Calibration in the Laboratory

Transcription

1 IVT Validation Week 2015 Calibration in the Laboratory 2015 The Lanese Group, Inc. Jerry Lanese Ph.D. The Lanese Group, Inc. 1

2 Outline Overview of laboratory data integrity Elements of the Laboratory Instrument Calibration Program The impact of new guidances on instrument calibration 2015 The Lanese Group, Inc. 2

3 It is the goal of every analyst and every quality control laboratory to report data that accurately reflect the measured parameters of the material under test The Lanese Group, Inc. 3

4 Each laboratory should implement procedures that provide the highest level of assurance of the quality of the data reported The Lanese Group, Inc. 4

5 Components of Data Quality Quality Control Check Samples System Suitability Tests Analytical Method Validation Analytical Instrument Qualification 2015 The Lanese Group, Inc. 5

6 Components of Analytical Instrument Qualification 4 Qs Design Qualification Installation Qualification Operational Qualification Performance Qualification Define your terms 2015 The Lanese Group, Inc. 6

7 The boundaries of qualifications activities are fuzzy. DQ IQ OQ PQ Define your terms 2015 The Lanese Group, Inc. 7

8 Why calibrate? What is calibration? Where do we find the requirements for calibration? Who in the organization is responsible for calibration? 2015 The Lanese Group, Inc. 8

9 Regulations and standards requiring calibration and providing limited guidance on what should be in a calibration program 21CFR58 21CFR211 21CFR111 21CFR820 ICH-Q7A ISO 9001 ISO ISO ISO The Lanese Group, Inc. 9

10 Guidance on calibration requirements USP<1251> USP<41> 2015 The Lanese Group, Inc. 10

11 General requirement Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained. 21CFR211.68(a) 2015 The Lanese Group, Inc. 11

12 Laboratory controls include: The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used The Lanese Group, Inc CFR (b)(4)

13 Calibration Suitable intervals Written program Specific directions Schedules Limits of accuracy and precision Remedial action 2015 The Lanese Group, Inc. 13

14 The message is consistent Program should include: Schedule Specific procedures Intervals Limits of accuracy and precision Status identification Standard traceability Measurement uncertainty Training Records 2015 The Lanese Group, Inc. 14

15 Program should include remedial action Calibrate Investigate product impact 2015 The Lanese Group, Inc. 15

16 Calibration goes beyond a regulatory requirement it is good business, good science. Calibration is an element of the Quality System 2015 The Lanese Group, Inc. 16

17 Life cycle Intended use 2015 The Lanese Group, Inc. 17

18 Warning letter Your SOP ***, requiring the Quality Control Manager to ensure that in-house calibration of all scales and balances is performed *** at an interval*** with ***a class*** standard weights was not followed. Calibrations of the ***a brand name*** scale used to weigh active ingredients were performed with only ***a class*** weights for a period of 11 months (February 2007 to January 2008) The Lanese Group, Inc

19 Personnel qualifications Personnel shall have Education Experience Training GMP Skill 21CFR The Lanese Group, Inc. 19

20 Operational Qualification or Calibration 2015 The Lanese Group, Inc. 20

21 Calibration Actions designed to provide assurance that a measuring device gives accurate results The Lanese Group, Inc. 21

22 Operational Qualification (OQ) Establishing the documentary evidence that a sub-system or set of equipment is capable of repeated operation within the limits defined in the specifications The Lanese Group, Inc. 22

23 After initial qualification Operational Qualification is used as synonymous with Calibration 2015 The Lanese Group, Inc. 23

24 Calibration The comparison of a measurement system of unverified uncertainty to a measurement system of quantified uncertainty to detect or correct any deviation from required performance specifications The Lanese Group, Inc. 24

25 Calibration More specifically, calibration is the practice of verifying critical measurement equipment performance (accuracy/ precision) using NIST traceable standards The Lanese Group, Inc. 25

26 Relationship Laboratory program to corporate program. Laboratory program to site program The Lanese Group, Inc. 26

27 Corporate Guidance Laboratory Calibration Program Records Site Calibration Procedure Specific Calibration Procedures 2015 The Lanese Group, Inc. 27

28 Relationship Calibration to maintenance The Lanese Group, Inc. 28

29 Responsibility When contract calibration service is involved: Procedure preparation Procedure approval Training Assuring contractor follows procedures 2015 The Lanese Group, Inc. 29

30 Responsibility Procedure Format Preparation Review Approval 2015 The Lanese Group, Inc. 30

31 Responsibility General test equipment Thermometers Recorders Weighing devices Laboratory specific equipment Chromatographs Spectrophotometers 2015 The Lanese Group, Inc. 31

32 Responsibility Scheduling Remedial action 2015 The Lanese Group, Inc. 32

33 Responsibility Review and approval of calibration records Maintenance of calibration records 2015 The Lanese Group, Inc. 33

34 Responsibility Assuring that appropriate instrumentation is used. Assuring that instrumentation that is not calibrated is not used The Lanese Group, Inc. 34

35 Calibration Program Getting instruments into the system Decommissioning instruments Remedial Actions Scheduling Establishing intervals TAR Instrument classification Establishing Tolerances 2015 The Lanese Group, Inc. 35

36 Calibration Program - Element 1 Process to get all instruments into the program. User: Receives new instrument. Completes instrument data form. Calibration manager Completes form. Assures procedures in place. Places instrument into calibration program The Lanese Group, Inc. 36

37 Calibration Program - Element 1 Process to get all instruments into the program. Form User responsibility Instrument description Make Model Identification Serial number Internal Identification Intended use Location Range of use Process tolerance Other 2015 The Lanese Group, Inc. 37

38 Calibration Program - Element 1 Process to get all instruments into the program. Form Calibration Manager Establish Classification Calibration points Calibration tolerance Calibration interval 2015 The Lanese Group, Inc. 38

39 Calibration Program - Element 2 Remove instrument from system 2015 The Lanese Group, Inc. 39

40 Calibration Program - Element 3 Classify the devices GMP Critical Non-critical Utility Non-GMP Safety Environmental Other 2015 The Lanese Group, Inc. 40

41 GMP Critical Device Potential direct impact on product (test results) quality Recorded in GMP record Used to make decisions that can impact quality Used to release product Not business, environmental or safety critical 2015 The Lanese Group, Inc. 41

42 GMP Non-Critical Device No potential direct impact on product (test result) quality Used to make decisions to improve laboratory test efficiency May be redundant, or up-stream of final critical device Not recorded in batch or QC record Calibrated same as critical 2015 The Lanese Group, Inc. 42

43 GMP Utility Device Used only by maintenance technicians Used only for troubleshooting equipment operation May have little stated accuracy or reading resolution (color coded; on/of) Includes output control circuits May not need to be calibrated 2015 The Lanese Group, Inc. 43

44 Gowning Example Sterile HVAC(simplified) Roughing Filter TI 1 TI 2 DPI 1 Damper Pre- Filter Coil HEPA OA Utility RA DO 1 Damper Operator Heat Transfer Fluid V 1 FT 1 TI 3 Sterile Suite TR 2 FIT 1 Non-critical Critical Microbiological testing area DPI The Lanese Group, Inc. 44 J Busfield

45 Calibration Program Element 4 Limits of accuracy Process calibration tolerance Limit beyond which product (test result) quality may be compromised Trigger an out-of-tolerance Dependent upon process tolerance Limits of precision 2015 The Lanese Group, Inc. 45

46 Process calibration tolerance How much error are you willing to accept in the measurement? Risk analysis Should be based on science and the knowledge of the process. A factor in determination of interval 2015 The Lanese Group, Inc. 46

47 Process calibration tolerance Limit beyond which product (test result) quality may be compromised Assigned to GMP critical instruments only Greater than calibration limits Trigger out-of-tolerance event Based on process requirements Process limits Process studies Development studies Design space 2015 The Lanese Group, Inc. 47

48 Test Accuracy Ratio TAR Test Uncertainty Ratio (TUR) Most programs require at least 4:1 Process calibration tolerance should be less than 1/4 th process tolerance Standard should be at least 4 x accuracy of calibrated instrument (4 x process calibration tolerance) 2015 The Lanese Group, Inc. 48

49 Test Accuracy Ratio Standard Accuracy ±0.31 C Calibration Limit ±0.75 C Process Calibration Tolerance ±1.25 C Process Tolerance ±5 C 2015 The Lanese Group, Inc. 49

50 Temperature measuring device in stability chamber Stability SOP states: control temperature to 27 C ± 1 C Calibration procedure states: Process calibration tolerance: ± 1 C 2015 The Lanese Group, Inc. 50

51 Test Accuracy Ratio Standard Accuracy ±0.06 C Calibration Limit ±0.15 C Process Calibration Tolerance ±0.25 C Process Tolerance ±1 C 2015 The Lanese Group, Inc. 51

52 Calibration Program - Element 5 Process for establishing and changing intervals. Interval will drive the schedule The Lanese Group, Inc. 52

53 Calibration Interval Based on: Calibration tolerance Data First interval 2015 The Lanese Group, Inc. 53

54 Instrument response with time Instrument response compared to standard Process Calibration Tolerance Time 2015 The Lanese Group, Inc. 54

55 Instrument response with time Instrument response compared to standard Process Calibration Tolerance Calibration Limit Time 2015 The Lanese Group, Inc. 55

56 Calibration Program Element 6 Scheduling and record keeping 2015 The Lanese Group, Inc. 56

57 Calibration Program - Element 7 Specific procedures Each category of instrument Pressure gauge Thermometer HPLC Each specific instrument 2015 The Lanese Group, Inc. 57

58 Suggestion Procedure for each category of instrument Test sheet for each instrument in the category 2015 The Lanese Group, Inc. 58

59 Specific procedure considerations Format Test process Interval Range Test points Standards Limits for accuracy and precision Remedial action Work sheet 2015 The Lanese Group, Inc. 59

60 Calibration Program - Element 8 Remedial action Driven by an as-found, out-of-tolerance observation. Should not be the responsibility of the calibration unit Sounds like Deviation Investigation followed by CAPA 2015 The Lanese Group, Inc. 60

61 Additional considerations Traceable standards Known uncertainty Suitable Maintain records Status known Do not use equipment not meeting standards 2015 The Lanese Group, Inc. 61

62 Impact of new guidance 2015 The Lanese Group, Inc. 62

63 Some things to consider USP <41> USP <1251> ICH Q10 ICH Q8 ICH Q9 USP Stimulus Article on Test Method Validation EU Chapter The Lanese Group, Inc. 63

64 Questions 2015 The Lanese Group, Inc. 64

65 IVT Validation Week 2015 Calibration in the Laboratory 2015 The Lanese Group, Inc. Jerry Lanese Ph.D. The Lanese Group, Inc. 65

66 Contact Information Jerry Lanese The Lanese Group, Inc Catalina, Leawood Kansas The Lanese Group, Inc. 66