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GMP News
27 May 2004
 

New FDA Draft Guidances on
"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 not mandatory in the US, where dossiers can be submitted in the CTD format. It should be emphasized that the CTD (1) only describes a harmonized format of the dossier; it does not give any advice or recommendation regarding the content of the dossier, as to which there are still different regional requirements.

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

In January 2003 the 'Drug Product-Guideline (‚Guidance for Industry, Drug Product: Chemistry, Manufacturing, and Controls Information', Draft Guidance, January 2003 (4)) was revised, in January 2004 the draft of the ‚Drug Substance Guidance' was published for comments (‚Guidance for Industry, Drug Substance: Chemistry, Manufacturing, and Controls Information', Draft Guidance, January 2004, (5)). Both guidances provide recommendations on the chemistry, manufacturing, and controls (CMC) information to be submitted for drug substances and drug products to ensure 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 the drafts Drug Substance- and the Drug Product-Guidance are being compared (see Table 1).

Especially the draft of the Drug Substance Guidance causes serious concerns when compared to the other drug-substance-relevant guideline, the ICH Q7a Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. It seems that the new draft is not in line with ICH Q7a – especially with regard to the definitions given there (e.g. the different wordings of the active moiety that is called 'Drug Substance' in the new draft of the Drug Substance Guidance, but is called 'active pharmaceutical ingredient' in ICH Q7a) – nor with FDA's current risk-based philosophy. On the whole, it seems that the requirements defined in the draft of the Drug Substance Guidance are stricter than those defined before.

It will be interesting to see if and what kind of industry's comments will be considered by the authorities.
  
At this year's 7th APIC/CEFIC European Conference on Active Pharmaceutical Ingredients (held in Lisbon / Portugal from 20-22 October 2004) the revision of the Drug Substance Guidances will be one of the topics. Dr. Guirag Poochikian, FDA, will give a lecture about 'An update of FDA CMC Guidances – Drug Substance and BACPAC II' (Friday, 22 October 2004, 08.00-09.00h). Please click here for further information about the conference. 

 
Table 1: Comparison of the Chapters of CTD, Module 3, Quality and the revised 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

  

3.2.P DRUG PRODUCT

  

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

3.2.A APPENDICES

X. Appendices

XI. Appendices

3.2.R REGIONAL INFORMATION

XI. Regional Information

XII. Regional Information

3.3 LITERATURE REFERENCES

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

  
 

Glossary

Glossary

Literature:
  1. The Common Technical Document (CTD), Internet:
    http://www.ich.org/
  2. Guideline for submitting supporting documentation in drug applications for the manufacture of drug substances, February 1987, Internet:
    http://www.fda.gov/cder/guidance/drugsub.pdf
  3. Guideline for submitting supporting documentation in drug applications for the manufacture of drug products, February 1987, Internet:
    http://www.fda.gov/cder/guidance/drugprod.htm
  4. FDA, Guidance for Industry ‚Drug Product – Chemistry, Manufacture, and Controls', Draft Guidance, January 2003, Internet:
    http://www.fda.gov/cder/guidance/1215dft.pdf
  5. FDA, Guidance for Industry, Drug Substance – Chemistry, Manufacture, and Controls', Draft Guidance, January 2004, Internet:
    http://www.fda.gov/cder/guidance/3969dft.pdf
  6. ICH Guideline: The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality - M4Q; Quality Overall Summary of Module 2, Module 3: Quality, Internet:
    http://www.ich.org/MediaServer.jser?@_ID=556&@_MODE=GLB

Author:
Dr Barbara Jentges
CONCEPT HEIDELBERG