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17 December 2012EMA/INS/GMP/758453/2012Compliance and InspectionEVALUATION GUIDE FOR GMP REGULATORYCOMPLIANCE PROGRAMMEAudit Checklist(Revision 2 including API and common with Canada and PIC/S)7 Westferry Circus Canary Wharf London E14 4HB United KingdomTelephone 44 (0)20 7418 8400 Facsimile 44 (0)20 7418 8595E-mail info@ema.europa.eu Website www.ema.europa.euAn agency of the European Union European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged.
1 - Legislative and Regulatory Requirements andScopeSummary of the Audit ChecklistSub-component1A - Empowering legislation1B - Conflict of interest2 - Regulatory directives and policiesImportanceCriticalVeryimportantEvaluation methodDocumentation reviewDocumentation reviewOn-site evaluation at Inspectorate2A - Procedures for designating inspectorsVeryimportantDocumentation review2B - Enforcement Policies-Evaluated as part of sub-component7B2C - Code of conduct/ Code of ethicsVeryimportantDocumentation review2D - Training certification policies/guidelines-Evaluated as part of sub-component4C2E - Alert/crisis managementpolicies/procedures/guidelines-Evaluated as part of sub-component8A2F - Organisational structure-Evaluated as part of sub-component11A3A - Details/ scope of GMPCriticalDocumentation review3B - Process validation-Evaluated as part of sub-component3A4A - Staffing: Initial qualificationVeryimportantDocumentation reviewOn-site evaluation at Inspectorate4B - Number of inspectorsVeryimportantDocumentation reviewOn-site evaluation at Inspectorate4C - Training programmeVeryimportantDocumentation reviewOn-site evaluation at Inspectorate4D - QA mechanism to assure effectiveness oftraining programme-Evaluated as part of sub-component4C5A - Inspection strategyVeryimportantDocumentation reviewOn-site evaluation at Inspectorate5B - Pre-inspection preparationVeryimportantDocumentation reviewOn-site evaluation at InspectorateObserved inspections5C - Format and content of inspection reportsVeryimportantDocumentation reviewObserved inspections5D - Inspection methodology-Evaluated as part of sub-components5E5E - SOP for conducting inspectionsCriticalDocumentation reviewObserved inspections5F - Inspection procedures - n reviewOn-site evaluation at InspectorateObserved inspections5G - Inspection procedures – Storage ofinspection dataImportantDocumentation reviewObserved inspections6 - Inspection performance standard6A - Performance standardsVeryimportantEvaluated as part of sub-component11A7 - Enforcement powers and procedures7A - Provision for written notice of violations-Evaluated as part of sub-component7B7B - Non-compliance managementCriticalDocumentation reviewOn-site evaluation at Inspectorate7C - Appeal mechanismImportantDocumentation reviewOn-site evaluation at Inspectorate7D - Other measures-Evaluated as part of sub-components7B8A - Alert mechanismsCriticalDocumentation reviewOn-site evaluation at Inspectorate8B - Crisis management mechanisms-Evaluated as part of sub-component8A8C - Alert performance standardsImportantDocumentation review9A - Access to laboratoriesCriticalDocumentation reviewOn-site evaluation at LaboratoryOn-site evaluation at Inspectorate9B - SOPs for analytical supportVeryimportantDocumentation reviewOn-site evaluation at Laboratory9C - Validation of analytical methodsVeryimportantDocumentation reviewOn-site evaluation at Laboratory10A - Sampling and audit procedureVeryimportantDocumentation reviewOn-site evaluation at LaboratoryOn-site evaluation at Inspectorate3 - GMP Standards4 - Inspection resources5 - Inspection procedures8 – Alert and crisis systems9 - Analytical capability10 - Surveillance programmeJAP Audit ChecklistEMA/INS/GMP/758453/2012Page 2/18
JAP Audit ChecklistEMA/INS/GMP/758453/2012Page 3/1810B - Recall monitoring-Evaluated as part of sub-component7B10C - Consumer complaint systemCriticalDocumentation reviewOn-site evaluation at Inspectorate10D - Adverse reaction reporting system/procedures-Not evaluated - not consideredwithin the scope of a GMPregulatory compliance programme.10E - Medicinal product defect reportingsystem/ procedures-Evaluated as part of sub-component10C
Component11 - Quality management systemJAP Audit ChecklistEMA/INS/GMP/758453/2012Page 4/18Sub-component11A - Quality management systemImportanceCriticalEvaluation methodDocumentation reviewOn-site evaluation at InspectorateOn-site evaluation at Laboratory
Glossary Articles Any item such as products (active pharmaceutical ingredient, finished medicinal products, investigational medicinal products, or anyintermediates), containers, packages, labels, documentation, etc. Component/Sub-Component Elements of a GMP regulatory compliance programme. For additional information on the level of importance and theevaluation methods, refer to the table “Summary of the Audit Checklist” provided at the beginning of this document. Dosage form Pharmaceutical form Equivalent Not necessarily identical, but leading to the same result. GMP regulatory compliance programme Includes components such as the supporting infrastructure of legislative and regulatory requirements, GMPstandards, inspection/enforcement resources and procedures, performance standards, alert and crisis system, analytical capability, surveillanceprogramme and quality management systems. Key performance indicators (KPI) Performance indicators established for planning and reporting on the components/sub-components of a GMPregulatory compliance programme. Manufacture Fabricate as defined in relevant GMP guidelines. Medicinal products Drug products Official Medicines Control Laboratories (OMCL) Laboratories used for the purpose of official testing. Pharmacovigilance Surveillance of adverse reactions reporting. Product Active pharmaceutical ingredient, finished medicinal product, investigational medicinal products, or any intermediate. Product defect Quality defect related to a product such as Out-of-Specifications (OOS), etc.General Notes The entire checklist must be used for the assessment/evaluation of GMP regulatory compliance programme as regards active pharmaceutical ingredientsand medicinal products. This checklist is used as a high level document. It is meant to detail the “WHAT” and not the “HOW”. The “HOW” is expected to be covered in a lowerlevel document such as a guidance document or a procedure.JAP Audit ChecklistEMA/INS/GMP/758453/2012Page 5/18
IndicatorsIndicatorNumber1Method of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionDROSEISub-component 1A Legislative and regulatory requirements and scope - Empowering legislation (Critical)The legislation identifies key delegations/functions in the organisation/regulatory authority assignedxfor overall responsibility of the GMP regulatory compliance programme.xx2The authority to designate inspectors is vested in legislation.3The identity of designated inspectors and scope of jurisdiction of legislation are available tocompanies being inspected.4There is legal authority for an inspector to enter at any reasonable time in any place where activepharmaceutical ingredients and medicinal products are manufactured, imported and exported.x5There is legal authority for taking samples and submitting them to designated laboratories.x6There is legal authority for obtaining evidence such as documents, photographs/videos of premisesand equipment.x7There is legal authority to open and examine any article subjected to legislation.x8There is the legal authority to seize or detain articles believed to be in violation.x9The legislation allows entry to a private dwelling.10Legislation requires that the person who has the responsibility of the site where active pharmaceuticalxxJAP Audit ChecklistEMA/INS/GMP/758453/2012Page 6/18.OSELOI
IndicatorsIndicatorNumberMethod of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionDROSEI.ingredients and medicinal products are manufactured, imported and exported, to cooperate and notobstruct an inspector.11Legislation requires a marketing authorisation holder and a manufacturer of medicinal product toreport to the regulatory authority any serious adverse medicinal product reactions.x12Legislation requires a marketing authorisation holder and a manufacturer of active pharmaceuticalingredients or of medicinal product to document any product defect impacting its quality.x13Legislation requires the marketing authorisation holder and the manufacturer to notify a competentregulatory authority upon commencement of a recall of medicinal product and to submit pertinentinformation.All companies that manufacture, import, export medicinal products are required to hold amanufacturing authorisation or be identified as holder of a manufacturing authorisation or as aregistered company for active pharmaceutical ingredients.14xx15The holder of the manufacturing authorisation is required to notify the regulatory authority ofsignificant changes or of conditions, which may affect the quality, safety or efficacy of a medicinalproduct.x16Legislation requires that the manufacturing authorisation include: the address of each site, themanufacturing activities, the category of medicinal products and the dosage form.x17Legislation prohibits the sale and processing of active pharmaceutical ingredients and medicinalproducts under unsanitary conditions or leading to adulteration.x18GMPs are legal requirements.19The legislation specifies that a manufacturer and/or a person is liable for a defective medicinalxxJAP Audit ChecklistEMA/INS/GMP/758453/2012Page 7/18OSELOI
IndicatorsIndicatorNumberMethod of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionDROSEIOSELproduct and provides for prosecution and/or penalties upon conviction20There is legislative authority to suspend, revoke or amend a manufacturing authorisation.x21Active pharmaceutical ingredients and medicinal products intended for exportation only are coveredin the legislation as the products intended for the domestic market.xSub-component 1B Legislative and regulatory requirements and scope - Conflict of interest (Very important)22A policy/guideline exists that details the situations regarded as conflict of interest.23Employees are required to declare their compliance with the conflict of interest policy.xxxSub-component 2A Regulatory directives and policies - Procedures for designating inspectors (Very important)24A process for designation of inspectors exists.xSub-component 2B Regulatory directives and policies - Enforcement PoliciesIncluded under sub-component 7B. Enforcement powers and procedures - Non-compliance management.25Sub-component 2C Regulatory directives and policies - Code of conduct/ Code of ethics (Very important)xA policy/guideline exist that details situations regarded as Code Of Conduct/Code Of Ethics.Sub-component 2D Regulatory directives and policies - Training certification policies/guidelinesIncluded under sub-component 4C. Inspection resources - Training programme.Sub-component 2E Regulatory directives and policies - Alert/crisis management policies/procedures/guidelinesIncluded under sub-component 8A. Alert and crisis systems - Alert mechanisms.Sub-component 2F Regulatory directives and policies - Organisational structureJAP Audit ChecklistEMA/INS/GMP/758453/2012Page 8/18xOI
IndicatorsIndicatorNumberMethod of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionDROSEIIncluded under sub-component 11A. Quality management systemSub-component 3A GMP Standards - Details/ scope of GMP (Critical)2627GMPs are covered within a regulatory framework.xThe GMP regulatory framework covers all GMP requirements including but not limited to:Quality management, premises, equipment, personnel, sanitation, raw material testing, manufacturingcontrol, quality control department, packaging material testing, finished product testing, records,samples, stability and sterile products.xSub-component 3B GMP Standards - Process validationIncluded under sub-component 3A GMP Standards - Details/ scope of GMP.Sub-component 4A Inspection resources - Staffing: Initial qualification (Very important)28The minimum qualifications for GMP inspectors are defined29Duties of staff involved in the GMP regulatory compliance programme are defined.30Evidence exists that the GMP inspectors meet the minimum qualifications.xxxxSub-component 4B Inspection resources - Number of inspectors (Very important)31The number of inspectors dedicated to the GMP inspection programme is sufficient to meet theprescribed inspection frequency/inspection programme.xxSub-component 4C Inspection resources - Training programme (Very important)32A training programme for inspectors is established and records are maintained.JAP Audit ChecklistEMA/INS/GMP/758453/2012Page 9/18xxOSELOI
IndicatorsIndicatorNumber33Method of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionA mechanism to evaluate the effectiveness of training exists.DROSEIxxOSELOISub-component 4D Inspection resources - QA mechanism to assure effectiveness of training programmeIncluded under sub-component 4C Inspection resources - Training programme.Sub-component 5A Inspection procedures - Inspection strategy (Very important)34Documents that describe the work expected, anticipated results and resources applied to fulfil thefunctions of GMP inspections are available.xx35A scheduling system identifies companies due for inspections within a set time frame.xxSub-component 5B Inspection procedures - Pre-inspection preparation (Very important)36A procedure details the requirements for pre-inspection activities, and is followed.37The inspection plan is based on the company’s GMP compliance history, critical activities and type(s)of dosage forms or products manufactured.xxxxxSub-component 5C Inspection procedures - Format and content of inspection reports (Very important)38A procedure for the format and content of inspection reports is available.39Observations are factual and are based on proper interpretation of applicable legislation.40Observations are classified/categorised according to risk.41Assessment of the company’s overall compliance rating is in line with the inspection findings.42Inspection reports are completed in the required reporting format and timeframe.Sub-component 5D Inspection procedures - Inspection methodologyJAP Audit ChecklistEMA/INS/GMP/758453/2012Page 10/18xxxxxx
IndicatorsIndicatorNumberMethod of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionDRIncluded under sub-components 5E. Inspection procedures - SOP for conducting inspectionsOSEIOSELOISub-component 5E Inspection procedures - SOP for conducting inspections (Critical)43A procedure details the requirements for conducting inspections and is followed.44Critical stages and parameters of manufacturing processes are assessed.45Qualification and validation are assessed.46The inspection plan is adjusted, where warranted, based on the findings of the inspection.47The depth of the inspection is in line with the inspection findings.xxxxxxSub-component 5F Inspection procedures - Post-inspection activities (Very important)48A procedure details the requirements for post-inspection activities, and is followed.49Inspection findings and conclusions are subject to an internal review.xxxxSub-component 5G Inspection procedures - Storage of inspection data (Important)50A policy/procedure is available for the storage of inspection data.51An inspection report database (or archive) is maintained in a secure and controlled manner.xSub-component 6A Inspection performance standard - Performance standards (Very important)Included under sub-component 11A Quality Management System - Quality management systemSub-component 7A Enforcement powers and procedures - Provision for written notice of violationsIncluded under sub-component 7B Enforcement powers and procedures - Non-compliance managementJAP Audit ChecklistEMA/INS/GMP/758453/2012Page 11/18xxx
IndicatorsIndicatorNumberMethod of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionDROSEISub-component 7B Enforcement powers and procedures - Non-compliance management (Critical)Recall procedures/mechanisms and records are available.xxxx54GMP certificates, manufacturing authorisation suspension/withdrawal procedures/mechanisms areavailable and a list of suspended/withdrawn authorisations/GMP certificates is maintained.xx55Seizure procedures/mechanisms and records are available.56Prosecution procedures/mechanisms and records are available.xxxx52There is provision for written notice of violations to be sent to the company.53Sub-component 7C Enforcement powers and procedures - Appeal mechanism (Important)57Appeal procedures/mechanisms and records are available.xxSub-component 7D Enforcement powers and procedures - Other measuresIncluded under sub-components 7B Enforcement powers and procedures - Non-compliance managementSub-component 8A Alert and crisis systems - Alert mechanisms (Critical)58Two-Way alert procedures/mechanisms and records are available.xxSub-component 8B Alert and crisis systems - Crisis management mechanismsIncluded under sub-component 8A Alert and Crisis systems - Alert mechanismsSub-component 8C Alert and crisis systems - Alert performance standards (Important)59Performance standards for the transmission of two-way alert and management of crisis system areestablished and are followed.JAP Audit ChecklistEMA/INS/GMP/758453/2012Page 12/18xxOSELOI
IndicatorsIndicatorNumberMethod of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionDR61Sub-component 9A Analytical capability - Access to laboratories (Critical)The regulatory authority has access to laboratories capable of conducting necessary analyses for thepurpose of official testing.Regulatory Authority’s or contract laboratories are qualified according to a recognised standard.62All reported products defects are documented and investigated.60OSEIOSELxxxxxxSub-component 9B Analytical capability - SOPs for analytical support (Very important)63Documents are available that detail the work expected, anticipated results and resources applied tofulfil the functions of the laboratories.xx64Procedures covering all elements of laboratory operations are available and are followed.xxSub-component 9C Analytical capability - Validation of analytical methods (Very important)65The test method validation guideline is equivalent to the ICH standard and records are available.xxSub-component 10A Surveillance programme - Sampling and audit procedure (Very important)66The market surveillance programme for active pharmaceutical ingredients and medicinal products isdeveloped involving at least the inspection and laboratory departments using risk managementprinciples and covers dosage forms of different medicinal product types.67The market surveillance programme performance is reviewed annually and records of review areavailable.xSub-component 10B Surveillance programme - Recall monitoringIncluded under sub-component 7B Enforcement powers and procedures - Non-compliance managementJAP Audit ChecklistEMA/INS/GMP/758453/2012Page 13/18xxxxOI
IndicatorsIndicatorNumberMethod of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionDROSEIOSELSub-component 10C Surveillance programme - Consumer complaint system (Critical)68A consumer complaint system/procedure and records are available.69Issues of high risk are investigated immediately.70Compliance staff and or inspection staff can access complaint information.71All reported products defects are documented and investigated.xxxxxxSub-component 10D Surveillance programme - Adverse reaction reporting system/ proceduresNot evaluated - not considered within the scope of a GMP regulatory compliance programme.Sub-component 10E Surveillance programme - Medicinal product defect reporting system/proceduresIncluded under sub-component 10C Surveillance programme - Consumer complaint systemSub-component 11A Quality management system - Quality management system (Critical)72The quality management system is defined based on a recognised international standard.73The quality manual covers all elements of GMP regulatory compliance programme.7475Key performance indicators (KPI) for the overall GMP regulatory compliance programme areestablished and available.The quality management system has been implemented and is followed.76A documentation control system is in place.77Quality audit plans and records are available.JAP Audit ChecklistEMA/INS/GMP/758453/2012Page 14/18xxXXXxxxxxxOI
IndicatorsIndicatorNumberMethod of EvaluationDR: Documentation ReviewOSEI: On-Site Evaluation at InspectorateOSEL: On-Site Evaluation at LaboratoryOI: Observed InspectionDR78Management reviews ensure the performance of the quality management system on an annual basis.JAP Audit ChecklistEMA/INS/GMP/758453/2012Page 15/18OSEIOSELxxOI
ANNEX EVALUATION GUIDE FOR GMP REGULATORYCOMPLIANCE PROGRAMME– AUDIT CHECKLISTIMPLEMENTATION OF EC LEGISLATION AND GUIDANCE RELATED TO GMPHUMAN AND VETERINARY – ALL RELEVANT ARTICLES TO BE CHECKEDEC )1. Directive 2001/83/EC, as amended by Directive 2004/27/EC – Human Medicinal Products2. Directive 2001/82/EC, as amended by Directive 2004/28/EC – Veterinary Medicinal Products40(1) (2)40(3)Authorisation for manufactureAuthorisation for import44(1) (2)44(3)41Requirements for applicant in order to obtain manufacturing authorisation4542Granting of authorisation4643-4546Time limits for the handling of the applicationObligations of holder of manufacturing authorisation47-4950(a) Services of the adequate staff(b) Comply with national legislation of the Member State concerned(c) Give prior notice of changes(d) Allow inspections(e) Enable qualified person to carry out its duties(f) Comply with GMP rules47Implementation through Directive and Guidelines51Guidelines including annexes as published under EUDRALEXVolume 4 - Medicinal Products for Human and Veterinary Use : GoodManufacturing l-4/home.htm)Principles of GMP for active substances used as starting materials48Requirement of qualified person5249Conditions of qualification of qualified person and professional background5351Responsibilities of qualified person5556Enforcement of qualified person’s obligations5653Application to homeopathic medicinal products57111Detailed Provisions for inspections at premises of manufacturers (please list indetail each aspect of implementation of this article)80JAP Audit ChecklistEMA/INS/GMP/758453/2012Page 16/18
EC le(Veterinary)MS to ensure that holder of a manufacturing authorisation furnishes proof ofthe control tests to be carried out in compliance with marketing authorisation(Administrative batch protocol review)81Official Control Batch Release Testing (May-Provision)82Subject2. Directive 2003/94/EC (Human) – and Directive 91/412/EEC (Veterinary) –GMP1Scope of application of GMP rules2Repeated inspections by MS3Comparable standards to Compilation of Community ompproc.html) Quality Systems framework Procedures related to Rapid Alerts Procedures related to GMP Inspections Forms used by Regulators (GMP inspection report format, manufacturers authorisation) Procedures related to Centralised Procedures4Responsibility of manufacturer and importerCompliance of medicinal products and investigational medicinal products manufacturing (in EC orwhether imported) with GMP5Obligations of the manufacturer: Manufacturing operations in accordance with information in application Adaptation to scientific and technical progress6Quality assurance system7Qualified personnel at the manufacturing site, job descriptions of qualified personnel, trainingHygiene programme8Premises and equipment9Documentation Manufacturing procedures Traceability of batches Protection of data processing systems10Production Pre-established procedures, resources ValidationJAP Audit ChecklistEMA/INS/GMP/758453/2012Page 17/18
11Quality control Quality control department Quality control laboratories Final control of finished products12Work contracted out Written contract Clearly defined responsibilities No sub-contracting Respect of GPM and allow inspections13Implementation of a system for recording and reviewing complaintsImplementation of a system for product recall14ArticleSelf inspectionSubject3. Directive 2001/20/EC Good Clinical Practice13 (1)13 (2)13 (3)ArticleAuthorisation for total and partial manufacturing of investigational medicinal productsQualified person for investigational medicinal productsGMP for manufacturing and testing of investigational medicinal productsSubject4. Directive 2005/28/EC Good Clinical Practice91011-1213212223General conditions for a manufacturing and import authorisationApplicant s requirements to obtain an authorisationObligations of competent authorityObligations of holder of an authorisationRequirements related to inspectorsTeams of InspectorsInspection Procedures ( here: only in relation to GMP verification)JAP Audit ChecklistEMA/INS/GMP/758453/2012Page 18/18
The entire checklist must be used for the assessment/evaluation of GMP regulatory compliance programme as regardsactive pharmaceutical ingredients and medicinal products. This checklist is used as a high level document. It is meant to detail the "WHAT" and not the "HOW". The "HOW" is expected to be covered in a lower
