Qualification of analytical instruments

Qualification of electronic balance, pH meter, UV, FTIR and GC

1. ‘ Qualification of Analytical Instruments ’ Presented by: Facilitated to : Mr. L. Sanathoiba Singha M. Pharm 1 st Semester Department of Pharmaceutical Analysis. Dr. C. Sreedhar Head of Department Department of Pharmaceutical Analysis. A presentation on Karnataka College of Pharmacy Bengaluru-64, Karnataka. 1

2. 1. ELECTRONIC BALANCE DESIGN QUALIFICATION: The supplier has ISO 9001:2000 certification. INSTALLATION QUALIFICATION: Checking of all requirements set during the selection of instrument such as electricity, humidity, temperature, etc. Allowing sufficient shelf space for the equipment, SOPs, operating manuals, etc. Comparing equipment, as received, with purchase order, including accessories, spare parts, etc. Checking documentation for completeness like operating manuals, maintenance instructions, health and safety instructions, etc. Checking equipment for any damage. Reading the supplier’s safety instructions, if there are any. Installing hardware following the manufacturer’s recommendation. Switching on the electronic balance and ensuring that all the modules power up. Preparing an installation report 2

3. Test procedure Acceptance limits Test frequency Remarks Measurement of reference weight by using 10mg, 50mg, 100mg, 500mg, 1g, 5g, 10g and 20g. Comparing the actual results with reference weights. 0.1% Daily or when used, whatever is longer with internal reference weights. Yearly with traceable external weights through instrument vendor. External standard should be traceable to national standard. OPERATIONAL QUALIFICATION: PERFORMANCE QUALIFICATION: Defining weights and weight classes to be used. Defining acceptance limits of results. Defining test intervals. Defining corrective actions on what to do if the electronic balance does not meet the criteria, in other words if the results are out of specification. Operational qualification for electronic balance. 3

4. 2. pH METER DESIGN QUALIFICATION: Selection of a manufacturer that can satisfy the needs of the laboratory. S hould have ISO 9001 certification. INSTALLATION QUALIFICATION: Checking of all requirements set during the selection of instrument such as electricity, humidity, temperature, etc. Allowing sufficient shelf space for the equipment, SOPs, operating manuals, etc. Comparing equipment, as received, with purchase order, including accessories, spare parts, etc. Checking documentation for completeness like operating manuals, maintenance instructions, health and safety instructions, etc. Checking equipment for any damage. Reading the supplier’s safety instructions, if there are any. Installing hardware following the manufacturer’s recommendation. Switching on the pH meter and ensuring that all the modules power up. Preparing an installation report. 4

5. PERFORMANCE QUALIFICATION: A log book is prepared for operators and service technicians to record all equipment related activities in chronological order. Parameter to be checked Typical frequency Typical tolerance limit Slope Each day of use or before each series of measurements 95.0 to 105.0% Offset (pH asymmetry) +/-30mV (offset of manufacturer +/-0.5 pH units at defined temperature) Reference buffer solution +/-0.05 pH units Test procedure Acceptance limits Test frequency Remarks Calibration with buffer solution at pH 7 and pH 4. Verification with buffer solution at pH 5 or pH 6. <0.005 pH units Before each use Buffer solutions are commercially available in either tablet or solution form. Some pH meters also have a temperature sensor, which should be calibrated every six months. The electrodes should be washed between each measurement and the buffers should be visually checked for cleanliness and absence of microbial growth before each use. OPERATIONAL QUALIFICATION: 5

6. 3. UV-VISIBLE SPECTROPHOTOMETER DESIGN QUALIFICATIONS: General considerations Feature Consideration Instrument set-up and control Pc based or integrated system. Software control of operating conditions and parameters. Data acquisition, processing and presentation needs. In-built diagnostic facilities. Self-testing diagnostics. Detector options. Source options. Sample introduction and throughput Sample throughput, presentation and introduction needs. Sample thermostating requirements. Sample volume requirements. Materials of construction Resistance to corrosion, contaminated by solvents and sample. 6

7. Contd … Feature Consideration Installation requirements Size and weight in shipped form. Access restrictions to permanent site. Operational requirements Limitations on, requirements for and expected consumption of services, utilities, and consumables ( e.g. lamps). Ventilation requirements. Controlling software embedded or separate package. Environmental conditions Environmental conditions within which, or range over which, the instrument is required to work within specification. Recyclability of instrument. Maintenance and support Ease of user maintenance and cleaning. Cost, longevity and availability of spares and parts. Cost and availability of service contacts and technical support. Suggested intervals between and procedures for maintenance and calibration of the instrument. The period for which support (qualification, maintenance, parts, etc.) for the instrument can be guaranteed. Training requirements The level of skill required to operate the instrument and details of any training necessary and courses provided by the supplier. Accessories Desired adaptation of the system Documentation Clarity and ease of use of documentation ( e.g. operating manuals, qualification protocols, model SOPs). Manuals available as separate hardcopies or computer files ( e.g. on CD ROM), or held as digitally embedded copies within the instrument. Unique document identification by version number and date of issue. Health and safety Health and safety and environmental issues and /or requirements. Significant generation of ozone. 7

8. Design Qualification of UV-Visible Spectrophotometer Feature Consideration Photometric drift Stability of the measurement over time, making comparisons meaningful. Stray light Affects accuracy and linearity Data collection Expression of data on % absorption or % transmission scales. Single or repeat scan facility. Single or multiple wavelength monitoring. Full spectra data ( e.g. diode array). Data manipulation Spectra subtraction. Spectral derivatives. Audit trail facility. Is raw data uncorruptable ? Back-up and restore capabilities. Data storage No storage. Embedded memory. File transmission to external device. Stored output via optical or magnetic media. System security. Data output Inbuilt hardcopy output-data only, spectrum only, data+ spectrum. PC based data processing. Custom report generation. 8

9. INSTALLATION QUALIFICATION: The instrument has been delivered as ordered, e.g. according to the DQ or purchase order. T he instrument has been checked and verified as undamaged. The appropriate documentation has been supplied and it is of correct issue and uniquely identified by part number, version number and date. Details of recommended service and calibration intervals (carried out by the supplier) have been provided. Intervals, methods and instructions for user-maintenance and calibration have been provided along with contact points for service and spare parts. The correct hardware, firmware and software have been supplied and it is of correct tissue and uniquely identified by part number. Information has been provided on consumables required during the normal operation of the instrument. The selected environment for the instrument system is suitable, with adequate room for unpacking, installation, operation and servicing, and have appropriate services and utilities have been provided. Health and safety and environmental information relating to the operation of the instrument have been provided and the proposed working environment is consistent with these requirements. The response of the instrument to the initial application of power is as expected and checked for any deviations. OPERATIONAL QUALIFICATION: Test procedure Acceptance limits Test frequency Remarks Wavelength maxima of holmium oxide solution is measured at 241, 287, 361 and 536 nm. ±1 nm in UV range ±3 nm in visible range Six months Standard is traceable to national standard. Wavelength accuracy- holmium oxide solution Wavelength accuracy- holmium oxide filter Test procedure Acceptance limits Test frequency Remarks Wavelength maxima of holmium oxide filter is measured at 361, 418 and 536 nm. ±1 nm in UV range ±3 nm in visible range Six months Filter is traceable to national standard. 9

10. Test procedure Acceptance limits Test frequency Remarks wavelength A 1%/1cm Limits Absorption of potassium chromate solution is measured. 235 (min) 257 (max) 313 (min) 350 (max) 124.5 144.0 48.6 106.6 122.9-126.2 142.4-145.7 47.0-50.3 104.9-108.2 Six months Standard is traceable to national standard. Absorption intensity Test procedure Acceptance limits Test frequency Remarks Absorption of 1.2% potassium chloride solution at 200 nm is measured against water. Absorption at 200 nm >2.0 AU Six months Alternative standards: Sodium nitrite Sodium iodide. Stray light Test procedure Acceptance limits Test frequency Remarks Transmission of cuvette (water) against air. Quartz cuvettes: 85% at 220 nm 88% at 240 nm b) Glass cuvettes: 85% at 356 nm 88% at 650 nm Six months Standard is traceable to national standard. Control of cuvette 10

11. Test procedure Acceptance limits Test frequency Spectrum of toluene is measured from 260 to 275 nm. Ratio of peak height to valley is calculated. Absorbance ratio peak to valley at 266/269 nm > 1.5 Six months Wavelength resolution PERFORMANCE QUALIFICATION: Parameter Reason Procedure Wavelength calibration Critical to accuracy of results. Can be determined using only two calibration wavelengths, preferably bracketing the analytical wavelength. Photometric accuracy Critical to accuracy of results Can be determined for particular absorbance at particular wavelengths using calibrated filters or cuvettes filled with standard solutions. Linearity of photometric response Critical to accuracy of results Can be determined by checking the accuracy of a number of normal absorbances across the desired absorbance range. Extrapolation beyond highest standard is inadvisable. Signal to noise ratio Important for sensitivity and limit detection Can be determined from the response of a detector to a dilute standard solution and/or a blank. Stray light Important measure of ‘health’ of whole system Record uncorrected spectrum in single beam mode for double beam instruments or with baseline correction switched off for single beam instruments. 11

12. Parameter Reason Procedure Software accuracy and precision, derivatives Importance for precise and accurate measurement of peaks including partially resolved, broad and asymmetric peaks- does it do its sums properly? Is the software fully and correctly loaded? Does manipulation and storage corrupt the raw data? Can be determined and verified using software packages or using reference materials. Where instruments are designed to accept checking using datasets, these should be used. The extent of checks may need to satisfy regulatory requirements. Absorption Important for accuracy and precision of results, checks that the optical faces of the cell are parallel. Can be determined by filling the cell with water, measuring at required wavelength(s), using air as the reference and repeating the process after rotating the cell through 180°. Contd … 12

13. 3. FT-IR SPECTROMETER DESIGN QUALIFICATION: Supplier must provide documented evidence that the product has been designed, developed and manufactured in a quality environment e.g. ISO 9001:2000 certification. Supplier must provide phone and on-site support in case of defects. Supplier must provide information through the internet on availability of new firmware upgrades. The below is a sample of technical attributes that may be considered in design qualification of an FT-IR spectrometer and may be adapted if necessary. Attribute Specifications Detector range The optical bench shall include a DTGS detector with a frequency range of 7400 to 350 cm -1 . It shall include a compressed air interferometer - The instrument shall come with an air-cooled standard infrared source - Special resolution The instrument shall have a spectral resolution not exceeding 1.0 cm -1 . 13

14. Attribute Specifications Wave number accuracy Wave number accuracy shall be better than ±0.01 cm -1 . The interferometer shall have at least four basic velocity levels; software shall permit the selection of a greater number of velocities between the basic levels. - The mirror’s greatest velocity shall allow a speed of at least five sweeps per second. - The laser and infrared beams must be coaxial to enable rapid, easy alignment of the system, depending on the samples or accessories. - The optical bench shall have a main experimentation module with a device to allow purging with nitrogen. - At purchase, the main experimentation module shall be designed so that it can receive 13 and 5 mm potassium bromide pellets. - Contd … INSTALLATION QUALIFICATION: Equipment is compared as received with purchase order, including software, accessories, spare parts and consumables. Documentation checked for completeness of operating, maintenance instructions, standard operating procedures for testing and safety, validation certificates and health and safety instruments. Equipment is checked for any damage. The supplier’s instruction for installation is read. The supplier’s safety instructions are read, if there are any. Hardware (computer, equipment, fittings and tubings for fluid connections, power cables, data flow and instrument control cables) is installed following the manufacturer’s recommendation. The instruments are switched on and ensured that all modules power up and an electronic self test is performed. Any deviations are recorded. Software is installed on computer following the manufacturer’s recommendation. Correct software installation is verified. A backup copy of software is made. Peripherals e.g. printers and equipment modules are configured. 14

15. Contd … A list with a description of all hardware are identified and made, including drawings where appropriate. A list with a description of all software installed on the computer is made. Equipment manuals and SOPs are listed. An installation report is prepared. OPERATIONAL QUALIFICATION: Test procedure Acceptance limits Test frequency Remarks Measurement of polystyrene spectrum at 1144, 1680, 2167 and 2307 nm. The results are compared with reference values. ±2 nm Daily Standard should be traceable to national standard. Wavelength accuracy Control of 0 and 100% Test procedure Acceptance limits Test frequency Control at 0 and 100%. 1% transmission (measured at 4000 cm -1 ) Daily and after changing measurement parameters Wavelength resolution Test procedure Acceptance limits Test frequency Resolution of polystyrene at 2870 / 2851 and at 1589 / 1883 nm. T (band 2870 cm -1 – band 2851 cm -1 ) 18 T (band 1589 cm -1 – band 1583 cm -1 ) 12 Daily 15

16. Test procedure Tansmission minima (cm -1 ) Acceptable tolerance (cm -1 ) Recording the spectrum of a polystyrene film which has transmission minima (absorption maxima) at the wave numbers given in the next column. 3060.0 ±1.0 2849.5 ±1.0 1942.9 ±1.0 1601.2 ±1.0 1583.0 ±1.0 1154.5 ±1.0 1028.3 ±1.0 Wave number scale Test procedure Acceptance limits The minimum energy ratio value for at least one of the following is measured and it is compared to the vendor’s specifications: -Energy at 3990 cm -1 / energy at 2000 cm -1 - Energy at 3400 cm -1 / energy at 1300 cm -1 Energy ratio test specifications vary for each spectrometer configuration and must be referred to the manufacturer’s specifications. Detector Energy ratio 16

17. Test procedure Peak -to-peak noise betweeen RMS (root mean square) noise between Limits (%T) The maximum noise level is recorded for each of the regions given in the next two columns. 4050 cm -1 and 3950 cm -1 2050 cm -1 and 1950 cm -1 1050 cm -1 and 950 cm -1 550 cm -1 and 450 cm -1 4050 cm -1 and 3950 cm -1 2050 cm -1 and 1950 cm -1 1050 cm -1 and 950 cm -1 550 cm -1 and 450 cm -1 Noise level test specifications vary for each spectrometer configuration and must be referred to the manufacturer’s specifications. Signal/ noise ratio Test procedure Limits (%T) When using a polystyrene film of approximately 35 µ m in thickness as standard at the wavelength of 2925 cm -1 and 700 cm -1 , almost complete absorption of the irradiated energy can be observed. With this test, the remaining transmission is measured. As the maximum absorption can be observed at 700cm -1 negative values may be observed. The objective of the test is to evaluate if, despite the fact that there is almost complete absorption, energy is still detectable. Non-valid results are an indication of a non-linear behavior of the detector and the electronic system . Results vary for each spectrometer configuration and must be referred to the manufacturer’s specifications. Zero test Test procedure Wavenumber (cm -1 ) Upper limit (A) The automated function of the instrument is used to perform this test (If automation is not available then a background spectrum is recorded). This test checks the presence of peaks that signal a contamination problem. 3100.0-2800.0 0.1 1800.0-1600.0 0.1 1400.0-1100.0 0.2 Contamination test 17

18. PERFORMANCE QUALIFICATION: Description Wave number (cm -1 ) Standard Value (FTIR-8400S) Remarks Power spectrum gives the plot of portion of signal’s power (energy per unit time) falling within the given frequency bins. This test estimates the intensity of power spectrum at a specified wave number. 4600 10% or more of max When the measured intensity is equal to or larger than the criterion value, the test is passed. 4000 25% or more of max 3000 50% or more of max Maximum value 50.0 700 10% or more of max 500 2% or more of max 403 0.5% or more of max 351 0.01% or more of max Power spectrum Wave number accuracy The wave number scale is usually calibrated by the use of several characteristics wave numbers of a polystyrene film: 3060.0 (±/-1.5) cm -1 2849.5 (±/-1.5) cm -1 1942.9 (±/- 1.5) cm -1 1601.2 (±/-1.0) cm -1 1583.0 (±/-1.0) cm -1 1154.5 (±/-1.0) cm -1 1028.3 (±/-1.0) cm -1 The software then judges whether the values are within the allowable range and the program labels the results ‘PASS’ if all the peak numbers are within the range. 18

19. Wave number reproducibility: This program specifies three points to measure the peak wave numbers. Then it obtains the actual peak wave numbers at each point by measuring the polystyrene film twice. It should satisfy 5 cm -1 around 3000 cm -1 of polystyrene absorption wave number, 1 cm -1 around 1000 cm -1 . The software determines whether the differences between each of two measurements are within the allowable range and it labels the result ‘PASS’ if they are within the range. Transmittance reproducibility: This program specifies peak wave number at three points and the transmittance at each point is measured twice. The transmittance reproducibility should satisfy 0.5% T when the several points of polystyrene absorption from 3000 cm -1 to 1000 cm -1 are measured twice. Then it is determined whether the differences between the two data are within the range. The FTIR abnormalities or large changes over short term and long term is assessed by these tests. The two parameters checked by this program are : Energy spectrum test- Power spectra obtained in the inspection are compared with reference data and the spectra are checked for changes over long periods. 100% T line spectra are calculated for power spectra and are measured continuously in inspection and the spectra are checked for changes over short periods. Polystyrene test- Evaluation is performed using differences between spectra obtained for polystyrene film in inspection and the stored reference data. When the differences are within the standard, it passes the test. 19

20. 5. GAS CHROMATOGRAPHY (GC) DESIGN QUALIFICATION: Supplier must provide documented evidence that the product has been designed, developed and manufactured in a quality environment e.g. ISO 9001:2000 certification. Supplier must provide phone and on-site support in case of defects. Supplier must provide information through the internet on availability of new firmware upgrades. INSTALLATION QUALIFICATION: Equipment is compared as received with purchase order, including software, accessories, spare parts and consumables. Documentation checked for completeness of operating, maintenance instructions, standard operating procedures for testing and safety, validation certificates and health and safety instruments. Equipment is checked for any damage. The supplier’s instruction for installation is read. The supplier’s safety instructions are read, if there are any. Hardware (computer, equipment, fittings and tubings for fluid connections, power cables, data flow and instrument control cables) is installed following the manufacturer’s recommendation. The instruments are switched on and ensured that all modules power up and an electronic self test is performed. Any deviations are recorded. Software is installed on computer following the manufacturer’s recommendation. Correct software installation is verified. A backup copy of software is made. Peripherals e.g. printers and equipment modules are configured. 20

21. OPERATIONAL QUALIFICATION: Test procedure Acceptance limits Test frequency Five injections of a standard. Calculation of relative standard deviation. <1% RSD (Relative Standard Deviation) Yearly Precision of peak retention times Precision of peak areas Test procedure Acceptance limits Test frequency Five injections of a standard. Calculation of relative standard deviation. <2% RSD Yearly Accuracy of the temperature of the column oven Test procedure Acceptance limits Test frequency Remarks Temperature in column oven is measured and compared with setpoint . ±1°C Yearly The temperature measurement device should be calibrated and traceable to a national standard. Precision of heated zone temperature Test procedure Acceptance limits Test frequency Remarks Actual temperature is m easured and compared with setpoints at 50,70 and 90°C 2°C Yearly The temperature measurement device should be calibrated and traceable to a national standard. 21

22. Precision of injection Test procedure Acceptance limits Test frequency Five injections of a standard. Calculation of relative standard deviation. <2% RSD Yearly Carryover of injection Test procedure Acceptance limits Test frequency Blank solvent is injected after standard. Peak ratio is measured between blank and standard injection. <5% Yearly PERFORMANCE QUALIFICATION: Detector linearity 22

23. Procedure Acceptance criteria Blank is injected followed by ‘detector linearity solutions’ and the peak responses are recorded. A standard plot is drawn between the concentrations vs the peak responses. The plot should be linear and regression coefficient (R 2 ) should not be less than 0.99. Flow rate accuracy: The digital flow meter is connected to the detector outlet port. The carrier gas flow is set and wait till it reaches the set flow. The observed flow in replicate is noted. The procedure is repeated for other carrier gases such as hydrogen and air. The flow rate of carrier gas should be ±10% of set flow System precision: 20ml of methanol, ethanol and acetone is transferred into 100ml volumetric flask and made up with ethyl acetate. Blank is injected followed by standard preparation in six replicates. The areas and retention times are noted down. The %RSD (Relative standard deviation) of retention time should not be more than 1.0% and peak area NMT (not more than) 5.0% Detector noise and Drift test: After GC is ready, the system is run up to 15 minutes through single run. When the run is completed noise and drift is calculated through software. The acceptance values are: Noise not more than 100µV. Drift not more than 2500µV/hr. 23

24. REFERENCES: Huber L. Validation and Qualification in Analytical Laboratories . Informa Healthcare USA, New York. 2007 ( 2 ).11-19. Chan C. C, Lee Y. C, Lam H and Zhang X. M. Analytical Method Validation and Instrument Performance Verification . John Wiley & Sons, Inc., Hoboken, New Jersey. 2004.137-148. Krull I. S and Swartz M. E. Operational and Performance Qualification . LCGC North America, April, 2002, 20 (4) , 356-362. Gowrisankar D, Abbulu K, Souri O. B and Sujana K. Validation and Calibration of Analytical Instruments . Journal of Biomedical Sciences and Research, 2010, 2 (2) , 89-99. 24

25. End of presentation Thank you ! 25