THIS PRESENTATION COVERS Lack of Data Integrity is NOT a Single ‘Disease’ Attributes of Successful Remediation Observations and Corrective Actions FDA Specified Data Integrity RemediationCopyright 2016, Unger Consulting Inc., All Rights Reserved2

LACK OF ‘DATA INTEGRITY’ IS NOT A SINGLE ‘DISEASE’ Good Documentation Practices, Paper Records Good Documentation Practices, Electronic Records Predicate Rules and Chapters / Annexes 21 CFR Part 11 and Annex 11 Computer System Validation Laboratories, Manufacturing, ERP, Complaints Not Validated For Intended Use Multiple Sourced Data Associated with Same EventNot in Agreement Cannot Discern Altered or Deleted Data Data Not Available or Not ProvidedCopyright 2016, Unger Consulting Inc., All Rights Reserved3

ATTRIBUTES OF SUCCESSFUL REMEDIATION These Pro le s Rarel E ist I Isolatio ; It’s OfteMore Widespread Than You Think Understand The Scope Of The Issues And Take AHOLISTIC Approach Identify And Fix The Root Cause It May Be Costly In FTEs, Consultants, Hardware /Software Establish a Data Governance ProgramCopyright 2016, Unger Consulting Inc., All Rights Reserved4

ATTRIBUTES OF SUCCESSFUL REMEDIATION Establish a Data Governance Program Within QMS Provides A Framework And Executive Level Ownership Incorporates Remediation Into The QMS Investigations and Corrective Actions Permits Risk Based Evaluation and Prioritization ofActivities Consistency in Communication and Goals Ultimately Extend to GCP and GLP Activities Addressed in MHRA, PIC/S and WHO GuidanceCopyright 2016, Unger Consulting Inc., All Rights Reserved5

EXAMPLES WITH REMEDIATIONDuplicate HPLC Injections, Represents Testing Into Compliance Evaluate ALL HPLC Injections To Ensure They Are Appropriate Clarify When ‘Pre-injections’ Can Be Performed And How TheyAre To Be Identified. Revise SOP, Train Staff, Include InInternal Audit ProgramStand Alone Instrumentation Has Shared Passwords And NoAudit Trail Capability Upgrade Software If Possible Purchase New Compliant Instrumentation / Software Interim Fix, Use Log Book DocumentationCopyright 2016, Unger Consulting Inc., All Rights Reserved6

EXAMPLES WITH REMEDIATIONComputer Systems Not Validated For Intended Use Identify all GXP Computer SystemsEvaluate Validation Status of ALL Computer SystemsRemember ‘Requirements’, Configuration and TestingDocument the EvidenceAccess to Computer Systems Not Controlled Establish And Follow The Process Revise As Staff Change Positions Ensure Appropriate Privileges AssignedCopyright 2016, Unger Consulting Inc., All Rights Reserved7

EXAMPLES WITH REMEDIATION Excel Calculation Spreadsheets Not Qualified /Validated / Controlled. Often Firms Don’t KnowHow Many They Have Or Where They Are Stored Switch To Capability Within Existing Software (ForExample, Empower) Minimize Their Use, If Not, Then Control Their Development, Validation, Use, RevisionAnd RetirementCopyright 2016, Unger Consulting Inc., All Rights Reserved8

EXAMPLES WITH REMEDIATION GMP Documents Discarded Training Discipline Data Modified or Data Deleted Defer to End of PresentationCopyright 2016, Unger Consulting Inc., All Rights Reserved9

DOCUMENTATION AND PRACTICES Addressing Documentation Practices FrequentlyRequires Changes In The Quality System Data Governance Data Collection, Processing, Review GMP Audit Program and Inspection Prep CMOs and Contract Labs Not Simply SOP Revisions and Retraining Every Employee Plays an Important RoleCopyright 2016, Unger Consulting Inc., All Rights Reserved10

EXAMPLES AND REMEDIATION Electronic Data Review / Approval Paper printout is not your GMP Data Clarity In Review and Approval SOP Training and Expertise for Review Staff Alignment Of Paper And Electronic Records Equipment LogsScale PrintoutsLaboratory NotebooksLaboratory Log-in And DestructionCopyright 2016, Unger Consulting Inc., All Rights Reserved11

FDA IDENTIFIED ‘DATA INTEGRITY REMEDIATION’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. We acknowledge that you are using a consultant to audityour operation and assist in meeting FDA requirements. In response to this letter, provide the following.A. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Yourinvestigation 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 toexclude.* 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 partsof our fa ilit ’s operatio s i hi h ou dis o ered data i tegrit lapses.* A comprehensive retrospective evaluation of the nature of the testing and manufacturing data integritydeficiencies. We recommend that a qualified third party with specific expertise in the area where potential batcheswere identified evaluate all data integrity lapses.12Copyright 2016, Unger Consulting Inc., All Rights Reserved

B. A current risk assessment of the potential effects of the observed failures on the quality of yourdrugs. Your assessment should include analyses of the risks to patients caused by the release ofdrugs affected by a lapse of data integrity, and risks posed by ongoing operations.C. A management strategy for your firm that includes the details of your global corrective action andpreventive action plan. Your strategy should include:* A detailed corrective action plan that describes how you intend to ensure the reliability and completenessof 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 thescope and depth of the current action plan is commensurate with the findings of the investigation and riskassessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMPrelated data at your firm.* Interim measures describing the actions you have taken or will take to protect patients and to ensure thequality of your drugs, such as notifying your customers, recalling product, conducting additional testing, addinglots 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, staffingimprovements) designed to ensure the integrity of your company’s data.* A status report for any of the above activities already underway or completed.13Copyright 2016, Unger Consulting Inc., All Rights Reserved

Copyright 2016, Unger Consulting Inc., All Rights Reserved14

CONTACT INFO:Barbara W. r to: for Blog entries on warningletters and form 483 analysis including data integrity issues2015 Data Integrity: Warning Letter Deficiencies And Eudra GMPReports Of Non-compliance.Non-compliance Please email me and I’ll send a copy.Copyright 2016, Unger Consulting Inc., All Rights Reserved15

Electronic Data Review / Approval Paper printout is not your GMP Data Clarity In Review and Approval SOP Training and Expertise for Review Staff Alignment Of Paper And Electronic