1. Good Laboratory Practices Michael C. Olson Director, Division of Field Science Office of Regulatory Affairs U.S. Food & Drug Administration Phone – 301-827-1232 e-mail – Molson@ora.fda.gov

2. DEPARTMENT OF HEALTH AND HUMAN SERVICES FOOD AND DRUG ADMINISTRATION

4. DFS Policy National Check Sample Program Training Personnel and Facilities Research Publications Equipment Purchases Programs, Compliance Issues Accreditation

5. FIELD STAFFING 386 Chemists 208 Microbiologists 25 Biologists 16 Entomologists 15 Engineers/Physicists 23 Research Scientists 122 Technicians/Aides/Sample Custodians 24 QA/Safety/Haz Waste Personnel Total 819 Analysts (Also….89 Managers, 30 + Science Advisors)

6. Changing Roles FDA ANALYST’S ROLE PASTFUTURE Sample Analysis x x Inspections x Monitor Contracts x

7. Activities You add value by Analyzing samples Reviewing worksheets Participating in inspections Providing Technical Assistance

8. Activities You add value by Developing/Improving Methods Creative Problem-Solving Interacting with customers and co-workers

9. Outputs Your Work Products Are Legal Document Serve as a basis for regulatory action…they should be: legiblewell organized concisecomplete scientifically soundtimely

10. Personal Characteristics 1.Integrity 2.Integrity 3.Integrity 4.Positive work ethic 5.Dedicated to the mission 6.Continuous learning 7.Inquisitive 8.Team player

11. ORA Lab Types 13 ORA Laboratories: 5 Regional Labs (“Mega-Labs”) 4 District Labs 4 Specialty Labs

12. ORA Lab Types Regional Labs (general servicing labs) Northeast Regional Lab (New York) Southeast Regional Lab (Atlanta) Arkansas Regional Lab (Jefferson, AR) Pacific Regional Lab Southwest (Irvine, CA) Pacific Regional Lab Northwest (Bothell, WA)

13. ORA Lab Types District Labs (general servicing labs) Kansas City District (Lenexa, KS) Denver District (Lakewood, CO) Detroit District (Detroit, MI) San Francisco District (Alameda, CA)

14. ORA Lab Types Specialty Labs Philadelphia District (Pharmaceuticals) San Juan District (Pharmaceuticals) Winchester Engineering and Analytical Center (WEAC: Winchester, MA) (Engineering, Radio nuclides) Forensic Chemistry Center (FCC, Cincinnati) (criminal analysis support)

15. ORA Lab Types Specialized Analyses Within General Servicing Labs –Seafood Products Research: Seattle Lab –Metals Analysis: San Francisco Lab –Animal Drug Research and Analysis: Denver Lab –Nutritional Analysis: Atlanta Lab –Total Diet Program: Kansas City Lab –Dioxin Analysis: Arkansas Lab

16. ORA Lab Activities Food Analysis Chemistry: –Pesticide Residues –Metals –Mycotoxins –Seafood Toxins –Nutrients –Radio nuclides –Antibiotics –Food Additives –Color Additives

17. ORA Lab Activities Food Analysis, cont… Microbiology –Bacterial Pathogens –Salmonella –Listeria –Coliforms –Shigella –E. Coli 0157:H7 –C. Botulinum –C. Perfringens –Campulobacter –B. Cereus –S. Aureus

18. ORA Lab Activities Food Analysis, cont… Can Seam Analysis Sensory (organoleptic) Sanitation (Filth)

19. ORA Lab Activities Pharmaceutical Analysis Chemistry: –Potency –Identity –Impurities/Degradants –Release Rate

20. ORA Lab Activities Pharmaceutical Analysis Cont… Microbiology –Sterility –Particulates –Endotoxins

21. ORA Lab Activities Veterinary Product Testing Medicated Feeds Feeds / BSE

22. ORA Lab Activities Medical Device Testing Condoms/Gloves X-Ray devices Microwave Ovens In-Vitro Diagnostics

23. ORA Lab Activities Other Activities Research Collaborative Studies Petition Validations Inspections Private Lab Audits Outreach

24. Numbers of Samples FY 03 Workplan Import 29K Domestic 20K Total 49 K Foods 40K Pharmaceuticals 2K Vet foods and Drugs 5K Medical Devices 2K

25. Quality Initiatives in ORA Three interrelated issues concerning the quality of laboratory data. –ORA Wide Quality Management System initiative –Revision of ORA Laboratory Quality Assurance Program –Agency wide Laboratory Accreditation

26. ORA Wide Quality Management System [ QMS] 1997 – Move to National Quality System with focus on building in quality Based on International Organization for standardization, ISO 9000 quality standards Recognize internationally

27. ORA Wide Quality Management System [ QMS] ORA Wide Systems Approach –Includes Headquarters and Field Operations Investigations Laboratory Compliance Administrative

28. ORA Wide Quality Management System [ QMS] ORA Quality principles –Implementation of a system of control where you plan, manage, and monitor all critical activities which significantly affect the quality of a product or service.

29. ORA Wide Quality Management System [ QMS] Senior Management Quality Goals –Increase management’s assurance of work quality –Provide consistent and uniform application of ORA requirements –Protect ORA’s knowledge base –Improve work products and processes

30. Quality Assurance (what is it)? Assuring what is there is really there Assuring the level is what you report Assuring you did not add it through contamination. Assuring if you report negative findings it really isn’t there.

31. Traditional QA Operations ORA Quality Assurance Program, 1988 –General Guidance –Specific Procedures left to each office –Covered all branches (IB, compliance, lab, admin)

32. Traditional QA Operations Quality of Equipment –Periodic performance check schedule –Periodic performance check procedure –Performance check log –Instrument repair log –(Instrument Monitor)

33. Traditional QA Operations Laboratory Portion: –Quality of equipment –Quality of Standards –Quality of Analytical Work –Quality of Documentation –Sample Accountability –National Check Sample Program

34. Traditional QA Operations Quality of Standards –Identification of Primary vs. Secondary –Testing of secondary standards –Handling, storage, and security criteria

35. Traditional QA Operations Quality of Analytical Work –Critical review of original / check analyses –On-Site reviews

36. Traditional QA Operations Sample Accountability –Sample Accountability Records –Sample storage and security –Sample disposition

37. Traditional QA Operations National Check Sample Program –Sample Selection: by Ad-Hoc Committee Full range of field programs Methods recognized as suitable Standard equipment Homogeneous sample available and not too costly

38. Traditional QA Operations Quality of Documentation –Supervisory Review of Worksheets –Internal Lab Audit of Worksheets –Oral Reviews

39. Traditional QA Operations National Check Sample Program http://web.ora.fda.gov/dfs/check_sample.htm http://web.ora.fda.gov/dfs/check_sample.htm PURPOSE: –To evaluate field lab capability in full range of programs –To demonstrate that results from various field labs are analytically equivalent –To Identify and resolve problems that’s may be uncovered

40. Traditional QA Operations National Check Sample Program –Originating Laboratory Obtain sample Assess suitability of message Assess suitability of sample Upon DFS concurrence, distribute sample Analyze sample as participating laboratory

41. Traditional QA Operations National Check Sample Program –Participating Laboratory Analyze sample as normal regulatory procedure, using specified instructions Document as a normal regulatory sample –(no check analysis) Submit worksheet package to DFS

42. Traditional QA Operations National Check Sample Program –Division of Field Science Evaluate lab submissions Generate final report

43. ORA Laboratory Accreditation Driving force – –ACRA, charge at 1997 Lab Directors Conference. –Facilitate Harmonization: MRA’s and equivalency of health protection systems with other countries. –Seafood’s Program with Canada Exchange of laboratory data with USDA Labs Exchange of laboratory data with State Labs –Food Safety initiative Pilot FSIS/State Labs/CDC/FDA

44. ORA Laboratory Accreditation Driving Force – –1997 Justice Department Inspector General Report on the FBI Crime Laboratory The findings: –scientifically flawed testimony and reports in four cases including the World Trade Center, and Oklahoma City federal building bombings

45. 1997 Justice Department Inspector General Report on the FBI Crime Laboratory The findings continued: Inaccurate testimony Examiners without scientific qualifications Incomplete or missing documentation

46. 1997 Justice Department Inspector General Report on the FBI Crime Laboratory The findings continued: –Insufficient documentation of test results –Failure by FBI management to resolve issues of incompetence –Failure of management to resolve scientific disagreements –Failure to pursue lab accreditation

47. Benefits of Lab Accreditation Opportunity to formalize and improve lab quality systems Complies with ISO internationally recognized standards Improve: Uniformity/consistency/credibility

48. Benefits of Lab Accreditation Assessment of quality system and technical competency by outside ISO recognized accreditation body The increased focus on quality, and resulting training will improve the science base

49. Disadvantages of Lab Accreditation Accreditation does not provide guarantees about all test results Costs: –FTE’s for drafting policy and procedures documentation, and maintenance of program –Accreditation Fees

50. ISO/IEC International Standard 17025 General Requirements for the Competence of Testing and Calibration Labs Includes all requirements that testing labs have to meet to demonstrate that they operate a quality system, are technically competent, and can generate technically valid results Compliance with 17025 also assures compliance with ISO 9001

51. ISO 17025 “Say what you do, and do what you say” Incorporates many of our existing procedures Improves document control Improves operational control Improves uniformity among labs Allows for international recognition

52. ISO 17025 “Say what you do, and do what you say” Standards are very general Laboratories write policies, procedures, and work instructions to comply with 17025 standards Flexibility in interpretation

53. ISO 17025 “…contains all of the requirements that testing and calibration laboratories have to meet if they wish to demonstrate that they operate a quality system, are technically competent, and are able to generate technically valid results.”

54. ISO/IEC International Standard 17025 General Requirements for the Competence of Testing and Calibration Labs Fourteen “Management Requirements” elements: –4.1 Organization –4.2 Quality System –4.3 Document Control –4.4 Review of requests, tenders, contracts –4.5 Subcontracting of tests and calibrations –4.6 Purchasing services and supplies

55. ISO/IEC International Standard 17025 General Requirements for the Competence of Testing and Calibration Labs 4.7 Service to the client [Centers, Headquarters] 4.8 Complaints 4.9 Control of Nonconforming [OOS] testing 4.10 Corrective Action 4.11 Preventive Action 4.12 Control of Records 4.13 Internal Audits 4.14 Management

56. ISO/IEC International Standard 17025 General Requirements for the Competence of Testing and Calibration Labs Ten “technical requirements” elements. –5.1 General –5.2 Personnel –5.3 Accommodation and environmental conditions –5.4 Test and calibration methods, and method validation

57. ISO/IEC International Standard 17025 General Requirements for the Competence of Testing and Calibration Labs –5.5 Equipment –5.6 Measurement traceability –5.7 Sampling –5.8 Handling of test and calibration items [samples] –5.9 Assuring the quality of test and calibration results –5.10 Reporting the results

58. Methods: Selection 17025 Requirement: –Appropriate for the Intended Use –Meet the needs of the clients* *lab makes determination when client does not specify –Standard Methods Preferable* *published in international, regional, or national standards, in technical journals, or by manufactures of equipment –Non-Standard Methods Require Validation

59. Methods: Selection Traditional FDA Policy: “Official Methods:” specified in FD&C Act or Code of Federal Regulations –USP Methods –AOAC methods, sometimes –PAM methods –NDA/ANDA approved methods

60. Methods: Selection Traditional FDA Policy: Non-Official but Mandated Methods: –compliance programs –assignments –require “verification”

61. Methods: Selection Traditional FDA Policy: Non-Official Methods –Journal Articles –LIBs –In-house methods –Require validation

62. Methods: Validation 21CFR 211.165 (e) (Drug GMPs: Product Testing) The accuracy, sensitivity, specificity, and reproducibility of test methods…shall be established and documented…in accordance with 211.194 (a) (2)

63. Methods: Validation 21CFR 211.194 (a) (2) (Laboratory Records) The statement shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested..

64. Methods: Validation 21CFR 211.194 (a) (2) (cont.) (If the method employed is in the current revision of the United State Pharmacopeia, National Formulary, Association of Official Analytical Chemists Book of Methods, or in other recognized standard references, or is detailed in an approved new drug application… a statement indicating the method and reference will suffice.)

65. Methods: Validation 21CFR 211.194 (a) (2) (cont.) The suitability of all testing materials used shall be verified under the actual conditions of use.

66. Methods: Validation USP. Section VALIDATION of an analytical method is the process by which it is established, by scientific studies, that the performance characteristics of the method meet the requirements for the intended analytical applications.

67. Methods: Validation ISO/IEC 17025,5.4.5.1 VALIDATION is the confirmation by examination and the provision of objective evidence that the particular requirements for a specific intended use are fulfilled.

68. Methods: Validation ISO/IEC 17025,5.45.1 Minimum validation criteria: All critical characteristics should be defined and agreed upon by the end user of the method.

69. Methods: Validation Analytical Characteristics (Validation Parameters) –Accuracy –Precision –Specificity –Limit of Detection –Limit of Quantitation –Linearity –Range –Robustness –Ruggedness

70. Methods: Validation Accuracy The measure of agreement between the experimentally determined value and the true value of the analyte. (Recovery, spike)

71. Methods: Validation Precision The repeatability or degree of scatter in results obtained from multiple analyses of a homogeneous sample. (RSD of multiple trials)

72. Methods: ValidationSpecificity The ability of a method to accurately measure an analyte in the sample matrix. (compare to matrix blank; use method generally accepted as specific, i.e. MS, IR)

73. Methods: Validation Limit of Detection The Lowest level of an analyte that can be detected above the background on a particular test instrument. (signal: noise ratio)

74. Methods: Validation Limit of Quantitation The lowest level of an analyte that can be quantitatively determined with an acceptable level of accuracy and precision. (signal: noise ratio)

75. Methods: Validation Linearity The determination of the sample concentration range where the analyte response is directly proportional to the analyte concentration. (standard curve, linear regression)

76. Methods: Validation Range The upper and lower concentration interval over which the analytical procedure has an acceptable accuracy, linearity, and precision. (standard curve, LOQ)

77. Methods: Validation Robustness The ability of a method to remain unaffected by small, usually deliberate, variations in method parameters. (minor changes in instrumental parameters, solvent composition, etc.)

78. Methods: Validation Ruggedness The ability of a method to perform acceptably in the hands of a competent analyst in a different laboratory, or with different instruments of the same type. (inter-lab or intra/lab collaborative study)

79. Methods: Validation Occasionally misunderstood point: Most validation parameters are done in a single laboratory…usually the originating laboratory.

80. Methods: Validation Do you need to do each of these all the time? ?????? -Accuracy -Precision -Specificity -Limit of Detection -Limit of Quantitation -Linearity -Range -Robustness -Ruggedness

81. Methods: Validation Answer: Do what makes sense scientifically!! Remember the validation definitions:..verified under the actual conditions of use..for the intended analytical applications..the particular requirements for a specific intended use

82. Methods: Validation Categorization of Methods (ref. USP Data Elements Required for Validation: -Quantitation of Major Ingredients -Quantiation of Trace Ingredients -Qualitative Tests -Performance Tests

83. Methods: Validation Examples Major Ingredients, Quantitative Determination: LOD and LOQ not required, Accuracy and Precision are critical Trace Ingredients, Qualitative Determination: LOD and Specificity are critical, Precision not required Trace Ingredients, Quantitative Determination: LOD, LOQ, Accuracy, and Precision probably all critical

84. Methods: Validation References –USP, Section –ISO/IEC 17025 – Section 5.4.5 –CDER: Guideline for Submitting Samples and Analytical Data for Methods Validation –CVM: Guideline for Collecting and Submitting Analytical Data for Validation of Methods

85. GMP Principles Involved 21 CFR 211.165 (f) Drug products failing 21 CFR 211.165 (f) Drug products failing meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant criteria.

86. CDER Violations of Laboratory GMP’s –Majority of enforcement actions –Majority of objectionable observations for Domestic and Foreign Inspections

87. Laboratory CGMP Problems Include Lack of Documentation Lack of proper instrument calibration and maintenance Test methods not validated System suitability tests not performed Laboratory data not reviewed by second person for accuracy

88. Laboratory CGMP Problems Include [cont’d] Out of specification {OOS} test results Lack of/ inadequate stability program Stability test methods not shown to be stability indicating Improper sample and/or standard storage Untrained Lab personnel Lack of /inadequate standard operating procedures

89. Laboratory CGMP Problems Include [cont’d] Improper use of secondary [ non-USP] standards Lack of /inadequate drug component or finished product testing Equipment cleaning test methods are not appropriately validated Lack of laboratory data integrity Lack of impurity profile

90. Laboratory GMP’s of the Future “OSP-17025’ & SPECIFIC Requirements ?