Type II Drug Master File Guide Section "I"

I. SPECIFICATIONS, TEST METHODS, AND SAMPLING PLAN USED FOR RAW MATERIALS

1. List of Starting Materials

A list of Starting Materials should be listed. The source of the Starting Material need not be identified, but may be requested.

2. Specifications and Test Methods

Acceptance specifications and tests defining identity, quality, and purity should be provided. The analytical test methods should be briefly described.

3. Sampling Plan

The sampling plan for starting materials, reagents, solvents, auxiliary materials, intermediates and drug substance should be described, giving the basis for the plan. It should satisfy appropriate statistical considerations. Please refer to 21 CFR 211.170 Reserve Samples.

A specific identify test should be performed, as well as an assay, with limits for impurities. In those cases where impurities (e.g., positional isomers of aromatic compounds) could be carried through to the drug substance, a purity profile should be provided. Assurances or statements of quality from the supplier are acceptable for the profile, provided that the manufacturer establishes the reliability of the supplier's analyses through validation, initially and at appropriate intervals. These statements from suppliers should include specifications and results and should indicate the type of method used for analyses.

II. SPECIFICATIONS, TEST METHODS, AND SAMPLING PLAN USED FOR REAGENTS, AUXILIARY MATERIALS AND SOLVENTS

1. List of Reagents, Auxiliary Materials and Solvents

2. Specifications and Test Methods

The specifications and test methods for each such material should be stated, and/or a statement of quality provided. The applicant should describe the specific identity test performed (unless omitting such a test that has been otherwise justified, e.g., because of hazard). The extent of additional testing performed - whether by the supplier or by the applicant - should be based on the role of the chemical in the synthesis. For example: a base (e.g., sodium hydroxide) used to neutralize excess acid in a synthetic reaction mixture would not normally require extensive purity testing; in contrast, an optically active organic acid used in a resolution step (e.g., one enantiomer or dibenzoyltartaric acid) would require such additional testing.

3. Sampling Plan

III. SPECIFICATIONS, TEST METHODS, AND SAMPLING PLAN USED FOR INTERMEDIATES

1. List of Intermediates

2. Specifications and Test Methods

(a) Pivotal Intermediates

Any pivotal intermediate should be described in adequate detail (i.e., be well characterized) and be subject to rigorous examination procedures as part of the specifications and tests, including thorough chromatographic examination so as to avoid overloading impurities arising from alternative syntheses. Such rigorous examination need not be routine but may be needed in special circumstances such as when the supplier or synthesis is changed. The degree of testing and the level of purity required for a pivotal intermediate should increase as its position in the synthesis scheme approaches the final intermediate.

(b) Key Intermediates

The specifications should be adequate to assure that the molecular architecture necessary for the final product, as well as the requisite degree of purity, have been attained.

Specifications and tests for final intermediate should be nearly as extensive and stringent as those for the drug substance itself, because this is the last opportunity to monitor purity and impurities before the final reaction.

3. Sampling Plan

IV. IN-PROCESS CONTROLS

The regulations require that controls (specifications and tests) be employed at selected stages of the synthetic process to assure that the synthetic and purification procedures are operating properly and that the intermediate tested is suitable for subsequent processing. The choice of which steps in the process to test, and the kind of testing required, are the responsibility of the applicant based on his experience during the development and verification of the total synthetic process. (Usually the critical reaction steps and intermediates are tested.)

Controls may be designed to (a) demonstrate that the desired product has been obtained; (b) determine a key physical property (e.g., melting point, optical rotation, etc.); (c) determine purity/impurity of the intermediate; (d) determine that the yield is within the normal range. When appropriate, testing may consist only of a test designed to monitor the progress of the synthesis (i.e., reaction completion).

V. SPECIFICATIONS, TEST METHODS, AND SAMPLING PLAN USED FOR THE DRUG SUBSTANCE

1. Specifications and Test Methods for Final Release

If the subject product is a USP product, then list here all tests and specifications from the official monograph, including supplements.

If the subject product is not a USP product, examples of tests and specifications that may be applicable are as follows: Appearance/description, Physical properties, Specific identify tests, Impurity profile and limits, and Assay.

* If applicable - Methods & Controls used in milling of final product.

2. Characterization of Reference Standard

If an official USP Reference Standard is used for analytical testing, include the batch number.

The reference standard can be defined as drug substance of the highest purity reasonably attainable, specifically prepared by independent synthesis or by (further) purification of existing production material, and shown to be authentic material by an extensive set of analytical tests. It is usually used for the structure elucidation work. If the synthesis differs from that in the application, full details should be provided. Any additional purification procedure should be described. The reference standard substance maintained by the applicant as the standard against which working standards are judged.

3. Specifications and Test Methods for Reprocessed Lots

If the reprocessing procedure employed necessitates testing beyond that required for normal production (lots that did not require reprocessing), these tests should be described in detail. For example, if it is determined that a failed lot must be recrystallized using a solvent not normally employed, their specifications and methods for that lot should include tests for that solvent. Please note that for any lot that the final recrystallization solvent is changed, you must consider the points mentioned in your Statement of Commitment (changes in synthesis).

4. Impurity Profile

5. Certificates of Analysis

Submit the certificates of analysis for three largest validated size batches reflecting current USP requirements and the manufacturing procedures as described in Section H.

VI. STABILITY PROTOCOL

1. Specifications and Test Methods

It is essential that stability indicating methods be used throughout all stability studies. These methods should be specific and must be able to differentiate products of degradation. The methods should also be validated.

Evidence that the method is stability indicating must be presented, even for compendial methods.

Manufacturers may be required to accelerate or force degradation of a product to demonstrate that the test is stability indicating.

2. Study Conditions and Designs

Primary Stability: Long-term, non-accelerated, data on the drug substance stored in the proposed container-closure system for marketing. This would be room temperature 25°-30°C (warehouse) aging conditions for BPCs that do not require refrigerated storage.

Accelerated Stability: These studies are designed to increase, or accelerate, chemical or physical degradation of a drug substance. The appropriate test condition is 40°C and not less than 75% relative humidity (RH) for 3 months for BPCs that do not require refrigerated storage. With these data, a 2 year expiration date is granted.

Note: When there are more than 2 years of Primary data available, the reanalysis date can be extended beyond 2 years dependent on the length of the room temperature study.

Sample Amount - Your program must indicate the sample amount is properly calculated.

Container/closure - The sample must be packed in a container/closure system that simulates the system used to market the BPC.

Sampling Times - You must have a timetable indicating sampling times for each stability program. For example:

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Months 0 1 2 3 6 9 12 18 24 36 48 60

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Primary † : * * * * * * * * * *

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Accelerated †† : * * * *

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† First 3 production lots and one yearly thereafter

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†† First 3 production lots only and lots subject to a significant manufacturing change.

Documentation - The data should be tabulated with a cross-reference to the analytical notebook.

3. Proposed Re-evaluation or Expiration Dating

You must propose an acceptable reanalysis date. Two years is granted with accelerated stability data and a long term study commitment (see item 4 below). If the BPC expires (one or more of the specifications cannot be met after a certain time interval), you should propose an expiration date (after which the material cannot be used).

4. Ongoing Stability Commitment

You must provide a stability commitment indicating how the studies will be performed. For example:

The first 3 production lots, and one production batch yearly thereafter, will be entered in the Primary stability trial. Results will be submitted as they become available. Any lots which may fall out of specification will be promptly withdrawn from the market.

VII. PRODUCT PROBLEM REPORT AND RESPONSE

This signed and dated statement describes how a file is maintained for all complaints regarding the drug substance. The written records in these files will be maintained at the administrative offices and will be readily available for inspection. The records will include the name and lot number of the product, as well as, the complainants name, complaint nature and reply. The Quality Assurance Director will determine whether or not a complaint warrants investigation. If an investigation is not warranted, a written record with reasons and names will be entered into the complaint file. If the complaint is investigated, records of the investigation and follow-up will be entered into the file.