Article 17 Instant tips for right and effective approach to solve HPLC
Contents
1. response increased detector noise 2 Bubbles in cell 2 a Keep cell clean b Use restrictor after cell c Degas mobile phase Table 52 General Potential cause 1 Corrosive abrasive damage 1 Flush buffer from LC and clean when not in use CONCLUSION HPLC is the widely utilized technique for the routine analysis of the drugs in pharmaceutical dosage forms Several problems may occur while performing the method development by RP HPLC The above explained trouble shooting guidelines will render immense help to the analyst to maintain the HPLC system to overcome problems if any happened and also keep the system in smooth way of running which reduces the operation cost The above said tips will assist to maintain the HPLC system perfectly and keeps the system out of routine problems which lessen the maintenance cost due to highest quality performance of the system It leads to successful operation of the HPLC system if the principle Commence with the suitable and apt questions seek the appropriate answers and ultimately the correct answers obtained will paves the way towards required solutions is perfectly applied REFERENCES Skoog DA West DM Holler FJ Instrumental analysis 2011 8 edition 896 906 Gurdeep R Chatwal Instrumental methods of chemical analysis 2002 5 edition 2 566 2 568 B K Sharma Insturmental methods of chemical analysis 29 edition Goyel publications 2013 286 385 Sethi P D 2012 Quantit2. Potential cause 1 Loose end fitting 1 Tighten end fitting 2 Column packing in ferrule 2 Disassemble rinse ferrule reassemble 3 Improper frit thickness 3 Use proper frit see Frit selection guide chart Table 13 Detector leaks 4 Problems with the chromatogram Many problems in an HPLC system is sign to show the changes in the chromatograms Some of these can be solved by replacing the non functioning components of equipment or effecting modifications to the assay procedures Selection of the suitable column and mobile phase are key parts to obtain good chromatography WW JM r e L me A L Tailing Excellent As 1 0 1 05 W M Unacceptable Very poor As As BIA 10 of peak height Acceptable As 1 2 eae aon JN E e Figure 1 Peak tailing Due to secondary retention effects Residual silanol interactions and small peak elution on tail of large peak yields some irregular peaks tail Due to extra column effects contamination build up on column inlet heavy metals and bad column yields all imperfect peaks tails Table 14 Peak tailing Potential cause 1 Blocked frit 1 a Reverse flush column if allowed b Replace inlet frit c Replace column 2 Column void 2 a Fill void 3 Interfering peak 3 a Use longer column b Change mobile phase and or column selectivity 4 Wrong mobile phase pH 4 a Adjust pH b For basic compounds a lower pH usually provides more symmetric pea
3. 10 928 924 Berry V V Dolan J W LC Lig Chromatogr HPLC Mag 1983 1 406 407 Dolan J W LC GC 1996 14 5 378 382 Shoup R and Bogdan M LC GC 1989 7 9 742 744 Dolan J W LC trouble shooting 1989 7 224 Dalan J W L C Lig Chromatogr HPLC Mag 1984 2 834 836 Dalan J W Trouble shooting L C Lig Chromatogr HPLC Mag 1985 3 1050 1052 Tips and tricks of HPLC trouble shooting Agilent technologies available from www chem agilent com July September 2014 274 JCPS Volume 7 Issue 3
4. Potential cause 1 Power off 2 Fuse blown 2 Replace fuse 3 Controller setting or failure 3 a Verify proper setting b Repair or replace controller 4 Broken piston 4 Replace piston 6 Insufficient mobile phase 6 a Replenish reservoir b Replace inlet frit if blocked 5 Air trapped in pump head 5 Degas solvents bleed air from pump prime pump 8 Major leak 8 Tighten or replace fittings 7 Faulty check valve s 7 Replace check valve s 9 Faulty meter 9 Replace meter 10 Faulty pressure transducer 10 Replace transducer Table 7 Pressure dropping but not to zero Potential cause 1 Flow set too low 2 Leak in system 3 Improper column 4 Column temperature too high 5 Controller malfunction July September 2014 5 Repair or replace controller 261 JCPS Volume 7 Issue 3 www jchps com ISSN 0974 2115 Table 8 Pressure cycling 4 Insufficient degassing b Change degassing methods use degasser on line degasser 5 Leak in system 5 Locate leak and correct 6 Using gradient elution 6 Pressure cycling is normal due to viscosity changes Journal of Chemical and Pharmaceutical Sciences 3 Leaks Leaks are usually stopped by proper suitable tightening or replacing the loose fittings One must be aware particularly that if metal compression fittings are over tightened may allow leaks and plastic finger tights may wear out quickly If a fitting leak does not stop when the fitting is tig
5. mobile phase 1 Dissolve the sample in mobile phase 2 Ion pair separation only 2 Dissolve the sample in mobile phase Table 34 Loss of resolution Potential cause 1 Mobile phase contaminated deteriorated 1 Prepare new mobile phase causing retention time to change 2 Obstructed guard or analytical column 2 a Remove guard column and attempt analysis b Replace guard if necessary c If analytical column is obstructed reverse and flush if problem persists column may be fouled with strongly retained contaminants d Use appropriate restoration procedure if problem persists inlet 1s probably plugged e Change frit or replace column Table 35 All peaks too small Potential cause 1 Detector attenuation too high 1 Reduce attenuation 2 Detector time constant too large 2 Use smaller time constant 3 Injection size too small 3 Use larger sample loop 4 Improper recorder connection 4 Use correct connection July September 2014 270 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Table 36 All peaks too large Potential cause 1 Detector attenuation too low 1 Use larger attenuation 2 Injection size too large 2 Use smaller sample loop 3 Improper recorder connection 3 Use correct connection Figure 15 Ghost Peaks t Ghost Peaks Peaks which appear even when no sample is injected Problem Dirty Mobile Phase 20 100 MeOH Gradient No Sam
6. ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Instant tips for right and effective approach to solve HPLC trouble shooting P Ravisankar G Rajyalakshmi CH Devadasu G Devala Rao Faculty of Science Sri Chandrasekharendra Saraswathi Viswa Mahavidyalaya SCSVMV University Enathur Kanchipuram 631561 T N India Department of Pharmaceutical Analysis and Quality Assurance Vignan Pharmacy College Vadlamudi Guntur 522213 A P India Department of Pharmaceutical Analysis KVSR Siddhartha College of Pharmaceutical Sciences Vijayawada Andhra Pradesh India Address for Correspondence E mail banuman35 gmail com Mobile 09000199106 ABSTRACT HPLC is one of the prominent and potent analytical tool regularly employed for the analysis of drugs in pharmaceutical formulations Although HPLC method development has been improved by advanced innovative modifications in HPLC column technology and instrumentation day by day even though problems still arise from many sources Generally when ever more sophisticated unit is used problems cropped up affecting overall system performance each troubled component which needs to be settled by leaps and bounds In this review article different trouble shooting common problems are discussed and solutions to those problems while performing method development For easy understanding and reference the trouble shooting problems encountered with the HPLC system are o
7. ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Table 23 Retention time drifts Potential cause 1 Poor temperature control 1 Thermostat column 2 Mobile phase changing 2 Prevent change evaporation reaction etc 3 Poor column equilibration 3 Allow more time for column equilibration between runs Table 24 Abrupt retention time changes Potential cause L Flow rate change 2 Air bubble in pump 2 Bleed air from pump 3 Improper mobile phase 3 a Replace with proper mobile phase b Set proper mobile phase mixture on controller Baseline irregularities AU Teme Time Unstabilized System Detector Flow Cell Leak Time Air Bubble in Flow Cell Figure6 Non cyclic noise fluid path problems Table 25 Non cyclic noise fluid path problems Potential cause 1 Air in mobile phase detector cell or 1 a Degas mobile phase pump b Flush system to remove air from detector cell or pump 2 column contamination 2 Replace with a new column 3 Air bubbles in the flow path 3 Prime the pump once again and ensure that all solvents thoroughly degassed Time T me Defective Lamp High Sensitivity Figure 7 Non cyclic noise detector electronics problems July September 2014 266 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Table 26 Non cyclic noise detector electronics problems Potential cause 1 Detector not stable 1 Allow suff
8. ative Analysis of Drugs in Pharmaceutical Formulations 4 Edition CBS Publishers Pvt Ltd New Delhi 22 43 Ravisankar M Sereya K Ramaiah K A review on preventive maintenance and trouble shooting of HPLC International research journal of pharmacy 2012 3 9 34 38 Gupta V Jain AD Gupta K Development and validation of HPLC method International research journal of pharmaceutical amp applied sciences 2012 2 4 17 25 Azim Md Sabiretal Method development and validation International research journal of pharmaceutical analysis 2013 4 4 40 46 July September 2014 273 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Vibha gupta et al Development and validation of HPLC method international research journal of pharmaceutical applied sciences 2012 2 4 17 25 Ravisankar P Gowthami S Devala Rao G A review on analytical method development IJRPB 2014 2 3 1183 1195 Ranjit singh et al HPLC method development and Validation J Pharm Educ Res 2013 4 1 26 33 Kaushal C Srivasthava B Aprocess of method development A chromatographic approach j Chem Pharm Res 2010 2 2 519 545 M S Charde R T Bande A S Welankiwar J Kumar and R D Chakole Review common trouble shooting problems in RP HPLC IJAPA Vol 4 Issue 1 2014 07 11 Runser DJ maintaining amp troubleshooting HPLC systems 2001 10 16 Christianson and Dolan J W LC GC 1997 15
9. ause 1 Pressure abnormality 1 Mention in Section 2 2 Column oven problem 2 a Check settings adjust 3 Detector lamp failing 3 Replace lamp Table 44 Warning lamps L Pressure limit exceeded Table 45 Warning buzzers Potential cause 1 Solvent leak spill 2 Other warning buzzers Table 46 Squeaks and squeals 7 Details of Key problem areas and their preventive maintenance The LC s operator and service manuals may have additional suggestions for preventive maintenance in addition to the causes and solutions detailed in the following tables mentioned bellow Table 47 Reservoir 1 Blocked inlet frit 2 Degas mobile phase Table 48 Pump Potential cause 1 Air bubbles 1 Degas mobile phase 2 Pump seal failure 2 Replace 3 months 3 Check valve failure 3 Filter mobile phase use inlet line frit July September 2014 272 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Table 49 Injector Potential cause 1 Rotor seal wear 1 a Do not over tighten b Filter samples Table 50 Column Potential cause 1 Blocked frit 1 a Filter mobile phase b Filter samples c Use in line filter and or guard column 2 Void at head of column 2 a Avoid mobile phase pH gt 8 b Use guard column c Use pre column saturator column Table 51 Detector Potential cause 1 Lamp failure decreased detector 1 Replace 6 months or keep spare lamp
10. g flow is normal Potential cause 1 Faulty meter 1 Replace meter 2 Faulty pressure transducer 2 Replace transducer Table 3 Steady high pressure Potential cause 1 Flow rate set too high 2 Blocked column frit 3 Improper mobile phase precipitated buffer 4 Improper column 5 Injector blockage 6 Column temperature too low 7 Conteollenmalfinction 8 Blocked guard column 9 Blocked in line filter July September 2014 260 JCPS Volume 7 Issue 3 www jchps com Potential cause 1 Flow set too low 2 Leak in system 3 Improper column 4 Column temperature too high ISSN 0974 2115 Journal of Chemical and Pharmaceutical Sciences Table 4 Steady low pressure 5 Controller malfunction Potential cause 1 Flow rate set too high 2 Blocked column frit 3 Improper mobile phase precipitated buffer 4 Improper column 5 Injector blockage 7 Controller malfunction 4 Lower temperature 5 Repair or replace controller Table 5 Pressure climbing Solution 1 Adjust setting 2 a Back flush column if permitted b Replace frit c Replace column 3 a Use correct mobile phase b Wash column 4 Use proper column 5 Clear blockage or replace injector 7 Repair or replace controller 6 Column temperature too low 6 Raise temperature 8 Blocked guard column 9 Blocked in line filter 8 Remove replace guard column Remove replace in line filter Table 6 Pressure dropping to zero
11. htened a little take off the fitting out and inspect the damage e g distorted ferrule or particles on the sealing surface damaged fittings should be discarded and replaced Table 9 Leaky fittings Potential cause 1 Loose fitting iF pa 3 a Loosen and retighten 2 Stripped fitting 3 Over tightened fitting Solution Tighten Replace b Replace 4 Dirty fitting 4 Disassemble and clean Table 10 Leaks at pump Potential cause 1 Loose check valves 1 a Tighten check valve do not over tighten b Replace check valve 2 Loose fittings 3 Mixer seal failure 3 a Replace mixer seal b Replace mixer 4 Pump seal failure 5 Pressure transducer failure 6 Pulse damper failure 7 Proportioning valve failure 8 Purge valve 4 5 2 Tighten fittings do not over tighten Repair or replace Repair or replace 6 7 a Check diaphragms replace if leaky b Check for fitting damage replace 8 a Tighten valve Replace pulse damper b Replace purge valve Table 11 Injector leaks 4 Improper syringe needle diameter 5 Waste line siphoning Solution 1 Rebuild or replace injector 2 Replace loop 3 Adjust 4 Use correct syringe 5 Keep waste line above surface waste 6 Waste line blockage July September 2014 6 Replace waste line 262 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Table 12 Column leaks
12. icient time to stabilize 2 Detector lamp malfunction 2 If the lamp energy is below that recommended for normal detector operation replace the lamp 3 Contaminated Scratched reference 3 Replace the working electrode electrode Figure 8 Cyclic noise detector related problems Time Time Time Temperature Fluctuations Cycling Equipment Insufficient Stabilization Table 27 Cyclic noise detector related problems Potential cause Solution 1 Long term detector temperature problems 1 The heater cycles on and off to maintain the detector temperature 2 Ambient temperature fluctuations 2 Stabilize the air temperature around the instrument and allow the system to return to equilibrium 3 Replace the working electrode 3 Contaminated reference electrode Broad peaks Due to loss of column efficiency column void and large injection volume causes all peaks become broad which shows imperfect results Owing to Possible late elution from previous sample ghost peak high molecular weight sample protein or polymer causes to become some peaks broad SA t JAAA A AAL Figure 9 Broad peaks 267 JCPS Volume 7 Issue 3 July September 2014 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Table 28 Broad peaks Potential cause 1 Mobile phase composition 1 Prepare new mobile phase changed and detector Check for column leaks Check for detector leaks c Check pump for leaks sal
13. jection solvent 1 a Reduce injection volume e b Use weaker injection solvent Table 19 Tailing early peaks more than later ones Potential cause 1 Extra column effects 1 a Re plumb system shorter narrower tubing b Use smaller volume detector cell Table 20 Increased tailing as k increases Potential cause Solution 1 Secondary retention effects reversed phase mode 1 a Add tri ethylamine basic samples b Add acetate acidic samples c Add salt or buffer ionic samples d Try a different column 2 Secondary retention effects normal phase mode 2 a Add tri ethylamine basic compounds b Add acetic acid 3 Secondary retention effects 1on pair 3 a Add tri ethylamine basic samples Table 21 Acidic or basic peaks tail Potential cause 1 Inadequate buffering 1 a Use 50 100 mm buffer concentration b Use buffer with pKa equal to pH of mobile phase z Gradient 1 n3 Gradient 2 Peak removed by allowing more time for final step MilliVolts b Oo Response O 5 10 15 20 25 30 Time Minutes Figure 5 Extra peaks Table 22 Extra peaks Potential cause 1 Other components in sample 2 Late eluting peak from previous 2 a Increase run time or gradient slope injection b Increase flow rate 3 Vacancy or ghost peaks 3 a Check purity of mobile phase b Use mobile phase as injection solvent c Reduce injection volume July September 2014 265 JCPS Volume 7 Issue 3
14. ks 5 Sample reacting with active sites 5 a Add ion pair reagent or volatile basic b Change column modifier July September 2014 263 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences U Ler Normal Fronting i Symmetry lt 0 9 Figure 2 Peak fronting Table 15 Peak fronting Potential cause 1 Increase column temperature 2 Wrong sample solvent 2 Use mobile phase for injection solvent 3 Sample overload 3 Decrease sample concentration Normal Chromatography Abnormal Chromatography Figure 3 Split peaks Table 16 Split peaks Potential cause 1 Contamination on guard or analytical column inlet b Replace guard if necessary c If analytical column is obstructed reverse and flush d If problem persists column may be fouled with strongly retained contaminations e Use appropriate restoration procedure f If problem persists inlet 1s probably plugged g Change frit or replace column 2 Sample solvent incompatible with 2 a Change solvent whenever possible mobile phase b Inject samples in mobile phase MAS A 2 Figure 4 Distortion of larger peaks Oo PPM July September 2014 264 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Table 17 Distortion of larger peaks Potential cause 1 Sample overload 1 Reduce sample size Table 18 Distortion of early peaks Potential cause 1 Wrong in
15. ple 2 The detector not being switched on or 2 Switch on the detector blockage between the injector and detector lines 3 Sample or mobile phase preparation has 3 preparation of mobile phase or sample been performed correctly has been performed correctly Normal Chromatography Abnonnal Chromatography Figure 11 Smaller than expected peaks Table 30 Smaller than expected peaks Potential cause 1 Wrong injection volume 1 Inject the correct volume 2 Detector problem 2 Zero the detector output which the syringe draws the sample volume in the one in situ is incorrect Figure 12 Early eluting peaks broad Normal Chromatography Abnormal Chromatography Table 31 Early eluting peaks broad Potential cause 1 Sample over load 1 Dilute the sample or inject a lower volume to stop equilibrium disruption 2 Detector time constant incorrect 2 Correct the detector time constant July September 2014 269 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Normal Chromatography Abnormal Chromatography Figure 13 Flat topped peaks Table 32 Flat topped peaks Potential cause 1 Large injection volume of dilute sample 1 Injection of small volume of dilute sample 2 Recorder input error 2 Adjust the recorder input voltage Figure 14 Negative peaks Nonnal Chromatography Abnormal Chromatography Table 33 Negative peaks Potential cause 1 Highly adsorbing
16. ple injected 5 Problems with the injector The problems are usually detected while using the injection valve Table 37 Manual injector hard to turn Potential cause 1 Damaged rotor seal 1 Rebuild or replace valve 2 Rotor too tight 2 Adjust rotor tension Table 38 Manual injector hard to load Table 39 Auto injector will not turn Table 40 Auto injector other problems Potential cause 1 Blockage 1 Clear or replace blocked portion 2 Jammed mechanism 3 Faulty controller 3 Repair or replace controller 6 Problems detected by smell sight and sound All senses must be used to identify HPLC problems Habit of taking a few minutes each day need to be cultivated to expose all senses except taste to know how far the HPLC performs properly which help to identify problems quickly For example often a leak can be detected by smell before it is seen The majority of problems are identified by sight which is shown the following tables July September 2014 271 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Table 41 Solvent smell Potential cause 1 a Check system for injector leaks 1 Leak b Check system for loose fittings Table 42 Hot smell Potential cause Solution 1 Overheating module 1 a Check for proper ventilation adjust b Check temperature setting adjust c Shut module off see service manual Table 43 Abnormal meter readings Potential c
17. rganized into five major categories such as pressure abnormalities leaks problems with the chromatograms injector problems and remedies and lastly other problems identified by smell sight and sound and to be settle them and they are presented in the guide in the form of tables apart from textual matter for easy reference Key words Possible causes Solution HPLC troubleshooting INTRODUCTION The practice of HPLC is now 45 years old Certainly HPLC Skoog DA 2011 Gurdeep R Chatwal 2002 B K Sharma 2013 Sethi P D 2012 1s one of the most outstanding analytical techniques for identification and quantification of drugs either in their active pharmaceutical ingredient or in their formulations throughout the process of their discovery manufacturing and development Its chief aim is to provide timely logical process when troubleshooting maximizes the system operation to get good chromatographic practices Wherever necessary figures are inducted for understanding lucidly This enables the guide to use quickly and efficiently by the operators with varied experience Quick tips are included at the end of each section to resolve trouble shooting rapidly even by the less experienced HPLC users also Analytical methods must be validated to give reliable data for regulatory submissions These methods are essential for a number of purposes including testing for QC release testing of stability samples testing of reference materials and to provide data
18. s Locating and correcting the problem A systematic approach is best to identify any problems when troubleshooting the HPLC system This guide is organized into five major categories of symptoms to help quickly identify the source of the various problems e Pressure abnormalities are discussed in Table 1 8 Discussion on leaks shown in Table 9 13 Problems with the chromatograms are shown in Table14 36 and Figures 1 to 15 Discussion on Injector problems and remedies in Table 37 40 Discussion on other problems detected by smell sight and sound in Table 41 52 Prevention Many liquid chromatography LC problems can be prevented with routine maintenance For example replacing pump seals at regular intervals to every pump seal failure and its associated problems as well as preventive maintenance practices to reduce their frequency 2 Abnormal pressure A change in the operating pressure is a sign that there may be a problem The solution is indicated in the last column against each relevant potential cause to rectify the problem perfectly for proper functioning of the system Table 1 No pressure reading no flow Potential_cause 1 Power off 2 Fuse blown 2 Replace fuse 3 Controller setting or failure 3 a Verify proper setting b Repair or replace controller 4 Broken piston 5 Air trapped in pump head 6 Insufficient mobile phase 7 Faulty check valve s 8 Major leak 8 Tighten or replace fittings Table 2 No pressure readin
19. t build up and unusual noises d Change seals if necessary 4 Adjust settings 5 Extra column effects 5 a Inject smaller column e g 10 uL vs 100 uL or 1 10 a Column overloaded and 1 100 dilutions of sample b Detector response time or cell b Reduce response time or use smaller cell volume too large c Tubing between column and c Use as short a piece of 0 007 0 010 inch ID tubing as detector too long or ID practical too large d Recorder response time too d Reduce response time 6 Buffer concentration too low 6 Increase concentration 7 Guard column contaminated 7 Replace guard column 8 Column contaminated worn out 8 a Replace column with new one of same type low plate number b If new column provides symmetrical peaks flush old column with strong solvent 9 Void at column inlet 9 Open inlet end and fill void or replace column 10 Peak represents two or more 10 Change column type to improve separation Poorly resolved solvents 11 Column temperature too low 11 Increase temperature do not exceed 75 C unless higher temperatures are acceptable to column manufacturer 12 Detector time constant too large 12 Use smaller time constant O ATO Abnonnal Chromatography Figure 10 No peaks July September 2014 268 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Sciences Table 29 No peaks Potential cause 1 Wrong sample being injected 1 Inject correct sam
20. to support specifications Although HPLC method development Azim Md 2013 Vibha Guptha 2012 Ravisankar P 2014 Ranjit singh 2013 Kaushal C 2010 has been improved by advances column technology and instrumentation problems still arise The main purpose of this guide is to utilize an easy reference tool to enable to meet suitably the trouble shooting problems Ravisankar M 2012 Gupta V 2012 Charde MS 2014 Runser Dj 2001 Christianson 1997 Berry VV 1983 Dolan J w 1996 Shoup R 1989 Dolan J W 1984 1985 1989 immediately in the day to day to run the HPLC system perfectly Troubleshooting strategy Any troubleshooting strategy involves 5 steps they are 1 Identification of the problem 2 Awareness of the causes of the problem 3 Isolation of the exact cause of the problem 4 Rectifying the problem if able 5 Returning the unit to routine use or referring the problem to your maintenance manager Trouble shooting process The following systematic approach should be followed logically so that the exact cause of the problem can be found 1 To gather the facts 2 To check the simplest things first 3 To compare the performance obtained to the expected performance 4 To enlist possible causes 5 Work through the possible causes step by step duly checking the outcome from any changes done July September 2014 259 JCPS Volume 7 Issue 3 ISSN 0974 2115 www jchps com Journal of Chemical and Pharmaceutical Science
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