1 / 63

FDA/EU Compliance for Quality Control Laboratories

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

normam
Download Presentation

FDA/EU Compliance for Quality Control Laboratories

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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

  2. 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

  3. GMP and ISO 17025 Laboratory Compliance Sampling Sample handling&storage Testing Data review and approval Record archiving Avoid cross Contamination Ensure sample integrity Clear specifications & test protocols Primary & secondary review Handling OOS Ensure data Integrity @ availability Representative Sampling Sampling plan 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%

  4. 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

  5. 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

  6. Develop Procedures and other Documents PolicyMaster 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

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

  13. 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

  14. ICH Q2 Method Parameters and Tests Well Characterized Biological Products

  15. Intermediate Precision Example • Minimum: 2 days, 2 operators, 2 instruments, • Calculate overall RSD

  16. Examples for Acceptance Criteria Quantitative Impurities in Finished Drugs

  17. Example: Report Summary Table

  18. 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

  19. Design Qualification Installation Qualification Operational Qualification Performance Qualification USP 1058 Equipment Qualification - 4Q Model • User requirement specifications • Functional specifications • Operational specifications • Vendor 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

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

  21. 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

  22. Documentation of On-going PQ Testing System Suitability Testing. Day-by-Day Example: HPLC System

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

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

  25. Sampling • Sampling process well planned, executed according to the plan and documented in the sampling protocol • Clean equipment to avoidcross 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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

  31. (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

  32. 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

  33. 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

  34. 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

  35. Raw Data (1996) 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. 211.194 (e). Predicate rule Study regulation and check if the print-out has all records

  36. 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

  37. 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. Raw data not saved Study regulation and check if the print-out has all records

  38. 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 (available until July 15, 2015

  39. Thank your very much for your attention. Questions?

  40. 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.aspxoffer 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 Ludwig Huber

  41. Appendix Examples for FDA Warning Letters related to Laboratories and how to avoid them Reference: www.fdawarningletter.de

  42. Training Training needs • 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: www.fdawarningletter.com (W-228)

  43. 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: www.fdawarningletter.com (W-228)

  44. 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

  45. 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

  46. 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

  47. 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>

  48. 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

  49. Equipment IQ/OQ • 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) PQ Perform IQ/OQ/PQ for Equipment Ref: www.fdawarningletter.com

  50. 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

More Related