FDA/EU Compliance for Quality Control Laboratories

FDA/EU Compliance for Quality Control Laboratories
4/24/2017 FDA/EU Compliance for Quality Control Laboratories Ludwig Huber, Ph.D Chief Advisor, Global FDA Compliance Ludwig Huber Phone: Page 1

Overview Planning for GMP compliance
4/24/2017 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

GMP and ISO 17025 Laboratory Compliance
4/24/2017 GMP and ISO Laboratory Compliance Sampling Sample handling& storage Testing Data review and approval Record archiving Representative Sampling Sampling plan Avoid cross Contamination Ensure sample integrity Clear specifications & test protocols Primary & secondary review Handling OOS Ensure data availability Compliance across all workflow steps Validation of analytical methods & procedures Equipment calibration testing & maintenance Qualification of material Traceability Control of non-conforming testing Qualification of personnel Controlled environmental conditions Written procedures Incremental costs: 20-30%

Plan for GMP/ISO 17025 Compliance
4/24/2017 Plan for GMP/ISO 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

Contents of the Master/Quality Plan
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 or

Develop Procedures and other Documents
Policy Master Plan High level, strategic documentation (regulations, business, quality) Training Maintenance Validation, Audits Process related documentation, approaches (SOPs) Written procedures Product/event related documentation (work instructions, also called SOPs or test scripts, protocols) Test procedures Operation manuals, QC procedures Compliance Records (batch/event related documentation) Product test records, batch records, validation results, training records, chromatograms Check Regulations Use the same set throughout the organization

Build the Right Organizational Structure and Assign Tasks (Example)
4/24/2017 Build the Right Organizational Structure and Assign Tasks (Example) Director Finance & Admin. Human Resources Laboratory Mgmt. Quality Assurance IT/IS Safety Officer Lab 1 Lab 2 Lab 3 Avoid Conflicts of Interest

Maintain qualification
Qualify Personnel Job description Define requirements - what is the assigned task? Identify knowledge Determine gaps Make a plan to fill the gaps Train Evaluate training Document ongoing Maintain qualification 1/2 year or yearly reviews

Evaluate and document success of the training
Documenting Training Job description Qualification requirements Trainings Supervisor (name, signature) Name Type, content Education Experience Date Duration Gaps, Trainings plan This documentation should be kept separated from other personnel files, for example performance evaluations Evaluate and document success of the training

Qualify Suppliers and Materials
Documenting internal and external experience Mail audit with follow up Direct audit Criteria Product risk Supplier risk #3. is most time consuming and recommended for high volume and high risk suppliers

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) Labeling

Preparation of Working Standards
Primary Standard Certified Reference Material Secondary Standard Company Internal Reference Material Working Standard Method Validation Equipment Calibration System Performance Check

Validate Analytical Methods
4/24/2017 Validate Analytical Methods Sample matrix Compounds Equipment, Location Definition Method Scope Optimize method parameters Define performance characteristics Acceptance criteria Define Validation Criteria Validation Report Validation Plan Develop test cases Preliminary tests Final tests Test SOPs System Suitability tests Analytical quality control Define Routine Tests

Method Parameters and Tests
ICH Q2 Method Parameters and Tests Parameter Tests (examples) Accuracy Minimum at 3 concentrations, 3 replicates Precision Repeatability Intermediate Reproducibility Minimum of 9 determinations over the specified range Over 3 days, 2 operators, 2 instruments, Only required if testing is done in different laboratories Specificity Prove with specific methods: HPLC, DAD, MS, dif. columns Limit of detection Visual approach, S/N >= 3 Limit of Quantitation 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

Intermediate Precision Example
Sample Day Operator Instrument 100% conc. (3x) 1 2 3 Minimum: 2 days, 2 operators, 2 instruments, Calculate overall RSD

Examples for Acceptance Criteria
Quantitative Impurities in Finished Drugs Parameter Test Accuracy 90 – 110%, 80 – 120% at specifications limit Precision Repeatability Intermediate Reproducibility <1.5 % RSD (up to 15% at LOQ) <2.0 % RSD (higher at LOQ) < 3% RSD (higher at LOQ) Specificity Peak resolution >1.5 (related substances) or >2 (main peak) Peak purity check with UV DAD or MS Limit of Detection N/A Limit of Quantitation 0.05% Linearity visual inspection of linearity curve, r>0.9900 Range o.k. if accuracy, precision, linearity criteria are met

Example: Report Summary Table
Validation Parameter Measure Acceptance criteria Results Accuracy Recovery – Conc1 Recovery – Conc2 Recovery – Conc3 97 – 103 % 99% 100% Method Precision RSD ≤ 1.5 % 0.4% Intermediate Precision ≤ 2.0 % 0.8% Specificity Peak Resolution Factor R R for all peaks >1.5 All peaks >2.0 Linearity Correlation Coefficient Visual inspection of plot ≥ Linear response plot 0.9900 Shows linearity Range Precision at 3 concentrations Recovery at 3 Conc. 97 – 103% <1% 99.6% Robustness Column Temp. ±2 C Mobile Phase ±2 % Sample extraction time -20 % Compound stability 6 days Recovery in spec. <3% degradation R for all peaks >2.0 R for all l peaks >2.0 Recovery in spec <2% degradation

Maintain, Calibrate and Qualify Equipment and Computers
4/24/2017 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

Equipment Qualification - 4Q Model
4/24/2017 USP 1058 Equipment Qualification - 4Q Model User requirement specifications Functional specifications Operational specifications Vendor qualification Design Qualification Installation Qualification Operational Qualification Performance Qualification Check arrival as purchased Check proper installation of hardware and software Validation Report Validation Plan Test of operational functions Performance testing Test of security functions Test for specified application Preventive maintenance On-going performance tests

OQ Test - Example yes 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: mg Date Weight 1 Weight 2 Test engineer Name Signature Weight 3 o.k. yes 9999.8 999.9 100.0 Hughes 2/3/06

4/24/2017 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

Documentation of On-going PQ Testing
System Suitability Testing. Day-by-Day Test # Date Time T10 T11 T12 T13 T14 Comment Bl noise Tailing factor Peak resol Precis. #1 Precis. #2 mm/ day a=am p=pm Accept Limit <1x10-4 Accept Limit <1.3 Accept Limit >2.0 Accept Limit <1% Passed/ failed Test # Date Time T10 T11 T12 T13 T14 Comment 001 08/04 06.20 p 4.5x10-5 1.1 2.3 0.61 0.50 passed 002 003 004 Example: HPLC System

Computer System Validation Phases
4/24/2017 Computer System Validation Phases User requirement specifications Functional/config. specifications Vendor qualification Design Qualification Configuration Configuration design Configuration implementation Validation Plan Installation Qualification Check arrival as purchased Check proper installation of hardware and software Validation Report Operational Qualification Test of configuration specifications Test of functional specifications Test of security functions Test for user requirement specifications Preventive maintenance Performance Qualification

Implement Procedures for Sample Analysis
Sampling Sample handling Testing Data review and approval Sampling Sample handling& storage Testing Data review and approval

4/24/2017 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 Sample handling& storage Testing Data review and approval

Reserve Samples (GMP only)
4/24/2017 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

4/24/2017 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 Sample handling& storage Testing Data review and approval

Review and Approval of Test Results
4/24/2017 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 Sample handling& storage Testing Data review and approval

Handling Failure Investigations / Out-of-Specification Test Results
4/24/2017 GMP only 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

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 Checklist

(e)-Records Maintenance and Archiving
4/24/2017 (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 Sample handling& storage Testing Data review and approval Record archiving

Conduct Internal Laboratory Audits
4/24/2017 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

Audit Documents for Internal and External Inspections
4/24/2017 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

Prepare Your Organization for FDA and other Inspections
4/24/2017 Prepare Your Organization for FDA and other Inspections 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

Electronic raw data not saved
Hybrid system Operating parameters were maintained with the relevant xxx. However, electronic raw data was not saved (W-167). Electronic raw data not saved 21 CFR Part 211: (e) Complete records shall be maintained of all stability testing performed in accordance with Sec (e). Predicate rule Study regulation and check if the print-out has all records

FDA Enforcement: Mio$ 500 Fine
4/24/2017 FDA Enforcement: Mio$ 500 Fine 2012 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

Raw Data (May 2013) Raw data not saved
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. Raw data not saved Study regulation and check if the print-out has all records

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) Seminar reference material, e.g., ppt presentations (available until July 15, 2015

Thank your very much for your attention.
Questions?

Thank You I would like to thank All attendees for your attention
4/24/2017 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: offer expires on July 15, 2013 Check topics and details of 100+ audio/video seminars Audio: Video: Ludwig Huber

Appendix Examples for FDA Warning Letters related to Laboratories and how to avoid them Reference:

Training Training needs Shift workers
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) Shift workers Develop a training plan for each employee with identification of training needs Document all training activities including on the job training and training of shift workers Ref: (W-228)

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) Develop and implement a supplier assessment program Regularly test incoming material Ref: (W-228)

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) Develop procedure for validation of analytical methods Follow ICH Q2 for selecting test parameters and conditions

Method Changes Failure to maintain complete records of any modification of an established method employed in testing [21 CFR § (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

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

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>

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) HPLC Injector/Detector/Carry Over Testing Test HPLC for all parameters as specified

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) IQ/OQ PQ Perform IQ/OQ/PQ for Equipment Ref:

FDA Warning Letters - Equipment
4/24/2017 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) Calibration program Learn about details of equipment qualification Develop, implement and enforce procedures for equipment calibration and qualification

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) Invalid GC calibration not investigated Investigate and document the root cause for failed calibration and qualification Develop a corrective action plan

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. Operators not trained on Instrument Calibration Train operators when conducting instrument qualification and document the training Request training certificate when done by equipment suppliers

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. No requalification of equipment Develop a program for equipment calibration and calibration. Include a schedule Conduct regular requalification of equipment

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) Legacy System not validated and controlled Develop a procedure for validation and change control of legacy system.

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) Test results don't meet acceptance criteria Develop a test plan. Part of it should be to define test cases acceptance criteria a procedure in case the criteria are not met. During the review procedure, check if tests results meet acceptance criteria

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) Computer controls not authorized Authorize users for specific functions Define user rights per procedure Reference:

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 (W-245) 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

"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“ Insufficient number of SST test runs Study USP requirements for System Suitability Testing Develop , implement and audit tests

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.. (W-229) Develop SOP for data review by analyst and independent second person Include review of electronic audit trail

Data manipulation without justification
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) Data manipulation without justification Justify and document any data modification

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) Data changed without audit trail Record any changes to data in an audit trail Reference:

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) No procedures for data backup Procedures and technical controls for secure back-up

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

FDA/EU Compliance for Quality Control Laboratories

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