27/05/2013 1 How to deal with regulatory GLP inspections. Th. Helder 2 Definition GLP Compliance Monitoring: The periodic inspection of test facilities and/or auditing of studies for the purpose of verifying adherence to GLP Principles 1 27/05/2013 OECD Council Decision-Recommendation C(89)87(Final) 3 Part I: GLP Principles and Compliance Monitoring Member Countries shall i. establish national procedures for monitoring compliance with GLP Principles, based on laboratory inspections and study audits ii. designate a national authority or authorities to discharge these procedures iii. …... Recommendation to apply Annexes I and II Annex II to OECD Council Decision-Recommendation 4 C(89)87(Final): Revised guidance for the conduct of laboratory inspections and study audits 2 27/05/2013 5 The Inspector Revised Guide No. 3: Inspectors should not concern themselves wth the scientific design of the study or the interpretation of the findings of studies with respect to risks for human health or the environment. These are the responsibility of those Regulatory Authorities to which the data are submitted for regulatory purposes. Before the Inspection 6 Probably requested and sent to inspectors: § floor plans § organograms § list of personnel, study directors § master schedule (GLP & non-GLP) § list of equipment § list of SOPs 3 27/05/2013 Regular GLP Inspection 7 1. Introductory meeting 2. Short tour 3. Review of documentation: personnel files, master schedule, SOPs, organograms, etc. 4. Inspection of laboratory areas 5. Study audits 6. QA interview 7. Exit meeting Introductory meeting 8 Who should attend: §Management §Head of QA §Heads of departments (also technical) §Study directors §Selected QA staff ? 4 27/05/2013 Introductory meeting 9 §Inspectors will outline of purpose and scope of inspection. §Management should give presentation of test facility: overview of history, departments, type of research etc. (best: PowerPoint presentation, 20-30 minutes). Introductory meeting 10 §Inspectors will ask for (updated) documentation : master schedule, study plans, SOPs, organisation charts, floor plans,CVs, training programs/records, list of SDs, list of consultants, etc. §Preliminary inspection scheme probably be given, otherwise ask for. §Offer room to work in. 5 27/05/2013 Short tour 11 §To familiarize the inspectors with the premises §Not more than an hour §Just give short explanations on what is done at the various locations Things to arrange 12 §Always escort the inspectors when inspecting §Inspectors will need a room to work in §No need to be present all the time, when inspectors are reading or auditing studies §QA must be present when inspectors are interviewing personnel or discussing studies with study directors and/or personnel 6 27/05/2013 For QA 13 §Always escort the inspector §Introduce department heads, study directors to inspector §Do not interrupt his interview, unless really necessary §Make sure the group is not over 6 persons §Make notes Review of Documentation 14 Make sure that: 1. Tasks and responsibilities are properly described and updated, organograms are correct 2. CV’s and training records &c are updated, signed, and kept in the archive 3. Copies of diplomas, certificates etc. of all personnel are included in files 7 27/05/2013 Review of Documentation 15 Make sure that: §master schedule is updated §indexes to SOPs and equipment are available §lists of study directors and other personnel are present Standard Operating Procedures 16 Points of concern: §immediate availability §procedures for revision/updating §authorisation/distribution §historical files §conciseness §no unofficial SOPs, draft SOPs §hand-written changes 8 27/05/2013 Facility inspection, all areas 17 Inspector will ask, look for and check: • what is done in this area and by whom • who has overall responsibility • to demonstrate activities • to see SOPs, notebooks, records • identification of study materials Facility inspection, all areas 18 Inspector may ask, look for and check: • calibration and maintenance schemes and records of equipment (refrigerators, pipettes, &c) • expiry dates, use and disposal of materials, solutions, chemicals &c • cleanliness, general housekeeping • assess suitability of design and location, adequate degree of separation • environmental control and monitoring procedures 9 27/05/2013 Animal house 19 Points of concern: §restricted entry, hygiene measures §adequacy for test systems and testing needs §satisfactory quarantine arrangements §isolation possibilities §health and behaviour monitoring and recordkeeping §water, bedding, filter systems §light/dark cycles Animal house 20 Points of concern: §adequate environmental conditions equipment §checks/records on environmental conditions §cleanliness of cages, racks, floors, etc. (procedures, records) §removal/disposal of waste and refuse §separate adequate storage areas for feed, bedding, etc. 10 27/05/2013 Test Systems 21 Points of concern: §as specified by study plans §adequate identification; records of receipt, use, disposal §proper identification of housing/containers §separation of studies Test Systems 22 Points of concern: §separation of animal species §possible interference of studies §environment (T, humidity, light cycles) as specified §recording of receipt, handling, care, health §recording of examination, morbidity, mortality, behaviour, treatment 11 27/05/2013 Test and Reference Substances 23 §records on receipt, handling, sampling usage, storage and disposal (full custody!!) §labeling §storage conditions Test and Reference Substances 24 §records on identity, purity, composition, stability determination §procedures for determination of homogeneity and stability of mixtures §samples for analytical purposes (not shortterm) 12 27/05/2013 Computerized systems 25 §Documentation (application descriptions, SOPs) §Maintenance and validation (disaster recovery) §Location (no interference, uninterrupted electrical supply) §Security (physical, logical) Computerized systems 26 §Change control (retrospective evaluation) §Data handling (back-ups, critical data) §Archiving (access control, long-term integrity, continuous readability) §Quality Assurance (training, specialist auditors, read-only access) 13 27/05/2013 Study audits 27 §Number of studies to be audited depends on number of studies performed, types of studies, number of study directors, &c. Study audits 28 Inspector will ask for complete file : §study plan §all raw data §records, notebooks §personnel files §correspondence §samples §pathology material: blocks, slides, &c 14 27/05/2013 Study audits 29 Points of interest: §sufficient involvement of study director? §study plan and amendments signed and dated? §measurements, observations, examinations in accordance with study plan and SOPs? §direct, accurate, legible records, signed and dated? Study audits 30 Points of interest: §changes of raw data? §reliable, accurate and validated equipment and computerised systems? 15 27/05/2013 Study audits 31 Points of interest in report: §correct study director's GLP compliance statement? §correct QA Statement? §amendments? §archive location list? Archiving 32 Points of concern: §appropriateness of archive facilities • security • water/fire/shock resistant • specific storage conditions §assignment of archivist, archive personnel §archivist tasks, responsibilities 16 27/05/2013 Archiving 33 Points of concern: §retrieval procedures §access procedures, records §inventory §retaining period, transfers §e-archiving Quality Assurance Programme 34 The inspector will check: •qualifications and responsibilities of all QA personnel • independency from study performance • QA schedule(s), identification of critical phases • extent and depth of study- and facility-based inspections • process-based inspections 17 27/05/2013 Quality Assurance Programme 35 The inspector will check: •extent and depth of study audits • reporting • actions taken • role in contract labs • other tasks Exit Meeting 36 • Will be held at end of inspection • Attendance: same as introducory meeting • Lead inspector will issue “List of Observations” • Items on this list may be shortly discussed 18 27/05/2013 Exit Meeting 37 •Management will be requested to reply on the list in 2-3 weeks • Reply must include all remedial actions taken or in preparation • Decision on GLP status of test facility will be made after receipt of reply • Inspection report will then be written and sent to test facility management GLP-Status 38 Not in compliance (NIC): § major deviations found, reliability of data not ensured § data not accepted, until lab is reinspected at own request Pending (Pen): § deviations found, not correctable within 1 month § reinspection including study audits after 3–6 months In compliance (IC): § no or minor deviations, correctable within 1 month 19 27/05/2013 Confidentiality 39 Confidential are: All information on GLP inspections and study audits except • list of laboratories inspected • areas of expertise • dates and nature of inspections • GLP compliance status of laboratories • study audit reports (for sponsors only, upon request) Full inspection and audit reports only available for laboratory and government authorities. Reports remain the property of the Dutch Government. The auditee's conduct I § Answering the questions – answer correctly – do not volunteer information – be not unco–operative – don't talk yourself into trouble – do not bluff § Taking actions – take action immediately if possible – otherwise make a plan Source: Allan J. Sayle, 1988 20 27/05/2013 The auditee's conduct II § Taking notes – for yourself – for the personnel involved – for management – as evidence Source, Allan J. Sayle, 1988 The "Dirty Dozen" I § Time wasting § The "Cook's tour" § Provocation § Fixed ballot § The "Special case" § Trial of strength Source: Allan J. Sayle, 1988 21 27/05/2013 Time Wasters § The waffler § The "dog and pony " show § The long lunch § The late arrival § The long way round § The forgotten document § Interruptions § The "clean room" § Lack of preparedness Source: Allan J. Sayle, 1988 The "Dirty Dozen" II § Insincerity § Pity § Absentees § Amnesia § Language barrier § Bribes Source: Allan J. Sayle, 1988 22 27/05/2013 45 Thank you !!! 23