Article

Comparison of Stability Testing Requirements of ICH with other International Regulatory Agencies
Patel Henal, Sudeendra Bhat R., Balamuralidhara V* and Pramod Kumar T.M. Pharmaceutical Quality Assurance Group, Dept. of Pharmaceutics, JSS College of Pharmacy, JSS University, Mysore.
Stability plays an important role in the drug development process. Present work aims to compare the stability testing (ST) requirements of International Conference on Harmonization (ICH) with other international regulatory agencies like World Health Organization (WHO), Association of South East Asian Nations (ASEAN) and European Agency for Evaluation of Medicinal and Health Products (EMEA). ICH guidelines describe stability testing requirements for new drug substance and drug product. WHO guidelines describe stability testing requirements for both new and existing Active pharmaceutical ingredients (APIs) and addresses information to be submitted in original and subsequent applications for marketing authorization of their related Finished pharmaceutical products (FPP) for human use. ST requirements for WHO are similar, except for the parameters like selection of batches and storage conditions. WHO guidelines have an additional requirement for long term storage condition (general case) and accelerated storage conditions (substance/product intended to be stored in refrigerator). ASEAN guideline mainly focuses on the requirements for stability testing of drug products along with new chemical entities (NCEs). The differences were observed in stress testing, selection of batches and real time storage conditions. EMEA guidelines discussed here are an extension of the note for guidance on stability testing requirements for new active substance and related products. It sets out the stability testing requirements for existing active substance and related finished product. The minimum time period to be covered by data at the time of submission during long term storage conditions differs from ICH guidelines. Key words: Stability testing, ICH, WHO, ASEAN, EMEA

Objective
The objective of the present work was to compare stability testing requirements of ICH with WHO, ASEAN and EMEA for various parameters such as: Stress testing (includes photo stability testing), selection of batches, container closure system, specification, storage conditions, testing frequency, stability commitment, evaluation, statements and labeling.

for stability testing from ICH guidelines for stability testing. However, they differ in certain aspects which are discussed below.

Comparison of ICH and EMEA guidelines5

Differences in some of the parameters of stability testing requirements for EMEA from ICH are given in Table 4.

1. ICH guidelines for stability testing

Introduction
Stability plays an important role in the drug development process. It explains several factors that affect the expiration dating of drug products, including the chemical and physical stability during the pre-clinical formulation stages, process development, packaging development, and post-marketing life. It allows the establishment of recommended storage conditions, retest periods, and ultimately product shelf-life and expiry dating. Although various international regulatory agencies have their stability testing requirements derived from parent ICH guidelines, they differ in some parameters of stability testing requirements1.

ICH guidelines define the stability data package for a new drug substance or drug product that is sufficient for a registration application within the three regions of the EC, Japan and the United States. Stability testing requirements as per ICH guidelines are discussed briefly in Table 1.

Conclusion
From the above work it can be concluded that though WHO guideline is derived from ICH parent guideline, they have some significant differences which defines its individuality as a separate guideline. ICH guideline defines stability testing requirements for new drug substances and drug products whereas WHO guideline applies to both new and existing APIs and their related finished products. The differences were observed in the following parameters: selection of batches, storage conditions and statements and labeling. ASEAN guideline mainly focuses on the stability testing requirements for drug products which include generics and variations along with NCEs. Minor differences were observed in the parameters like stress testing, selection of batches, storage conditions and testing frequency. Also, there are no intermediate conditions for carrying out stability testing as per ASEAN guidelines.

2. Comparison of ICH and WHO guidelines3

ICH guidelines discuss stability testing requirements for new drug substances and new drug products, whereas WHO guidelines apply to new and existing APIs and their related FPPs for human use (Table 2).

3. Comparison of ICH and ASEAN guidelines4

ASEAN guidelines majorly focus on the stability testing requirements for drug products. The drug products covered in this guideline include Generics and Variations along with NCEs. The difference in the requirements from ICH guideline is highlighted in Table 3.

Comparison of guidelines
Various international guidelines discussed here have derived their requirements

*Email id: baligowda@gmail.com Pharma Times - Vol. 43 - No. 09 - September 2011 21

Table 1. Stability testing requirements as per ICH guidelines

Parameters Stress testing Drug substances Stress testing recommendations: Temperature: Temperature above accelerated temperature (50C, 60C, 70C, etc.) Humidity: 25C/75% RH and 25C/90% RH Oxidation: Wide range of pH Photostability testing should be carried out on a single batch. Drug products Temperature: 50C or 60C for 1 month Temperature/humidity: 40C/75%RH, 25C/80%RH Photostability testing should be carried out.

Selection of batches

Data should be provided on at least three primary pilot scale batches.

Data should be provided on at least three primary batches. Two should be at least pilot scale batches.

Container closure system

Stability testing should be carried out in the same container closure system as that proposed for storage and distribution. It is the list of tests and proposed acceptance criteria which the drug substance should meet. Long term studies: 0, 3, 6, 9, 12, 18, 24 months and annually through the proposed re-test period. Accelerated: 0, 3, 6 months Intermediate: 0, 6, 9, 12 months

Container closure system for testing should be same as that proposed for marketing including any secondary packaging. List of tests and acceptance criteria for drug products. Same as that of drug substances.

Specification Testing frequency

Storage conditions

a. General case: Long term: 25C 2C/60%RH 5% RH or 30C2C/ 65%RH5% RH Intermediate: 30C 2C/65% RH 5% RH Accelerated: 40C 2C/75%RH 5% RH b. For drug substance intended to be stored in refrigerator: Long term: 5C 3C Accelerated: 25C 2C/60%RH 5% RH c. For drug substance intended to be stored in freezer: Long term: - 20C 5C

Storage conditions for general case, for the product intended to be stored in refrigerator and freezer is same as that for drug substance. a. Drug products packaged in semi-permeable containers: Accelerated:40C2C/NMT 25%RH

Stability commitment

If the data does not cover the proposed retest period granted at the time of approval, a commitment should be made to continue the stability studies post approval. Based on the evaluation of data re-test period should be established. A storage statement should be established based on the stability evaluation of the drug substance.

If the data does not cover the proposed shelf life granted at the time of approval, a commitment should be made to continue the long term studies through the proposed shelf life and the accelerated studies for 6 months post approval. Based on the evaluation of data shelf life should be established. Same as drug substances.

Evaluation Statements/ labeling

Pharma Times - Vol. 43 - No. 09 - September 2011

22

Table 2. Comparison of ICH and WHO guideline

Parameters Selection of batches Storage conditions ICH Data from at least three primary batches of the new drug substance should be provided. a. Long term storage conditions for drug substance and drug product: (general case) 25C 2C/60% RH 5% RH or 30C 2C/65% RH 5% RH b. Accelerated storage conditions for drug substance/product to be stored in refrigerator: 25C 2C/60% RH 5% RH WHO Data from at least two primary batches should be provided for stability testing of existing APIs. a. Long term storage conditions for drug substance and drug product: (general case) 25C 2C/60% RH 5% RH or 30C 2C/65% RH 5% RH or 30C 2C/75% RH 5% RH b. Accelerated storage conditions for drug substance/ product to be stored in refrigerator: 25C 2C/60% RH 5% RH or 30C 2C/65% RH 5% RH or 30C 2C/75% RH 5% RH

Table 3. Comparison of ICH and ASEAN guidelines

Parameters Stress testing ICH Temperature: temperature above accelerated storage conditions (50C, 60C, 70C) Humidity: 25C/75%RH and 25C/90%RH Selection of batches Data from at least three primary batches of the new drug substance should be provided. a. Product stored in permeable container: Not mentioned b. Product stored in impermeable container: Not mentioned c. General case (long term storage) 25C 2C/60% RH 5% RH or 30C 2C/65%RH 5% RH ASEAN Stress testing conditions is 40C 2C/75% RH 5% RH which is same as accelerated storage conditions. Data on at least two pilot scale batches are acceptable for conventional dosage forms and for product containing stable drug substances. a. Product stored in permeable container: 30C 2C/75%RH 5% RH b. Product stored in impermeable container: 30C 2C/RH not specified c. For NCE (real time storage), generics and variations: 30C 2C/75%RH 5% RH

Storage conditions

Table 4. Comparison of ICH and EMEA guidelines

Parameters Selection batches of ICH Data from at least three primary batches of the new drug substance should be provided. EMEA Option a: Drug substance (described in an official pharmacopoeial monograph): Stability information from accelerated and long term testing is to be provided on at least two production scale batches. Drug product: For conventional dosage form and when drug substances are known to be stable, stability data on at least two pilot scale batches are acceptable. Option b: Drug substance (not described in an official pharmacopoeial monograph): Stability information from accelerated and long term testing is to be provided on at least three pilot scale batches. Drug product: For critical dosage forms or when active substances are known to be unstable, stability data on three primary batches are to be provided. Two of the three batches should be of at least pilot scale; the third may be smaller. Storage conditions Long term storage conditions: minimum time period covered by data for new drug substances and drug products at the time of submission should be 12 months. Drug substance: Long term storage conditions: minimum time covered by data at the time of submission should be 6 months for both option a and b. Drug product: Long term storage conditions: minimum time covered by data at the time of submission should be - Option a: 6 months, Option b:12 months

Pharma Times - Vol. 43 - No. 09 - September 2011

23

EMEA stability testing requirements differ in the parameters such as stress testing, selection of batches and minimum time period covered by the data at the time of submission under various storage conditions for drug substances and drug products.

Bibliography
1. Kim H. Handbook of Stability Testing in Pharmaceutical DevelopmentRegulations, Methodologies and Best Practices, Springer; 2008:10-13. 2. h t t p : / / w w w . i c h . o r g / L O B / m e d i a / MEDIA419.pdf

3. WHO Technical Report Series, No. 953, Annex 2, Stability testing of active pharmaceutical ingredients and finished pharmaceutical products, 2009. 4. http://www.aseansec.org/home.htm 5. http://www.emea.eu.int

Pharma Times - Vol. 43 - No. 09 - September 2011

24