FDA/EU Compliance for Quality Control Laboratories Ludwig Huber, Ph.D Chief Advisor, Global FDA Compliance Ludwig Huber Phone: +49 7902 980582 E-mail: Ludwig_Huber@Labcompliance.com Page 1 Overview • • • • • • • Planning for GMP compliance Develop procedure and other documents Building the right laboratory organization Qualify personnel and document qualification Qualify suppliers and materials Validate analytical methods Calibrate and qualify equipment and computer systems • Implement procedures for sampling and sample analysis • Implement procedures for data review, approval and archiving © Copyright Ludwig Huber - LabCompliance Slide 2 GMP and ISO 17025 Laboratory Compliance Sampling Representative Sampling Sampling plan Sample handling& storage Data review and approval Testing Avoid cross Contamination Ensure sample integrity Clear specifications & test protocols Record archiving Primary & Ensure data secondary Integrity @ review availability Handling OOS Compliance across all workflow steps • Validation of analytical • Qualification of material methods & procedures • Traceability • Equipment calibration • Control of nontesting & maintenance conforming testing © Copyright Ludwig Huber - LabCompliance • Qualification of personnel • Controlled environmental conditions • Written procedures Slide 3 Plan for GMP/ISO 17025 Compliance Compliance master plan / Quality Plan • Guideline for effective and consistent implementation of GMP regulation • Documents the laboratory’s approach for compliance • Ensures efficiency AND consistency • Useful for audits to explain the laboratory’s approach towards compliance Project Plan • Outlines steps, tasks, deliverables and owners © Copyright Ludwig Huber - LabCompliance Slide 4 Contents of the Master/Quality Plan • • • • • • • • • • • © Copyright Policy Quality management documentation Organization and responsibilities Staffing and people qualification Selection and validation of analytical methods Equipment and computers Sampling and sample handling Reagents and calibration standards Testing Handling non-conformance Reporting and archiving Ludwig Huber - LabCompliance or Slide 5 Develop Procedures and other Documents Policy Master Plan High level, strategic documentation (regulations, business, quality) Training Maintenance Validation, Audits Test procedures Operation manuals, QC procedures Process related documentation, approaches (SOPs) Product/event related documentation (work instructions, also called SOPs or test scripts, protocols) Product test records, batch records, validation results, training records, chromatograms Compliance Records (batch/event related documentation) Use the same set throughout the organization © Copyright Ludwig Huber - LabCompliance Slide 6 Build the Right Organizational Structure and Assign Tasks (Example) Director Finance & Admin. Human Resources Lab 1 Laboratory Mgmt. Quality Assurance Lab 2 IT/IS Safety Officer Lab 3 Avoid Conflicts of Interest © Copyright Ludwig Huber - LabCompliance Slide 7 Qualify Personnel Job description 1. Define requirements - what is the assigned task? 2. Identify knowledge 3. Determine gaps 4. Make a plan to fill the gaps 5. Train 6. Evaluate training 7. Document 1/2 year or yearly reviews © Copyright Ludwig Huber - LabCompliance Slide 8 Documenting Training Job description Trainings Qualification requirements Supervisor (name, signature) Name Type, content Education Experience Date Duration Gaps, Trainings plan © Copyright This documentation should be kept separated from other personnel files, for example performance evaluations Ludwig Huber - LabCompliance Slide 9 Qualify Suppliers and Materials 1. Documenting internal and external experience 2. Mail audit with follow up 3. Direct audit Criteria • Product risk • Supplier risk #3. is most time consuming and recommended for high volume and high risk suppliers © Copyright Ludwig Huber - LabCompliance Slide 10 Incoming Quality Control of Material • Purchase from qualified suppliers • Limited sample testing • Number of tests depend on – Criticality of reference material – Experience with the supplier – Experience with initial tests • Retest after specified time period (e.g., after one year) © Copyright Ludwig Huber - LabCompliance Slide 11 Preparation of Working Standards Primary Standard Certified Reference Material Secondary Standard Company Internal Reference Material Working Standard Method Validation © Copyright Equipment Calibration Ludwig Huber - LabCompliance System Performance Check Slide 12 Validate Analytical Methods Definition Method Scope Define Validation Criteria Test Define Routine Tests © Copyright Sample matrix Compounds Equipment, Location Optimize method parameters Define performance characteristics Acceptance criteria Develop test cases Preliminary tests Final tests SOPs System Suitability tests Analytical quality control Ludwig Huber - LabCompliance Slide 13 Method Parameters and Tests Parameter Accuracy Tests (examples) Minimum at 3 concentrations, 3 replicates Precision Repeatability Intermediate Reproducibility Specificity Minimum of 9 determinations over the specified range Over 3 days, 2 operators, 2 instruments, Only required if testing is done in different laboratories Prove with specific methods: HPLC, DAD, MS, dif. columns Limit of detection Limit of Quantitation Visual approach, S/N >= 3 S/N >= 10, Standard deviation of response Linearity Min 5 concentrations: visual, correlation coefficient (r) Range 80 to 120% of test concentration, from linearity tests Well Characterized Biological Products © Copyright Ludwig Huber - LabCompliance Slide 14 Intermediate Precision Example Sample Day Operator Instrument 100% conc. (3x) 1 1 1 100% conc. (3x) 1 2 2 100% conc. (3x) 1 3 3 100% conc. (3x) 2 1 2 100% conc. (3x) 2 2 3 100% conc. (3x) 2 3 1 100% conc. (3x) 3 1 3 100% conc. (3x) 3 2 1 100% conc. (3x) 3 3 2 • Minimum: 2 days, 2 operators, 2 instruments, • Calculate overall RSD © Copyright Ludwig Huber - LabCompliance Slide 15 Examples for Acceptance Criteria Quantitative Impurities in Finished Drugs Parameter Accuracy Test 90 – 110%, 80 – 120% at specifications limit Precision Repeatability Intermediate Reproducibility Specificity Limit of Detection Limit of Quantitation Linearity Range © Copyright <1.5 % RSD (up to 15% at LOQ) <2.0 % RSD (higher at LOQ) < 3% RSD (higher at LOQ) Peak resolution >1.5 (related substances) or >2 (main peak) Peak purity check with UV DAD or MS N/A 0.05% visual inspection of linearity curve, r>0.9900 o.k. if accuracy, precision, linearity criteria are met Ludwig Huber - LabCompliance Slide 16 Example: Report Summary Table Validation Parameter Accuracy Method Precision Intermediate Precision Specificity Linearity Range Robustness © Copyright Measure Acceptance criteria Results Recovery – Conc1 97 – 103 % 99% Recovery – Conc2 97 – 103 % 100% Recovery – Conc3 97 – 103 % 100% RSD ≤ 1.5 % 0.4% RSD ≤ 2.0 % 0.8% Peak Resolution Factor R R for all peaks >1.5 All peaks >2.0 Correlation Coefficient ≥ 0.9900 0.9900 Visual inspection of plot Linear response plot Shows linearity Correlation Coefficient ≥ 0.9900 0.9900 Precision at 3 concentrations ≤ 1.5 % <1% Recovery at 3 Conc. 97 – 103% 99.6% Column Temp. ±2 C R for all peaks >1.5 R for all peaks >2.0 Mobile Phase ±2 % R for all peaks >1.5 R for all l peaks >2.0 Sample extraction time -20 % Recovery in spec. Recovery in spec Compound stability 6 days <3% degradation <2% degradation Ludwig Huber - LabCompliance Slide 17 Maintain, Calibrate and Qualify Equipment and Computers • Develop procedures for equipment purchasing, qualification, calibration and maintenance • Qualify the equipment • Identify defect or non-qualified equipment • Develop and implement maintenance and qualification schedule • Keep equipment under change control and re-qualify, if necessary • Record changes © Copyright Ludwig Huber - LabCompliance Slide 18 Equipment Qualification - 4Q Model Design Qualification Installation Qualification Operational Qualification Performance Qualification © Copyright User requirement specifications Functional specifications Operational specifications Vendor qualification Check arrival as purchased Check proper installation of hardware and software Test of operational functions Performance testing Test of security functions Test for specified application Preventive maintenance On-going performance tests Ludwig Huber - LabCompliance Slide 19 OQ Test - Example Instrument BestBalance Serial number 55236A Maximal weight 11 g Control weight 1 10,000 mg Limit +-10 mg Control weight 2 1,000 mg Limit: +-1 mg Control weight 3 100 mg Limit: +- 0.1 mg Date Weight 1 Weight 2 Weight 3 2/3/06 9999.8 999.9 © Copyright 100.0 o.k. Test engineer Name Signature yes Hughes Ludwig Huber - LabCompliance Slide 20 Why Companies in EU/US Choose Manufacturers Operational Qualification Services Tools • Some tests require traceable test tools • The tools typically need to be calibrated yearly Qualification • Test engineers must be formally qualified • Training must be regularly updated and thoroughly documented • Manufacturer engineer bring qualification certificates along • Manufacturer engineers can fix problems if OQ does not pass Documentation • Vendors provide inspection ready documentation Compliance • There are many FDA warning letters based on user’s OQ • I am not aware of a vendor’s OQ based warning letter © Copyright Ludwig Huber - LabCompliance Slide 21 Documentation of On-going PQ Testing System Suitability Testing. Day-by-Day Test # Date mm/ day Time a=am p=pm T10 T11 T12 T13 T14 Bl noise Tailing factor Peak resol Precis. #1 Precis. #2 Accept Limit >2.0 Accept Limit <1% Accept Limit <1% Accept Accept Limit Limit <1x10-4 <1.3 Test # Date Time T10 T11 001 08/04 06.20 p 4.5x10-5 1.1 Comment Passed/ failed T12 T13 T14 Comment 2.3 0.61 0.50 passed 002 003 004 Example: HPLC System © Copyright Ludwig Huber - LabCompliance Slide 22 Computer System Validation Phases Design Qualification Configuration Installation Qualification Operational Qualification Performance Qualification © Copyright User requirement specifications Functional/config. specifications Vendor qualification Configuration design Configuration implementation Check arrival as purchased Check proper installation of hardware and software Test of configuration specifications Test of functional specifications Test of security functions Test for user requirement specifications Preventive maintenance Ludwig Huber - LabCompliance Slide 23 Implement Procedures for Sample Analysis • • • • Sampling Sample handling Testing Data review and approval Sampling © Copyright Sample handling& storage Testing Ludwig Huber - LabCompliance Data review and approval Slide 24 Sampling • Sampling process well planned, executed according to the plan and documented in the sampling protocol • Clean equipment to avoid cross contamination • Representative • Sample location well defined • Sampling should not change properties • Should protect people taking the sample Sampling © Copyright Sample handling& storage Testing Ludwig Huber - LabCompliance Data review and approval Slide 25 Reserve Samples (GMP only) • Samples used for retesting of the original sample if the initial test results is non-conforming (out of specifications) in the event of customer complaints • Typical amount: 1.5 x sample amount • Should be visually inspected for deterioration at least once a year © Copyright Ludwig Huber - LabCompliance Slide 26 Sample Testing • Develop test program for APIs, finished drugs, raw material • Develop clear specifications • Document acceptance criteria and actual results • Document test procedures and test equipment • Formally review and approve test results – Analysts – Second person (technical & independent reviewer) • Document test conditions with test results Sampling © Copyright Sample handling& storage Testing Ludwig Huber - LabCompliance Data review and approval Slide 27 Review and Approval of Test Results • Develop and follow procedure for review of test results • Review by the analyst: what to look at, how to document • Review and approval by a second person • Release of test results Sampling © Copyright Sample handling& storage Testing Ludwig Huber - LabCompliance Data review and approval Slide 28 Handling Failure Investigations / Out-of-Specification Test Results • • • • Investigation required if a test result is out of specification Required to identify the root cause of a problem Should follow documented procedure Failure can be caused by individual testing, process error, or product problem • Maintain a list of all OOS test results • Corrective and Preventive Action Plans, Root Cause Analysis Follow FDA Guide: Investigating out of Specifications Test Results for Pharmaceutical Production © Copyright Ludwig Huber - LabCompliance Slide 29 Tasks and Responsibilities of the Analyst • Perform test correctly - be aware of potential problems - follow SOPs - follow good science • Stop testing in case of OOS results • Inform supervisor about OOS results • Retain test preparations - until data is reviewed and investigation is finished • Conducts and documents OOS, each step of laboratory failure investigations and investigation results © Copyright Ludwig Huber - LabCompliance Slide 30 (e)-Records Maintenance and Archiving • Study regulations: which records are required, for how long should they be archived? • Define raw data • Ensure track-ability of final results to raw data • Maintain integrity of data • When using electronic records, follow Part 11 • Ensure that electronic audit trail is available, activated and reviewed • Develop a strategy and procedures for backup, archiving and retrieval of data Sampling © Copyright Sample handling& storage Testing Data review and approval Ludwig Huber - LabCompliance Record archiving Slide 31 Conduct Internal Laboratory Audits • Should be part of any good quality system • Develop audit plan and schedule • Develop and implement a corrective and preventive action plan • Plan for follow up inspections • Conduct audit like FDA inspections • Develop table of contents for each audit report © Copyright Ludwig Huber - LabCompliance Slide 32 Audit Documents for Internal and External Inspections • • • • • • • Organization charts Standard Operating Procedures Study protocol Data storage worksheets Notebooks: paper and/or electronic Analytical raw data Instrument qualification, calibration and maintenance protocols • Records on personnel qualification © Copyright Ludwig Huber - LabCompliance Slide 33 Prepare Your Organization for FDA and other Inspections • • • • • • • © Copyright Develop SOP for FDA inspections Develop Checklist Train management and staff Conduct ‘FDA inspection like’ internal audits Establish an audit response team Review previous inspections and corrective actions Reserve and prepare meeting rooms Ludwig Huber - LabCompliance Slide 34 Raw Data (1996) • Operating parameters were maintained with the relevant xxx. However, electronic raw data was not saved (W-167). 21 CFR Part 211: (e) Complete records shall be maintained of all stability testing performed in accordance with Sec. 211.194 (e). Study regulation and check if the print-out has all records © Copyright Ludwig Huber - LabCompliance Slide 35 FDA Enforcement: Mio$ 500 Fine • • • • • 30 products were banned from the US market • GMP violations • Inadequate testing • Falsified data • Data integrity issues FDA Press release on Jan 25, 2012 Prevents temporary import for products from two sites in India Causes pay cut for company executives and directors Ranbaxy to hire consultant with expertise in data integrity Possible delay of generic versions of blockbuster drugs (e.g. Lipitor) with uncalculatabled costs © Copyright Ludwig Huber - LabCompliance Slide 36 Raw Data (May 2013) • During an audit of the data submitted in support of the xxx tablets, our investigator requested to review the electronic analytical raw data to compare the values for (b)(4) assay and degradation products. However, your firm provided only the printed copies of the raw data because your firm did not have the software program available to view the electronic raw data. Study regulation and check if the print-out has all records © Copyright Ludwig Huber - LabCompliance Slide 37 Resources • Agilent Primers – Analytical Instrument Qualification and System Validation) – Validation of Analytical Methods – Good Laboratory Practice and Good Manufacturing Practice – Understanding and Implementing ISO/IEC 17025 – Compliance for BioPharmaceutical Laboratories – Qualification and Validation for Supercritical Fluid Chromatography – Elemental Impurity Analysis in Regulated Pharmaceutical Laboratories – Genotoxic impurities in pharmaceutical products • Free tutorials (method validation, computer validation, GLP) www.labcompliance.com/tutorial • Seminar reference material, e.g., ppt presentations www.labcompliance.com/agilent © Copyright (available until July 15, 2015 Ludwig Huber - LabCompliance Slide 38 Thank your very much for your attention. © Copyright Ludwig Huber - LabCompliance Page 39 Thank You I would like to thank • All attendees for your attention • Agilent Technologies for invitation and organization Give feedback and choose any two from over 150 documents (value: $138) for free: SOPS and/or Validation examples. GOTO: www.labcompliance.com/misc/conferences/feedback.aspx offer expires on July 15, 2013 Check topics and details of 100+ audio/video seminars Audio: www.labcompliance.com/seminars/audio Video: www.labcompliance.com/seminars/video Slide 40 Ludwig Huber © Copyright Ludwig Huber - LabCompliance Appendix Examples for FDA Warning Letters related to Laboratories and how to avoid them Reference: www.fdawarningletter.de © Copyright Ludwig Huber - LabCompliance Slide 41 Training • Failure to adequately establish procedures for identifying training needs and ensure all personnel are trained to adequately perform their assigned responsibilities and the training is documented (228) • Your firm fails to document on the job training.(228) • Your firm failed to list second shift quality personnel, their positions, and to whom they report within the corporate quality structure.(228) 1. Develop a training plan for each employee with identification of training needs 2. Document all training activities including on the job training and training of shift workers Ref: www.fdawarningletter.com (W-228) © Copyright Ludwig Huber - LabCompliance Slide 42 Supplier and Material Qualification • There is no assurance that your firm establishes the reliability of the supplier's analyses through appropriate validation of the supplier’s test results at appropriate intervals (W-245) • There are no incoming component specifications for acceptance and no supplier quality agreements (W-254) 1. Develop and implement a supplier assessment program 2. Regularly test incoming material Ref: www.fdawarningletter.com (W-228) © Copyright Ludwig Huber - LabCompliance Slide 43 Method Validation • The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented (W-187) • Failure of your quality control unit/laboratory to ensure your analytical methods used to evaluate the stability of your APIs are validated to be stability indicating. (W-243) 1. Develop procedure for validation of analytical methods 2. Follow ICH Q2 for selecting test parameters and conditions © Copyright Ludwig Huber - LabCompliance Slide 44 Method Changes • Failure to maintain complete records of any modification of an established method employed in testing [21 CFR § 211.194(b)] (W-171) • Specifically, the records of laboratory methods stored in the xxx computer system do not include the identity of the person initiating method changes. (W-171) • Appropriate controls are not exercised over computers or related systems to assure that changes in analytical methods or other control records are instituted only by authorized personnel. (W-171) Develop SOP on how to authorize and document changes to analytical methods © Copyright Ludwig Huber - LabCompliance Slide 45 Method Transfer The analytical method have not been transferred between the issued laboratory and the two chemists currently working in the QC laboratory. (W-241) • The methods have been transferred before the two chemists were hired. • There are no records which document training in the two procedures. (W-241) • Methods that were validated at one facility and transferred to xxx site are being used without a methods transfer or revalidation protocol. (W-186) • Develop SOP for analytical method transfer. Follow USP <1224>, Train analysts in the receiving lab © Copyright Ludwig Huber - LabCompliance Slide 46 Verification of Compendial Methods Method verifications for compendial tests are not performed. Any method, including compendial methods, must be verified as suitable under actual conditions of use. This has not been done for any method provided by your clients. (W-247) Develop procedures for verification of compendial methods following USP <1226> © Copyright Ludwig Huber - LabCompliance Slide 47 FDA Warning Letter/483/EIR • Your firm failed to conduct injector and detector performance testing for the HPLC system (221) • For example, no HPLC injector and detector testing for linearity, accuracy, and precision were conducted, such as: 1) various injection volumes and standard concentration testing; 2) evaluation of detector for noise/drift; and 3) carryover testing to evaluate response at low levels to determine the detection of possible interferences that may affect peaks of interest (221) Test HPLC for all parameters as specified © Copyright Ludwig Huber - LabCompliance Slide 48 Equipment • Lacks documentation of installation and operation qualification of equipment (160) • The Validation Master Plan does not contain an operational qualification for xxx (164) • There is no requirement for a Performance Qualification protocol (164) Perform IQ/OQ/PQ for Equipment Ref: www.fdawarningletter.com © Copyright Ludwig Huber - LabCompliance Slide 49 FDA Warning Letters - Equipment • Failure to have a complete calibration program for the HPLCs in that the gradient accuracy and detector linearity is not being verified (W-110) • The equipment xxxx used to analyze the Caffeine product was not calibrated prior to use. (W-019) 1. Learn about details of equipment qualification 2. Develop, implement and enforce procedures for equipment calibration and qualification © Copyright Ludwig Huber - LabCompliance Slide 50 FDA Warning Letter/483/EIR • There was no documentation that an investigation was conducted to determine the root cause of the failed calibrations of the Gas Chromatograph (GC) • In addition, your firm failed to implement adequate corrective action to prevent recurrence.“ (WL-240) 1. Investigate and document the root cause for failed calibration and qualification 2. Develop a corrective action plan © Copyright Ludwig Huber - LabCompliance Slide 51 FDA Warning Letter/483/EIR • The quality control unit failed to adequately train personnel to perform their duties for Operation of the Gas Chromatograph, and failed to follow procedures in the conduct of GC Calibrations. 1. Train operators when conducting instrument qualification and document the training 2. Request training certificate when done by equipment suppliers © Copyright Ludwig Huber - LabCompliance Slide 52 FDA Warning Letter/483/EIR • The calibration program for your stability chambers is deficient ill that it does not include specific directions and schedules. • You do not perform re-qualification of the stability chambers. 1. Develop a program for equipment calibration and calibration. Include a schedule 2. Conduct regular requalification of equipment © Copyright Ludwig Huber - LabCompliance Slide 53 FDA Warning Letter/483/EIR • No IQ, OQ or PQ has been performed throughout the life of the system. No validation reports have been generated historically (for the legacy system). • The (system) has not been maintained under established procedures for change control. This is true throughout the life of this software application. (W-190) Develop a procedure for validation and change control of legacy system. © Copyright Ludwig Huber - LabCompliance Slide 54 FDA Warning Letter/483/EIR • The validation results do not meet the pre-determined acceptance criteria, and there was no documentation why the results were acceptable. The validation reports do not contain an evaluation of the validation data and activities. Nor does it contain validation analyses and conclusion (W-204) 1. Develop a test plan. Part of it should be to define test cases acceptance criteria a procedure in case the criteria are not met. 2. During the review procedure, check if tests results meet acceptance criteria © Copyright Ludwig Huber - LabCompliance Slide 55 FDA Warning Letter/483/EIR • Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel (W-198). • There were no written protocols to assign levels of responsibilities for the system (W-209) Authorize users for specific functions Define user rights per procedure Reference: www.fdawarningletter.com © Copyright Ludwig Huber - LabCompliance Slide 56 Sampling, Sample Handling • Failure to retain reserve samples of each batch of each API (W-173) • Representative samples are not taken of each shipment of each lot of components for testing or examination (W245) • Certain elements of sample integrity are addressed in other SOPs, but none of the procedures explicitly call for maintaining sample integrity throughout the testing of the sample. (W-247) Develop sampling plan and SOP for sampling Ensure representative sampling © Copyright Ludwig Huber - LabCompliance Slide 57 FDA Warning Letter/483/EIR • "System suitability conducted for Dissolution Assay per laboratory test methods evaluates only five replicate injections for Relative Standard Deviation (RSD). For NMT 3%. USP requires six replicate injections for instrument precision and accuracy“ 1. Study USP requirements for System Suitability Testing 2. Develop , implement and audit tests © Copyright Ludwig Huber - LabCompliance Slide 58 Data Review • Laboratory records do not include the initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness and compliance with established standards. (W-241) • In addition, your firm's review of laboratory data does not include a review of an audit trail or revision history to determine if unapproved changes have been made.. (W229) Develop SOP for data review by analyst and independent second person Include review of electronic audit trail © Copyright Ludwig Huber - LabCompliance Slide 59 Data Manipulation • Our investigators also found many instances with extensive manipulation of data with no explanation regarding why the manipulation was conducted. • This manipulation would include changing integration parameters or re-labeling peaks such that previously resolved peaks would not be integrated and included in the calculation for impurities (W-203) Justify and document any data modification © Copyright Ludwig Huber - LabCompliance Slide 60 FDA Warning Letter/483/EIR • • • Data stored on the computer can be deleted, removed, transferred, renamed or altered (W-209) There should be a record of any data change made, the previous entry, who made the change, and when the change was made. (W-209) No software changes in the study data could be detected as there was no audit trail capability (W-185) Record any changes to data in an audit trail Reference: www.fdawarningletter.com © Copyright Ludwig Huber - LabCompliance FDA Warning Letter/483/EIR • There are no procedures for backing-up data files and no levels of security access established“ (W-138) • You had not established an electronic data back-up procedure (W-185) Procedures and technical controls for secure back-up © Copyright Ludwig Huber - LabCompliance Slide 62 Data Archiving • Records are issued from the record storage room without any written checkout procedures, and instead upon verbal direction by the QA manager. (W-247) • The document control SOP lists “quality manager” and “technical manager” under“ Responsibility” for document control, but does not clarify the individual roles of each. (W-247) Develop procedure with responsibilities and technical controls for data archiving © Copyright Ludwig Huber - LabCompliance Slide 63