WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 863 - Thirty-fourth Report: Annex 10 - Guidelines for implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce: Appendix 1 - Model Certificate of a Pharmaceutical Product

WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 863 - Thirty-fourth Report
(1996; 200 pages)

Table of Contents

1. Introduction
2. The international pharmacopoeia and related activities
	2.1. Quality specifications for drug substances and dosage forms
	2.2. Test methodology
	2.3. International Nonproprietary Names for pharmaceutical substances
	2.4. International Chemical Reference Substances and International Infrared Spectra
3. Simple test methodology
4. Stability of dosage forms
	4.1. Guidelines for the stability testing of pharmaceutical products containing established drug substances
	4.2. Joint WHO/UNICEF study on the quality of selected drugs at the point of use in developing countries
5. Good manufacturing practices for pharmaceutical products
	5.1. Adoption of additional guidelines
	5.2. Further guidance on good manufacturing practices
6. Legal and administrative aspects of the functioning of national drug regulatory authorities
	6.1. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability
	6.2. The WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce
	6.3. Guiding principles for formulating national drug legislation
	6.4. Role of the pharmacist
	6.5. Model legislative provisions to update national legal texts to deal with counterfeit drugs
	6.6. Additional guidance
	6.7. Training activities
7. Quality assurance in the supply system
	7.1. Guidelines on import procedures for pharmaceutical products
	7.2. Guidelines for inspection of drug distribution channels
8. Terminology
Acknowledgements
References
Annex 1 - Guidelines for the graphic representation of chemical formulae
	1. Introduction
	2. Acyclic structures
	3. Cyclic structures
	4. Ionic structures
	5. Isotopically modified compounds
	6. Coordination compounds
	7. Stereochemistry
	8. Carbohydrates
	9. Steroids
	10. Terpenoids
	11. Prostanoids
	12. Alkaloids
	13. Antibiotics
	14. Polypeptides
	15. Polymers
	Acknowledgements
	References
Annex 2 - List of available International Chemical Reference Substances¹
Annex 3 - List of available International Infrared Reference Spectra
Annex 4 - General recommendations for the preparation and use of infrared spectra in pharmaceutical analysis
	1. Introduction
	2. Apparatus
	3. Method of verification of frequency scale and resolution
	4. Environment
	5. Use of solvents
	6. Preparation of the substance to be examined
	7. Identification by reference substance
	8. Identification by reference spectrum
	9. Reflectance techniques
Annex 5 - Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms
	General
	Definitions
	1. Stability testing
	3. Design of stability studies
	4. Analytical methods
	5. Stability report
	6. Shelf-life and recommended storage conditions
	References
	Official, international and national guidelines
	Appendix 1 - Survey on the stability of pharmaceutical preparations included in the WHO Model List of Essential Drugs: answer sheet
	Appendix 2 - Stability testing: summary sheet
Annex 6 - Good manufacturing practices: guidelines on the validation of manufacturing processes
	Introduction
	Glossary
	General
	1. Types of process validation
	2. Prerequisites for process validation
	3. Approaches
	4. Organization
	5. Scope of a process validation programme
	6. Validation protocol and report
	References
	Bibliography
Annex 7 - Good manufacturing practices: supplementary guidelines for the manufacture of investigational pharmaceutical products for clinical trials in humans
	1. Introductory note
	2. General considerations
	3. Glossary
	4. Quality assurance
	5. Validation¹
	6. Complaints
	7. Recalls
	8. Personnel
	9. Premises and equipment
	10. Materials
	11. Documentation
	12. Production
	13. Quality control
	14. Shipping, returns, and destruction
	References
Annex 8 - Good manufacturing practices: supplementary guidelines for the manufacture of herbal medicinal products¹
	1. Glossary
	2. General
	3. Premises
	4. Documentation
	5. Quality control
	6. Stability tests
	References
Annex 9 - Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability
	Introduction
	Glossary
	Part One. Regulatory assessment of interchangeable multisource pharmaceutical products
		1. General considerations
		2. Multisource products and interchangeability
		3. Technical data for regulatory assessment
		4. Product information and promotion
		5. Collaboration between drug regulatory authorities
		6. Exchange of evaluation reports
	Part Two. Equivalence studies needed for marketing authorization
		7. Documentation of equivalence for marketing authorization
		8. When equivalence studies are not necessary
		9. When equivalence studies are necessary and types of studies required
			In vivo studies
			In vitro studies
	Part Three. Tests for equivalence
		10. Bioequivalence studies in humans
			Subjects
			Design
			Studies of metabolites
			Measurement of individual isomers for chiral drug substance products
			Validation of analytical procedures
			Reserve samples
			Statistical analysis and acceptance criteria
			Reporting of results
		11. Pharmacodynamic studies
		12. Clinical trials
		13. In vitro dissolution
	Part Four. In vitro dissolution tests in product development and quality control
	Part Five. Clinically important variations in bioavailability leading to non-approval of the product
	Part Six. Studies needed to support new post-marketing manufacturing conditions
	Part Seven. Choice of reference product
	Authors
	References
	Appendix 1 - Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, December 1994)
	Appendix 2 - Explanation of symbols used in the design of bioequivalence studies in humans, and commonly used pharmacokinetic abbreviations
	Appendix 3 - Technical aspects of bioequivalence statistics
Annex 10 - Guidelines for implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce
	1. Provisions and objectives
	2. Eligibility for participation
	3. Requesting a certificate
	4. Issuing a certificate
	5. Notifying and investigating a quality defect
	References
	Appendix 1 - Model Certificate of a Pharmaceutical Product
	Appendix 2 - Model Statement of Licensing Status of Pharmaceutical Product(s)
	Appendix 3 - Model Batch Certificate of a Pharmaceutical Product
	Appendix 4 - Glossary and index
Annex 11 - Guidelines for the assessment of herbal medicines^1,2
	Introduction
	Assessment of quality
	Assessment of safety
	Assessment of efficacy
	Intended use
	Utilization of these guidelines
Annex 12 - Guidelines on import procedures for pharmaceutical products
	1. Introductory notes
	2. Objectives and scope
	3. Legal responsibilities
	4. Legal basis of control
	5. Required documentation
	6. Implementation of controls
	7. Procedures applicable to pharmaceutical starting materials
	8. Storage facilities
	9. Training requirements
	References
	Glossary
	Appendix - Special import controls for narcotic drugs and psychotropic substances¹
Back Cover

Appendix 1 - Model Certificate of a Pharmaceutical Product

Certificate of a Pharmaceutical Product¹

This certificate conforms to the format recommended by the World Health Organization (general instructions and explanatory notes attached).

No. of Certificate: _______________________________________________________________

Exporting (certifying) country: _____________________________________________________

Importing (requesting) country: ____________________________________________________

1. Name and dosage form of product:

_____________________________________________________________________________

1.1 Active ingredient(s)² and amount(s) per unit dose:³

_____________________________________________________________________________

For complete qualitative composition including excipients, see attached.⁴

1.2 Is this product licensed to be placed on the market for use in the exporting country?⁵ yes/no (key in as appropriate)

1.3 Is this product actually on the market in the exporting country? yes/no/unknown (key in as appropriate)

If the answer to 1.2 is yes, continue with section 2A and omit section 2B.
If the answer to 1.2 is no, omit section 2A and continue with section 2B.⁶

2A.1 Number of product licence⁷ and date of issue:

_____________________________________________________________________________

2A.2 Product-licence holder (name and address):

_____________________________________________________________________________

2A.3 Status of product-licence holder:⁸ a/b/c (key in appropriate category as defined in note 8)

2A.3.1 For categories b and c the name and address of the manufacturer producing the dosage form are:⁹

_____________________________________________________________________________

2A.4 Is Summary Basis of Approval appended?¹⁰ yes/no (key in as appropriate)

2A.5 Is the attached, officially approved product information complete and consonant with the licence?¹¹ yes/no/not provided (key in as appropriate)

2A.6 Applicant for certificate, if different from licence holder (name and address):¹²

_____________________________________________________________________________

2B.1 Applicant for certificate (name and address):

_____________________________________________________________________________

2B.2 Status of applicant: a/b/c (key in appropriate category as defined in note 8)

2B.2.1 For categories b and c the name and address of the manufacturer producing the dosage form are:⁹

_____________________________________________________________________________

2B.3 Why is marketing authorization lacking? not required/not requested/under consideration/refused (key in as appropriate)

2B.4 Remarks:¹³ ________________________________________________________________

_____________________________________________________________________________

3. Does the certifying authority arrange for periodic inspection of the manufacturing plant in which the dosage form is produced?

yes/no/not applicable¹⁴ (key in as appropriate)

If no or not applicable proceed to question 4.

3.1 Periodicity of routine inspections (years): _________________________________________

3.2 Has the manufacture of this type of dosage form been inspected? yes/no (key in as appropriate)

3.3 Do the facilities and operations conform to GMP as recommended by the World Health Organization?¹⁵

yes/no/not applicable¹⁴ (key in as appropriate)

4. Does the information submitted by the applicant satisfy the certifying authority on all aspects of the manufacture of the product?¹⁶

yes/no (key in as appropriate)

If no, explain: __________________________________________________________________

_____________________________________________________________________________

Address of certifying authority:

_____________________________________________________________________________

Telephone number: _______________________ Fax number: ___________________________

Name of authorized person:

_____________________________________________________________________________

Signature:

_____________________________________________________________________________

Stamp and date:

_____________________________________________________________________________

General instructions

Please refer to the guidelines for full instructions on how to complete this form and information on the implementation of the Scheme.

The forms are suitable for generation by computer. They should always be submitted as hard copy, with responses printed in type rather than handwritten.

Additional sheets should be appended, as necessary, to accommodate remarks and explanations.

Explanatory notes

¹ This certificate, which is in the format recommended by WHO, establishes the status of the pharmaceutical product and of the applicant for the certificate in the exporting country. It is for a single product only since manufacturing arrangements and approved information for different dosage forms and different strengths can vary.

² Use, whenever possible, International Nonproprietary Names (INNs) or national nonproprietary names.

³ The formula (complete composition) of the dosage form should be given on the certificate or be appended.

⁴ Details of quantitative composition are preferred, but their provision is subject to the agreement of the product-licence holder.

⁵ When applicable, append details of any restriction applied to the sale, distribution or administration of the product that is specified in the product licence.

⁶ Sections 2A and 2B are mutually exclusive.

⁷ Indicate, when applicable, if the licence is provisional, or the product has not yet been approved.

⁸ Specify whether the person responsible for placing the product on the market:

(a) manufactures the dosage form;

(b) packages and/or labels a dosage form manufactured by an independent company; or

(c) is involved in none of the above.

⁹ This information can be provided only with the consent of the product-licence holder or, in the case of non-registered products, the applicant. Non-completion of this section indicates that the party concerned has not agreed to inclusion of this information.

It should be noted that information concerning the site of production is part of the product licence. If the production site is changed, the licence must be updated or it will cease to be valid.

¹⁰ This refers to the document, prepared by some national regulatory authorities, that summarizes the technical basis on which the product has been licensed.

¹¹ This refers to product information approved by the competent national regulatory authority, such as a Summary of Product Characteristics (SPC).

¹² In this circumstance, permission for issuing the certificate is required from the product-licence holder. This permission must be provided to the authority by the applicant.

¹³ Please indicate the reason that the applicant has provided for not requesting registration:

(a) the product has been developed exclusively for the treatment of conditions -particularly tropical diseases - not endemic in the country of export;

(b) the product has been reformulated with a view to improving its stability under tropical conditions;

(c) the product has been reformulated to exclude excipients not approved for use in pharmaceutical products in the country of import;

(d) the product has been reformulated to meet a different maximum dosage limit for an active ingredient;

(e) any other reason, please specify.

¹⁴ Not applicable means that the manufacture is taking place in a country other than that issuing the product certificate and inspection is conducted under the aegis of the country of manufacture.

¹⁵ The requirements for good practices in the manufacture and quality control of drugs referred to in the certificate are those included in the thirty-second report of the Expert Committee on Specifications for Pharmaceutical Preparations (WHO Technical Report Series, No. 823, 1992, Annex 1). Recommendations specifically applicable to biological products have been formulated by the WHO Expert Committee on Biological Standardization (WHO Technical Report Series, No. 822, 1992, Annex 1).

¹⁶ This section is to be completed when the product-licence holder or applicant conforms to status (b) or (c) as described in note 7 above. It is of particular importance when foreign contractors are involved in the manufacture of the product. In these circumstances the applicant should supply the certifying authority with information to identify the contracting parties responsible for each stage of manufacture of the finished dosage form, and the extent and nature of any controls exercised over each of these parties.

The layout for this Model Certificate is available on diskette in WordPerfect from the Division of Drug Management and Policies, World Health Organization, 1211 Geneva 27, Switzerland.