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Sample Preparation for Elemental Impurities


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Presentation made by Nikki Schopp at Interphex 2014. “USP 233: Sample Preparation" this covers the importance of sample preparation, and looking at each sample on a case by case basis, in applying the US Pharmacopeial Convention’s (USP) chapter on limits <232> and procedures for elemental impurities <233>. Read more

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Sample Preparation for Elemental Impurities

  1. 1. Sample Preparation for Elemental Impurities Nikki Schopp, 3/19/14 SGS Life Science Services
  2. 2. Overview of Methods • Heavy Metals testing, currently performed per USP <231> – established over 100 years ago – undergoing a much needed update – toxicological data is being used to establish limits – Both toxic metals and metals used in processing are being addressed. • Elemental Impurities – USP <232>,<233> & <2032>;ICH Q3D (Draft) – USP, EP and ICH all expressed desire to be harmonized prior to implementation – Both metals addressed and limits are concerns.
  3. 3. Getting Started • When analyzing for trace metals using Inductively Coupled Plasma (ICP), sample preparation is critical. – The solubility of the test article is crucial, but not the primary factor when choosing a sample preparation method.
  4. 4. Sample Preparation Options Four sample preparation methods are typically used when performing Elemental Impurities testing. • Neat • In aqueous solutions • In organic solutions • Digested in a closed-vessel apparatus
  5. 5. Standard Preparation • The blank and standard solutions should be prepared in the same matrix as the sample, – solvent, acid concentration and stabilizers • Spike recovery studies need to be performed – Ensures method accuracy, specificity and precision when used as a quantitative method.
  6. 6. • Recommended Stabilizing Acids – Hydrochloric Acid- Osmium and Ruthenium – Nitric Acid – Cd, Pb, Hg, As, In, Cr, Ni and Cu – Nitric Acid/Hydrochloric Mixture- Pd, Pt, Rh, V – Hydrofluoric – Molybdenum • Other stabilizers – Gold for Hg Choosing a Diluent (1)
  7. 7. Choosing a Diluent (2) • Samples analyzed neat – choose a diluent for standards • Samples diluted in an acid – correct acid and concentration needs to be chosen • Consideration: Just because a test article is water soluble does not mean that the direct aqueous solution method is the best choice
  8. 8. Choosing a Diluent (3) • Organic solvents are not the easiest to run on ICP (spray chamber, nebulizer, instrument settings) • MeOH, EtOH, Chloroform • Concentration of organic solvent
  9. 9. Microwave digestion • Choosing the correct acid and heat profile • Interferences • Determing the proper mixture of acids to obtain stability and recovery (i.e. Os)
  10. 10. Validation Requirements • Accuracy – average % Recoveries must be – 70-150% at the limit – half the limit – 1.5x the limit • Precision – %RSD of calculated concentration NMT 20% • Ruggedness (Intermediate Precision) – two analyst – 3 different days – %RSD of calculated concentration NMT 25%
  11. 11. Case Study I – Direct Aqueous • Injectable Drug Product- 3 different sample preparations were needed • Solution 1 – 2% Nitric Acid Diluent for As, Hg, Ru, Cd, Pb, Cr, Mo, Pd and V • Solution 2 – 12% Nitric/8% Hydrochloric acid for Ni, Cu, Ir, Pt, Rh • Solution 3 – 2% Hydrochloric acid for Osmium
  12. 12. Case Study I (2) • Test Solution 1 weigh and dilute – with all injectables this is the first attempt during development. As, Hg, Ru, Cd, Pb, Cr, Mo, Pd and V all met requirements • Elements that did not meet requirements Level Ni Cu Rh Os Ir Pt 50% 63 58 59 62 59 65 100% 66 62 61 66 62 69 150% 66 61 56 62 59 66
  13. 13. Case Study I (3) • Test solution 2 used microwave digestion Remaining elements passed requirements, except Os • Test Solution 3 weigh and dilute, different acid- since Os is known to behave better with HCl, this was used as the diluent for Os.
  14. 14. Materials used for Development vs. Validation • Development and validation should be done on the final stage of the material of interest • Changing the process of manufacturing and purification of the material of interest can change recoveries, especially if acids and/or bases are used in the purification process • Development done on a material, all requirements are met, then validation begins on a purified product, some recoveries did not meet
  15. 15. Case Study II • Development done on unpurified material – sample preparation was weigh and dilute, all criteria were met • Validation performed on purified material • All recoveries were met except for Palladium -50% the limit average = 65% -100% the limit average= 67% -150% the limit= 66%
  16. 16. Case Study II (2) • Purification of the material inhibited the Palladium from being recovered • Currently in the process of re-developing a method
  17. 17. Case Study III • Development sample preparation on unpurified material – nitric acid, hydrogen peroxide heat in oven at 105°C • All recoveries meet criteria during development • Validation on purified material-all elements meet criteria except Palladium 50% limit avg recovery= 50.1% 100% limit avg recovery= 82.1% 150% limit avg recovery= 89.5%
  18. 18. Case Study III (2) • Re-developed the method using microwave digestion • All Elements meet criteria, even Palladium Pd 50% limit avg recovery= 101% Pd 100% limit avg recovery= 103% Pd 150% limit avg recovery= 99%
  19. 19. Summary • USP will not be giving specific sample preparations in the monograph • Sample Preparation for Elemental impurities will need to be determined on a case by case basis • Solubility plays a role however, it is not the final step in determining a sample preparation
  20. 20. Contact Information • Nikki Schopp, Team Leader Analytical Services, Life Science Services, SGS • • 616 Heathrow Dr. Lincolnshire IL 60069 • (847) 821-8900