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28 March 2019 EMA/CHMP/ICH/353369/2013 Committee for Human Medicinal Products ICH guideline Q3D (R1) on elemental impurities Step 5 Transmission to CHMP 26 April 2018 Adoption by CHMP 26 April 2018 Release for public consultation 26 April 2018 End of consultation on the Cadmium Inhalation PDE (deadline for 26 July 2018 comments) Final adoption by CHMP 28 March 2019 Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED GUIDELINE GUIDELINE FOR ELEMENTAL IMPURITIES Q3D(R1) Final version Adopted on 22 March 2019 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of ICH regions. ICH Q3D(R1) Guideline Q3D(R1) Document History Code History Date Q3D(R1) Revision of the Cadmium Inhalation PDE 22 March 2019 Adoption by the Regulatory Members of the ICH Assembly under Step 4. Q3D(R1) Revision of the Cadmium Inhalation PDE 18 May 2018 Endorsement by the Members of the ICH Assembly under Step 2 and release for public consultation. Corrigendum to correct: the modifying factor in the 16 December text of the safety assessment for Selenium 2014 (changed to 2 instead of 10 consistent with Section Q3D 3.1); and two references for consistency in the safety assessments for Barium (deleted reference) and Vanadium (revised reference). Approval by the Steering Committee under Step 4 12 November Q3D and recommendation for adoption to the ICH 2014 regulatory bodies. 30 September Q3D Addition of line numbers to facilitate the provision of comments by stakeholders. 2013 Post sign-off minor editorial corrections including: 26 July removal of references to Appendix 5 (pgs i & 13); 2013 deletion of redundant text (pg 4); change of Option 2 to Option 2a (pg 10); insertion of omitted text Q3D under Safety Limiting Toxicity (pg 35); removal of duplicated redundant text (pg 41); replacing references to “metals” in text and “metal” in Table A.4.7 title with “elementals” and “elements” (pg 73); and deletion of header Table A.4.10 (pg 75). Post sign-off corrigendum in: 14 June Table 4.1 W and Al were removed from the list of 2013 Q3D included elemental impurities in Class 2B and 3 respectively. Table A.2.1 the Class for Ni was changed to read 3 instead of 2. Approval by the Steering Committee under Step 2b 6 June Q3D and release for public consultation. 2013 Approval by the Steering Committee under Step 6 June 2013 Q3D 2a. 2 ICH Q3D(R1) Guideline Legal notice: This document is protected by copyright and may, with the exception of the ICH logo, be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided. The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder. 3 ICH HARMONISED GUIDELINE GUIDELINE FOR ELEMENTAL IMPURITIES Q3D(R1) ICH Consensus Guideline TABLE OF CONTENTS 1. INTRODUCTION .................................................................................................................. 2 2. SCOPE ..................................................................................................................................... 2 3. SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES ...................... 3 3.1 Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration ......................................................................................... 3 3.2 Other Routes of Administration ................................................................................................ 4 3.3 Justification for Elemental Impurity Levels Higher than an Established PDE ......................... 4 3.4 Parenteral Products ................................................................................................................... 5 4. ELEMENT CLASSIFICATION ........................................................................................... 5 5. RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES ..................... 6 5.1 General Principles .................................................................................................................... 7 5.2 Potential Sources of Elemental Impurities ............................................................................... 7 5.3 Identification of Potential Elemental Impurities....................................................................... 8 5.4 Recommendations for Elements to be Considered in the Risk Assessment ............................. 9 5.5 Evaluation ............................................................................................................................... 10 5.6 Summary of Risk Assessment Process ................................................................................... 11 5.7 Special Considerations for Biotechnologically-Derived Products ......................................... 11 6. CONTROL OF ELEMENTAL IMPURITIES ............................................................................... 12 7. CONVERTING BETWEEN PDES AND CONCENTRATION LIMITS.......................................... 12 8. SPECIATION AND OTHER CONSIDERATIONS .......................................................... 14 9. ANALYTICAL PROCEDURES ......................................................................................... 15 10. LIFECYCLE MANAGEMENT .......................................................................................... 15 GLOSSARY ..................................................................................................................................... 16 REFERENCES ................................................................................................................................ 21 APPENDIX 1: METHOD FOR ESTABLISHING EXPOSURE LIMITS ................................. 22 APPENDIX 2: ESTABLISHED PDES FOR ELEMENTAL IMPURITIES .............................. 25 APPENDIX 3: INDIVIDUAL SAFETY ASSESSMENTS ........................................................... 27 APPENDIX 4: ILLUSTRATIVE EXAMPLES ............................................................................ 76 1 ICH Q3D(R1) Guideline GUIDELINE FOR ELEMENTAL IMPURITIES Q3D(R1) 1. INTRODUCTION Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. There are three parts of this guideline: the evaluation of the toxicity data for potential elemental impurities; the establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern; and application of a risk-based approach to control elemental impurities in drug products. An applicant is not expected to tighten the limits based on process capability, provided that the elemental impurities in drug products do not exceed the PDEs. The PDEs established in this guideline are considered to be protective of public health for all patient populations. In some cases, lower levels of elemental impurities may be warranted when levels below toxicity thresholds have been shown to have an impact on other quality attributes of the drug product (e.g., element catalyzed degradation of drug substances). In addition, for elements with high PDEs, other limits may have to be considered from a pharmaceutical quality perspective and other guidelines should be consulted (e.g., ICH Q3A). This guideline presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product. 2. SCOPE The guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced
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