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DMF/CoS/CMC – Preparation & Filing
Purpose
European Drug Master File (EDMF) as well as US Drug Master File (USDMF) are special documents intended to provide sufficient and all inclusive information about the drug substance to the relevant authority with the main objective to serve as a reference data base in case of an application which refers to this DMF. The DMF helps the manufacturer to keep relevant information secret and at the same time to sell the product to different customers using this drug within there final application. DMF’s today are mostly prepared following the rules of Common Technical Documentation (CTD).
Prerequisites
  • Production process is well established and fixed in writing (Master production instructions).
  • Specifications of raw materials as well as of the final product are defined including specification of packaging material.
  • Inprocess controls, sampling points and procedures are clearly outlined.
  • Critical process steps are validated, equipment is qualified.
  • Analytical methods are validated.
  • Impurity profile is established.
  • Stability program is set up and first data are available.
  • Basic GMP requirements are fulfilled
Procedures
  1. Discuss with client about their requirements (EDMF, USDMF Type I and / or II)
  2. Make an initial assessment based on a questionnaire to check the overall status (Dependent on the result you can go on or there must be some improvements or a more detailed check – s. service package “Compliance Audit”)
  3. Prepare an offer (fixed rate based on the assessment results and the individual packages as asked by the customer).
  4. Sign the contract and project commence.
  5. Prepare the letter for authority to allow for DMF filing
  6. Basic information / training of relevant staff about DMF and necessary documents, document preparation
  7. Compilation and submission of relevant documents, data, and records by the manufacturer with the help of the domestic expert
  8. Do a chemistry and regulatory review of the submitted data including review of certificates of analysis and directly send information about all recognized deficiencies to the manufacturer for corrective actions
  9. Prepare 1st draft of DMF for review by the manufacturer and filling in the final blanks
  10. Finalize the DMF and translate into the relevant languages (Chinese and English language) including a last check by a German and/or American expert
  11. Filing the DMF to FDA and/or EMEA to receive the DMF No. including all correspondence and answering of open points
  12. Prepare a DMF type I (only USA) if required for giving information to FDA inspectors for on site inspections
  13. Filing the DMF type I to FDA and do the necessary correspondence if required
  14. Preparation of the site for authority inspection (FDA or EMEA) by a 2 days training or doing a mock inspection (s. separate service package)
  15. Accompanying the manufacturer during the inspection and coordination of follow up activities related to the official observations (e.g. 483 punch list of FDA)
Important Note
DMF (Drug Master File), CoS (Certificate of suitability) as well as CMC (Chemical Manufacturing and Control Documentation) are used for one and the same intention – to give evidence, that the drug substance (API – Active Pharmaceutical Ingredient) is suitable for its intended use and that the manufacturing process is well established and controlled. Content of DMF, CoS, and CMC are nearly equal. There are only differences in the kind of document preparation (forms to use) and the authority you have to contact (USDMF FDA; EDMF EMEA; CoS EDQM; CMC national bodies). Therefore above mentioned procedure is nearly equal for all the three types. Especially CoS does not replace an approval process. Approval authorities can require more information even if CoS is available.

For preparation of the final dossier today the CTD (Common Technical Doccument) format is to follow. This is accepted world wide. Therefore it is highly recommended also to prepare the substance dossiers in the same format.

Data required following the CTD are
BODY OF DATA
3.2.S DRUG SUBSTANCE
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure Description
3.2.S.1.3 General Properties
3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer(s)
3.2.S.2.2 Description of manufacturing process and process controls
3.2.S.2.3 Control of materials
3.2.S.2.4 Controls of critical steps and intermediates
3.2.S.2.5 Process validation and/or evaluation
S.2.6 Manufacturing process development.

S.3 Characterisation
3.2.S.3.1 Elucidation of structure and other characteristics
3.2.S.3.2 Impurities
3.2.S.4 Control of drug substance
3.2.S.4.1 Specification
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of analytical procedures
3.2.S.4.4 Batch analyses
3.2.S.4.5 Justification of Specification
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability

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