New FDA Draft Guidances on "Chemistry, Manufacturing, and Control Information (CMC)"

GMP News No. 424

27 May 2004

New FDA Draft Guidanceson
"Chemistry, Manufacturing, and Control Information (CMC)"

In Europe, new drug applications have to be submitted according to the CTD(Common Technical Document) format since 01 July, 2003. This is notmandatory in the US, where dossiers can be submitted in the CTDformat. It should be emphasized that the CTD (1) only describes aharmonized format of the dossier; it does not give any advice orrecommendation regarding the content of the dossier, as to which there arestill different regional requirements.

In order to provide recommendations on the chemistry, manufacturing,and controls (CMC) information structured to facilitate the preparation ofapplications submitted in the CTD format, it was necessary to revise the Guidelinefor submitting supporting documentation in drug applications for themanufacture of drug substances and the Guideline for submittingsupporting documentation in drug applications for the manufacture of drugproducts (2,3).

In January 2003 the 'Drug Product-Guideline (‚Guidance forIndustry, Drug Product: Chemistry, Manufacturing, and Controls Information',Draft Guidance, January 2003 (4)) was revised, in January 2004 the draftof the ‚Drug Substance Guidance' was published for comments (‚Guidancefor Industry, Drug Substance: Chemistry, Manufacturing, and ControlsInformation', Draft Guidance, January 2004, (5)). Both guidancesprovide recommendations on the chemistry, manufacturing, and controls(CMC) information to be submitted for drug substances and drug products toensure continued product quality. The guidances are related to Module 3,Quality, of the CTD (6). In Table 1 the chapters of CTD, Module 3 and thedrafts Drug Substance- and the Drug Product-Guidance are being compared(see Table 1).

Especially the draft of the Drug Substance Guidance causes seriousconcerns when compared to the other drug-substance-relevant guideline, theICH Q7a Good Manufacturing Practice Guide for Active PharmaceuticalIngredients. It seems that the new draft is not in line with ICH Q7a– especially with regard to the definitions given there (e.g. thedifferent wordings of the active moiety that is called 'Drug Substance' inthe new draft of the Drug Substance Guidance, but is called 'activepharmaceutical ingredient' in ICH Q7a) – nor with FDA's currentrisk-based philosophy. On the whole, it seems that the requirementsdefined in the draft of the Drug Substance Guidance are stricter thanthose defined before.

It will be interesting to see if and what kind of industry's commentswill be considered by the authorities.


Table 1: Comparison of the Chapters of CTD, Module 3, Quality and therevised Drug Substances and Drug Product Guidance for Industry

CTD Module 3

FDA Drug Substance
Draft Guidance (2)

FDA Drug Product
Draft Guidance (1)


I. Introduction

I. Introduction


II. Background

II. Background

3.1 Module 3 Table of contents


3.2.S Drug Substance

Drug Substance


3.2.S.1 General Information

III. General Information


3.2.S.2 Manufacture

IV: Manufacture


3.2.S.3 Characterisation

V. Characterization


3.2.S.4 Control of drug substance

VI. Control of Drug Substance


3.2.S.5 Reference Standards or Materials

VII. Reference Standards or Materials


3.2.S.6 Container Closure System

VIII. Container Closure System


3.2.S.7 Stability

IX. Stability




Drug Product

3.2.P.1 Description and composition of the drug product


III. Description and composition of the drug product

3.2.P.2 Pharmaceutical Development


IV. Pharmaceutical Development

3.2.P.3 Manufacture


V. Manufacture

3.2.P.4 Control of excipients


VI. Control of excipients

3.2.P.5 Control of drug product


VII. Control of drug product

3.2.P.6 Reference Standards or Materials


VIII. Reference standards or materials

3.2.P.7 Container Closure System


IX. Container Closure System

3.2.P.8 Stability


X. Stability


X. Appendices

XI. Appendices


XI. Regional Information

XII. Regional Information


XII. Literature References

XIII. Literature References


Attachment 1: Starting Materials for Synthetic Drug Substances

Attachment 1


Attachment 2: Starting Materials of Plant or Animal Origin





Dr Barbara Jentges


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