Implementation of ICH Q3D within the CEP Procedure

Recommendation

22/23 February 2024
Munich, Germany

API Regulatory Starting Materials
Definition, Manufacture, Assessment and handling post-approval Changes

In August 2016, the EDQM released a policy document entitled "Implementation of ICH Q3D in the Certification Procedure" (PA/PH/CEP(16)23). According to the literal adoption of the ICH Q3D Guideline in the General Chapter 5.20 of the European Pharmacopoeia, regulating the handling with elemental impurities within the CEP procedure is the next step for a consistent implementation of this guideline.

The document describes in two main chapters which data on elemental impurities are required for a new CEP application and for the revision/renewal of an existing CEP. An important part of the document is the Annex 1 providing the example of a risk management summary (RMS) which lists the 24 elements of the ICH Q3D guideline in a table. Applicants have to enter in the table limits and information about each element which is involved in the risk management or which has been added intentionally. Moreover, the intended routes of administration of the API, as well as its intended use have to be indicated.

Please find hereafter a short summary of the data on elemental impurities expected by the EDQM from an applicant or a CEP holder.

New application for a CEP with submission of a RMS

• All potential sources of impurities (e.g. raw materials, excipients, equipment, packaging) have to be discussed as well as the intentionally added elements
• All class 1 and 2A elements have to be considered. Class 3 elements should only be considered when a later use on humans (dosage form) is intended
• Each consideration has to be justified
• The control strategy should concentrate on the absence/presence of elemental impurities in the finished product, i.e. in the final API
• The absence of an elemental impurity means: convincing evidence that they are purged under a level of 30% of the calculated limit based on the dosage form and the daily intake (according to table A.2.2 of the ICH Q3D guideline) and derived from measurements of at least 3 commercial batches or at least 6 pilot batches of the finished product
• If necessary, a justified specification for elemental impurities in the final product should be indicated
• Results of the screening if several batches can support a RMS but cannot replace it
• Analytical methods don't have to be completely validated for screening investigations. But if they serve as control of the specification of the final product, they have to be described in detail and validated according to ICH Q2

The EDQM points out that the submission of a RMS is in any case advantageous.

New application for a CEP without submission of a RMS

• Analytical data have to be provided for each elemental impurity.
• A specification in the final product has to be indicated for each element intentionally added in the last synthesis step.
• For the analytical methods, validation data according to ICH Q2 have to be submitted.

Requirements for existing CEPs and CEP revisions

With the publication of edition 9.0 of the European Pharmacopoeia (January 2017), General Chapter 2.4.8 (Test for Heavy Metals) will be removed from the monographs for substances which fall under the scope of ICH Q3D. CEP holders won't be contacted individually by the EDQM unless their CEP contains a limit for elemental impurities which has been calculated according to option 2a of the General Chapter 5.20 set in edition 8 of the European Pharmacopoeia. In that case, a revision of the CEPs will be automatically initiated by January 2017.

In the following cases, CEPs revisions are possible, respectively necessary:

• The CEP holder submits only a RMS (without further changes to the manufacturing process of the control strategy). This possibility exists at any time during the lifecycle of the dossier.
• Changes to the manufacturing process: If the changes influence the elemental impurity profile, a RMS and/or supporting data have to be submitted. The validity of an already submitted RMS should be verified. If required, the RMS has to be updated.
• Changes to the control strategy (another analytical procedure or specification) without changes to the manufacturing process:  if the changes influence the elemental impurity profile, a RMS and/or supporting data have to be submitted. The validity of an already submitted RMS should be verified. If required, the RMS has to be updated.

The same requirements apply to CEPs whose renewal is pending. The EDQM recommends to submit a RMS in the course of the renewal of a CEP.

The regulations described in this policy document will apply as of September 1st 2016 for all new, renewed or revised CEPs. Notwithstanding the above, the document can be commented on via the EDQM helpdesk.

Note: At the 19th APIC/Cefic European Conference on Active Pharmaceutical Ingredients on 23 - 25 November 2016 in Barcelona, Spain, Hélène Bruguera -  head of EDQM's certification division - will present the latest developments in the CEP procedure. You can find more information at: www.api-conference.org.