Module 3 - Strategic case studies in practice

ICH H ARMONISED G UIDELINE

G UIDELINE FOR E LEMENTAL IMPURITIES

Q3D(R1)

ICH Consensus Guideline

T ABLE OF C ONTENTS

1. INTRODUCTION ..................................................................................................................2

2. SCOPE.....................................................................................................................................2

3. SAFETYASSESSMENT 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 ASSESSMENTAND 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. C ONTROL OF E LEMENTAL I MPURITIES ...............................................................................12

7. C ONVERTING B ETWEEN PDE S AND C ONCENTRATION L IMITS ..........................................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 SAFETYASSESSMENTS...........................................................27

APPENDIX 4: ILLUSTRATIVE EXAMPLES ............................................................................76

1