(1997; 248 pages) [French]
Product assessment and registration
The WHO Expert Committee on Specifications for Pharmaceutical Preparations has on several occasions discussed and adopted guidelines and other texts concerned with the assessment of pharmaceutical products and with registration requirements.
At its thirty-fourth meeting, the Expert Committee adopted guidelines for the assessment of herbal medicines. These guidelines, reproduced in Chapter 2, have been widely distributed to WHO Member States and were discussed at the Sixth International Conference of Drug Regulatory Authorities (ICDRA), held in Ottawa in October 1991. Their utility has been widely recognized.
Stability of pharmaceutical products
The problem of stability of pharmaceuticals has been addressed a number of times by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. The introduction to this subject in the thirty-first report of the Expert Committee reads as follows:
Inadequate storage and distribution of pharmaceutical products can lead to their physical deterioration and chemical decomposition, resulting in reduced activity and, occasionally, in the formation of toxic degradation products. Degradation is particularly likely to occur under tropical conditions of high ambient temperature and humidity; and it is not widely recognized that, because of the potential for chemical interaction between the active ingredients and excipients, drug dosage forms can be more vulnerable to degradation than pure drug substances.
The stability of a specific product is thus dependent, in a large measure, on its formulation, and its expiry date should be determined on the basis of stability studies carried out by the manufacturer. Studies undertaken with a view to determining the stability of a product under temperate conditions, however, do not necessarily provide a reliable indication of its shelf-life in tropical climates. In such cases, additional proof of stability should be requested from the manufacturer, who should assume responsibility for formulating a product that is stable under the climatic conditions prevailing in the countries of destination. Relevant information should be specifically requested by the national regulatory authority in the importing country within the context of the WHO Certification Scheme... It is obviously impossible to obtain satisfactory assurances when a product is purchased through an intermediary if its provenance is unknown to the purchaser. For domestically produced products, the regulatory authority should evaluate stability data furnished by the manufacturer. The procurement agencies and the pharmacists responsible for drug distribution should ensure that they are supplied with adequate information concerning the proper storage and handling of each product.
Specific guidelines on the stability of drug dosage forms were annexed to the Expert Committee’s report and are contained in Chapter 2. They provide a comprehensive statement on both the technical aspects of the subject and the responsibilities that devolve upon the manufacturer and all agencies and individuals responsible for the product throughout the distribution chain up to the time of the drug’s administration or delivery to the patient. The thirty-first report of the Expert Committee explains:
Within the distribution chain, the labelled expiry date on a pharmaceutical product has a dual significance: after this date, no formal assurance is provided regarding the condition of the product; and the manufacturer may no longer have legal liability for it. The Committee agreed that the use of time-expired stock should be entertained only in the most exceptional circumstances, when to withhold the stock would have serious consequences for patients. In every instance, the proposal to release such a product must be channelled through a pharmacist or other professional experienced in quality assurance and, when appropriate, referred to the competent authority, which must decide on the necessity for analysis and the period of time during which the product may be used, having regard to all relevant circumstances. Doctors and other health professionals using the product may need to be alerted to the situation. Procurement procedures should be reviewed and, if necessary, modified to prevent such situations arising in the future.
Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms were adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations at its thirty-fourth meeting, and are reproduced in Chapter 2. Recognizing that stability testing represents the evaluation of a pharmaceutical formulation in its final container, the Expert Committee emphasized that the same fundamental approach should be used for all products irrespective of whether the active ingredient was an established drug substance. Where sufficient information was already available on the chemical stability of the active ingredient, however, this could be taken into account. The availability of these guidelines was considered to be of special importance since they include advice on the stability testing of products for use in the more extreme climatic conditions found in many developing countries.
WHO has arranged for the conduct of accelerated stability studies on substances in the WHO Model List of Essential Drugs and has also sent out questionnaires to identify the products most likely to present stability problems. The accelerated stability studies are discussed in the twenty-eighth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. For newly introduced substances much information on stability is available, since in many countries this information is a mandatory requirement for registration of a new product and for determining expiry dates. By contrast, little information has been published on the degradation of long-established pharmaceutical substances (except for obviously unstable products) and, in many cases, their behaviour when exposed to extreme climatic conditions is uncertain.
For this reason, accelerated stability studies were carried out on long- established essential drug substances under standardized conditions (e.g. 30 days’ exposure to air at a temperature of 50 °C and a relative humidity of 100%). The appearance of degradation products was detected by thin-layer chromatography, supplemented (as necessary) by spectrophotometry, fluorescence reactions, high-performance liquid chromatography and chemical determinations. The substances were additionally exposed to a temperature of 70 °C under the same humidity conditions for a further 3-5 days. Negative results provided conclusive proof of the stability of the substance even under highly adverse conditions. All tests were carried out with light excluded since it is easy to protect substances from light during storage.
A document entitled “Accelerated stability studies of widely used pharmaceutical substances under simulated tropical conditions” (WHO/PHARM/86.529) contains the results of these accelerated stability studies and is available on request from the Quality Assurance unit, Division of Drug Management and Policies, WHO, 1211 Geneva 27, Switzerland.
Interchangeability of multisource (generic) pharmaceutical products
The final text in Chapter 2 provides guidance on registration requirements to establish the interchangeability of multisource (generic) pharmaceutical products. In adopting these guidelines at its thirty-fourth meeting, the WHO Expert Committee on Specifications for Pharmaceutical Preparations was pleased to note that they had already been adapted for local use by a number of WHO Member States and that positive feedback had been received especially with regard to the flexibility and clarity of the guidance. The guidelines were designed to allow a step-by-step approach tailored to the stage of development of a particular registration system and the needs and priorities of the national health authorities. They were intended to assist drug regulatory authorities and international organizations involved in the procurement of pharmaceutical products, and to provide manufacturers with an indication of the data required. It was recognized that these guidelines were a first step: they would need to be supported by training and advice on implementation.