate new chemical entities and new products obtained from biotechnology.
OBJECTIVE OF THE GUIDELINES:
* Establishment of a single set of global specifications for new drug substances and products.
* Guidance on the setting and justification of acceptance criteria and the selection of the test procedures.
A specification is defined as a list of tests, references to analytical procedures and appropriate acceptance criteria which are numerical limits, ranges or other criteria for the tests described.
SCOPE OF THE GUIDELINES:
The quality of the drug substances and product is determined by their:
* In-process control
* GMP controls
* Process validation
The guidelines cover:
* Solid dosage forms
* Liquid dosage forms
* Parenterals (small and large volume)
GENERAL CONCEPTS PERIODIC / SKIP TESTING:
Performance of specified tests at release on pre-selected batches and at pre determined intervals. This less than full schedule testing should be justified and presented to the regulatory authority prior to implementation.
Examples for solid dosage forms:
* Residual solvents
* Microbial testing
This concept may be implemented post-approval in accordance with GMP, if sufficient data are available.
PHARMACOPOEIA TESTS AND ACCEPTANCE CRITERIA:
Whenever appropriate pharmacopoeia methods should be utilized. A harmonized specification is possible only if the procedure and acceptance criteria defined are acceptable to regulatory authorities in all regions. The full utility of this guideline is dependent on the successful completion of harmonisation of pharmacopoeial procedures for several attributes commonly considered in the specification for new drug substances and products.
Specifications: Definition and Justification
* Lists of tests
* Reference to analytical procedures
* In process tests
* Periodic tests
* Other tests not conducted on a batch to batch basis.
Justification should refer to:
* Relevant development data
* Pharmacopoeial standards
* Test data of batches used in toxicology and clinical studies
* Results from accelerated and long term stability studies.
* Reasonable range of expected analytical and manufacturing variability.
STORAGE CONDITIONS: [STABILITY]
For the general case, the recommended long-term and accelerated storage conditions for Climatic Zones III and IV are shown below
Study storage condition minimum time period covered by data at submission:
* Long-term 300C ± 20C / 65% RH ± 5% RH 12 Months.
* Accelerated 400C ± 20C / 75% RH ± 5% RH 6 Months.
No intermediate storage condition for stability studies is recommended for Climatic Zone III and IV. Therefore, the intermediate storage condition is not relevant, when the principle of test period or shelf life extrapolation described in Q1E are applied.
Aqueous based drug products packaged in semi-permeable containers:
Aqueous based drug products packaged in semi-permeable containers, the recommended long term and accelerated storage conditions for Climatic Zone III and IV are given below
* Long-term 300C ± 20C / 35% RH ± 5% RH 12 Months.
* Accelerated 400C ± 20C / not more than 25% RH ± 5% RH 6 Months.
The ratio of water loss rates at a given temperature is calculated by the general formula:
(100 – Reference % RH) / (100 – Alternative % RH)
Alternative relative humidity ratio of water loss rates at a given temperature:
* 65% RH 35% RH 1.9
* 75% RH 25% RH 3.0
If it cannot be demonstrated that the drug substance or drug product will remain within its acceptance criteria when stored at 300C ± 20C / 35% RH ± 5% RH for the duration of the proposed retest period or shelf life, the following options should be considered:
1) Retest period or shelf li8fe
2) A more protective container closure system
3) Cautionary statements in the labelling
Tablet coated or uncoated, hard capsules:
Highly soluble throughout physiological pH range. Solubility at 370C ± 0.50C, dose + solubility < 250 ml, pH 1.2, 4.0, 6.8.
Rapidly dissolving drugs:
* Dissolution > 80 % in 15 minutes at pH 1.2, 4.2, 6.8.
* Relationship between disintegration and dissolution respectively disintegration more discriminating than dissolution.
Hardness / friability: If critical impact on drug quality acceptance criteria should be established.
Water content: If appropriate preferred Karl Fischer Titration, loss on drying may be acceptable.
It is advisable to test the drug product unless its components are tested before manufacture and the manufacturing process is known not to carry significant risk of microbial contamination. Skip testing may be appropriate.
* Based on antimicrobial preservative content
* Based on antioxidant preservative content
Parenteral Drug Products:
* Uniformity of dosage units
* Weight variation fill volume
* Uniformity of fill according to pharmacopoeial procedure
- Endotoxins Limulus Amoebocyte Test
An ICH guideline gives a stability data information (like temperature, RH at which conditions products are going to be stored) for all pharmaceutical products at different climatic conditions.
1. Schumacher, P. “ Aktuelle Fragen Zur Haltbarkeit Arzneimitteln [ Current Question on Drug Stability]” pharmazeutische Zeitung, 119: 321- 324, 1974.
2. Grimm, W. “Storage Conditions for Stability Testing – Long Term Testing And Stress tests”. Drug made in Germany, 28: 196-202, 1985 (Part I) and 29: 39-47, 1986 (Part II).
3. Dietz, R., Feilner, K., Gersty, F., Grimm, W. “ Drug Stability Testing-classification of countries according to climatic zone”. Drugs Made In Germany, 36: 99-103, 1993.
4. Grimm, W. “Extension of the International Conference on harmonization Tripartite Guidelines for Stability Testing of New Drug Substances and products to Countries of Climatic Zones III and IV” Drug development and Industrial Pharmacy, 24: 313-325, 1998.
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