Good Manufacturing Practices: WHO InspectionsTony Gould (Slides provided by Dr Andre van Zyl) Inspections To get started: Risk assessment (SOP) Scheduling Preparation Announce inspection Provide tentative inspection plan Inspect, prepare inspection report Review corrective action 2 | PQ Workshop, Abu Dhabi | October 2010 Inspections Inspections Done by teams of inspectors WHO inspector plus appointed from DRA (PICS member) Invite local inspector (DRA) Some cases observers and technical advisors Technical assistance (independent, no conflict of interest) 3 | PQ Workshop, Abu Dhabi | October 2010 etc) X X Other nonsterile APIs QC Laboratories CROs X X X 4 | PQ Workshop. isomerism.Current trends in Inspections RELATIVE RISK CATEGORY Guide to Manufacturer Risk Classification PRODUCT TYPE / ACTIVITY CRITICAL HIGH MEDIUM LOW Finished Products: Sterile finished products X X Non-sterile finished products APIs: Sterile APIs Nonsterile APIs where there is a special risk (e. Abu Dhabi | October 2010 .g. special risk of harmful impurities. polymorphism. global recall of batches • genotoxic substance (GMP. more than 80 deaths in USA • Investigated – FDA (GMP – sourcing of starting material. cleaning of tanks) • Morphic forms European law – FPP manufacturer's responsibility – Self. Abu Dhabi | October 2010 . economy – Initially mostly in Europe – now Asia (India and China) – control? 5 | PQ Workshop.APIs Why inspect? Quality – Heparin • Baxter – 2008. DRA Rationalization. Lopinavir /Ritonavir • Roche – 2008. contracted party. lack of control) – Nelfinavir. Abu Dhabi | October 2010 .API Parameters considered: • • • • • • • • • • • • 6 | Polymorphism Solubility in water Route of Synthesis Solvents used Impurities Sterile API Fermentation Toxicity Activity/potency Particle size Other properties to be considered Site compliance information (WHO/EDQM/Other) PQ Workshop. WHO GMP for APIs – ICH Q7 II. MATERIALS MANAGEMENT 7 | PQ Workshop. DOCUMENTATION AND RECORDS VII. LABORATORY CONTROLS XII. STORAGE AND DISTRIBUTION XI. VALIDATION V. PRODUCTION AND IN-PROCESS CONTROLS IX. Abu Dhabi | October 2010 . BUILDINGS AND FACILITIES VIII. PROCESS EQUIPMENT VI. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES X. PERSONNEL IV. QUALITY MANAGEMENT III. COMPLAINTS AND RECALLS XVI. REJECTION AND RE-USE OF MATERIALS XV.API XIII. REPACKERS. AND RELABELLERS 8 | PQ Workshop. CONTRACT MANUFACTURERS XVII. TRADERS. BROKERS. DISTRIBUTORS. CHANGE CONTROL XIV. Abu Dhabi | October 2010 . AGENTS. Increasing GMP requirements WHO GMP and Inspection of API manufacturers 9 | PQ Workshop. Abu Dhabi | October 2010 . APIMF 10 | PQ Workshop. route of synthesis. DMF. re-test dates vs expiry dates Incomplete dossier. Abu Dhabi | October 2010 .APIs Why inspect? Variations Change manufacturers and suppliers Different specifications. impurity profile Stability. BMR was not completed. No start time of the cooling process … no records of the temperature … for every 30 minute as required in the BMR… equipment logbook no entry… The SOP “cleaning of centrifuge bag” was incomplete…No evidence of: – dedicated bags – labeling of storage drums Also for fluid bed bags Risk of cross contamination 11 | PQ Workshop. Abu Dhabi | October 2010 .. although the step was already in progress.API Examples of observations of non-compliance in 2007 Batch records and SOPs Before steps were processed… a complete centrifugation operation before actual operation.. API Examples of major non-compliances (2009) Quality management – Lack of knowledge and experience – Deviations not reported – Change control incomplete Documentation – Recording of operations. release date before manufacturing date) – Storage and use . equipment cleaned in outside environment 12 | PQ Workshop. HVAC – poor design and controls – equipment cleaning – show product residue after cleaning. Abu Dhabi | October 2010 .FIFO Buildings and facilities – Water systems. also not reflecting all steps and full of errors – Incomplete process validation Materials management – Sampling (number of samples. Inspection of API manufacturers 35 30 25 20 15 10 5 0 2002 2004 2005 2006 2007 2008 2009 Number of sites Ave number observations 13 | PQ Workshop. Abu Dhabi | October 2010 . Abu Dhabi | October 2010 .Inspection of API manufacturers 2007 -2009. Inspections (disease areas) and number of observations Areas of non-compliance 40 35 30 25 20 15 10 5 0 Ave (total) obs per site Ave (Major) TB HIV/AIDS MAL 10 9 8 7 6 5 4 3 2 1 0 Major deficiencies Cross contamination Batch records Labeling Materials Management SOPs Cleaning 14 | PQ Workshop. Inspection of API manufacturers Summary of trends Number of inspections between '05 and '09 – 9 to 12. Low number in 2007 Highest number of inspections in India. Abu Dhabi | October 2010 . SOPs and documents. but lower number of major non compliances at malaria manufacturers Observations relating to material management. cleaning 15 | PQ Workshop. followed by China Observations range between 20 and 28 (low number in 2007) Lower number of observations in ARV manufacturers. Abu Dhabi | October 2010 .Inspection of FPP manufacturers To get started (FPP manufacturer): Product dossier submitted Listed as a manufacturer in a product dossier Assessment in progress Risk assessment Submit a SMF Announce inspection Provide tentative inspection plan Inspect. prepare inspection report – corrective action 16 | PQ Workshop. Inspection of FPP manufacturers Manufacturers: Normally over 4 days Covers all aspects of GMP – Quality management. Personnel – Utilities (e. Equipment. development batches and bio batches Quality control laboratory – specifications. Materials. Premises. Also data verification (dossier) including stability data. . Quality assurance. validation (process).g. Validation. Abu Dhabi | October 2010 . methods of analysis. . validation and qualification 17 | PQ Workshop. reference standards. water) . HVAC. Documentation. g. environmental monitoring) were lacking Incomplete (not detailed) qualification of HVAC. Abu Dhabi | October 2010 . water and computer systems 18 | PQ Workshop.FPP Findings Validation and qualification work was often incomplete Validation Master Plans (VMP) lacked details Validation policies as defined in the VMPs were not implemented Process validation was lacking Validated procedures (e. FPP Findings Insufficient filtration of air to production areas – No prevention of possible cross-contamination and contamination. shut down Filters: – not planned. monitored Pressure differential gauges not controlled. start up. or results not applied HVAC systems not controlled or monitored. tested (including installed filter leakage test). including filters No qualification of sampling areas and reverse unidirectional air flow units Temperature and RH mapping studies incomplete. classified. Abu Dhabi | October 2010 . including calibration and zero checks 19 | PQ Workshop. "As built" AHUs lacked components reflected in the schematic drawings. . new deviations opened on a deviation – Not authorized by production manager or QA prior to implementation – No assessment on impact. variations – Trends not reviewed / discussed – results merely reported Deviations – Not reported. some are opened.GMP . commitments. no routing to responsible persons – No qualification or validation – Wrong materials used (e. PQR – Not done annually – Not all data reported including starting materials. not additional testing Change control procedures not followed – No assessment on impact.g. MOC extension of PW loop) 20 | PQ Workshop.. Abu Dhabi | October 2010 . . software. errors not picked up – Computers. In process controls – Some less critical ones reported – Wrong results represented – Even though "fail" – reported as "pass" Qualification – – – – Often incomplete Wrong sequence Unreliable data "approved" and signed off despite non compliance with specifications. Abu Dhabi | October 2010 .GMP .. excel calculations Process validation – Lacking – Unreliable results 21 | PQ Workshop. re-testing was done. the results were recorded on a loose piece of paper. LIMS number 22 | PQ Workshop.g. method number.FPP OOS SOP for the reporting and investigation of Out of Specification (OOS) results not implemented No record of OOS results In case of an OOS. Abu Dhabi | October 2010 . no of samples. however. other sheets were not appropriately completed e. Abu Dhabi | October 2010 23 | . authorization by production supervisors up to 7 weeks after the rework was initiated.FPP Reworking materials / products: GMP allows in exceptional cases . Reworked batches were not subjected to additional testing including stability studies Only one of all the reworked batches was subjected to stability testing according to the stability plan. PQ Workshop. A rework was even initiated prior to the conclusion of the OOS investigation. Inappropriate authorization for the reworks including no prior authorization by QA.reworks were done on a routine basis. Inspection of FPP manufacturers Inspections by country 25 Number of sites 20 15 10 5 0 China Egypt India Country Morocco South Africa 2008 2009 Co-inspectors by country 14 Number of sites 12 10 8 6 4 2 0 Austr CH Es Fr Hu Country UK WHO SA DEN 2008 2009 Total 24 | PQ Workshop. Abu Dhabi | October 2010 . Abu Dhabi | October 2010 .Inspection of FPP manufacturers Observations 2008 and 2009 Number of observations 120 100 80 60 40 20 0 2008 Total 2009 Total 2008 Major 2009 Major 1 3 5 7 9 11 13 15 17 19 21 23 Number of sites Non compliant sites 10 8 25 Number 6 4 2 0 R H T M INJ OSD Disease group 2008 2009 Total 25 | PQ Workshop. Volunteers etc New York Times 2007 Data verification – identified misrepresentation of data Clinical part – Clinic. Pharmacy and related areas.Inspections of Contract Research Organizations (CROs) Clinical sites: Normally over 2 days Started 2004 -Covers all aspects of GCP and GLP – Ethical considerations. Protocol. data verification Bio-analytical part – Laboratory and data verification Statistical analysis 26 | PQ Workshop. Abu Dhabi | October 2010 . Abu Dhabi | October 2010 .27 | PQ Workshop. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Veterinary Medicine (CVM) May 2001 28 | PQ Workshop. Abu Dhabi | October 2010 .S.Inspections of Contract Research Organizations (CROs) Also: Guidance for Industry Bio-analytical Method Validation U. Abu Dhabi | October 2010 .Inspections of Contract Research Organizations (CROs) Clinical Part of the study Protocol. Ethics committee Volunteers Informed consent Source data and CRFs Bio-analytical part of the study Sample management Method validation and sample analysis 29 | PQ Workshop. Inspections of Contract Research Organizations (CROs) Main problems in some CROs: Many haven't done studies for "regulated market" submissions Lack of GCP and GLP regulations. Abu Dhabi | October 2010 . enforcement and compliance IEC not independent – set up by sponsors Manipulation of data No source data / records available (CRO and Sponsor) 30 | PQ Workshop. requirements. Abu Dhabi | October 2010 .Inspections of Contract Research Organizations (CROs) Examples of observations Half of the CRFs "missing" Source data destroyed accidently by fire or "monsoon" Sponsor claims the data were kept by the CRO. and the CRO claims the data were kept by the sponsor All data and retention samples destroyed as the product "expired" – even though the submission is still under evaluation 31 | PQ Workshop. Abu Dhabi | October 2010 .Inspections of Contract Research Organizations (CROs) Examples Half of the CRFs "missing" (at sponsor / CRO?). 43 appear to have been recorded from the same and single subject during a single session Manual integration and results not real 32 | PQ Workshop. destroyed as the product "expired" Out of 95 ECGs copied by the inspectors. source data destroyed accidently by fire or "monsoon". Inspections of Contract Research Organizations (CROs) Example: Numerous improper manual integrations were noted by the inspectors for QC samples. Such integrations were found both for the method validation and for the trial phase. 5: results were only obtained for 4 of the 6 QC samples and the results of 2 of these 4 samples fall out of acceptance limits. – subject No. Abu Dhabi | October 2010 . 5 and 20 should be rejected: – subject No. The status of the results of several QC samples was affected by these improper manual integrations Taking these corrected results into consideration the results of subjects No. 20: the results of both LQC samples fall out of acceptance limits. These integrations were corrected during the inspection by one staff member under control of one inspector. 33 | PQ Workshop.. Example discrepancies 34 | PQ Workshop. Abu Dhabi | October 2010 . Abu Dhabi | October 2010 .35 | PQ Workshop. Differences in chromatogram peak areas between the electronic raw data files and the printouts submitted to the WHO. 36 | PQ Workshop.Inspections of Contract Research Organizations (CROs) Recent observations included unreliable data such as: Discrepancies between electronic raw data files and data submitted in study reports for assessment. Batches that fail when data is calculated from raw data files during inspections (e. Inappropriate bio analytical method validation. for QC samples) even as these batches were presented as "passing" with values different from those actually obtained during subject sample analysis.g. Abu Dhabi | October 2010 . Improper manual integration of chromatograms observed during inspections even as "no manual integration" was reported. Number of inspections 60 50 40 30 20 10 0 2005 2006 2007 2008 2009 FPP API CRO QCL total 37 | PQ Workshop. Abu Dhabi | October 2010 . Abu Dhabi | October 2010 .That’s all… 38 | PQ Workshop.