How to gather the CMC documents?, and how to develop your knowledge as to manage the compilation of a harmonized CTD ?

Gathering of CMC (Chemistry, Manufacturing, Control) Documents

I. DS=AI=API

• The drug substance documentations can be compiled from one of the following three sources:

1.??Certificate of suitability (CEP).

2.??Drug master file (DMF).

3.??Complete information on the “3.2.S”sections.

• Supply chain department will be responsible to get the documents from the DS manufacturer.

? The number of Active Pharmaceutical Ingredients (API) suppliers must not exceed two sources for each API, unless reasonably justified.

1. COS:

? The DS section should refer to COS in the relevant sections in m 3.2.S.

? A complete copy of COS (including any annexes) should be provided in m 1 & in m 3 R.

? TSE-compliance can also be demonstrated by a CEP.

? COS submitted should clearly state the validity period.

? Available COS

https://extranet.edqm.eu/publications/recherches_CEP.shtml

2. Drug Master File (DMF) “Active Substance Master File (ASMF) “

?Complete DMF “Open Part” should be included in section 3.2.S in the CTD-format.

?A copy of the "Letter of Access- LOA" shall be included in m1 & addressed to the regulatory authority to where application is made.

?API manufacturer's restricted "closed part“ with original signed LOA is supplied to the authorities directly by active substance manufacturer in the CTD format.

?The following sections should be enclosed in Open part of DMF :

3.2.S.1 General information (All its 3 subsections)

????3.2.S.2.1 Manufacturer

?????3.2.S.2.2 Description of process & process controls

?????3.2.S.2.4 Control of critical steps & intermediates

3.2.S.3 Characterization (All its 2 subsections)

3.2.S.4 Control of drug substance (All its 5 subsections)

3.2.S.6 Container closure system

3.2.S.7 Stability (All its 3 subsections)

II. DP=FP

The quality & production technical documents will be provided by the following departments in the DP manufacturing site:

R&D / QA / Production / R.M./ QC / Packaging material / Stability

How to develop your knowledge?as to manage the compilation of?a harmonized CTD ?

Tips for DS harmonized docs compilation

?????CMC data – DS:

*If the product contains multiple DS, then documentation for each substance should be provided in its own m.3.2.s section.

*If a DS is manufactured at multiple sites or by multiple different manufacturing companies, documentation will be provided in m.3.2.s section.

* If there are 2 sources for the API, equivalency between the sources should be demonstrated in the application. For instance comparative stability & release data from one batch of the drug product manufactured using the API from alternate source(s) against the primary source are recommended.

* Certificate of Suitability (COS/CEP)

????????Valid CEP (https://extranet.edqm.eu/publications/recherches_CEP.shtml)

* 3.2.S sections are strongly bound.

*Drug Master File (DMF)

? All sections of DMF shall be available, except the following restricted sections which will be sent to HA directly by DS manufacturer enclosed within the LOA:

o Detailed information on description of manufacturing process & process controls (3.2.S.2.2).

o Control of materials (3.2.S.2.3).

o Control of critical steps & intermediates (3.2.S.2.4).

o Manufacturing process development (3.2.S.2.6).

?Adequate stability study data

?Method (validation/verification/transfer) reports to be provided.

?LOA is addressed to HA reviewing the dossier.

CMC data - DP:

?Pharmaceutical development:

*Overage in raw materials with sufficient justification to support the safety of the ingredients at the proposed level.

*Compatibility study is enclosed “if required: e.g. reconstitution diluents, excipients are different from reference product”

?The sterility assurance validation studies for terminally sterilized DP & aseptically filed DP.

?Method (validation/verification/transfer) reports to be provided.

?Microbial limit is included in FP specifications.

?Excipients related subsections are enclosed for non-compendial excipients.

?Sufficient container closure system documents “COA for all primary packaging materials”.

?Adequate stability study data (complying to ICH regulations)

?Commitment to conduct ongoing stability studies (at least one batch per year).

?Commitment to place the first three production batches on long-term stability studies through the proposed shelf life period.

?Commitment to conduct prospective process validation on three consecutive production batches (for nonsterile products).

?Harmonized production batch size range.

?Avoid missing any section from m1 to m5 without a proper justification.

?Dossier should be :

*Submitted in the appropriate format specified by HA and isn’t compiled as per recent regulations structure.

*Written in one of the official languages.

*Prepared as per m1 & 3.2.r section of the relevant HA.

?Enclose data about the usage of animal or human origin materials.

?MAH and manufacturing sites shall be unified in all data of dossier.

?ADR, confirm the reporting process as per each region/territory regulations.

?PV system & RMP documents to be enclosed as per HAs regulations.

*Check each region/territory regulations for serialization/Data matrix/track & trace.

*SmPC/PIL/Mock-ups:

?Specified DP packaging materials data in m1 sections, shall be inline with all eight sections of DP.

?DP Shelf life & storage conditions consistency with DP sections.

?Composition formula (API & excipients) data have to be similar to DP sections information.

?Indications must be complying to m4 & m5.

?In case of generic product, take care of innovator product patency & exclusivity data.

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