Practical Implementation of the Control of Elemental Impurities: EMA's new Guideline Draft

The "ICH Q3D Guideline for Elemental Impurities" was published in December 2014 as Step 4 document and released in August 2015 under No EMA/CHMP/ICH/353369/2013 as EMA's Scientific Guideline. The guideline came into effect in June 2016 for all medicinal products currently underlying a marketing authorisation procedure (new applications).

In the meantime, it became clear that implementing in practice the requirements of this guideline has been so complex and led to some marketing authorisation procedures being delayed. The ICH has already reacted to the situation and published 7 training modules on its website. Moreover, a concept paper announces a question & answer document.

On 12 July 2016, the draft of an EMA's guideline entitled "Implementation strategy of ICH Q3D guideline" (EMA/404489/2016) was published. The purpose of the document is to provide support for implementing ICH Q3D in the European context.

The draft comprises three chapters addressing the most important elements in relation with the implementation of the ICH Q3D requirements. The chapter "1. Different approaches to Risk Management" starts describing the two fundamental approaches to the performance of a risk assessment and the justification for a control strategy with regard to elemental impurities:

Drug Product Approach
Here, batches of the finished product are scanned by means of analytical (validated!) procedures to develop a risk-based control strategy. If - with this approach - the omission of a routine testing has to be justified, the authority expects a detailed and valid justification though, and not just analytical data from a few batches.

Component Approach
The guideline draft clearly gives its preference to this approach. The respective contribution of the different components of a medicinal product is considered with respect to the potential total impurity profile and compared to the PDE value from the risk assessment. All potential sources of impurity, for example from production equipment or from excipients of natural (mined) origin have to be considered in this assessment. This particularly applies to outsourced APIs; here, all pieces of information available from Active Substance Master Files (ASMFs) or Certificates of Suitability (CEPs) have to be used. Substances with a Ph.Eur. monograph should always comply with the elemental impurities limits of the corresponding monograph.

The chapter "2. Particulars for Intentionally Added Element(s)" deals with the common practice in many organic syntheses to add elements to increase the specificity of the chemical reaction and the yield. It is particularly critical when the last step of an API synthesis just before the end product uses a metal catalyst. In such a case, the authority expects a convincing evidence that the catalyst is purged to levels consistently below the control threshold (<30% of the PDE) by means of appropriate methods. All details about the API synthesis including the fate of the metals intentionally added have to be consistently described and documented in the marketing authorisation application or in the application for a CEP. If the routine testing of an elemental impurity is needed, the API manufacturer may determine a specification. This information will be required by the medicinal product manufacturer for his overall risk assessment.

The chapter "3. ASMF/CEP: dossier expectations and assessment strategy" explains who has to submit the risk assessment necessary for an ASMF or a CEP and how the dossier will be processed by the assessor of the regulatory authority. Basically, two scenarios are possible:

1. The API manufacturer submits a summary of a risk assessment/management for elemental impurities
Such information flows in the overall risk assessment of the medicinal product manufacturer and is assessed by the quality assessor/ CEP assessor within the marketing authorisation procedure. All data and documents used for the risk assessment should also be available for a GMP inspection.

2. The API manufacturer doesn't perform any risk assessment/ management.
The regulatory authority basically expects a detailed description of the API synthesis including data on all metal catalysts used. This as well as the analytical routine controls on elemental impurities performed by the API manufacturer will also be assessed by the quality assessor/ CEP assessor. Nevertheless, the assessor won't make a final conclusion in the ASMF or CEP assessment report with regard to the compliance with ICH Q3D. This will be done within the marketing authorisation procedure for the medicinal product.

The guideline draft can be commented on until 12 August 2016.