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

2. Copyright Overview Regulations along the drug life Comparison US FDA and China CFDA GMPs Overview on inspection items and key points Quality management system requirements applicable for the entire laboratory GMP controls applicable for all workflow steps Inspection items along the sample and data workflow Slide 2

3. Slide 3 GxP Regulations Along the Drug Life Clinical Trials I, II, III, IV Preclinical Development Drug Discovery Disease Discovery Basic Research Manufacturing incl. APIs QC Laboratories GLPGMPNot RegulatedGCP 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 Submission & Review IND NDA Post Marketing Surveillance Slide 3

4. Copyright US-FDA CFR 211 GMP CFDA GMP A.General provisions B.Organization and personnel C.Buildings and facilities D.Equipment E.Control of components, /containers/ F.Production and process controls G.Packaging and labeling controls H.Holding and distribution I.Laboratory controls J.Records and reports K.Returned and Salvaged Drug Products 1.General Provisions 2.Quality management 3.Organization and personnel 4.Premises and facilities 5.Equipment 6.Materials and products 7.Qualification and validation 8.Documntation management 9.Production management 10.Quality control and QA 11.Contract manufacture and (contract) analysis 12.Product distribution / recalls 13.Self inspections 14.Supplementary provisions Slide 4

5. Copyright Comparison of US FDA and China CFDA In general: requirements are similar CFDA GMPs more modern –Up-to-date elements of quality management systems –Internal audits –Contract manufactoring and contract laboratories –Uses common up-to-date terminology,e.g., qualification and validation CFDA GMPs more specific CFDA GMPs based on WHO GMPs (EU GMP like) Slide 5

6. Copyright 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 Slide 6

7. Copyright 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 use 2. 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 Slide 7

8. Copyright Slide 8 Laboratory Inspection Items and Key Points Sampling Sample handling TestingTest reports Record maintenance Sampling plan & sampling documenting reserve samples Sample identification & protection of sample integrity Monitoring the quality of test results, generate complete records Test conditions & test results, review and signatures Ensure long term record integrity & security GMP controls across all workflow steps 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, Trace forward Trace backward Slide 8

9. Copyright 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? Slide 9

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

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

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

13. Copyright 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 Slide 13

14. Documenting Material Supplier Selection ItemsRequiremResultsPassed Recognition in the market place□ yes □ no Experience with the vendor□ yes □ no Quality assurance ISO Certification□ yes □ no Efficient complaint handling□ yes □ no Support Provide Certificates of Analysis□ yes □ no Provide expiration dates□ yes □ no Provides test methods□ yes □ no Phone and onsite support□ yes □ no Product offering Certified Reference Material□ yes □ no Slide 14

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

16. Copyright 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? Slide 16

17. Copyright Procedure for Qualification of Personnel 1.Define requirements - what is the assigned task? 2.Identify knowledge - education, experience, training 3.Determine gaps, identify training needs 4.Make a plan to fill the gaps 5.Train 6.Evaluate training 7.Document 1/2 year or yearly reviews Job description Slide 17

18. Copyright Documenting Training and Effectiveness Job description Qualification requirements Name Education Experience Gaps, Trainings plan Trainings Type, content Supervisor (name, signature) Date Duration n This documentation should be kept separated from other personnel files, for example performance evaluations Slide 18

19. Copyright 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 Slide 19

20. Copyright Design Qualification Installation Qualification Operational Qualification Performance Qualification Equipment Qualification Phases 4Q Model (USP, CFDA 139) l User requirement specifications l Functional specifications l Operational specifications l Vendor qualification l Check arrival as purchased l Check proper installation of hardware and software l Test of operational functions l Performance testing l Test of security functions l Test for specified application l Preventive maintenance l On-going performance tests HP/Agilent way since 1990, USP since 2007, CFDA 2010 Slide 20

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

22. Copyright OQ Test - Example Date Weight 1Weight 2 Test engineer NameSignature Weight 3o.k. yes 9999.8 999.9 100.0Hughes 2/3/06 InstrumentBestBalance Serial number55236A Maximal weight11 g Control weight 110,000 mgLimit +-10 mg Control weight 21,000 mgLimit: +-1 mg Control weight 3100 mgLimit: +- 0.1 mg Instrument ID Acceptance criteria Actual results Slide 22

23. Copyright Equipment Maintenance Logs Log ID DateType of Maintenance Person Performing Maintenance Equipment Owner Comment ________ From ________ To E.g., routine/non routine ____________ Printed Name ___________ Signature _________ Printed Name ___________ Signature E.g., recalibrated ________ From ________ To ____________ Printed Name ___________ Signature __________ Printed Name ___________ Signature “Preventive maintenance plans and procedures should be established, and the maintenance and repair activities should be recorded.” (CFDA 80) Slide 23

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

25. Slide 25 Document Software Vendor Selection RequirementsResultsPassed 1) Company□ yes □ no Experience with the vendor□ yes □ no Recognition in the market place 2) Quality Assurance ISO Certification□ yes □ no Documented software development□ yes □ no 3) Product functions (provide detailed list)□ yes □ no 4) Services and Support Provide specifications list□ yes □ no Installation service□ yes □ no IQ/OQ services□ yes □ no Phone and onsite support□ yes □ no Slide 25

26. Copyright 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 )? All methods and method changes approved? Testing methods should be validated or verified (CFDA 12). Slide 26

27. Copyright Method Validation Parameters for different Method Tasks Analytical Task Identifi- cation Impurity Quantitative Impurity Qualitative Assay AccuracyNoyesNoYes Precision Repeatability Intermediate Reproducibility No Yes No Yes Yes SpecificityYes Limit of detectionNo YesNo Limit of quantitationNoYesNo LinearityNoYesNoYes RangeNoYesNoYes RobustnessExpected to be done during Method Development Slide 27

28. Slide 28 Example: Report Summary Table Validation Parameter MeasureAcceptance criteriaResults Accuracy Recovery – Conc1 (80%) Recovery – Conc2 (100%) Recovery – Conc3 (120%) 97 – 103 % 99% 100% Method Precision RSD≤ 1.5 %0.4% Intermediate Precision RSD≤ 2.0 %0.8% SpecificityPeak Resolution Factor RR for all peaks >1.5 All peaks >2.0 Linearity Correlation Coefficient Visual inspection of plot ≥ 0.9900 Linear response plot 0.9900 Shows linearity Range Correlation Coefficient Precision at 3 concentrations Recovery at 3 Conc. ≥ 0.9900 ≤ 1.5 % 97 – 103% 0.9900 <1% 99.6% Robustness Column Temp. ±2 C Mobile Phase ±2 % Sample extraction time -20 % Compound stability 6 days R for all peaks >1.5 Recovery in spec. <3% degradation R for all peaks >2.0 R for all l peaks >2.0 Recovery in spec <2% degradation Ludwig Huber Slide 28

29. Copyright 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 Slide 29

30. Copyright 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 Slide 30

31. Copyright 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) Slide 31

32. Copyright 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? Slide 32

33. Copyright System Suitability Testing SOP: When, how, acceptance criteria Is USP Chapter 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 Slide 33

34. Copyright 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 Slide 34

35. Copyright 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? Slide 35

36. Copyright 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 Slide 36

37. Copyright 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? Slide 37 CFDA GMP 4: The manufacturer should strictly implement GMP with integrity. Any falsification and fraud is forbidden.

38. Copyright 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 Slide 38