Marketing authorization No.:
(only to be completed when a change to or review of the marketing authorization is required)

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INDEX TO THE INFORMATION REQUIRED AND DATA SET

Page

Details of the product
Route(s) of administration
Visual description of the product
Visual description of the packaging
Proposed restrictions on sale or distribution. Choose the highest applicable classification in this order:

- Scheduled narcotic;
- Restricted prescription-only distribution (specify, for example, hospitals only);
- Prescription only;
- Pharmacy only;
- Over-the-counter (OTC).

Regulatory situation in other countries
Provide a list of the countries in which this product has been granted a marketing authorization. State for each:

C The restrictions on sale or distribution (as defined above but with additional comments as necessary); C Dosage form(s) and strengths; C Container/closure system.

List all countries where the product has been withdrawn from the market, or where an application for marketing has been rejected, deferred or withdrawn. State the reason in each case.

Properties of the active pharmaceutical ingredient(s)
Provide at least the following information:

X Chemical structure;
X If relevant, the isomeric nature of the active ingredient, including stereochemical configuration (e.g. racemate, pure (S)-isomer, 50/50 mixture of (Z)- and (E)- isomers);
X The solubility of the active ingredient in water at 25 or 37EC;
X The solubility of the active ingredient in other solvents, such as ether, ethanol, acetone, and buffers of different pH (if the active ingredient is acidic or basic);
X Other relevant physicochemical characteristics of the active ingredient, such as partition coefficient (usually octanol/water) and the existence of polymorphs;
X Copies of infrared, nuclear magnetic resonance (proton and C-13), ultra- violet and mass spectra;
X Information on the chemical stability of the API, and on physicochemical stability if relevant (e.g. formation of a hydrate, change of polymorphic form).

Sites of manufacture - Active pharmaceutical ingredient(s)
State the name and street address of each facility where manufacture (synthesis, production) occurs. Include any alternative manufacturers.
For domestic sites, attach a copy of the current site licence issued by this drug regulatory authority.
For each foreign site, attach a certificate issued by the competent authority in terms of Guideline 3 below. It may contain, as attachments, copies of GMP certification for other sites.

Route(s) of synthesis of active pharmaceutical ingredient(s)
(This information may not be available if the API is purchased via an intermediary instead of directly from the producer, in which case the manufacturer of the finished product should conduct a full set of tests on each batch.)
Provide details of the route of synthesis for each active pharmaceutical ingredient, including reagents and reaction conditions. Provide specifications for starting materials, reagents and intermediates in the synthesis. Comment on likely synthetic by-products and degradation products, and discuss the results in the certificates of analysis for each site and method of manufacture.
If available, provide a European certificate of suitability (17 and 28) with any appendices and the accompanying “Report A”. In this case, only an outline of the route of synthesis is needed.

Specifications for the active pharmaceutical ingredient(s)
Provide a list of tests and limits for results for the API. Include test methods in sufficient detail for them to be replicated by another laboratory. Provide the results of validation of the methods for assay of the API and of impurities. If the ingredient is tested on the basis of a monograph in a pharmacopoeia, it is sufficient to provide a copy of the monograph together with any test methods referenced but not duplicated in the monograph. Provide details of any specifications additional to those in the pharmacopoeia.
Provide certificates of analysis for at least two batches produced at each site of manufacture by each synthetic method, including results for impurities.

Stability testing of the active pharmaceutical ingredient(s)
Provide the results of stability testing of the active pharmaceutical ingredient. Describe the methodology used during stability studies; if this is identical to methodology described elsewhere in the data set, a cross-reference will suffice. If different methodology was used, provide validation of tests for impurities and assay (14), and for other tests as necessary (e.g. particle size testing).
If the API is well established, studies should be conducted according to the principles outlined in the relevant WHO Guidelines (Guideline 4 below). For new active ingredient and products, see the relevant ICH guideline (18).
Results should be included for physical as well as chemical tests, e.g., (where relevant) particle size and polymorphic form. The study should be designed to show whether trends in stability occur over time.
State the proposed shelf-life (or retest date) and justify it in terms of the results of stability testing and the labelled storage conditions.

Formulation
Provide the formulation for a typical batch and for an administration unit, e.g. one tablet, 5 ml of oral solution, or the contents of an ampoule or bag of large volume parenteral solution, etc. Include excipients that may be removed during processing (e.g. solvents), those that may not be added to every batch (e.g. acid and alkali for pH adjustment), and the qualitative and quantitative composition of any tablet coating, capsule shell and inked imprint on the dosage form. State any overages. State the function(s) of each excipient (e.g. antioxidant, lubricant, binder). Indicate any substances whose content may be varied (e.g. inked imprint, tablet coating) and state how the content is decided for each batch (e.g. “The active therapeutic ingredient is adjusted for water content to a constant dry weight content; the content of maize starch may be varied by up to +25% depending on manufacturing conditions”). Provide either validation data or a rationale to justify ranges in the content of excipients. Ranges should not be excessive nor should they be automatic (e.g. “All excipients may be varied by ± 10%”).

Sites of manufacture - Finished product
State the name and street address of each facility where any aspect of manufacture occurs, including production, sterilization, packaging and quality control. Indicate the activity performed at each site. Include any alternative manufacturers.
For domestic sites, attach a copy of the current site licence issued by this drug regulatory authority.
For each foreign site where the major production step(s) is/are carried out, attach a certificate issued by the competent authority in terms of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce (Guideline 2 below). Include the product information approved by that authority with, if available, the summary basis of approval (or similar) and any other material that the authority deemed relevant (Guideline 2, section 4.7).

Manufacturing procedure for the finished product
Provide an outline of the manufacturing procedure for the finished product, including packaging. Provide a copy of the master formula and a copy of a manufacturing record for a real batch. The master formula should include information listed in Guideline 1, section 14.23.

Specifications for excipients
Provide a list of tests and limits for results for each excipient, including solvents, liquids to adjust pH, coatings, capsule shell, and inked imprint (on the dosage form). Include test methods in sufficient detail for them to be replicated by another laboratory. If the ingredient is tested on the basis of a monograph in a pharmacopoeia, it is sufficient to provide a copy of the monograph together with any test methods referenced but not duplicated in the monograph. Provide details of any specifications additional to those in the pharmacopoeia. Include microbiological limits for materials of natural origin. Only colours permitted by the EU’s “List of permitted food colours”, the FDA’s “Inactive ingredient guide” or “Japanese Pharmaceutical Excipients” may be used (19-22).

Specifications for the finished product
Provide a list of tests and limits for results for the finished product, including sufficient detail of test methods for them to be replicated by another laboratory. If the product is tested on the basis of a monograph in a pharmacopoeia, it is sufficient to provide a copy of the monograph together with any test methods referenced but not duplicated in the monograph. Provide details of any specifications additional to those in the pharmacopoeia.
Provide both release and expiry limits for results.
Provide the results of validation of the assay method for this formulation. For pharmacopoeial methods, provide data which demonstrate that the method is applicable to this formulation.

Container/closure system(s) and other packaging
Give a detailed description of the container/closure system(s), including any liner or wadding, and provide details of the composition of each component. Describe other (e.g. outer) packaging, and state what materials they are made from. Provide the specifications for any part of the container/closure system(s) which comes into contact with the product or is protective. For parenteral products, components that will at any stage come into contact with any part of the product must comply with requirements specified by the BP, EP, JP or USP.

Stability testing of the finished product
Provide the results of stability testing of the formulation in each of the proposed marketing packs. Results of testing related formulations and/or the same formulation in other packaging may be provided as supporting information, but there must be at least some data on the product as it is. Describe the methodology used during stability studies; if this is identical to methodology described elsewhere in the data set, a cross-reference will suffice. If different methodology was used, provide validation of tests for impurities and assay (14), and for other tests as necessary (e.g. particle size testing).
If the product is a well established drug in an immediate release dosage form, studies should be conducted according to the principles outlined in the relevant WHO guidelines (Guideline 4 below). For new active ingredient and products, see the relevant ICH guidelines (18).
For most types of product, results should be included for physical as well as chemical tests, e.g. (where relevant) the presence of particles in a solution and the dissolution rate of solid oral dosage forms. The study should be designed to show whether trends in the properties of the products are confirmed over time.
State the proposed shelf-life and justify it in terms of the results of stability testing, the difference between release and expiry specifications, and the labelled storage conditions.
Data should also be provided on the product’s stability during any processing prior to use that may be recommended on the label or in product information, such as reconstitution of a powder, dilution of an injection, or dispersion of a tablet.

Container labelling
Labelling should include at least the items listed in Guideline 1 below, section 14.11, namely:

(a) The name of the product;
(b) A list of the active ingredients (using INNs if applicable - Guideline 8 below), showing the amount of each present in a dosage unit, and a statement of the net contents of the container, e.g. number of dosage units, weight or volume;
(c) The batch number assigned by the manufacturer;
(d) The expiry date in an uncoded form;
(e) Any special storage conditions or handling precautions that may be necessary;
(f) Directions for use, and any warnings or precautions that may be necessary;
(g) The name and address of the manufacturer, company or person responsible for placing the product on the market;
(h) The names of any excipients known to be a safety concern for some patients, e.g. gluten, metabisulfite, parabens, ethanol, or tartrazine.

The labelled storage conditions should be achievable in practice in the distribution network.
For containers of less than or equal to 10 ml capacity that are marketed in an outer pack such as a carton, and the outer pack bears all the required information, the immediate container need only contain items (b),(c), (d), (g) - or a logo that unambiguously identifies the company - and the name of the dosage form or the route of administration.

Summary of pharmacology, toxicology and efficacy of the product
For each of the following types of application, provide full information on safety and efficacy as defined in guidelines by the European Union, the US Food and Drug Administration, or the Japanese Ministry of Health and Welfare: new active ingredients, new indications, new patient populations, other amendments to product information, new routes of administration, new dosage forms, all modified-release dosage forms, and new combinations of active ingredients. Note that a complete data set of the type expected for a new API is not usually required when the same API is already available on the same market, e.g. in a different dosage form. Supply at least the data required by the guidelines named above, e.g. for a modified release product.
As an alternative to providing the full data set, it is acceptable to provide a WHO-type certificate issued by the competent authority (Guideline 2 below). As recommended in Guideline 2, the certificate should be accompanied by the product information and any patient information leaflet(s) as approved in the country issuing the certificate. A full data set on quality is required even when a WHO-type certificate is provided.
Where (1) the new product is an alternative brand of an existing product (same active ingredient, dosage form and strength) or (2) a WHO-type certificate is provided instead of full data on safety and efficacy, provide, for the information of the DRA, a summary of toxicological, pharmacological and clinical information on each API. This should be based on the scientific literature and fully referenced. Copies of key texts should be attached. Published literature reviews in refereed journals are particularly helpful. The cited literature should relate as closely as possible to the product for which the application is submitted, for example in terms of the intended route of administration, patient population, indications etc. Include recent publications if possible.

Interchangeability
Discuss the interchangeability of the product with existing brands in this market, using Guideline 5 below as a basis. Include reference to quality, stability, therapeutic equivalence, product information and labelling. Discuss the sensitizing potential of excipients in the new formulation. Provide data on therapeutic equivalence as necessary.

Product information
Provide the draft product information based on WHO’s “sample product information sheet” (Guideline 6 below, p.15-16). Provide copies of the approved product information in other countries, where available. (If available in more than five countries, provide only the product information for two key countries.) Where a monograph exists in either WHO Model Prescribing Information or the national or WHO model formulary, product information should usually include all the information in that monograph, provided that it is appropriate to circumstances prevailing in the Member State. Information on adverse reactions should conform to CIOMS guidelines (Guideline 7 below). Product information should not allude to unapproved indications, nor should it be speculative. Favourable comparisons with other products will only be permitted if there is a sound basis, for example in the literature.
Note that it will be a condition of marketing authorization that all promotion of the product be consistent with the product information once the content has been agreed) and with Guideline 6.

Patient information and package inserts
Provide copies of all package inserts and any information intended for distribution with the product to the patient. These should be consistent with the product information and should comply with Guideline 6.

Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s)
When there are differences between the product for which this application is submitted and that marketed in the country or countries which provided WHO-type certificate(s), provide arguments and/or data to support the applicability of the certificates despite the differences. Depending on the case, it may be necessary to provide validation data for differences in site of manufacture, specifications, formulation, etc.
Note that only minor differences are likely to be acceptable. Differences in container labelling need not normally be justified.