Agilent Technologies, Inc. · NYSE:A
Agilent Technologies — Technical Presentation (2016)
31 slides from Agilent Technologies's technical presentation, 2016
Slide 1: Lessons from Pharmaceutical Laboratory related FDA Warning Letters
Lessons from Pharmaceutical Laboratory related FDA Warning Letters The Agilent Critical Compliance Seminar 2016 Ludwig Huber Ludwig_huber@labcompliance.com
Slide 2: Overview
Overview • FDA Inspections and reports • GMP compliance along the sample and data workflow • Recent FDA warning letters & 483s and recommendations how to avoid FDA warning letters related to – Requirements for quality systems – Requirements for workflow steps • Responding to Warning Letters and 483’
Slide 3: FDA Inspection Documentation
FDA Inspection Documentation • 483 Form Inspection Observation – only deviations listed – written for inspection exit meeting • Establishment Inspection Report (EIR) – very detailed (20-40 pages) – more like an inspection protocol • Warning letter – With significant deviations – Reviewed by FDA cent
Slide 4: What about Europe
What about Europe • EMA launched new version of the EudraGMDP website • Incudes statements of non-compliance with GMP and positive GMP certificates • Information includes company name, location, issue date, nature of no-compliance and the action taken by issuing authority in order to protect public
Slide 5: Example from EudraGMDP Website
Example from EudraGMDP Website Issue Date March 21 2014 Company and location Nature of non-compliance : It was not possible to confirm the validity of stability testing data. Several falsified and inaccurate results had been reported in long term stability and batch testing. Discrepancies between el
Slide 6: Typical Warning Letter Statement
Typical Warning Letter Statement • Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. • Include an explanation of each step taken to prevent the recurrence of violations and copies of supporting
Slide 7: Missing Roles and Responsibilities
Missing Roles and Responsibilities • Deviation Data security protocols are not established that describe the user's roles and responsibilities in terms of privileges to access, change, modify, create, and delete projects and data (242) • Root Cause (assumed) The company was not aware that user roles
Slide 8: Compliance across the GMP Lab
Compliance across the GMP Lab Trace forward Trace backward Sample Record Sampling Testing Test reports handling maintenance Sampling plan & Sample Monitoring the Test conditions Ensure representative identification & quality of test & test results, data record sampling, statistics protection of resu
Slide 9: Poor Quality System
Poor Quality System • It is apparent that you have not implemented a robust quality system at your firm. • Be advised that corporate management is responsible for ensuring the quality, safety, and integrity of drugs • FDA strongly recommends that your corporate management immediately undertake a com
Slide 10: No on-going GMP Training
No on-going GMP Training • Our review of your firm's training program disclosed that there was no requirement for on-going CGMP training of employees. • The firm only had an initial CGMP training and did not provide regular CGMP training to all employees involved in the manufacture of drug products.
Slide 11: No Supplier Quality Agreement
No Supplier Quality Agreement • Failure to establish and maintain the requirements, including quality requirements that must be met by suppliers. • For example, your firm has not specified quality requirements for suppliers, maintained lists of approved suppliers and developed written procedures des
Slide 12: Method Validation
Method Validation • The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented (W-187) The FDA frequently mentions these four parameters as the only required validation parameters, They are listed in CFR 211 but not sufficient. You need to do
Slide 13: Compendial Methods not Verified
Compendial Methods not Verified • Method verifications for compendial tests are not performed. Any method, including compendial methods, must be verified as suitable under actual conditions of use (W-274). Demonstrate that your laboratory is suitable to run compendial methods under actual conditio
Slide 14: No Formal Method Transfer
No Formal Method Transfer • The firm failed to determine the acceptability of ten methods prior to using them in the QC laboratory through formal method transfer procedures (282) • Methods that were validated at one facility and transferred to xxx site are being used without a methods transfer or re
Slide 15: No Equipment Qualification Program
No Equipment Qualification Program • The calibration procedure for HPLC systems is inadequate in that it did not include the detector’s linearity, injector’s reproducibility, and accuracy of temperature settings for the column heater (W-097) • Failure to have an adequate qualification (calibration)
Slide 16: No Failure Investigations for failed Calibrations
No Failure Investigations for failed Calibrations • There was no documentation that an investigation was conducted to determine the root cause of the failed calibrations of the Gas Chromatograph. • In addition, your firm failed to implement adequate corrective action to prevent re-occurrence..(W-240
Slide 17: No Computer Validation at the Users Site
No Computer Validation at the Users Site • During the inspection, I asked if the computer software has been validation to assure that it performs for it's intended use. • I was told that the software was validated by the manufacturer. The managing director provided me a copy of the letter the receiv
Slide 18: Excel Spreadsheets not Validated and Controlled
Excel Spreadsheets not Validated and Controlled • The calculation for residual solvent uses an Excel spreadsheet that has not been qualified. We are concerned about the data generated by your QC laboratory from non- qualified and uncontrolled spreadsheets • The use of the Excel® spreadsheets in anal
Slide 19: Inadequate System Suitability Testing
Inadequate System Suitability Testing • Methods do not include system suitability tests to ensure that the system is operating properly (W-162) • No System Suitability performance before running testing (132) • The SOP requirement for the assay analysis of xxx was not followed in that the HPLC syste
Slide 20: No SOP for Inadequate Handling of Out-of-Trend Results
No SOP for Inadequate Handling of Out-of-Trend Results • There is no standard operating procedure in place that describes the steps to be followed during an Out-of-Trend (OOT) Investigation • Besides, the "OOT Investigation" performed was inadequate. (W-241) 1. Study requirements for handling OOT re
Slide 21: Examples for Data Integrity Issues
Examples for Data Integrity Issues FDA Observations • Failure to maintain complete data derived from all lab tests • Failure to record activities at the time they are performed • Not reporting failing results • Conducting unofficial testing (trial injections) • Disabling electronic audit trails, una
Slide 22: No Procedure for Chromatographic Peak Integration and Re-integration
No Procedure for Chromatographic Peak Integration and Re-integration • The inspector documented that HPLC processing methods (including integration parameters) and re-integrations are executed without a pre-defined, scientifically valid procedure • A QC operator interviewed during the inspection sta
Slide 23: Trial Sample Injections not Recorded
Trial Sample Injections not Recorded • Our investigators identified your practice of performing trial sample injections for HPLC analyses. • For example, trial injections of stability samples were acquired in the “Test” folder prior to official testing. Immediately after the trial injections were co
Slide 24: Incomplete Raw Data
Incomplete Raw Data • Your Quality Unit failed to provide all spectra and raw data associated to the reports. (W-248) • The laboratory records do not include raw data to support the evidence of sample preparation, standards preparation and did not include a statement of the weight or measure of the
Slide 25: Electronic Raw Data not Saved
Electronic Raw Data not Saved • Operating parameters of the spectroscopy system were maintained with the relevant test records. However, electronic raw data was not saved (W-167). 21 CFR Part 211: (e) requires that complete records shall be maintained of all stability testing performed in accordance
Slide 26: Missing Audit Trail
Missing Audit Trail • Data stored on the computer can be deleted, removed, transferred, renamed or altered (W-209) • There is no audit trail or log of data changes that are made to the information in the database. (W-224) Develop procedural and technical controls to ensure electronic audit trail I
Slide 27: Electronic Audit Trail not Reviewed
Electronic Audit Trail not Reviewed • 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 a procedure for reviewing electronic audit trail Inform you laboratory staff that audit tr
Slide 28: Manipulation of Printed Raw Data
Manipulation of Printed Raw Data • Your firm's laboratory analyst had modified printed raw data related to the IR Spectra test • Your quality control unit failed to detect that IR spectra were being substituted by a laboratory employee and detect the manipulation or alteration of laboratory document
Slide 29: No Access to Information During Inspection
No Access to Information During Inspection • During the inspection, an analyst removed a USB thumb drive from a computer controlling an HPLC. When asked to provide the drive, the analyst instead exited the room with the thumb drive. • After approximately 15 minutes, management provided our investiga
Slide 30: Responding to Inspection Deviations
Responding to Inspection Deviations • Fully understand the content of each deviation in the exit meeting • Respond in time (15 days for FDA Warning Letters and 483s) • Address each item separately in the response • Start with a statement that you understand and accept the deviation • If some deviati
Slide 31: Resources
Resources www.labcompliance.com/agilent (available until April 30, 2016) • Agilent Primers – Analytical Instrument Qualification and System Validation – Understanding and Implementing ISO/IEC 17025 – Compliance for BioPharmaceutical Laboratories Version 2 (2015) – Compliance by Design“ for Quality C