Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French] View the PDF document
Table of Contents
Open this folder and view contentsIntroduction
Open this folder and view contents1. National drug regulation
Close this folder2. Product assessment and registration
View the documentGuidelines for the assessment of herbal medicines1,2
Close this folderStability of drug dosage forms1
View the document1. Introduction
View the document2. General considerations
Open this folder and view contents3. Responsibility of parties involved in the assurance of drug stability
View the document4. Use of terms
View the document5. Less stable drug substances
View the documentReferences
Open this folder and view contentsGuidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms1
Open this folder and view contentsMultisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability1
Open this folder and view contents3. Distribution
Open this folder and view contents4. The international pharmacopoeia and related activities
Open this folder and view contents5. Basic tests
Open this folder and view contents6. Laboratory services
Open this folder and view contents7. International trade in pharmaceuticals
Open this folder and view contents8. Counterfeit products
Open this folder and view contents9. Training
View the documentSelected WHO publications of related interest
View the documentBack cover

1. Introduction

For industrially manufactured pharmaceutical products, especially those entering international commerce and/or distributed in territories with adverse climatic conditions, stability poses serious problems. Adequate stability may be achieved only through the combined efforts of all parties involved in product development, manufacture, registration, national quality surveillance, distribution, and use. It was pointed out at the Conference of Experts on the Rational Use of Drugs [Nairobi, 1985 (1)] that “no tests or certification schemes can prevent the gradual deterioration of products passing through a storage and distribution system and subjected to prolonged heat, humidity, rough handling and careless dispensing”.

The stability and expiry date of a product depend on its formulation and conclusions from stability studies carried out by the manufacturer during product development and cannot be assessed by simple analysis of the final product. Mandatory use of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce (2), which makes it possible to establish the true origin of the product and to distinguish between registered and unregistered products, can go a long way to providing assurance of product stability. The reason for this is that registration of a dosage form in the exporting country means that the formulation has been examined by an independent government authority for its pharmaceutical characteristics, including stability, based on submission of results of stability studies carried out by the manufacturer and, where applicable, of bioavailability studies. It is acknowledged, however, that stability studies conducted for temperate climates may not be fully relevant to storage and distribution in countries with extreme climatic conditions and that additional proof of stability under extreme conditions may need to be requested from the manufacturers. In the absence of registration in the exporting country buyers have to rely solely on the firm’s assurance and on their own professional knowledge to assess relevant stability data submitted by the firm. When the product is purchased from a broker, the manufacturer is often not known at all. In these cases, it is virtually impossible to obtain reliable information on product stability.

In 1979 the WHO Expert Committee on Specifications for Pharmaceutical Preparations, in the text on quality assurance in the pharmaceutical supply system annexed to its report, noted that an important facet of quality assurance concerns storage. It pointed out further that “inadequate... storage can lead to physical deterioration and chemical decomposition, resulting in a reduction in activity... as well as the formation of possibly harmful degradation products” (3). At a later date other aspects, such as microbiological instability and impaired bioavailability, started to be considered.

The importance of factors related to storage, such as expiry dating (shelf-life), has been recognized. The Twenty-fifth World Health Assembly requested the Director-General in 1972 to undertake a study of the most feasible means of indicating, by a uniform system of marking, the limits of shelf-life of pharmaceutical products under the recommended conditions of their storage, as well as the date of manufacture and batch number (resolution WHA25.61).

In the past WHO has addressed some of the issues related to drug stability and storage. Recommendations have been formulated on the inclusion of the batch number, expiry date and date of manufacture in the text of drug labels (3-5). Results of accelerated stability studies and a manual for simplified tests permitting the detection of gross degradation of the least stable substances have been published (6).

The Organization is often asked for information and advice with regard to stability of finished pharmaceutical products. Particular interest in the issue of drug stability was expressed by many delegates at the Forty-first World Health Assembly, in 1988, during the discussion on the implementation of the revised drug strategy. The present document is an attempt to summarize basic principles in this area. It is addressed to policy-makers, health ministries, manufacturers, procurement agencies, and workers in the distribution system. It may be supplemented in future by technical advice in specific areas.

The document is concerned with industrially manufactured dosage forms and not with those prepared in the pharmacy or reconstituted in the hospital. Although many points discussed apply also to preparations of biological origin and radiopharmaceuticals, this document is not primarily intended for that purpose. The use of terms that occur most frequently in discussing these issues is explained in section 4.

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