A novel calibration strategy for residual solvents analysis by static headspace gas chromatography

Transcription

1 A novel calibration strategy for residual solvents analysis by static headspace gas chromatography Keith Freebairn Strategic Technologies Stevenage, UK 1

2 Introduction We have substantial experience over recent years of using a calibration strategy that involves the use of historically-derived stored response factors rather than the labour-intensive reference to calibration standards This strategy offers improved performance provided that it is adopted as part of a very rigorous Quality by Design approach 2

3 Old ways. Samples analysed by project teams using a range of hand-crafted solvent methods Standards prepared on the day Analysts - Wide range of skills and knowledge Relatively poor understanding of methodology - and sources of variability 3

4 Old ways the result Poor understanding of method performance and variability Poor method robustness Higher costs 4

5 New ways A standardised approach Fixed method Fixed infrastructure instrument, equipment ways of working etc. Reduced variability No standard preparation System suitability assessment Automation Instrument assessment of quality 5

6 A cultural shift.. A cultural shift is currently taking place in the Pharma industry This concerns the adoption of Quality by Design principles For analytical purposes this is all about understanding the performance and variability associated with analytical methods 6

7 QbD and analysis - Standardisation of approach and platform technology Standardisation is a key enabler in a QbD world 6 years developing analytical systems that provide standardised solutions for our key analytical tasks GSK has developed a QbD approach to the lifecycle of analytical methods* *Application of the principles of Quality By Design to Analytical Methods..Phil Borman, PhRMA API Workshop, Colorado, 26 th Sept

8 Standardisation and platform technology - analysis Why? Enhanced quality of output Greater efficiency Ease of use Lower method diversity Greater opportunities to exert control Enables continuous improvement Reduced method variability 8

9 A solvents analyser.mk1 Based on Agilent 6890 GC CTC combipal headspace analyser DB-624 column Samples dissolved in DMSO 11 min chromatographic run 9

10 A solvents analyzer.mk1 A conventional approach but automated Sample headspace taken by heated syringe directly into the chromatograph Instrument calibrated at the start of each day using five injections of a mixed solvent standard (containing 22 solvents). A further standard is run after every 8 sample injections a rolling response factor is calculated throughout the day and applied to the samples under analysis 10

11 A solvents analyzer.mk1 Launched in May 2002 Dedicated instrument always ready walk-up format Standardised method Custom user interface 22 common process solvents On-board system suitability and quality checks 11

12 12

13 Mk1 analyser The same excellent separation every day of the the year always available high performance - guaranteed Minutes pa Methanol Ethanol Acetone Propan2ol Acetonitrile Dichloromethane MEK Butan1ol Dioxan DMF Ethylacetate MIBK Toluene nhexane Tetrahydrofuran Isopropylacetate Pyridine Diethylether TBME Isopropylether Cyclohexane Heptane DMSO

14 Mk1 analyser - metrics Analysed ca 10,000 samples on 4 instruments over 2.5 years Total number of mixed standards :- 12,000 23,000 injections in total 14

15 Standardisation - Automated integration Solvents analyser integrated over 7000 chromatograms between July 02 and July 03 Not one was re-integrated - illustrates the power of standardisation and platform technology

16 Box Plot displaying variability of Retention Times Acetone Acetonitrile ichloromethane Diethyl ether Ethanol Ethyl Acetate Hexane Iso-propyl ether MEK Methanol Propan-2-ol TBME Retention Time GC solvents analyser Retention time reliability Variation typically ±0.05min for Acetone over 2.5 years, 3 sites

17 Mk1 solvents analyser Typical trend data for acetone response over 2.5 years 4 instruments Acetone Response / 07/ / 01/ / 07/ / 01/ / 07/ / 01/ 2005 Date 17

18 Acetone area response Variation about ±16% St Dev St Dev Acetone Peak area trend plot over a 2.5 year period for standards single site data with ±3Standard Deviation limits superimposed 18 11/07/ /01/ /07/ /01/ /07/ /01/2005 Date

19 Measurements systems analysis (MSA) Set up designed experiment to look at variability associated with the following aspects Injector Precision Concentrated standard preparation Working standard preparation Analyst Site The study concluded that the main source of error is concerned with preparing the standards 19

20 Acetone Peak Area Data from MSA Graphical representation of variability associated with preparation of standards Significant difference in instrument response at some sites cprep preparer (code) analyst Site (code) Raw Data 20 Substantial variability in the preparation of standards at two sites

21 MSA study conclusions Historical Acetone area response data (one site) with estimated variability of standard preparations from MSA Study The majority of the variability seen in the historical response dataset is accounted for by the preparation of standards 21

22 A counter-intuitive conclusion Analyser performance could be significantly improved if an average response factor is used rather than a response factor obtained on a given day 22

23 a Mk 2 analyser Use instrument-specific response factors generated over a period of 2 years to give an average response factor for that instrument Calibrate electronically using the historically generated mean response factor Check response using reference mixture containing only three solvent components that are representative of the total (system suitability) 23

24 Mk 2 solvents analyser launched September 2005 System suitability test for three component test mixture (PCS) Check areas (+/-20%) also indirect check on retention behaviour Check peak tail <1.5 Check DMSO >800 checks injection has been made this indirectly checks the ramp is correct Check blank If there are any issues with system suitability instrument will stop 24

25 Design requirements Fundamental requirements for calibration:- Consistently identify target peak Consistently integrate standards and sample peaks without interference Consistently establish target response factor Sample response to be within calibrated linear range 25

26 Typical PCS Test Solutions 12 overlays, one site, Jan 06 to Nov DMSO Response pa Acetone Tetrahydrofuran Pyridine Minutes Retention Time Time

27 Typical Blank Solutions 12 overlays, Stevenage, Jan 06 to Nov DMSO Response pa Dimethyl sulphide Pyridine Minutes Retention Time Time

28 Acetone Total number area of response std points = 4600 over for 4 yrs single 4 mths instrument over 4½ years Peak Area Nov-01 Mar-03 Aug-04 Dec-05 Apr-07 Date Acetone Area WUS Acetone Area EOVI Upper limit (+20%) Lower limit (-20%) Expected area Total number of Std points = 4600 over ~4½ years

29 Experimental uncertainty associated with Mk2 analyser factors contributing to overall variance Estimated variance Note: Time effect/s not studied Injector variability -Dispensing Standard -Crimping of Vial -Working Standard Preparer -Working Standard Preparations -Site -Instrument -Gas Supply & Flow Small amount of this variability will still be associated with preparing samples ~1% Eliminated by using historic data to set response factors Eliminated by using Sitespecific response factors 20 0 Acetone Peak Area -Stock Std Solution Preparer Eliminated by using historical data to set response factors 29

30 Benefits of using a Stored Response Factor ±16% ±15% Acetone Peak Area Response Historical Data ±3 St Dev Variability associated with preparing standards from MSA ±3 St Dev ±3% Variability associated with error * from MSA ± 3 St Dev *Injector variability Dispensing Standard Crimping of Vial 105 Historical Data + Variability MSA + Standards Variability MSA + error Variability 30

31 Accuracy reference to external benchmarks Results for beverage analysis by Mk2 solvents analyser plotted against label ethanol content 16 Label Ethanol Content %v/v English beer #1 English beer #2 Dutch lager Californian white wine ±0.1%v/v (±2%) Ethanol content by Mk2 solvents analyser %v/v 31

32 Summary Stored response factors offer improved method performance A platform approach offers excellent stability, reliability and opportunities to both understand and control method variability 32

33 Acknowledgements - Phil Borman - Colin Donaghy - Marion Chatfield