Elemental impurities and their measurement. a: 119 Magowar Rd, Girraween 2145 p: (02) f: (02)

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1 Elemental impurities and their measurement

2 A change is on its way. The new millennium has brought with it a rethink of the approach to heavy metals testing in pharmaceuticals. In addition to the simple colour development method, the BP and USP now include general methods requiring individual assays of specific elements. The colour test has been used for over 100 years. It has the advantages of simplicity, reliability and ability to detect a number of analytes.

3 Are methods and <231> broken? The colour test has significant drawbacks: Which elements is it meant to control? Sample processing and evaluation is manual and takes some skill. Workup is not optimised for volatile elements. Not particularly sensitive, sensitivity differs for different elements. Limit varies for different elements because of differences in response to lead.

4 Different metals respond differently

5 BP SC IV Q. Metal Catalyst or Metal Reagent Residues Describes general approach to control of these metals Option of either a specific limit or specifications set by calculated PDE s Refers to BP Appendix VIII W for methodologies. Requirements are additional to those specified in monographs. Pharmaceutical companies are not supposed to perform extensive tests on metal residue findings of unknown sources to comply with this guideline. They may rely on general information from trustworthy suppliers.

6 SC IV Q. Classification and limits

7 BP Appendix VIII W: Determination of Metal Catalyst or Metal Reagent Residues General approach to testing. Does not provide limits or specific test methods. Includes flow charts, discusses validation and system suitability requirements. Validation required for each metal/impurity combination. Fairly prescriptive in its validation requirements specifies protocol and acceptance criteria Recovery triplicate determination at 3 concentration levels % of limit with recoveries of % for mean at each level Direct dissolution in water, organic solvent or digestion. Sealed digestion required for volatile elements.

8 BP Appendix VIII W: Determination of Metal Catalyst or Metal Reagent Residues

9 USP The first to review the heavy metals test. 3 general chapters: <232>, <233>, <2232> <232> toxicology and calculation of limits <233> test methods and validation requirements If analytical procedure of <232> is used validation is not required method includes steps which demonstrate the method performance <2232> applies to dietary supplements. <233> risk based approach, but Cd, As, Hg and Pb must be tested.

10 Harmonisation: Draft ICH Guideline Q3D: Guideline for elemental impurities Safety assessment of elemental impurities. Calculation methods for determining specification limits for ingredients or finished products from permitted daily exposure limits for each element or use set limits Classification of elemental impurities Class 1 As Cd Hg Pb toxic through all routes of administration Class 2a geologically abundant Class 2b elements which may be added to process Class 3 dependant on route of administration Class 4 low toxicity Toxicological data for 24 elements

11 Launch dates

12 Launch Dates 1 st December USP <231> replaced in all monographs by USP <233>. Method <231> will no longer appear in the USP. 2013: BP SC IV Q. Metal Catalyst or Metal Reagent Residues 5 years allowed to fully implement new BP requirements BP SC IV Q. does not apply to veterinary products

13 Analytical Procedures

14 Pros Sealed Digestion Methods Complete digestion of organic materials. (BP system suitability test: a clear solution is obtained). Suitable for volatile elements. Matrix independent. Cons Requires skilled operator and specialist knowledge. Safety risk unless manufacturers instructions followed. Low sample quantity leads to high dilution (typically x 100)

15 GFAAS ICP-OES ICP-MS 7.5 ppb Cd 10 ppb Cd

16 Instrument options GFAAS ICP-OES ICP-MS Purchase Price Running Costs Space / installation Speed of analysis Operator Training Method development Solution Volume High salt solutions LOD (typical) 10 ppb 10 ppb ppt

17 Conclusion Analysis of metal impurities is about to become much more complex. Specifications will need to be set on a case by case basis. Decisions will need to be made on the most suitable analytical technique to test to these specifications. ICP-MS may become a necessary tool in place of a test which only requires about $30 worth of glassware and a fume cupboard to carry out.

18 Acknowledgements Chemika gratefully acknowledges the supply of an ICPE OES 9000 demonstration instrument by Shimadzu Oceania.