Module 3 - Strategic case studies in practice

ICH Q3D(R1) Guideline

used to demonstrate that component-specific limits for each element in each component of a drug product assure that the PDE will be met. ( ) ∑ = ⋅ ≥ N 1k k k MC day g PDE µ (2) k = an index for each of N components in the drug product C k = permitted concentration of the elemental impurity in component k (µg/g) M k = mass of component k in the maximum daily intake of the drug product (g) An example using this option is provided in Appendix 4 Tables A.4.4 – A.4.5. Option 3: Finished Product Analysis: The concentration of each element may be measured in the final drug product. Equation 1 may be used with the maximum total daily dose of the drug product to calculate a maximum permitted concentration of the elemental impurity. An example using this option is provided in Appendix 4, Table A.4.6. 8. S PECIATION AND O THER C ONSIDERATIONS Speciation is defined as the distribution of elements among chemical species including isotopic composition, electronic or oxidation state, and/or complex or molecular structure. When the toxicities of different species of the same element are known, the PDE has been established using the toxicity information on the species expected to be in the drug product. When elemental impurity measurements are used in the risk assessment, total elemental impurity levels in drug products may be used to assess compliance with the PDEs. The applicant is not expected to provide speciation information; however, such information could be used to justify lower or higher levels when the identified species is more or less toxic, respectively, than the species used in the monographs in Appendix 3. When total elemental impurity levels in components are used in the risk assessment, the applicant is not expected to provide information on release of an elemental impurity from the component in which it is found. However, such information could be used to justify levels higher than those based on the total elemental impurity content of the drug product. 9. A NALYTICAL P ROCEDURES The determination of elemental impurities should be conducted using appropriate procedures suitable for their intended purposes. Unless otherwise justified, the test should be specific for each elemental impurity identified for control during the risk assessment. Pharmacopoeial procedures or suitable alternative procedures for determining levels of elemental impurities should be used. 10. L IFECYCLE M ANAGEMENT The quality systems and management responsibilities described in ICH Q10 are intended to encourage the use of science-based and risk-based approaches at each lifecycle stage, thereby promoting continual improvement across the entire product lifecycle. Product and process knowledge should be managed from development through the commercial life of the product up to and including product discontinuation. Knowledge gained from development combined with commercial manufacturing experience and data can be used to further improve process understanding and process performance. Such improvements can enhance controls on elemental impurities. It is recognized that the elemental impurity data available for some components is somewhat

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