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Lab Inspections based on US FDA and China GMPs

Lab Inspections based on US FDA and China GMPs. The Agilent Pharma Compliance and Validation Seminar and Workshop. Dr. Ludwig Huber Ludwig_huber@labcompliance.com. Overview. Regulations along the drug life Comparison US FDA and China CFDA GMPs

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Lab Inspections based on US FDA and China GMPs

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  1. Lab Inspections based on US FDA and China GMPs The Agilent Pharma Compliance and Validation Seminar and Workshop Dr. Ludwig Huber Ludwig_huber@labcompliance.com

  2. Overview • Regulations along the drug life • Comparison US FDA and China CFDA GMPs • Overview on inspectionitemsandkeypoints • Quality managementsystemrequirementsapplicablefortheentirelaboratory • GMP controlsapplicablefor all workflowsteps • Inspectionitemsalongthe sample anddataworkflow

  3. GxP Regulations Along the Drug Life Clinical TrialsI, II, III, IV Manufacturingincl. APIsQC Laboratories Basic Research Disease Discovery Drug Discovery Preclinical Development Not Regulated GLP GCP GMP PostMarketingSurveillance NDA IND Submission & Review Part 11 applies for computers that are used in all FDA regulated areas GLP: Good Laboratory Practices GMP: Good Laboratory Practices GCP: Good Clinical Practices GLP+GCP+GMP = GxP = Predicate Rules IND = Investigational New Drug NDA: New <drug Application Slide 3

  4. US-FDA CFR 211 GMP CFDA GMP • General Provisions • Quality management • Organization and personnel • Premises and facilities • Equipment • Materials and products • Qualification and validation • Documntation management • Production management • Quality control and QA • Contract manufacture and (contract) analysis • Product distribution / recalls • Self inspections • Supplementary provisions • General provisions • Organization and personnel • Buildings and facilities • Equipment • Control of components, /containers/ • Production and process controls • Packaging and labeling controls • Holding and distribution • Laboratory controls • Records and reports • Returned and Salvaged Drug Products

  5. Comparison of US FDA and China CFDA • In general: requirementsaresimilar • CFDA GMPs more modern • Up-to-date elementsofqualitymanagementsystems • Internal audits • Contractmanufactoringandcontractlaboratories • Usescommonup-to-date terminology,e.g., qualificationandvalidation • CFDA GMPs morespecific CFDA GMPs based on WHO GMPs (EU GMP like)

  6. Level of Detail – Equipment Qualification US FDA (211.68) • Equipment shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained China CFDA (article 90) • Equipment should be regularly calibrated and checked according to procedures, in order to ensure their proper functioning. Calibration and checks should be recorded accordingly. So far no difference

  7. Level of Detail – Equipment Qualification China CFDA • Article 139: Equipment and testing instruments should be qualified 1. Design qualification is to verify that the design of the equipment is suitable for the intended use2. Installation qualification is to verify that the premises, facilities and equipment have been built and installed in accordance with their design specifications;3. Operational qualification is to verify that the premises, facilities and equipment operate in accordance with their design specifications;4. Performance qualification is to verify that the premises, facilities and equipment, under normal operating procedures and process conditions, can consistently meet performance specifications; • Article 144: Qualification and validation should not be considered as a one time activity. After initial qualification and validation, requalification or revalidation should be carried out. Similar to USP <1058>

  8. Laboratory Inspection Items and Key Points Trace forward Trace backward Sampling Sample handling Testing Test reports Record maintenance GMP GMP controls across all workflow steps Monitoring the quality of test results, generatecomplete records Test conditions & test results, review and signatures Sampling plan & sampling documentingreserve samples Sample identification & protection of sample integrity Ensure long term record integrity & security • Validation of analytical methods & procedures • Equipment calibration testing & maintenance • Qualification of material • Handling Out-of-specification results • Qualification of personnel • Controlled environmental conditions • Written procedures Quality management system controls across the laboratory Organization, documentation control, complaint handling, corrective & preventive actions, supplier & subcontractor management, internal audits, change management, management reviews, product reviews, continuous improvement, QS Slide 8

  9. Inspecting the Laboratory Quality System • Quality manual and or policy? • Org. chart with responsibilities? • Supplier assessment program? • Chemicals, reference standards, equipment? • Internal audit program? • Change control procedures? • Regular management review? • Risk management? • Complaint handling • Continuous improvement • Corrective and preventive action plans? Is there a documented QS system and is it followed?

  10. Build the Right Organizational Structure - avoid conflict of interest - Director Finance & Admin. Human Resources Laboratory Mgmt. Quality Assurance IT/IS Safety Officer Lab 1 Lab 2 Lab 3

  11. Develop GMP Compliant Documentation PolicyMaster Plan High level, strategic documentation(regulations, business, quality) Training Maintenance Validation, Audits Process related documentation, approaches(SOPs) Written procedures Test procedures Operating manuals, QC procedures Product/event related documentation(work instructions, also called SOPs or test scripts, protocols) Laboratory records(event related documentation) Product test records, validation results, training records, chromatograms, log-book entries

  12. Use Consistent Documentation Across the Company • Validation master plan • Supplier qualification • Risk assessment • Validation procedures • Templates for records • Improves efficiency • Improves consistency

  13. Reference and other Materials and Supplies • Supplier assessment? • ISO 9000? • Check of incoming material? • Procedure? • Procedure for preparation of working standards from primary standards? • Procedure validated? • Reagents/chemicals labeled? • Date of preparation, concentration, expiration date? Is the material in in the box same as the label

  14. Documenting Material Supplier Selection

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

  16. Personnel • Adequate number in line with assigned tasks? • Descriptions of tasks and requirements for each job? • Qualification records? • Training plans? • Training plans followed? • Trainings documented? • Verification and documentation of effectiveness? • Ongoing evaluation? • GMP training? Are there enough qualified people for the assigned task?

  17. Procedure for Qualification of Personnel Job description • Define requirements - what is the assigned task? • Identify knowledge - education, experience, training • Determine gaps, identify training needs • Make a plan to fill the gaps • Train • Evaluate training • Document ongoing Maintain qualification 1/2 year or yearly reviews

  18. Documenting Training and Effectiveness 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

  19. Equipment • List of all equipment? • Calibration? • Timely? • Qualification? • Timely? • Maintenance? • Labeling with status • calibrated, out-of-service? • Log-books? • Records: qualification/calibration/maintenance? Is the instrument suitable for the intended use

  20. Design Qualification Installation Qualification Operational Qualification Performance Qualification Equipment Qualification Phases 4Q Model (USP <1058>, CFDA 139) • 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 HP/Agilent way since 1990, USP since 2007, CFDA 2010

  21. DQ – Selected Functional Specs Verifies that the design of the equipment is suitable for the intended use (CFDA 139)

  22. 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 • Instrument ID • Acceptance criteria • Actual results

  23. Equipment Maintenance Logs “Preventive maintenance plans and procedures should be established, and the maintenance and repair activities should be recorded.” (CFDA 80)

  24. Computer System Validation – 4Q+ • User requirement specifications • Functional/config. specifications • Vendor qualification Design Qualification Configuration • Configuration design • Configuration implementation • E.g., User acess rights Validation Plan Validation Report • Check arrival as purchased • Check proper installation of hardware and software Installation Qualification • Test of configuration specifications • Test of functional specifications • Test of security functions Operational Qualification • Test for user requirement specifications • Preventive maintenance Performance Qualification

  25. Document Software Vendor Selection Slide 25

  26. Analytical Methods and Procedures • SOP for validation? • Validation parameters, tests, acceptance criteria defined? • Verification of standard methods? • SOP for method transfer? • Scope defined? • Change control? • When is revalidation required (USP chapter <621>)? • All methods and method changes approved? Testing methods should be validated or verified (CFDA 12).

  27. ICH Q2 Method Validation Parameters for different Method Tasks

  28. Example: Report Summary Table Ludwig Huber Slide 28

  29. Sampling and Sample Handling • Developing a sampling plan • Documentation of the sampling system • Ensure representative sampling: a major FDA concern • Prevent deterioration during sample transfer • Maintain and document sample integrity • Keeping and regularly inspect reserve/reference samples Sampling Sample handling&storage Testing Data review and approval

  30. Easy to handle Easy to read Sampling Plan Contents • Type of sampling equipment • Sampling method • Sampling frequency • Sample amount • Exact sampling location and places • Documentation how representative sampling is ensured • Any safety or other precautions • Amount of reserve/reference samples • Instructions for cleaning and storage of sampling tools

  31. Reserve/Reference Samples - • 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 • Reserve/reference samples should be taken from the same homogeneous material that was originally collected from the lot, tested, and yielded the original results. CFDA: The reference samples should be visually examined at least once a year during storage period (article 225) US FDA: Reserve samples should be visually inspected every year for possible deterioration (FDA)

  32. Sample Handling • SOP: transfer, registration, labeling • Ensure sample integrity? • Storage conditions: temperature, humidity? • Avoid cross contamination? • Storage and inspection of reserve samples? • Sample stability during storage time before analyzed? • Sample tracking? How did you ensure sample integrity?

  33. System Suitability Testing • SOP: When, how, acceptance criteria • Is USP Chapter <621> followed for chromatography? • Are critical parameters defined for non-chromatographic systems? • Is the frequency defined by procedures? • Are procedures followed? • Are results documented? • Are deviations handled by failure investigations? Do system suitability tests check for critical parameters

  34. Sample Testing • Develop test program for APIs, finished drugs, raw material • Document clear specifications before testing • Document acceptance criteria and actual results • Ensure qualification of equipment • 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

  35. Inspection Questions related to Out-of-Specification Test Results • Can you show me a list of OOS results from the last 6 months? • Is there a procedure for OOS situations? • Are investigations completed in a timely manner? • Are investigations documented properly? • Are investigation findings subject to proper review? • Does the procedure include root cause analysis, impact analysis, and corrective actions and preventive actions?

  36. Data Review and Approval • Procedure for review: who, what, when, checklist? • Review if technically correct? • All peaks resolved? • Correct chromatographic baseline • Correct calculations? • Unexpected peaks? • All supporting material available • Chromatograms, spectra? • All raw and meta data available? • Review and approval by second person? • Supervisor? QA? Are test results reviewed, approved and documented

  37. Recording and Archiving of Data • Raw data defined? Are records complete? • Procedure on how to maintain and archive records • Paper, electronic, original electronic format, standard files? • Integrity of paper records • Permanent ink? • Original record readable after change? • Integrity of electronic records? • Part 11 controls, e.g., electronic audit trail? • Electronic archiving system • Validated, secure, availability of data? Which controls are in place to ensure data integrity? CFDA GMP 4: The manufacturer should strictly implement GMP with integrity. Any falsification and fraud is forbidden.

  38. FDA Statement about Deleting HPLC e-Raw Data after Printing • The printed paper copy of the chromatogram would not be considered a “true copy” of the entire electronic raw data used to create that chromatogram, as required by 21 CFR 211.180(d). • The chromatogram does not generally include, for example, the injection sequence, instrument method, integration method, or the audit trail, of which all were used to create the chromatogram or are associated with its validity • Therefore, the printed chromatograms used in drug manufacturing and testing do not satisfy the predicate rule requirements in 21 CFR Part 211. • The electronic records created by the computerized laboratory systems must be maintained under these requirements http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124787.htm

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