"Q3D: Impurities: Guideline for Metal Impurities" - a new ICH Concept Paper

The ICH has published a Concept Paper on the development of a guideline which would harmonise the limits of metal impurities in the three large economic areas Europe, USA and Japan. For new medicines or drugs that are already marketed in Europe, a document about the limitation of metal impurities already exists, called: „Guideline on the specification limits for residues of metal catalysts or metal reagents" (EMEA/CHMP/SWP/4446/2000). However, this guideline only applies to Europe. Similar guidelines with instructions on the control of metal impurities in the other two geographical regions either do not exist or contain different requirements from the respective national authorities. Yet, as the ICH's mission is to develop harmonised guidelines for the drug and API industry in the three economic areas, it was thus logical to start "Step 1" of the ICH process to face the significant issue of metal impurities.

The Concept Paper called "Q3D: Impurities: Guideline for Metal Impurities" is not already the draft of a guideline, it is first of all a document which justifies the need for such an important and useful regulation. In brief, the justification is based on the following:

  • The Q3A guideline classifies impurities as organic, inorganic and residual solvents. The Q3A, Q3B and Q3C guidelines describe the control of organic impurities and residual solvents. There is no respective regulation for the metals mentioned in Q3A under "inorganic impurities". These will have to be worked out in the development of the new Q3D guideline. 
  • In the past few years, the risk factors on metal have dramatically changed. In contradiction, pharmacopoeial methods used for the quantitative assessment are most of the time no longer up-to-date (e.g. detection of metal traces from pipelines and manufacturing equipment via a sulphide precipitate). Most heavy metal limits have little basis on toxicology. 
  • The existing Q3A, Q3B and Q3C guidelines have already been integrated into the pharmacopoeial standards. An analogue inclusion of modern analytical standards for the control of metal impurities into the different pharmacopoeias would be a definitely useful complement and a significant progress.

The authors of the Concept Papers point out that the Q3D guideline to be developed will also contain aspects of risk assessment and respective regulations for the control of the supply chain. They recommend to form an expert work group composed of chemists and toxicologists to develop the document following the provisions of the already existing EMA-Guideline. The question now is to see how quick the formation of this expert working group will be and if the defined 1 to 2 year-period of time for the development of the guideline will be sufficient.

Dr Gerhard Becker
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)

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