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ICH Issues Q3D step 2b Elemental Impurities Guideline; USP & EMA Take Action

Posted by Jim Menoutis on Wed, Aug 28, 2013 @ 05:17 PM

The International Conference on Harmonization (ICH) has started the consultation period on elemental impurities. ICH Q3D - Impurities: Guideline for Elemental Impurities - laying out limits for metallic impurities in pharmaceutical ingredients and preparations and detailing the testing procedures used to detect and measure them.  With the July 26, 2013 issuance of the guideline, Q3D has now entered step 2b of a five-step implementation process. There is a six-month comment period which gives  the industry and other stakeholders time to forward their comments.

The aim of the document is to provide a single approach for controlling metal impurities - including a list of specific metals to be limited and the appropriate limits for these metals - that will be the same in the US, Europe and Japan and so avoid uncertainty and duplicative testing procedures.

The guideline covers three main areas: toxicity testing; establishing Permitted Daily Exposure (PDE) limits for impurities of toxicological concern; and process controls to limit the introduction of impurities into the medicinal product during manufacturing. And, the guideline notes that elemental impurities can be introduced intentionally into medicinal products during synthesis or may be present as contaminants, for example arising through interactions with processing equipment.

With ICH now at the 2b stage it is expected that the US Pharmacopeia (USP) will start the process of finalizing its own guidance in this area, which is contained in two USP General Chapters - <232> Elemental Impurities: Limits and <233> Elemental Impurities: Methods - which had been due to come into effect earlier this year.

Concerns about a possible divergence between USP and ICH guidance prompted The US Pharmacopeia to issue,  on May 24, 2013 , a Compendial Notice indicating that the effective date of the new General Notices section on  Elemental Impurities  has been deferred from the May 1, 2014 target.   As a result, there “is no requirement for any drug product in the USP-NF to comply” with the already published Chapters <232> Limits and <233> Procedures.  In addition, “the proposed omission of General Chapter <231> Heavy Metals also has been deferred.

This decision by the USP Executive Committee of the Council of Experts is a result of significant comments received by USP in response to the publication of the draft General Notice  in the Pharmacopeial Forum volume 39 (1) (January 2013).   Many comments pointed to concerns about a possible divergence between USP and ICH guidance. The proposed new General Chapters <232> Limits and <233> Procedures on Elemental Impurities prompted the creation of a group representing the interests of excipient suppliers, pharma manufacturer and fine chemicals companies - collectively called the Coalition for Rational Implementation of the USP Elemental Impurities Requirements - to lobby for a harmonized approach.

The USP notice refers to the main issue raised by industry groups, stating  “These deferrals will allow USP to work closely with ICH Q3D to align their activities with the implementation of General Chapters <232> and <233>. The deferral also allows USP to work with those affected by the new elemental impurity standards.  In this regard, USP plans to form an Advisory Group on the Implementation of General Chapters <232> and <233>.” 

This cooperation between USP and ICH will result in a more harmonized standard, and allow industry to adapt to the change from the outdated Heavy Metals testing methodologies and limit requirements with the knowledge that the standard will be global.

Also following the issuance of the guideline,  the European Medical Agency (EMA) has deferred the Metal Catalyst compliance date of September 1, 2013 for existing marketed products. In a letter to the European. Federation of Pharmaceutical Industries and Associations, the EMA  Committee for Medicinal Products for Human Use (CHMP)  agreed "to delay the application of the current Guideline on the specification limits for residues of metal catalysts or metal reagents (EMEA/CHMP/SWP/4446/2000) to existing marketed products until the ICH Q3D guidance is finalised."   CHMP also released   ICH guideline Q3D on elemental impurities for consultation as  EMA/CHMP/ICH/353369/2013 with the deadline for comments by December 31, 2013.

It is also anticipated that the FDA will post in the Federal Register the ICH Q3D step 2b document shortly as well as the guidance to industry on Elemental Impurities.

The ICH Guideline For Elemental Impurities can be found here:

Topics: Elemental Impurities, FDA, USP <232>, USP <233> elemental Impurities, ICH, Q3D, Q3D, EMA, CHMP