Guidelines on the implementation of the WHO certification scheme on the quality of pharmaceutical products moving in international commerce
Provisions and objectives
1.1 A comprehensive system of quality assurance must be founded on a reliable system of licensing and independent analysis of the finished product, as well as upon assurance obtained through independent inspection that all manufacturing operations are carried out in conformity with accepted norms, referred to as “good manufacturing practices” (GMP).
1.2 In 1969, the Twenty-second World Health Assembly, by resolution WHA22.50, endorsed requirements for Good Practices in the Manufacture and Quality Control of Drugs (1) (referred to henceforth as “GMP as recommended by WHO”). These comprise internationally recognized and respected standards that all Member States are urged to adopt and to apply. These requirements have since been revised twice. The first revision was adopted by the Health Assembly in 1975 in resolution WHA28.65 (2). A second revision of the requirements is included in the Thirty-second report of the WHO Expert Committee on Specifications for Pharmaceutical Products (3).
1.3 These standards are fully consonant with those operative within the countries participating in the Convention for the Mutual Recognition of Inspection in Respect of the Manufacture of Pharmaceutical Products, and other major industrialized countries. They also provide the basis for the WHO Certification Scheme on the Quality of Pharmaceutical Products moving in International Commerce (referred to henceforth as “the Scheme”) recommended initially in resolution WHA22.50 (1). The Scheme is an administrative instrument that requires each participating Member State, upon application by a commercially interested party, to attest to the competent authority of another participating Member State that:
a specific product is authorized to be placed on the market within its jurisdiction or, if it is not thus authorized, the reason why that authorization has not been accorded;
the plant in which it is produced is subject to inspections at suitable intervals to establish that the manufacturer conforms to GMP as recommended by WHO; and
all submitted product information, including labelling, is currently authorized in the certifying country.
1.4 The Scheme, as subsequently amended in 1975 (2) and 1988 (4), by resolutions WHA28.65 and WHA41.18, is applicable to finished dosage forms of pharmaceutical products intended for administration to human beings or to food-producing animals.
1.5 Provision for certification of active ingredients is also included within the scope of the Scheme. This will be the subject of separate guidelines and certificates.
Eligibility for participation
2.1 Any Member State intending to participate in the Scheme may do so by notifying the Director-General of the World Health Organization, in writing, of:
its willingness to participate in the Scheme;
any significant reservations it intends to observe relating to this participation; and
the name and address of its national drug regulatory authority or other competent authority.
2.2 These notifications will be subsequently announced in the monthly WHO Pharmaceutical Newsletter. An updated consolidated list will be published annually in the Newsletter and will be available to governments at other times from: the Division of Drug Management and Policies, WHO, 1211 Geneva 27, Switzerland. (See also section 3.3)
2.3 A Member State may opt to participate solely to control the import of pharmaceutical products and active substances. This intention should be stated explicitly in its notification to the World Health Organization.
2.4 A Member State intending to use the Scheme to support the export of pharmaceutical products should first satisfy itself that it possesses:
an effective national licensing system, not only for pharmaceutical products, but also for the responsible manufacturers and distributors;
GMP requirements, consonant with those recommended by WHO, to which all manufacturers of finished pharmaceutical products are required to conform;
effective controls to monitor the quality of pharmaceutical products registered or manufactured within its country, including access to an independent quality control laboratory;
a national pharmaceuticals inspectorate, operating as an arm of the national drug regulatory authority, and having the technical competence, experience and resources to assess whether GMP and other controls are being effectively implemented, and the legal power to conduct appropriate investigations to ensure that manufacturers conform to these requirements by, for example, examining premises and records and taking samples;
administrative capacity to issue the required certificates, to institute inquiries in the case of complaint, and to notify expeditiously both WHO and the competent authority in any Member State known to have imported a specific product that is subsequently associated with a potentially serious quality defect or other hazard.
2.5 Each Member State assumes the responsibility to determine, through a process of self-evaluation, whether it satisfies these prerequisites. The Scheme contains no provision, under any circumstance, for external inspection or assessment, either of a competent national authority or of a manufacturing facility. However, should a Member State so wish, it could approach WHO, or a well-recognized Drug Regulatory Authority, to occasionally delegate consultants to act as advisors in the course of national inspections, and inspector training activities.
Issuing a certificate
4.1 The certifying authority is responsible for assuring the authenticity of the certified data. Certificates should not bear the WHO emblem, but a statement should always be included to confirm whether or not the document is issued in the format recommended by WHO.
4.2 When the applicant is the manufacturer of the finished dosage form, the certifying authority should satisfy itself, before attesting compliance with GMP, that the applicant:
applies identical GMP standards to the production of all batches of pharmaceutical products manufactured within the facility, including those destined exclusively for export.
consents, in the event of identification of a quality defect consonant with the criteria set out in section 5.1, to relevant inspection reports being released, in confidence, to the competent authority in the country of import, should the latter so require.
4.3 When the applicant is not the manufacturer of the finished dosage form, the certifying authority should similarly satisfy itself B in so far as it has authority to inspect the records and relevant activities of the applicant B that it has the applicant’s consent to release relevant reports on the same basis as described in section 4.2 (b) above.
4.4 GMP as recommended by WHO assigns to the manufacturer of the finished dosage form responsibility for assuring the quality of active ingredients. National regulations may require that suppliers of active ingredients be identified in the product licence, but the competent authority may have no power to inspect them.
4.5 Notwithstanding this situation, a certifying authority may agree, on a discretionary and voluntary basis, and at the request of a manufacturer, to undertake an inspection of a manufacturer of active ingredients to satisfy specific requirements of a requesting authority. Alternatively, pending the development of specific guidelines for active pharmaceutical ingredients, the certifying authority may be able to attest that the manufacturer is an established supplier of the substance in question to manufacturers of finished dosage forms licensed for marketing under its jurisdiction.
4.6 Whenever a product is purchased through a broker or another intermediary, or when more than one set of premises has been involved in the manufacture and packaging of a product, the certifying authority should consider whether it has received sufficient information to satisfy itself that those aspects of the manufacture of the product for which the applicant is not directly responsible have been undertaken in compliance with GMP as recommended by WHO.
4.7 The certifying authority should officially stamp and date all copies of product information submitted to it in support of an application for a certificate and intended to be appended to the certificate.
Every effort should be made to ensure that certificates and all annexed documentation are consonant with the version of the product licence operative on the date of issue.
When available, the certifying authority will add a Summary Basis of Approval or any other material the authority deems relevant. Translation by an applicant of these materials into a widely used language, preferably English, shall be deemed to satisfy the provision of 3.10.
4.8 Any additional attachment to a certificate submitted by the applicant, such as price lists of products for which bids are offered, should be clearly identified as not comprising part of the attestation made by the certifying authority.
4.9 To avert potential abuse of the Scheme, to frustrate attempts at falsification, to render routine authentication of certificates by an independent authority superfluous and to enable the certifying authority to maintain comprehensive records of countries to which specific products have been exported, each certificate should identify the importing country and be stamped on each page with the official seal of the certifying authority.
If requested, an identical copy, clearly marked as duplicate, should be forwarded by the certifying authority on demand directly to the importing country authority.
Notifying and investigating a quality defect
5.1 Each certifying authority undertakes to institute enquiries into any quality defect reported in a product exported in accordance with the provisions of the Scheme, on the understanding that:
the complaint is transmitted, together with the relevant facts, through the competent authority in the importing country;
the complaint is considered to be of a serious nature by the latter authority; and
the defect, if it appeared after delivery of the product into the importing country, is not attributable to local conditions.
5.2 In the case of obvious doubt, a participating national authority may request WHO to assist in identifying an independent quality control laboratory to carry out tests for the purposes of quality control.
5.3 Each certifying authority undertakes to inform WHO and, as far as is possible, all competent national authorities, of any serious hazard newly associated with a product exported under the provisions of the Scheme or of any criminal abuse of the Scheme directed, in particular, to the export of falsely labelled, spurious, counterfeited or substandard pharmaceutical products. On receipt of such notification, WHO will transmit the message immediately to the competent national authority in each Member State.
5.4 WHO stands prepared to offer advice should difficulty arise in implementing any aspect of the Scheme or in resolving a complaint, but it cannot be a party to any resulting litigation or arbitration.
Quality control of drugs. In: Twenty-second World Health Assembly, Boston, Massachusetts, 8-25 July 1969. Part 1: Resolutions and decisions, annexes. Geneva, World Health Organization, 1969: 99-105 (Official Records of the World Health Organization, No. 176).
Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce. In: Twenty-eighth World Health Assembly, Geneva, 13-30 May 1975. Part 1: Resolutions and decisions, annexes. Geneva, World Health Organization, 1975: 94-95 (Official Records of the World Health Organization, No. 226).
Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second Report. Geneva, World Health Organization, 1992: 14-79 (WHO Technical Report Series, No. 823).
WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce. In: Forty-first World Health Assembly, Geneva,
2-13 May 1988. Resolutions and decisions, annexes. Geneva, World Health Organization, 1988: 53-55 (Document WHA41/1988/REC/1).
In order to facilitate understanding, this glossary explains terms in the Guidelines and/or refers to relevant sections. It is considered as supplementary information and not as being a formal part of the Scheme.
For clarity, all definitions that have been taken from the glossary of the WHO Technical Report Series No. 823, 1992 are preceded by an asterisk.
Abuse of scheme: (see item 4.9 and 5.2 of Guidelines)
Active ingredients: (see item l.5, 4.4 and 4.5 of Guidelines)
Addresses of competent authorities: (see item 2.2 and 3.3 of Guidelines)
Applicant: The party applying for a Product Certificate. This is normally the product licence holder. In all instances, having regard to commercial confidentiality of certain data, the competent authority in the exporting country must obtain permission to release these data from the product licence holder, or, in the absence of a product licence, from the manufacturer.
Authentication of certificates: (see item 4.9 of the Guidelines)
*Batch (or lot): A defined quantity of a starting material, packaging material, or product processed in a single process or series of processes so that it can be expected to be homogeneous. In the case of continuous manufacture, the batch must correspond to a defined fraction of the production, characterized by its intended homogeneity. It may sometimes be necessary to divide a batch into a number of sub-batches, which are later brought together to form a final homogeneous batch.
Batch certificate: A document containing information, as set out in Annex 3 of the Guidelines for use, will normally be issued for each batch by the manufacturer. Furthermore, exceptionally a batch certificate may be validated or issued by the Competent authority of the exporting country, particularly for vaccines, sera and other biological products. The batch certificate travels with every major consignment (see also item 3.14 of Guidelines).
*Batch number: A distinctive combination of numbers and/or letters which specifically identifies a batch on the labels, the batch records, and the certificates of analysis, etc.
*Bulk product: A product that has completed all processing stages up to, but not including, final packaging.
Certifying authority: This is the competent authority that issues product certificates. It shall ensure that it possesses the capacities listed in item 2.4 of the Guidelines.
Charges for product certificates: (see item 3.11 of Guidelines)
Competent authority: This is the national authority as identified in the formal letter of acceptance in which each Member State informs WHO of its intention to participate in the Scheme. The competent authority can issue or receive certificates. The extent of participation should be indicated in the letter of acceptance. (see item 2.1 of the Guidelines) WHO makes available upon request a continuously updated list of addresses of competent authorities and, when applicable, the specific conditions for participation.
Competence and evaluation of national authority: (see item 2.4, 2.5 and 4.2 of Guidelines)
Dosage form: The form of the completed pharmaceutical preparation, e.g. tablet, capsule, elixir, suppository.
Drug regulatory authority: An authority appointed by the government of a Member State to administer the granting of Marketing Authorizations for pharmaceutical products in that country.
*Finished product: A product that has undergone all stages of production, including packaging in its final container and labelling.
Free sale certificate: (see item 3.2 of Guidelines)
GMP certificate: (see item 3.2 of Guidelines)
Importing agents, guidelines for: (see item 3.4 of Guidelines)
Language of product certificates: (see item 3.10 of Guidelines)
Licence holder: An individual or a corporate entity being in the possession of a marketing authorization of a pharmaceutical product.
Licensee: An individual, or corporate entity responsible for the information, the publicity, the pharmacovigilance, the surveillance of batches, and if applicable of their withdrawal, for a pharmaceutical product, whether or not it be the holder of the marketing authorization.
Limits of certification by competent authority: (see item 3.12 and 4.8 of Guidelines)
Lot: (see batch)
*Manufacture: All operations of purchase of materials and products, production, quality control, release, storage, shipment of finished products, and related controls.
*Manufacturer: A company that carries out at least one step of manufacture. (For categories of manufacturer see Appendix 1, Explanatory Note No. 7)
Marketing authorization: (see product licence)
Pharmaceutical product: Any medicine intended for human use or veterinary product administered to food-producing animals, presented in its finished dosage form or as an active ingredient for use in such dosage form, that is subject to control by pharmaceutical legislation in both the exporting state and the importing state.
Product: (see pharmaceutical product)
Product certificate: A document containing the information as set out in Appendix 1 of the Guidelines that is validated and issued for a specific product by the competent authority of the exporting country and intended for use by the competent authority in the importing country or – in the absence of such an authority – by the drug procurement authority. (see also item 3.5 of the Guidelines)
Product information: This is the approved product information referred to in item 4.7 of the Guidelines and item 2.A.5 of the Product Certificate. It normally consists of information for health professionals and the public (patient information leaflets) as approved in the exporting country, and when available, a data sheet or a Summary of Product Characteristics (SPC) approved by the regulatory authority.
Product licence: An official document issued by the competent drug regulatory authority for the purpose of marketing or free distribution of a product. It must set out, inter alia, the name of the product, the pharmaceutical dosage form, the quantitative formula (including excipients) per unit dose (using international nonproprietary names or national generic names where they exist), the shelf-life and storage conditions and packaging characteristics. It also contains all information approved for health professionals and the public (except promotional information), the sales category, the name and address of the licence holder, and the period of validity of the licence.
Product licence holder: (see licence holder)
*Production: All operations involved in the preparation of a pharmaceutical product, from receipt of materials, through processing and packaging, to completion of the finished product.
Registration: Any statutory system of approval required at national level as a precondition for introducing a pharmaceutical product onto the market.
Registration certificate: (see product licence)
Specifications: See Appendix 3, Batch Certificate, footnote 7.
Statement of licensing status: (see item 3.13 of Guidelines and Annex 2)
Summary Basis of Approval: This refers to the document prepared by some national regulatory authorities, that summarizes the technical basis on which the product has been licensed. (see item 4.7 of Guidelines and explanatory note 9 of the product certificate contained in Annex 1)
Summary Product Characteristics (SPC): Product information as approved by the regulatory authority. The SPC serves as the basis for production of information for health personnel as well as for consumer information on labels and leaflets of medicinal products and for control of advertising. (see also Product information)
Tenders and brokers: (see item 4.6 of Guidelines)
Transmission of product certificate: (see item 3.8 and 4.9 of Guidelines)
Validity of product certificate: (see item 3.9 of Guidelines)
When to request a product certificate: (see item 3.5 of Guidelines )
WHO responsibility: (see item 5.4 of Guidelines)