1. QC - THE OUT-OF-CONTROL PROBLEM 謝 昆 穎 Assistant Product Manager, CDG BIO-RAD Laboratories, Taiwan Branch

2. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch QC - THE OUT-OF-CONTROL PROBLEM

3. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch What quality control rules are applied

4. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch

5. Which rules tell about which kinds of errors? Random error  Rules that look for points that are in the tails or the distribution or measure the width of the distribution  1 3s, R 4s Systematic error  Rules that count consecutive measurements beyond a certain limit  2 2s, 4 1s, 10 x

6. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch "idea" of QC

7. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch An accuracy problem, or increase in systematic error would changes the mean of the histogram, therefore shifting all the control values in one direction, higher or lower.

8. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch A precision problem, or increase in random error would cause the standard deviation to increase, therefore widening the expected distribution of control values, causing some values to be higher and some to be lower.

9. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch QC - THE OUT-OF-CONTROL PROBLEM 1.Change Old Habits - Recognize Problems 2.Develop Good Habits - Solve Problems

10. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Bad Habit #1: Repeat the control

11. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Bad Habit # 2: Try a new control Another myth is that the control is "bad". It is true that sometimes controls are short sampled, are used beyond the stability date, have been stored improperly, or were prepared incorrectly. Why does this happen?

12. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Bad Habit # 3: Recalibrating Frequent recalibration can indicate 1.Defective SPC protocol (rules applied, mean, and range in use) 2.Instrument malfunction 3.Sub-optimal reagent quality 4.Failure to follow the manufacturer's instructions and schedule for maintenance.

13. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Develop Good Habits Good Habit #1: Inspect the control charts or rules violated to determine type of error Good Habit #2: Relate the type of error to potential causes Good Habit #3: Consider factors in common on multi-test systems Good Habit #4: Relate causes to recent changes Good Habit #5: Verify the solution and document the remedy

14. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Good Habit #1: Inspect the control charts or rules violated to determine type of error Determine the type of error  Random error ?  Systematic error ?  random and systematic error have different causes

15. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Sources of Random Error Power supply Double pipetting of control sample Misplacement of control sample within the run Air bubbles in water supply Random air bubbles in reagent or sample pipette system Incorrect reconstitution of the control product Inappropriate storage of control in frost-free freezers Use of non-reagent grade water in the test system Operator technique

16. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Sources of Systematic Error Improper alignment of sample or reagent pipettes Drift or shift in incubator chamber temperature Inappropriate temperature/humidity levels in the testing area Change of reagent or calibrator lot Deterioration of reagent while in use, storage or shipment Deterioration of calibrator while in use, storage or shipment Deterioration of control product while in use, storage or shipment Incorrect handling of control product (e.g., freezing when not recommended) Inappropriate storage of control products in frost-free freezers Failing light source Use of non-reagent grade water in the test system Recent calibration Change in test operator Specimen carry-over Obstruction of tubing

17. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Good Habit #2: Relate the type of error to potential causes 1.Systematic errors are most often related to reagent or calibration problems.  A sudden shift is usually due to a recent event such as Replacement of reagent, introduction of a new reagent lot number, a recent calibration, or change in calibrator lot number.  Systematic trend Slowly deteriorating reagent, a calibration shift, a change in instrument temperature, or a deteriorating filter or lamp. 2.Random error are much more difficult to identify and resolve Bubbles in the reagent, reagent lines, sampling or reagent syringes, or improperly mixed/dissolved reagent, pipet tips not fitting properly, a clog in the pipettor, imprecise pipettor, the power supply, and even power fluctuations. Making 10 back to back determinations. This step may identify further imprecision problems.

18. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch

19. Good Habit #3: Consider factors in common on multitest systems Only one test or with many tests? One test involved Apply the first two steps (for example, determine the type of error and relate it to possible causes). Several tests involved Consider what, if anything, the tests have in common. Ask the following questions:  Do all the tests have small or large samples sizes  Do they use the same filter  Do they use the same lamp and tests without the problem use a different lamp  Do the tests all use the same mode of detection (endpoint vs. rate, MEIA vs. FPIA)  Are all the tests calibrated or are they verified  Have certain mechanical components in common or certain optical components in common

20. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch

21. Good Habit #4: Relate causes to recent changes Replacement of reagent Introduction of a new reagent lot number A recent calibration Change in calibrator lot number Tip: When performing troubleshooting, use a systematic and logical approach in isolating the cause. Make only one change at a time and document each action taken.

22. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Good Habit #5: Verify the solution and document the remedy

23. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch Keys to a Productive Review of the Laboratory Quality System Issues to Consider Statistical out-of-control events. Frequency of outliers (QC values outside the established total allowable error limits) during the period or across periods. The amount of bias present, if any.

24. © 2009, Bio-Rad Laboratories, Inc. – Taiwan Branch

27. Thank you