Analysis of inorganic What are the applications and impurities in what are the benefits? pharmaceuticals by ICP-MS Life Sciences Solutions Unit Katja Kornetzky Solutions Manager for Process Development & Manufacturing QA/QC November 2007 ICP-MS in pharmaceutical analysis November 2007
Overview • ICP-MS: The Technique • Applications in Pharmaceutical Analysis • The Agilent ICP-MS Compliance Software • Conclusion • Literature ICP-MS in pharmaceutical analysis November 2007
What is ICP-MS? I nductively C oupled P lasma M ass S pectrometry Elemental analysis with: • Wide elemental coverage • Very low detection limits • Fast analysis times (all elements at once) • Wide analytical working range (up to 9 orders) • Simple spectra • High matrix tolerance • Isotopic information � Viable alternative to ICP-OES or GFAAS* *OES = Optical Emission Spectrometry, GFAAS = Graphite Furnace Atomic Absorption Spectrometry ICP-MS in pharmaceutical analysis November 2007
Agilent 7500cx ICP-MS System with Collision Reaction Cell (CRC) Multi-element interference removal by Fast simultaneous dual on-axis octopole reaction cell mode detector (9 orders dynamic range) Cell gas inlet High temperature 27MHz plasma generator Plasma Octopole Off-axis lens Low flow sample High frequency introduction system hyperbolic quadrupole ICP-MS in pharmaceutical analysis November 2007
Why is ICP-MS unique? ICP-MS can: • measure almost any element at ppt to ppm levels in almost any material • measure all elements in a single analysis • distinguish different element species (speciation) Main requirements in pharmaceutical analysis are: • high sensitivity • good matrix tolerance • low levels of interferences • ease of coupling to speciation techniques (CE, IC, LC and maybe GC) ICP-MS in pharmaceutical analysis November 2007
Pharmaceutical applications Pharmaceutical waste water (EPA-regulated) Drug discovery / drug development: • Analysis of individual forms of drug compounds using target element analysis • Simple metal analysis during development of metal-based drugs QA/QC and process development: • National Pharmacopeia (e.g. USP, EP, JP) Testing – Impurity limit tests – Metals in active pharmaceutical ingredients (API) • QC of natural products – toxic impurities • Toxic element impurities (e.g. heavy metals) Clinical trials: – Simple metal analysis for active component confirmation – Monitoring of the metabolites of an administered drug ICP-MS in pharmaceutical analysis November 2007
Regulated pharmaceutical and clinical applications Pharmacopeia Testing • Impurity limit tests (general tests or based on individual monographs)* • Quantitative metal content of API (USP monographs), e.g. Pt in platinum-containing drugs* QC of natural products • Heavy metal impurities in herbal remedies • Heavy metal contaminations in TCM ** (ICP-MS in China Pharmacopeia since June 1, 2005) Metal Impurities • Catalyst or reagent residues in raw materials, pharmaceutical substances and final products as well as packaging materials (extractables/leachables) • New EMEA draft guideline: specification limits for metal catalysts residues Clinical Trials • Metallodrugs (e.g. Pt-containing drugs for cancer treatment) * None of these use ICP-MS. Instead Atomic Absorption Spectrophotometry (AAS), colorimetry and gravimetry are applied. ** TCM = Traditional Chinese Medicines ICP-MS in pharmaceutical analysis November 2007
Conventional ICP-MS applications Simple metal analysis in pharmaceuticals, raw materials and clinical samples ICP-MS in pharmaceutical analysis November 2007
USP Methodology • Atomic Absorption Spectroscopy – e.g. USP limit tests for <206> Al, Cr*, Rh*, Mo** • Colorimetry – e.g. USP limit tests for <231> heavy metals, <241> Fe, <251> Pb, <211> As • Titration – e.g. USP limit test for <261> Hg • UV spectroscopy – e.g. USP limit tests for <291> Se, <211> As • Gravimetry – e.g. Pt content in Cisplatin, Carboplatin (UPS monographs) *Alprostadil monograph ** Monograph for ammonium molybdat injection ICP-MS in pharmaceutical analysis November 2007
QC of traditional Chinese medicines (TCMs) Chinese Pharmacopoeia 2005, Appendix IX NEW ! Agilent Application Notes: • Determination of Toxic Elements in Traditional Chinese Medicine Using Inductively Coupled Plasma Mass Spectrometry , P/N 5989-5591EN • Evaluation of Conventional ICP-MS and ORS-ICP-MS for Analysis of Traditional Chinese Medicines , P/N 5989-2570EN ICP-MS in pharmaceutical analysis November 2007
Example: Determination of heavy metals in herbal medicines We wish to thank Hua Zhang, Yan-zhi Shi and Ying-feng Wang at the Capital Normal University in Beijing, China for their permission to publish the results from their scientific study* Shugan pill exceeds legal limits for Hg (0.2 ppm) and As (2.0 ppm) [2005 Pharmacopoeia of the People’s Republic of China] Agilent Application Note 5989-5591EN *Hua Zhang is a Postgraduate Student in the Chemistry Department and Yan-zhi Shi and Ying-feng Wang are Professors in the Analytical Center, all at Capital Normal University in Beijing, China. ICP-MS in pharmaceutical analysis November 2007
Metal impurities – Leachables from pharmaceutical packaging materials 1. Interaction between formulation and packaging material results in components migrating into the drug product 2. These components may be toxic or affect the stability of the drug product 3. Storage conditions impact leaching (heat, UV radiation, storage time) Typical leachables are: • Small organic molecules [monomers, excipients, reaction by-products], • Metal ions and trace elements (e.g. aluminum, cadmium, chromium, copper, lead, manganese, and zinc) “Metal ions can affect the stability of the formulation, catalyze the degradation of the active pharmaceutical ingredient (API) and cause unqualified degradates to form, or pose a toxicity threat on their own.” KYLE A. FLlSZAR, DAVID WALKER and LEONARDO ALLAIN, Profiling of Metal Ions Leached from Pharmaceutical Packaging Materials, PDA Journal of Pharmaceutical Science and Technology, Vol. 60, No.6, November-December 2006 ICP-MS in pharmaceutical analysis November 2007
Guideline on the specification limits for residues of metal catalysts EMEA* draft guideline dated January 2007 Objective: “Recommend maximum acceptable metal residues arising from the use of metals as catalysts or reagents in the synthesis of drug substances and excipients.” Since the use of catalysts or reagents is restricted to defined chemical reactions in the synthesis of pharmaceutical substances, limitation of residues in these substances is sufficient, and in general there is no need to set limits for metal residues in the final medicinal products containing these substances . * European MEdicinal Agency : Its main responsibility is the protection and promotion of public and animal health, through the evaluation and supervision of medicines for human and veterinary use. The EMEA is responsible for the scientific evaluation of applications for European marketing authorization for medicinal products ICP-MS in pharmaceutical analysis November 2007
Metal catalyst residues EMEA classification and concentration limits ICP-MS in pharmaceutical analysis November 2007
ICP-MS for routine analysis in drug discovery & clinical trials Clinical samples require • High sensitivity (measurement of low-level trace elements) • Excellent matrix tolerance (biological matrices) • Large number of samples analyzed daily Matrix tolerance is an essential part of clinical analysis • High potential for matrix contamination of the ICP-MS system, if the matrix is not effectively decomposed • Resulting deposits may adversely affect instrument performance • Efficiency of plasma determines matrix tolerance ICP-MS in pharmaceutical analysis November 2007
Example 1: sanofi-aventis (UK) High throughput assay for oxaliplatin Increased sample throughput and improved reliability with an Agilent 7500a ICP-MS Success Story Pub. No. 5989-7077EN “An Agilent 7500 ICP-MS instrument was chosen as the replacement equipment because of the excellent matrix tolerance, lower backgrounds, larger dynamic range and smaller footprint.” ICP-MS in pharmaceutical analysis November 2007
Example 2: Long-term sample analysis Matrix tolerance is of major importance An efficient plasma design: • reduces matrix load on the interface and vacuum system (less signal drift) • reduce the maintenance • increases ionisation efficiency of key trace elements, e.g. Zn, Cd and Hg • removes interferences by efficient decomposition of matrix-based polyatomic species Isla Strang and Alan Cox with 2 Agilent 4500 ICP-MS systems. Courtesy of Centre for Analytical Sciences, Sheffield ICP-MS in pharmaceutical analysis November 2007
Advanced ICP-MS applications – speciation ICP-MS as a sensitive detector with high specificity for established separation techniques ICP-MS in pharmaceutical analysis November 2007
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