Identification, Quantitation and Control of Trace Level Genotoxic Impurities in Organic Synthesis Intermediates and Final Products
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1 Identification, Quantitation and Control of Trace Level Genotoxic Impurities in Organic Synthesis Intermediates and Final Products CoSMoS Aug 2011
2 GSK Internal Control Strategy Process Control Strategy GRA (Genotoxin Risk Assessment) Analytical Control Strategy (The Method) Define the target Keeping it simple Method development Genotoxin impurity control in API - Case Study Page 2
3 Genotoxin Risk Assessment (GRA) Review of Process Chemistry Identify potential genotoxic reagents, intermediates, side reaction products DEREK screen for mutagenicity alerts Ames test for those potential impurities of concern Assess the probability that a impurity will carry through to API Define strategy (up-front control vs. control in API) Spiking and purging studies Specified impurity in intermediate Specified impurity in API Review of Degradation Chemistry Theoretical assessment for formation genotoxic degradation products Identification of degradation products in forced degraded samples Page 3
4 Risk Mitigation: Analytical Control Define the Target TAL (Target Analyte Level derived from staged TTC) Obtain a well characterized reference material Keeping it Simple Limit test by first intent Fit for purpose matches control requirements Straightforward validation Easier transfer into QC environment Standardize instrument platform R&D and manufacturing sites Dedicated to trace analysis to maintain maximum sensitivity Agilent LC/UV system equipped with single quad MSD Agilent GC system equipped with FID/ECD/MSD Page 4
5 Method Development Strategy Evaluation of Physiochemical Properties of Analyte and Matrix Solubility Volatility Technique complexity increases Sample prep Dilute & Inject (DI) Head Space (HS) LLE/SPE extraction Derivatization Separation LC, GC Others? Detection UV, FL, FID, ECD MS (SIM) MS/MS (MRM) Mingjiang Sun, David Q. Liu, and Alireza Kord, A Systematic Method Development Strategy for Determination of Pharmaceutical Genotoxic Impurities, Organic Process Research & Development 2010, 14, Page 5
6 Volatile analytes alkyl halides and sulfonate esters Non-volatile analytes Stable for direct Analysis? No Problem Analyte No Stable for direct Analysis? yes yes Non-halogenated e.g. ethyl acrylate, benzene Alkyl halide e.g.ch 3 CH 2 Cl Alkyl Sulfonates basic acidic Neutral e.g. oxygen rich HS (or DI) GC-MS HS GC/ECD (or MS) Q-amine LC/MS Positive ESI or APCI Negative ESI or APCI Ion coordination LC/MS Mingjiang Sun, David Q. Liu, and Alireza Kord, A Systematic Method Development Strategy for Determination of Pharmaceutical Genotoxic Impurities, Organic Process Research & Development 2010, 14, Page 6
7 Method Development Problem Analytes Poor analyte stability Poor analyte detectability (insufficient S/N) Stabilize by analytical environment? no Stabilize chemically Introduce chromophore, basic functionality, or fluorophore chemically yes Temperature control e.g. CH 3 I by (HS) GC/ECD Matrix deactivation e.g. sample matrix ph control in LC/MS Chemical Derivatization followed by Simplest analytical approach LC/UV, GC/MS, LC/MS etc. Mingjiang Sun, David Q. Liu, and Alireza Kord, A Systematic Method Development Strategy for Determination of Pharmaceutical Genotoxic Impurities, Organic Process Research & Development 2010, 14, Page 7
8 Genotoxin Analysis Case Study Genotoxic Impurity Comments Method Primary Analine (PA) Intermediate Q Nitro-aromatic 1 (NA1) Starting Material CL Nitro-aromatic 2 (NA2) Intermediate CL Q = Quantitative Method (0.4 to 20 ppm) CL = Combined Limit Test Method ( Sum to 1.2 ppm) Core Structure of Genotoxic Impurities Page 8
9 PA - Direct Analysis Method PA Stability at 4 C (with API) Concentration (ng/ml) Time (minutes) y = -0.03x R 2 = PA instability rules out Dilute and Inject approach Page 9
10 Evaluation of Derivatization Acetic Anhydride: Formation of acetylated-pa Rapid reaction (minutes) MS analysis showed complete derivatization Acetylated-PA showed stability of about 5-6 days PA reference standard (salt): co-solvent DMF Significant improvement over the direct method Page 10
11 PA Method Parameters HPLC column: Zorbax SB-C8, 150mm x 4.6mm X 3.5µm Column flow: 1mL/min Injection volume: 10µL Mobile Phase: A: 95:5 water:acetonitrile with 0.1% v/v formic acid B: 5:95 water:acetonitrile with 0.1% v/v formic acid Sample Preparation: 10 mg/ml Diluent 14% DMF: 86% AA Gradient: Linear gradient from 100% A to 100% B in 12 minutes Bench-top HPLC/MSD 1100 and 1200 series SIM: Monitoring of [M+H] + and [M+Na] + Page 11
12 Example Chromatogram: 4.6ng/mL (0.5 ppm) MSD1 TIC, MS File (S:\STAFFF~1\RTP\ANALYT~1\SHAFIEI\EE322355\01119_46.D) API-ES, Pos, SIM, Frag: 50 TIC Area: MSD1 358, EIC=357.7:358.7 (S:\STAFFF~1\RTP\ANALYT~1\SHAFIEI\EE322355\01119_46.D) API-ES, Pos, SIM, Frag: [M+H] + 22% of TIC Area: min MSD1 380, EIC=379.7:380.7 (S:\STAFFF~1\RTP\ANALYT~1\SHAFIEI\EE322355\01119_46.D) API-ES, Pos, SIM, Frag: [M+Na] + 78% of TIC Area: min min Page 12
13 Validation of 1ppm Limit Test Derivatization Method M SD1 TIC, M S File (C:\CHEM3 2\1\DATA\EE \EE \EE _ D ) ES-API, SIM, Frag: 5 0 M SD1 TIC, M S File (C:\CHEM3 2\1\DATA\EE \EE \EE _ D ) ES-API, SIM, Frag: ppm PA Limit Test Standard Validation Data Linearity R 2 = Range = 0.5 to 2.0 ppm Std Precision = 3.9% (n=6) S/N >> 10:1 for 1ppm Limit Standard Standard Solution Stability 6 Days (1 ppm, 10ng/mL) PA in API min Page 13
14 Linearity of Derivatized PA (TIC and [M+Na] + ) Peak Area Plot for Total Ion Peak Area vs. PA Concentration y = x x R² = y = 10782x R² = Apparent quadratic response observed for TIC signal over required range for analysis Conc (ng/ml) Total Ion Linear ( Total Ion) Poly. ( Total Ion) Plot for Sodium Adduct Ion Peak Area vs PA Concentration y = x x R² = y = x R² = Sodium Adduct Ion Linear (Sodium Adduct Ion) Poly. (Sodium Adduct Ion) Effect is coming from the contribution of the [M+Na] + signal and is attributed to depletion of background levels of Na + in the source particularly at higher concentrations Page 14
15 Linearity of Derivatized PA Using [M+H] + Plot for Molecular Ion Peak Area vs Concentration of PA Peak Area y = x R² = Concentration (ng/ml) Molecular Ion Linear (Molecular Ion) Poly. (Molecular Ion) Page 15
16 Impact of DMF Level on Sample Stability Rate of PA Formation with Time ppm Time (minutes) 14% DMF 5% DMF Page 16
17 Investigation of Derivatization Efficiency for Standards Efficiency for Acetylation using Different PA Standards PA is present in API as the freebase PA Hydrochloride Salt Historical reference material supplied at start of project Relatively stable in solid state Limited solubility in organic solvents (Required 14% DMF co-solvent) PA Freebase Not routinely isolated as part of the synthetic route Isolated and supplied to us for this standard comparison Too unstable to use as reference material Acetylated PA (pre-derivatized) Requested and supplied for purposes of monitoring derivatization efficiency Possible use as routine reference material Non-mutagenic Page 17
18 The Devil s in the Derivatization (or is it the DMF?) Standard Comparison Standard Agreement (%) Acetylated PA (prederivatized) vs. PA Freebase 100 Acetylated PA (prederivatized) vs. PA Hydrochloride Salt 84 Absolute derivatization efficiency in the presence of a million-fold access of API is unknown: Samples spiked with PA freebase at multiple levels showed recovery >85% Page 18
19 mau mau mau Stock Standard Impurity Profiles DAD1 B, Sig=250,8 Ref=480,8 (EE330633\ D) Area: Area: DAD1 B, Sig=250,8 Ref=480,8 (EE330633\ D) Area: Area: DAD1 B, Sig=250,8 Ref=480,8 (EE330633\ D) Area: PA Hydrochloride Salt Area: PA Freebase Pre-derivatized Acetyl -PA min min min Page 19
20 DMF:Acetic Anhydride Chemistry N O H + O O O N + O H O O O N O O O O PA NH 2 PA NH 2 PA N O PA N N Abdelaziz Mekhalfia, Roger Mutter, William Heal and Beining Chen, Unexpected formation of N, N-disubstituted formamidines from aromatic amines, formamides and trifluoroacetic anhydride, Tetrahedron 62 (2006) Page 20
21 Key Learning's: Solid state form of reference standard can be critical Should match solid state form of the analyte in actual sample Impact on derivatization efficiency Stay away from DMF as a co-solvent for acetylation reactions Reinforces the need to use limit test and direct analysis methodology Page 21
22 NA1 and NA2 Method MSD1 TIC, MS File (C:\HPCHEM\1\DATA\EE379555\EE \EE379555_ D) ES-API, Pos, SIM, Frag Method Conditions: Phenyl Column, 150 x 3.0 mm id Isocratic: 90:10 (buffer:acn ) Buffer: 25 mm NH4CHO2 ph 3.7 Flow Rate 0.5 ml/min Temperature: 35 C Injection Volume: 15µL Positive ion ESI MSD, SIM [M+H] Area: Sample Preparation 30 mg/ml 50:50 (buffer:acn) min Page 22
23 Summary for Nitro-aromatic (NA) Impurities NA Method Validation: Specificity Sensitivity Filed Accuracy Stability Precision limit test Linearity Robustness Conducted but not filed/required for Not conducted Transfer to manufacturing site as combined limit test at 1.2 ppm Page 23
24 Acknowledgements: Rocky Davis Kevin Facchine Hamid Shafiei David Liu Ming Sun Claire Haylock Fiona King Jason Ejimadu Lin Bai Byron Johnson Biren Joshi Dan Reynolds GSK Genotox Technique Network GSK RTP Structural Characterization Group Page 24
25 Back up slides Page 25
26 Classification of Analytical Methods and Validation Limit Test (analyte level very low or not observed relative to TTC/TAL) Specificity Sensitivity ( 3:1) Accuracy/Recovery Limit Test (analyte level near the TTC/TAL) Specificity Sensitivity ( 10:1) Accuracy/Recovery Precision Solution Stability Optional Linearity (narrow range) Quantitative (need numerical numbers for analyte) All the above plus Linearity and Range, DL and QL Consider Limited Robustness (instrument / sample prep) Page 26
27 Selectivity Interference (<10%) Resolution (> 5) Sensitivity S/N > 20:1 Accuracy Consistent and Adequate Recovery Yes Robustness Validation Not Performed No Perform Robustness Validation Separation Technique and MS Parameters Sample Preparation Page 27
28 Method Validation Summary Expanded and validated the derivatization method for quantitation in API Specificity Intermediate precision Standard Solution stability Sample Solution Stability Linearity Sensitivity/Quantitation limit Recovery (Accuracy?) 94%-100% in DP; >85% in API Derivatization efficiency (Accuracy) between PA hydrochloride salt Acetyl-PA (prederivatized) PA freebase Robustness DOE instrument parameters sample prep Page 28
29 Derivatization Method Development (cont d) Does this reaction fully derivatize PA (multiple reaction sites)? Yes, with excess of acetic anhydride acetic anhydride as the main diluent Does acetic anhydride fully derivatize the API? Yes, in less than 15 minutes API is derivatized Good chromatographic separation between the acetylated API and acetylated PA (method selectivity) Limit of Detection direct analysis and AA derivatization methods showed detectability below 0.2ppm (method sensitivity) Page 29
30 PA Methodology Overview AMES positive Penultimate intermediate Initially developed as a Limit Test Subsequently needed fully quantitative method Support of process chemistry Assess PA as potential degradation product (API and DP) Final PA specification not clearly defined TTC Weight of evidence (related compounds) COMET assay Converted to limit test manufacturing release method much better control of PA Final PA specification clearly defined (1.2 ppm) Page 30
31 Assess selectivity, sensitivity and recovery. The following recommendations are for guidance only Is peak of interest free from interference? Is analyte free from interferences at greater than 10% of the analyte level To be used for guidance, for example: For LCMS/GCMS is resolution between API and genotoxin of interest > 5? For LCMS/GCMS is resolution between any impurity and genotoxin of interest within a SIM/SIR chromatogram > 1.5? Resolution > 2.0 between API and genotoxin of interest (applicable to chromatographic techniques other those which utilize mass spectrometric detection Does the method demonstrate acceptable S/N for the analyte standard at the TAL? Does the method exceed guidance? e.g. is sensitivity > 20? No Yes Robustness testing is not required If any areas of concern were highlighted during method development, (for example, effect of ph, column, solution stability, sample prep variability) or the analysis requires a quantitative method that may need to be transferred, consider limited robustness testing. Refer to DoE expert for guidance. Robustness testing should be considered Consider performing reduced method robustness based on the guidance below. Please note the following examples are for guidance only and robustness testing of genotoxin methods is not limited to these parameters. Consider method history from development and the use of a priority matrix when designing the robustness experiments and seek advice from your local DoE expert. Sample Preparation If priority matrix suggests robustness testing of sample prep, refer to DOE Guidance Documents Separation Technique For GC and HPLC, if priority matrix suggests robustness testing, refer to DOE Guidance Documents Detection Technique MS UV and other detectors Parameters to assess: Demonstrate acceptable instrument performance over duration of run sequence or determine run sequence limit over which acceptable analysis can be obtained Parameters to assess: Refer to DOE Guidance Documents Page 31
32 Literature reference for DMF:AA Chemistry Page 32
33 Method Validation Summary Repeatability: Injector Precision (1ppm 1.4% RSD n=12, 5ppm 1.0% RSD n= 12) 1 analyst, 3 Days, Single instrument (n= 18, 1.1ppm with 1.6% RSD) 3 analyst, 1 Day, 2 instruments (n=24, range ppm) Linearity: r 2 = , range ng/mL ( ppm) Selectivity: UV for API, Blanks Accuracy: Spiking with PA Freebase Spike Level 1ppm (91% recovery n=4) Spike level 50ppm (96% n=4) Spike Level 8000ppm (98% n=2) Standard Solution stability (6 days) Sample Solution Stability (24 hours) Quantitation limit (0.4ppm determined average S/N 64:1, n=3) Robustness Instrumental DOE (inj vol, pk width, Frag Vol, inj rinse) Sample Prep DOE (fresh dil, old dil, %H 2 O in DMF, %DMF in dil, AA vendor) Page 33
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