G. ARTICLE(S) - COMPONENTS AND COMPOSITION

I. DESCRIPTION OF THE ACTIVE PHARMACEUTICAL INGREDIENT

A description of the Active Pharmaceutical Ingredient would include International trade name, Chemical name, CAS number, Empirical formula, molecular weight, structural formula, physical form, etc.

II. MANUFACTURE OF THE ACTIVE PHARMACEUTICAL INGREDIENT

There are two principal reasons for providing a detailed presentation of the synthetic pathway and/or manufacturing process. First, a particular synthetic pathway will typically be uniquely associated with a set of impurities (actual and potential), and also a specific solid-state form. The impurities may have significant clinical or toxicological effects. When a change is made or proposed in a synthetic process, a different ratio or even different set of impurities may arise, and the control testing may need modification. Second, knowledge of the synthetic pathway provides additional evidence to support the proposed chemical structure.

1. List of Starting Materials, Reagents, Auxiliary Materials, Solvents and

Intermediates

(a) Starting Material

(b) Reagents and Auxiliary Material

(c) Solvents

(d) Intermediates

2. Synthesis

Provide complete information on the synthesis, from starting material(s) to the bulk drug substance. The description should contain a diagrammatic flow chart of the whole synthesis and a written statement for each step of the synthesis.

(a) Flow Chart

(b) Description of the Synthesis

i. Step 1:

ii. Step 2:

(c) Impurity Profile

(i) Known Impurities

(ii) Potential Impurities

(d) Purification of the Active Pharmaceutical Ingredient

The description of the purification of the crude drug substance and its isolation from the final reaction step mixture should be given in detail and include:

- Yield ranges of crude

- Crude purity tests

- Description of isolation and purification

- Alternative purification procedures

- Yield range of the purified product

- Evidence of purity

This testing and information may be necessary only on initial production batches, once the purification process has been verified or validated.

Changes in the Synthesis

Proposed changes in the synthesis should be submitted as an amendment to the DMF. When the route of synthesis is changed, comparative analytical data (i.e. a complete purity profile) made by each route should be provided. When there is a change in the solvent used for the final crystallization of THE ACTIVE PHARMACEUTICAL INGREDIENT, it should be examined for changes in crystalline form and/or solvation. The product must meet its original specifications for crystalline form and/or solvation.

(e) Milling/Micronization/Sieving

(f) Demonstration of the Chemical Composition of the Product

Demonstration of the chemical composition of the product would include: for e.g., elemental analysis, mass spectrum, x-ray diffraction, NMR, IR, and UV.

(g) Physical Characteristics of the Product would include: for example, particle size, bulk density.

III. MANUFACTURE OF THE REFERENCE STANDARD

Submit a full description of the preparation of any reference standard substance used, including the description of the purification steps.

IV. PACKAGING AND LABELING

Instructions for packaging and labeling must be included in the MPRs. All packaging and labeling components must be identified in the records.

Give reference to, and/or a copy of, your SOP governing this.

Include specimens of all other identification labels not previously included in any other section of this DMF.

1. Packaging

Describe how your product is packaged. Give details on the materials used for package liners, seals, and outer drums. Include current specifications sheets from the suppliers of each component.

2. Labeling

The Quality Control department must have written procedures for label issuing, reconciliation and record keeping. The procedure shall reconcile the quantities of labels issued, used, and returned.

Provide actual inner and outer drum identification labels in English.