ISPE NORDIC COP CLEAN UTILITIES SEPTEMBER TUUSULA FINLAND. Timo Kuosmanen STERIS Finn-Aqua

Transcription

1 ISPE NORDIC COP CLEAN UTILITIES SEPTEMBER TUUSULA FINLAND Timo Kuosmanen STERIS Finn-Aqua Timo_Kuosmanen@steris.com

2 AUDIT TRAIL IN CRITICAL UTILITIES MONITORING CURRENT TRENDS

3 CONTENTS BACKGROUND NEW GUIDANCES AUDIT TRAIL RISK ASSESSMENT EXAMPLE BENEFITS Q&A

4 BACKGROUND Risk Management and Data Integrity have been hot topics recently both in EU and US FDA guidance Part 11, Electronic Records; Electronic Signatures Scope and Application, August 2003, referred to exercising enforcement discretion with respect to certain part 11 requirements: That is, we do not intend to take enforcement action to enforce compliance with the validation, audit trail, record retention, and record copying requirements of part 11 as explained in this guidance. Revised EU GMP Annex 11 in operation June 2011 New draft guidances released for comments recently Recent FDA Warning Letters reveal CGMP violations involving data integrity 4

5 BACKGROUND: Recent Warning Letters 5

6 BACKGROUND: Recent Warning Letters 6

7 BACKGROUND: Consequences Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. In response to this letter, provide the following. 1. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include: A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude. Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party. An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility s operations in which you discovered data integrity lapses. A comprehensive retrospective evaluation of the nature of all data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential batches were identified should evaluate all data integrity lapses. 2. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations. 7

8 BACKGROUND: Consequences 3. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include: A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all of the data you generate, including analytical data, manufacturing records, and all data submitted to FDA. A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm. Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring. Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company s data. A status report for any of the above activities that are already underway or completed. If you cannot complete corrective actions within 15 working days, state your completion date and reasons for delay. 8

9 NEW GUIDANCES FDA draft document issued April 2016 FDA expects that data be reliable and accurate CGMP regulations and guidance allow for flexible and risk-based strategies to prevent and detect data integrity issues. Firms should implement meaningful and effective strategies to manage their data integrity risks based upon their process understanding and knowledge management of technologies and business models. In recent years, FDA has increasingly observed CGMP violations involving data integrity during CGMP inspections. 9

10 NEW GUIDANCES PIC/S draft guidance August 2016 GOOD PRACTICES FOR DATA MANAGEMENT AND INTEGRITY IN REGULATED GMP/GDP ENVIRONMENTS Good data management practices influence the integrity of all data generated and recorded by a manufacturer and these practices should ensure that data is accurate, complete and reliable. While the main focus of this document is in relation to data integrity expectations, the principles herein should also be considered in the wider context of good data management. 10

11 NEW GUIDANCES BACKGROUND The way in which regulatory data is generated has continued to evolve in line with the introduction and ongoing development of supporting technologies, supply chains and ways of working. Systems to support these ways of working can range from manual processes with paper records to the use of computerised systems. However the main purpose of the regulatory requirements remains the same; having confidence in the quality and the integrity of the data generated and being able to reconstruct activities remains a fundamental requirement. 11

12 NEW GUIDANCES WHO Technical Report Series No. 996 Annex 5, 2016 Guidance on good data and record management practices However, in recent years, the number of observations made regarding good data and record management practices (GDRP) during inspections of good manufacturing practice (GMP) (1), good clinical practice (GCP) and good laboratory practice (GLP) has been increasing. The reasons for the increasing concern of health authorities regarding data reliability are undoubtedly multifactorial and include increased regulatory awareness and concern regarding gaps between industry choices and appropriate and modern control strategies. Contributing factors include failures by organizations to apply robust systems that inhibit data risks, to improve the detection of situations where data reliability may be compromised, and/or to investigate and address root causes when failures do arise. For example, organizations subject to medical product good practice requirements have been using validated computerized systems for many decades but many fail to adequately review and manage original electronic records and instead often only review and manage incomplete and/or inappropriate printouts. These observations highlight the need for industry to modernize control strategies and apply modern quality risk management (QRM) and sound scientific principles to current business models (such as outsourcing and globalization) as well as technologies currently in use (such as computerized systems). 12

13 COMMON ELEMENTS Data integrity (ALCOA) Emphasis on following technological advancements and modernizing QMS systems to include data management and data integrity Training program to include company s data integrity policy and data integrity SOPs Concern over shared login accounts Risk assessment and risk management Validation of computerised systems Data reviews/internal audits including audit trails 13

14 ALCOA (PIC/S guidance) Data Integrity Attribute Attributable Legible Contemporaneous Original Accurate Requirement It should be possible to identify the individual who performed the recorded task. All records must be legible the information must be readable in order for it to be of any use. The evidence of actions, events or decisions should be recorded as they take place. The original record can be described as the first-capture of information, whether recorded on paper (static) or electronically. Ensuring results and records are accurate is achieved through many elements of a robust Pharmaceutical Quality Management System. This can be comprised of: equipment-related factors such as qualification, calibration, maintenance and computer validation. policies and procedures to control actions and behaviours, including data review procedures to verify adherence to procedural requirements deviation management including root cause analysis, impact assessments and CAPA trained and qualified personnel who understand the importance of following established procedures and documenting their actions and decisions. 14

15 DEFINITION OF AUDIT TRAIL FDA, draft guidance 2016 MHRA WHO For purposes of this guidance, audit trail means a secure, computer-generated, timestamped electronic record that allows for reconstruction of the course of events relating to the creation, modification, or deletion of an electronic record. An audit trail is a chronology of the who, what, when, and why of a record. Audit trails are metadata that are a record of critical information (for example the change or deletion of relevant data) that permit the reconstruction of activities. The audit trail is a form of metadata that contains information associated with actions that relate to the creation, modification or deletion of GXP records. An audit trail provides for secure recording of life-cycle details such as creation, additions, deletions or alterations of information in a record, either paper or electronic, without obscuring or overwriting the original record. An audit trail facilitates the reconstruction of the history of such events relating to the record regardless of its medium, including the who, what, when and why of the action. 15

16 AUDIT TRAIL AND RISK ASSESSMENT Source FDA, August 2003 EU Annex 11 We recommend that you base your decision on whether to apply audit trails, or other appropriate measures, on the need to comply with predicate rule requirements, a justified and documented risk assessment, and a determination of the potential effect on product quality and safety and record integrity. We suggest that you apply appropriate controls based on such an assessment. Audit trails can be particularly appropriate when users are expected to create, modify, or delete regulated records during normal operation. Consideration should be given, based on a risk assessment, to building into the system the creation of a record of all GMP-relevant changes and deletions (a system generated "audit trail"). 16

17 PAPER BASED AUDIT TRAIL Source PIC/S MHRA Art 23 of Directive 2001/83/EC If no electronic audit trail system exists a paper based record to demonstrate changes to data may be acceptable until a fully audit trailed (integrated system or independent audit software using a validated interface) system becomes available. These hybrid systems are permitted, where they achieve equivalence to integrated audit trail, such as described in Annex 11 of the PIC/S GMP Guide. If no audit trailed system exists a paper based audit trail to demonstrate changes to data will be permitted until a fully audit trailed (integrated system or independent audit software using a validated interface) system becomes available. These hybrid systems are acceptable, where they achieve equivalence to integrated audit trail, such as described in Chapter 4 of the GMP Guide. If such equivalence cannot be demonstrated, it is expected that GMP facilities should upgrade to an audit trailed system by the end of 2017 (reference: Art 23 of Directive 2001/83/EC). After an authorization has been issued, the authorization holder must, in respect of the methods of manufacture and control provided for in Article 8(3)(d) and (h), take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods. 17

18 AUDIT TRAIL REVIEW Source FDA, draft guidance 2016 EU Annex 11 MHRA FDA recommends that audit trails that capture changes to critical data be reviewed with each record and before final approval of the record. Audit trails subject to regular review should include, but are not limited to, the following: the change history of finished product test results, changes to sample run sequences, changes to sample identification, and changes to critical process parameters. FDA recommends routine scheduled audit trail review based on the complexity of the system and its intended use. Audit trails need to be available and convertible to a generally intelligible form and regularly reviewed. Routine data review should include a documented audit trail review. When designing a system for review of audit trails, this may be limited to those with GxP relevance (e.g. relating to data creation, processing, modification and deletion etc). Audit trails may be reviewed as a list of relevant data, or by a exception reporting process. An exception report is a validated search tool that identifies and documents predetermined abnormal data or actions, which requires further attention or investigation by the data reviewer. 18

19 STERIS FINN-AQUA EQUIPMENT Are Audit Trails mandatory in SFA critical utility equipment? How to utilize risk assessment? How to perform risk assessment? How to mitigate data integrity risks? How STERIS may help? 19

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21 INITIAL RISK ASSESSMENT Category Yes No Justification Direct impact? Steam may have impact on patient safety and product quality GxP critical? Manufacturing equipment regulated by GxP 21 CFR part 11 applies? No electronic records generated, no permanent data memory Data integrity impact? Parameters and calibration have an impact on data integrity Complex? One pump, less than 5 valves and one pressure PID Novelty? Several hundreds installations worldwide 21

22 IDENTIFY REQUIRED CONTROLS FOR DATA INTEGRITY Controls Yes No Justification Access control Password system with different roles, lockable cabinets Calibration Data accuracy I/Otesting Separate Service Menu for testing purposes System prompts Calibration, factory data upload/download Limiting parameter ranges Invalid or unrealistic values not accepted Sensor fault alarms May indicate instrument manipulation Critical process alarms Aborting conductivity alarm Configuration specifications SOP s for calibration and configuration Backup functionality Parameters and calibration co-efficents Life cycle model GAMP5 implemented QMS Certified quality management system at STERIS Finn-Aqua Audit trail No electronic records 22

23 RISK BASED DECISIONS If needed, more options are available Traditional chart recorder available as an option à limited functionality, paper records Paperless recorder available as an option à recorder manufacturer s specified CFR part 11 functionality, electronic records On special request: Audit trail available SIEMENS standard tools and software A secure, computer-generated, time-stamped electronic record that allows for reconstruction of the course of events relating to the system access, process parameter changes, alarms and calibration events Ability to detect audit trail manipulation Available both in human readable and electronic format, can be exported 23

24 BENEFITS Demonstrate risk based approach to data security Audit trail review with search and filtering capability Ability to detect unsuccessful login attempts Ability to detect changes to system parameters Ability to detect unscheduled calibration events Ability to monitor alarm events Ability to re-construct events and actions during failure investigations Visibility limited to system administrators 24

25 Q&A Questions? 25