EMA's new Guideline on the Implementation of the ICH Q3D Guideline in the EU

On 8 March 2017, the EMA published the guideline entitled "Implementation strategy of ICH Q3D guideline" (EMA/CHMP/QWP/115498/2017). This document is the final version of the draft (EMA/404489/2016) of the same name from July 2016 which had been open for comment 4 weeks long. We reported in "Practical Implementation of the Control of Elemental Impurities: EMA's new Guideline Draft" in July 2016.

The objective of the guideline is to provide medicinal product manufacturers with support regarding the implementation of the ICH Q3D "Guideline on Elemental Impurities".

Compared to the draft version, the final guideline which has been published now contains notable changes. Those are:

  • Analytical methods for the determination of elemental impurities have to be validated for the intended purpose.
  • A summary of the risk assessment with regard to the elemental impurities has to be submitted in the marketing authorisation dossier in Module 3 and in the Quality Overall Summary in Module 2 of the CTD.
  • The guideline concedes that the observation of the requirements laid down in ICH Q3D is also possible with limited knowledge of the possible sources of elemental impurities by means of a risk assessment - based on some process and product understanding. If one waives such an assessment, routine testing of the medicinal product for all elements listed in ICH Q3D has to be performed.
  • The procedure for both approaches "Drug Product Approach" and "Component Approach" is described more clearly. In the "Drug Product Approach" for example it is pointed out that analytical data alone are not sufficient to justify the omission of a specification for an element whereas in the "Component Approach" the contribution of elemental impurities from each potential source along the manufacturing process is identified, evaluated and summarized.

When the supplier of a component - e.g. an excipient - has no information about where and how the medicinal product manufacturer uses the component in question, it is almost impossible to set a specification for the impurities. One possibility is to use Option 1 from ICH Q3D setting limits for elements with a daily administration of 10 grams.

One requirement of evidence has been included unchanged: all elements intentionally added, like for example metal catalysts used in the last step of the synthesis, have to be below the control threshold of 30% of the PDE in the final API product. This is different from the requirement laid down in the ICH Q3D Guideline according to which this limit has to be complied with for the finished product but not for the API.

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