Course ISO 17025 oriented Internal Auditors Pierre Morel Ministry of Health ANVISA / GGLAS Slide 001 National

Agency for Sanitary Surveillance www.anvisa.gov.br Quality Systems and Laboratory Quality System: necessary and sufficient conditio n? Quality Systems in Laboratories System compulsory voluntary system Summary ISO 17025 Internal Auditing Organization Management System Document Control Anal ysis Critical Applications Outsourcing Acquisition Customer Complaints and Corre ctive Action Job control test nonconforming Improvement Action Preventive Control of records Internal audits Management review Technical Requirements Staff Accommodation and environmental conditions and validation methods Sampling Handling Equipment Tra ceability of test items Quality Assurance Presentation of results AUDIT Exercises National Agency for Sanitary Surveillance Slide 002 www.anvisa.gov.br Quality and Systems Laboratory Slide 003 National Agency for Sanitary Surveillance www.anvisa.gov.br Quality System: necessary and sufficient condition? What are the three pillars that support the Quality of a Laboratory? Slide 004 National Agency for Sanitary Surveillance www.anvisa.gov.br Quality Systems in Laboratories SYSTEM or SCOPE VOLUNTEER VOLUNTEER COMPULSORY Laboratory, Management and Suppor t Services Every company MAIN FOCUS Managerial and Technical ISO 17025 ISO 9000 VOLUNTEER Technical and Managerial and Technical Data Security Technical and Product Safet y Slide 005 BPL

Laboratory and Field COMPULSORY COMPULSORY whole company GMP National Agency for Sanitary Surveillance www.anvisa.gov.br Accrediting agency in Brazil SYSTEM accrediting agency Accreditation INMETRO ANVISA INMETRO Qualification / C ertification Bodies Accreditation Systems INMETRO Qualification Certification AN VISA ANVISA Slide 006 ISO 17025 ISO 9000 BPL GMP National Agency for Sanitary Surveillance www.anvisa.gov.br System compulsory (third) Product Registration Slide 007 National Agency for Sanitary Surveillance www.anvisa.gov.br Mandatory system (2 / 3) BEFORE THE REGISTER REGISTER PRODUCT Specifications Emp.: Quality Control and GMP Org.Fisc: Product Control and Audit ing GMP Effectiveness Emp.: Market Org.Fisc: Monitoring the Impact Assessment on Health and Environment Studies in GLP and GCP (Good Clinical Practices) AFTER THE RECORD Emp.: Org.Fisc Monitoring: Monitoring Slide 008 National Agency for Sanitary Surveillance www.anvisa.gov.br Mandatory system (3 / 3) Register Products Product Safety Assessment - Directive 67/548/EEC (Dangerous Substances Directive) - Regulation 793/93/EC Sorts and lists as well as determine the minimum labeling Test Substances new 30 0 existing substances - Directive 1999/45/EEC (Dangerous Preparations Directive) - REACH (Registration , Evaluation and Authorization of Chemicals) Classifies the use of BPL

Since 2006, testing of all products of a T or more at BPL Slide 009 National Agency for Sanitary Surveillance www.anvisa.gov.br Voluntary Advantages Towards Quality Visibility Marketing Register and save knowhow of top management involvement Lower cost of non-quality National Agency for Sanitary Surveillance Disadvantages An apparent greater rigidity Cost Analysis time greatest Bureaucra cy Slide 010 www.anvisa.gov.br Why implement a quality system in a laboratory? PERFORMANCE Deployment Quality System Loss of Memory " Recovering Memory "lost" + Reengineering Improvement National Agency for Sanitary Surveillance WEATHER Slide 011 www.anvisa.gov.br ISO 17025 Slide 012 National Agency for Sanitary Surveillance www.anvisa.gov.br Chapters 2 auditable Chapter 4: Requirements Management Chapter 5: Technical Requirements National Agency for Sanitary Surveillance www.anvisa.gov.br 4.13 - Internal Audits "The laboratory shall periodically, and according to a predetermined schedule an d procedure, conduct internal audits of its activities to verify that its OPERAT IONS CONTINUE TO MEET THE REQUIREMENTS OF THE SYSTEM AND THE QUALITY OF THIS STA NDARD." National Agency for Sanitary Surveillance www.anvisa.gov.br Prepare the system for external audit, regarding: the structure of the system, p

rocesses, documentation, people audited; Other Objectives of Internal Audit and trigger the development of strategies to respond to the questioning of the a uditor in relation to: the auditee, the person accompanying the GQ interview. National Agency for Sanitary Surveillance www.anvisa.gov.br Step prior to the audit (for the auditor and the audited): Reading and Interpretation of ISO 17025 National Agency for Sanitary Surveillance www.anvisa.gov.br Chapter 4: Requirements Management National Agency for Sanitary Surveillance www.anvisa.gov.br 4.1 - Organization National Agency for Sanitary Surveillance www.anvisa.gov.br Major Changes of ISO / IEC 17025:2001 for the NBR / IEC 17025:2005 ISO 4.1 - Org anization 4.1.5 - The laboratory must: a) have managerial and technical personnel who, irr espective of other responsibilities, has the authority and resources needed to p erform their duties, including implementation, maintenance and improvement of ma nagement system, and to identify the occurrence of deviations of the management system or procedures for testing and / or calibrations, and to initiate actions to prevent or minimize such departures (see also 5.2). 4.1.5 k) ensure that its personnel are aware of the relevance and importance of their activities and how they contribute towards achieving the objectives of the management system. 4.1.6 - Top management shall ensure that appropriate communication processes are esta blished in the laboratory and that there is communication about the effectivenes s of the management system. National Agency for Sanitary Surveillance www.anvisa.gov.br Organization Structure A Manager. A Technical Manager (Manager eventually takes the two functions). A Q uality Manager with access to the manager, preferably connected to it. Analysts, glassware washers outsourced or not. All key functions have a substitute. All w ith education, training and experience appropriate point. weak National Agency for Sanitary Surveillance Weakness www.anvisa.gov.br 4.2 - Management System

National Agency for Sanitary Surveillance www.anvisa.gov.br Major Changes of ISO / IEC 17025:2001 for the NBR / IEC 17025:2005 ISO 4.2 - Sys tem Management (1 / 2) 4.2.2 .- The policies of the management system on the quality of the laboratory, including a statement about the quality policy must be defined in a quality man ual (whatever denomination). The real objectives should be established and criti cally reviewed during management review. The quality policy statement should be issued under the authority of top management. It should include at least the fol lowing: 4.2.2. c) the purpose of the management system with respect to quality. 4.2.2. e) the commitment of the leadership of laboratory compliance with this ru le and the continuous improvement of the effectiveness of the management system. National Agency for Sanitary Surveillance www.anvisa.gov.br Major Changes of ISO / IEC 17025:2001 for the NBR / IEC 17025:2005 ISO 4.2 - Man agement System (2 / 2) 4.2.3 - Top management shall provide evidence of its commitment to the developme nt and implementation of management system and also to the continuous improvemen t of its effectiveness. 4.2.4 - Top management shall communicate to the organiza tion the importance of meeting customer requirements as well as to statutory and regulatory requirements. 4.2.7. - Top management shall ensure that the integrit y of the management system is maintained when changes are planned and implemente d the management system. National Agency for Sanitary Surveillance www.anvisa.gov.br Quality Policy Management Commitment to Good Laboratory Practice and Professional customer serv ice management statement about the level of service Purposes of the Laboratory M anagement System with respect to quality. All the staff involved and implement p olicies and procedures comply with ISO 17025 Compliance Continuous Improvement Objectives: - General Quality Policy - specific, with action plan National Agency for Sanitary Surveillance www.anvisa.gov.br Sample Quality Policy "Our services address both the internal requests of our Company as external requ ests; Customer internal or external link is the most important of our Organizati on, using standard methods and ABNT OECD Daphnia, algae and fish, thus evaluatin g the toxicity of effluents and products; work in an environment of constant sci entific and technological innovation; Our Human Resources are the most important components of our heritage. Therefore, we maintain an ongoing program of educat ion and training, all staff involved are maintaining our Quality System NBR / IS O 17025 that represents the mainstay of our development, is of fundamental impor tance to continue our continuous improvement, therefore we want to be a referenc e nationally and internationally. "

National Agency for Sanitary Surveillance www.anvisa.gov.br 4.2.2: Quality Policy Disclosure: - Via the meeting (s) of information - via posters in the Laboratory, the Manage ment and crossing areas. Audit: - Dissemination (meetings, posters, interviews) - the content front: item 4.2.2, will be implemented in the company. National Agency for Sanitary Surveillance www.anvisa.gov.br Management Commitment: auditable? Track results; via meeting minutes of critical analysis, mainly through intervie ws. National Agency for Sanitary Surveillance www.anvisa.gov.br 4.3 - Control of documents National Agency for Sanitary Surveillance www.anvisa.gov.br What are the documents? Internally generated or obtained from external sources; Examples: - - - - - - - - Regulations & standards, methods of test or calibration, softwar e, specification sheets, instructions, manuals, policy statements, procedures; Various means: electronic or paper Weakness National Agency for Sanitary Surveillance www.anvisa.gov.br Responsibility for documentção Archiving is not stacking. Filing is easy; recover is not! It is more convenient to centralize file, so as to: - Concentrating the shelving in a person and a system capable - not disperse the documents and related responsibilities on th em. National Agency for Sanitary Surveillance Weakness www.anvisa.gov.br 4.4 - Critical analysis of requests, tenders and contracts

National Agency for Sanitary Surveillance www.anvisa.gov.br Critical analysis of requests, tenders and contracts requirements adequately Poi nt defined, documented and understood weak. Capacity and resources to meet. Meth od selected to attend. Contract accepted by both parties. Records point of this analysis. weak National Agency for Sanitary Surveillance www.anvisa.gov.br 4.5 - Subcontracting National Agency for Sanitary Surveillance www.anvisa.gov.br Subcontracting subcontractor responsible. Subcontracting informed to you. Regist ration of contractors Weakness National Agency for Sanitary Surveillance www.anvisa.gov.br 4.6 - Purchase of services and supplies National Agency for Sanitary Surveillance www.anvisa.gov.br Purchased services and supplies Politics and supplies for the selection and purchase of services and supplies. I nspection supplies, reagents and consumables. Evaluation suppliers of consumable s, supplies, and services. Keep track of the evaluations. The approved list. Weakness National Agency for Sanitary Surveillance www.anvisa.gov.br 4.7 - Customer Service National Agency for Sanitary Surveillance www.anvisa.gov.br Major Changes of ISO / IEC 17025:2001 for the NBR / IEC 17025:2005 ISO 4.7 - Cus tomer Service 4.7.2. - The laboratory shall seek feedback, both positive and negative, of its customers. The feedback should be used to analyzed to improve the management sys tem, the activities of testing and calibration, and customer service. Note - Exa mples of types of feedback include customer satisfaction surveys and review of t est reports or calibration with Customers

National Agency for Sanitary Surveillance www.anvisa.gov.br Customer service Cooperation with clients to: - Clarify request - Monitor the performance of the laboratory Feedback (feedback), both positive and negative ensuring confidentiality since other clients. Weakness National Agency for Sanitary Surveillance www.anvisa.gov.br 4.8 and 4.11 - Complaints and Corrective Actions National Agency for Sanitary Surveillance www.anvisa.gov.br Complaint: When the system failed and the failure came to the Customer National Agency for Sanitary Surveillance www.anvisa.gov.br 4.8 and 4.11: Complaints and Corrective Actions Complaints: policy, procedure, records of complaints, investigations and correct ive actions; Corrective action: - - - - Weakness policy and procedure; Analysis of causes: a root cause determination, selection and implementation; Monitoring: effectiveness of actions; Additional audits. National Agency for Sanitary Surveillance www.anvisa.gov.br 4.9 - Control of works by testing and / or non-compliant calibration National Agency for Sanitary Surveillance www.anvisa.gov.br Job control testing and / or non-compliant calibration Policy and procedure ensuring that: - Be designated responsibilities and authori ties - are taken the first actions - an evaluation - are made to fix - where nec essary, the Customer is notified - is defined responsibility for the resumption of work . Corrective action. National Agency for Sanitary Surveillance www.anvisa.gov.br

4.10 - Improvement National Agency for Sanitary Surveillance www.anvisa.gov.br Major Changes of ISO / IEC 17025:2001 for the NBR / IEC 17025:2005 ISO 4.10 - Im provement 4.10. - The laboratory shall continually improve the effectiveness of its manage ment system through the use of quality policy, quality objectives, audit results , data analysis, corrective and preventive actions and management review. National Agency for Sanitary Surveillance www.anvisa.gov.br 4.12 - Preventive Action National Agency for Sanitary Surveillance www.anvisa.gov.br Preventive action Weakness PREVENTIVE ACTION NOT CONFUSED WITH CORRECTIVE ACTION should be identified neede d improvements and potential sources of nonconformities action plans developed, implemented and monitored. Procedures. National Agency for Sanitary Surveillance www.anvisa.gov.br 4.13 - Control of records National Agency for Sanitary Surveillance www.anvisa.gov.br Control of records Procedures for identifying, collecting, indexing, access, filing, storage, maint enance and disposal records legible records. Prevent damage, deterioration and l oss. Speedy recovery. Retention time established. Insurance records and confiden cailidade. Protection and back up of electronic records. Technical records - ori ginal observations at the time of implementation - responsible for sampling - sc ratched errors, correct value to the side, initialed changes. - Measures for equ ivalent electronic data (Audit Trail) National Agency for Sanitary Surveillance Weakness Weakness www.anvisa.gov.br 4.14 - Internal audits

National Agency for Sanitary Surveillance www.anvisa.gov.br Internal audits Periodically (annually), according to the schedule and procedure, corrective act ions, if necessary, notify customers; Records. National Agency for Sanitary Surveillance www.anvisa.gov.br 4.15 - Management review National Agency for Sanitary Surveillance www.anvisa.gov.br Major Changes of ISO / IEC 17025:2001 for the NBR / IEC 17025:2005 ISO 4.15 - Ma nagement review 4.15.1 - ... The review should consider: ... complaints, recommendations for imp rovement. ... ... National Agency for Sanitary Surveillance www.anvisa.gov.br Management review Periodically (annually), according to the schedule and procedure; The review sho uld consider: - suitability policy and procedures - personnel management reports - the result of internal audits - corrective and preventive actions - external audit - Results of interlaboratory comparisons and proficiency tests; - Change i n the volume and type of work - Customer Feedback - Complaints - Recommendations for improvement - Other relevant factors. Records. Actions taken within a reaso nable period and combined. National Agency for Sanitary Surveillance Weakness www.anvisa.gov.br Chapter 5: Technical Requirements National Agency for Sanitary Surveillance www.anvisa.gov.br 5.1 - General "Several factors determine the correctness and reliability of tests and / or cal ibrations performed by the laboratory. These factors include contributions from: human factors (5.2) accommodation and environmental conditions (5.3), methods o f testing and calibration and validation of methods (5.4), equipment (5.5); meas urement traceability (5.6) sample (5.7); handling of test and calibration items (5.8). National Agency for Sanitary Surveillance www.anvisa.gov.br

5.2 - Personnel National Agency for Sanitary Surveillance www.anvisa.gov.br Major Changes of ISO / IEC 17025:2001 for the NBR / IEC 17025:2005 ISO 5.2 - Per sonal 5.2.2 - ... The training program should be appropriate to the tasks of the lab, current and planned. Should be evaluated the effectiveness of the training actio ns taken. National Agency for Sanitary Surveillance www.anvisa.gov.br Formation Human Resources Training Experience Competence Slide 093 National Agency for Sanitary Surveillance www.anvisa.gov.br 5.3 - Accommodation and environmental conditions National Agency for Sanitary Surveillance www.anvisa.gov.br 5.3 - Accommodation and environmental conditions Such facilities to facilitate correct performance of tests and / or calibrations . Technical requirements that may affect the results should be documented. Segre gation of areas to avoid cross contamination. Access and use of controlled areas . Good housekeeping. National Agency for Sanitary Surveillance www.anvisa.gov.br 5.4 - Methods of testing and calibration and validation of methods National Agency for Sanitary Surveillance www.anvisa.gov.br 5.4 - Methods of testing and calibration and validation of methods Appropriate methods for validation: - Modified standard methods - methods developed by the laboratory. Weakness Participation in programs interlaboratorais. Point Estimation of measurement unc

ertainty. Good poor cleaning and storage. Control data: Calculations and data tr ansfers subject to appropriate checks. National Agency for Sanitary Surveillance www.anvisa.gov.br Validation Flowchart Method Validated method Meets No reply Strength Meets No reply Unstable Accuracy Meets Stability Stable No reply No specific or selective Specificity / Selectivity Specific or selective Precision Meets No reply Does not meet the requirements Limit of quantitation Operating range Meets No reply Linearity Meets National Agency for Sanitary Surveillance www.anvisa.gov.br Roadmap to the Calculation of Uncertainties 1. 2. 3. 4. 5. 6. Specify the measurand; identify the sources of uncertainty; quantify the compone nts of uncertainty; Calculate the combined uncertainty; Calculate the expanded u ncertainty; analyze the contributions of uncertainty. National Agency for Sanitary Surveillance

www.anvisa.gov.br 5.5 - Equipment National Agency for Sanitary Surveillance www.anvisa.gov.br 5.5 - Equipment Properly equipped laboratory. Equipment. Calibrated equipment. Equipment operate d by authorized personnel. Each item identified. Procedures for handling, transp ort, storage, use and planned maintenance National Agency for Sanitary Surveillance www.anvisa.gov.br 5.6 - Traceability of measurement National Agency for Sanitary Surveillance www.anvisa.gov.br 5.6 - Traceability of measurement "All equipment used for testing and / or calibrations, including equipment for a uxiliary measurements (eg environmental conditions) having a significant effect on the accuracy or validity of the result of the test, calibration or sampling s hall be calibrated prior to entering service . calibrations and measurements tra ceable to SI. Traceable standards and procedures for transport and storage. Part icipation in interlaboratory programs whenever possible. Calibration should be p erformed within the RBC. Intermediate checks with the procedure. National Agency for Sanitary Surveillance www.anvisa.gov.br 5.7 - Sampling National Agency for Sanitary Surveillance www.anvisa.gov.br 5.7 - Sampling When you perform, plan and procedures. Deviations, additions and deletions requested by the Customer registered. Records National Agency for Sanitary Surveillance www.anvisa.gov.br 5.8 - Handling of test and calibration items National Agency for Sanitary Surveillance www.anvisa.gov.br 5.8 - Handling of test and calibration items Procedures for transportation, receipt, handling, protection, storage, retention and / or removal. Identification system. Upon receipt, registration of deviatio ns. Procedures and appropriate facilities for avoiding deterioration, loss or da mage.

National Agency for Sanitary Surveillance www.anvisa.gov.br 5.9 - Quality assurance of results of testing and calibration National Agency for Sanitary Surveillance www.anvisa.gov.br Major Changes of ISO / IEC 17025:2001 for the NBR / IEC 17025:2005 ISO 5.9 - Qua lity Assurance, test results and calibration 5.9.2 - Data quality control must be reviewed and, when they are out of predefin ed criteria, planned action shall be taken to correct the problem and prevent in correct results are reported. National Agency for Sanitary Surveillance www.anvisa.gov.br 5.9 - Quality assurance of results of testing and calibration Quality control procedures to monitor the validity of tests and calibrations per formed; This monitoring may include: Analyzed data and actions to correct the problems. - Regular use of certified reference materials - Participation in programs inter laboratory comparison or proficiency testing - retesting or recalibration of ret ained items; - Correlation of results of different features of an item. National Agency for Sanitary Surveillance www.anvisa.gov.br 5:10 - Presentation of results National Agency for Sanitary Surveillance www.anvisa.gov.br 5:10 - Presentation of results With accuracy, clarity, objectivity, without ambiguity and in accordance with an y specific instructions in methods. Must include all information requested by th e Customer Items 5.10.2,3 and 4 depict the minimum content of a report. When opi nions and interpretations are included, they are highlighted and the bases docum ented.€Results of tests performed by subcontractors must be clearly identified. Amendments identified. National Agency for Sanitary Surveillance www.anvisa.gov.br Auditing National Agency for Sanitary Surveillance www.anvisa.gov.br

Auditing Defined in ISO 9000/2000 as: "A systematic, independent and documented process f or obtaining evidence and evaluating it objectively to determine the extent to w hich the criteria are met." National Agency for Sanitary Surveillance www.anvisa.gov.br AUDIT - Meetings and Execution Opening Meeting Meetings Brokers (Auditor and RA) Intermediate Implementation Me eting (Team of auditors) Meeting Closure National Agency for Sanitary Surveillance www.anvisa.gov.br MEETING OPENING Objective: • Present the team and establish the ground rules for the audit. Opening Meeting Executive Meeting Interim Meeting Closure Some Topics for the Opening Meeting Agenda • Scope and Objectives • Audit plan and Methods; • Sampling; • Confidentiality; • Logistics; • Safety Requirements; • Questions. National Agency for Sanitary Surveillance www.anvisa.gov.br IMPLEMENTATION The relationship between auditors and audited is critical to a su ccessful audit. • • • How to communicate? How to listen? How to ask? Opening Meeting Executive Meeting Interim Meeting Closure National Agency for Sanitary Surveillance www.anvisa.gov.br IMPLEMENTATION - Communication • Objective • Search: • Structuring ideas; • Organize messages; • Generate respo nses; • Show behaviors and attitudes • Observe: • the audited as the behaviors a nd attitudes; • interactions auditor and auditee. Opening Meeting Executive Meeting Interim Meeting Closure National Agency for Sanitary Surveillance www.anvisa.gov.br ENFORCEMENT - How to listen? • Pay attention as to: • themes; • content. • Suspend judgments; • Eliminate dis tractions; Opening Meeting Executive Meeting Interim Meeting Closure necessary. • Seek clarification when

National Agency for Sanitary Surveillance www.anvisa.gov.br IMPLEMENTATION - Communication WHAT TO AVOID: • Reactions exaggerated; • Make interruptions when someone is spe aking; • Watch: • without looking; Opening Meeting Executive Meeting Interim Meeting Closure • only what we want to hear; • pretend you're watching. • Disperse thought. National Agency for Sanitary Surveillance www.anvisa.gov.br IMPLEMENTATION - Questions • What? • Why? • Where? • Who? • When? • How? Opening Meeting Executive Meeting Interim Meeting Closure National Agency for Sanitary Surveillance www.anvisa.gov.br IMPLEMENTATION - Questions They must: • generate relevant information. They must: • suggest answers; • cont ain words or emotional implications. Opening Meeting Executive Meeting Interim Meeting Closure National Agency for Sanitary Surveillance www.anvisa.gov.br IMPLEMENTATION To perform an audit as well: • Opening Meeting Executive Meeting Interim Meeting Closure Establish appropriate climate; • Putting the auditee at ease; • Make use of questioning appropriate. National Agency for Sanitary Surveillance www.anvisa.gov.br MIDWAY MEETING: • Auditor and Quality Manager • With a team of auditors Allow: • Opening Meeting Executive Meeting Interim Meeting Closure Ensuring the effectiveness of the audit; • •

The service scope; Confronting and analyze the NC's. National Agency for Sanitary Surveillance www.anvisa.gov.br CLOSING MEETING • • Topics for Agenda Opening Meeting Executive Meeting Brokers Recapitalação Scope and Objectives • Audit plan and Methods; • Report NC'se obse rvations; • Corrective actions and deadlines; Answer to: • do not leave the discussion of the NC's to the final closing meetin g; • recognize the achievements; • diplomacy. National Agency for Sanitary Surveillance www.anvisa.gov.br Thank you e. .. ... Good Auditing ...!!! Pierre Morel pajmorel@uol.com.br Slide 123 National Agency for Sanitary Surveillance www.anvisa.gov.br