1. SEMINAR ON, PRESENTED BY, POONAM Y AGHARA M – PHARM DEPT. OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L. M. COLLEGE OF PHARMACY AHMEDABAD

2. OUTLINES..... Why Computer Validation ? List of Guidance Documents. General Principles of Software Validation. OTS Software Use in Medical Devices. Electronic Records, Electronic Signatures ( 21 CFR Part 11 ) Guidance Document for Computerized System used in Clinical Trials. Validation of Electronic Spreadsheet. Introduction to Validation Master Plan. Definition of ERP System Possible Questions References

3. WHY COMPUTER VALIDATION

4. COMPUTER APPLICATIONS Data and Information Management Systems Problem Solving Applications Communication Aids ( e- MAIL, DIMS ) Laboratory Automation ( LIMS, HPLC, DISSOLUTION, MICROBALANCES ) Process Control Computerised System used for Clinical Trials and Manufacturing of Medical Devices

5. April 1999Computerized Systems Used in Clinical Trials September 1999Off-The-Shelf Software Use in Medical Devices August 2001Electronic Records; Electronic Signatures – Validation January 2002General Principles of Software Validation August 2003Electronic Records; Electronic Signatures - Scope and Application 21 CFR Part 11Electronic Records; Electronic Signatures 21 CFR Part 820Quality System Regulation

6. GENERAL PRINCIPLES OF SOFTWARE VALIDATION Software used as a component, part, or accessory of a medical device Software that is itself a medical device Software used in the production of a device Software used in implementation of the device manufacturer's quality system January 11, 2002, CDRH, CBER

7. GUIDELINE SAYS ….. Least Burdernsome and Specific Approach SOFTWARE VALIDATION Validation during each activity of life cycle model 21 CFR Part 820 OTS Software Validation (device manufacturer responsible) Simulated Use Environment and User Site Testing Overall design validation for the system Validation Coverage / Extent of Validation Validation Documentation Self-Validation not followed Validation Master Plan Premarket Submission to : ODE CDRH CBER Postchange Software Validation Documentation Updation

8. SOFTWARE LIFE CYCLE MODEL Quality Planning System Requirements Definition Detailed Software Requirements Specification Software Design Specification Construction or Coding Testing Installation Operation and Support Maintenance Retirement

9. OTS SOFTWARE USE IN MEICAL DEVICES Guidance for premarket submission to FDA 3 Level of Concerns Documentation ( Basic and Special) Corneal Topographer (Minor Level of Concern Device) Implantable Medical Device Programmers (Major Level of Concern Device) September 9, 1999

11. 21 C F R P A R T 11 ELECTRONIC RECORDS ELECTRONIC SIGNATURES Was issued in March 1997 Records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted Submission to FDA and also to comply with Predicate Rules (The Act,The PHS Act) Three major concerns demanded the revision of 21 CFR Part 11 1. unnecessarily restrict the use of electronic technology 2. significantly increase the costs of compliance 3. discourage innovation and technological advances Revised and issued in August 2003

12. WHAT DOES PART 11 REQUIRE

13. 21 CFR PART 11 applicable for….. Records maintained in electronic format in place of paper format (PredicateRules and FDA) No predicate rule requirement but it is in electronic format --- No CFR Part 11 Records maintained in electronic format in addition to paper format (Predicate Rules and FDA) Records maintained in electronic format (Predicate Rules, but not required by FDA) Electronic Record used for generating submission if not required by Predicate Rules is not a part of CFR Part 11 and vice versa Electronic signatures that are intended to be the equivalent of handwritten signatures, initials, and other general signings (Predicate Rules)

14. APPROACH TO SPECIFIC PART 11 REQUIREMENTS..... Validation Audit Trail Legacy Systems Copies of Records Record Retention

15. Key Principles of Validating Electronic Recordkeeping Computer Systems System Requirements Specifications Documentation of Validation Activity Dynamic Testing Static Verification Techniques Extent of Validation Independence of Review Revalidation

16. System Requirements Specifications Documentation of user requirements/intended use Computer system implements needs correctly Documentation of Validation Activity Validation Plan Validation Procedure Validation Report

17. Dynamic Testing Key testing consideration Testing Condition Normal Stress Actual Performance Testing Simulation Test User-Site Test Software testing Structural Testing (White Box Testing) Functional Testing (Black Box Testing) Program Build Testing

18. Static Verification Techniques Static analyses Technical reviews Extent of Validation Risk with the system System’s Complexity

19. Independence of Review Third Party Person of the Organisation Revalidation As per requirement of user By system upgradation During routine servicing and maintenance Network like internet

20. IS IT NECESSARY TO VALIDATE COMPUTERIZED SYSTEMS USED IN CLINICAL TRIALS April 1999 USFDA

21. VALIDATION OF ELECTRONIC SPREADSHEET Automating analytical data calculations from various laboratory analyses Tracking and summarizing product complaints Gathering and summarizing clinical trial data collection and analyses Validation of Electronic Spreadsheet is necessary in order to evaluate key drivers : Authenticity, Data and System Integrity, and Confidentiality Should comply with Predicate Regulations 21 CFR Part 11

22. HISTORY OF ELECTRONIC SPREADSHEET ELECTRONIC SPREADSHEET YEAR OF DEBUTLAUNCHER VisiCalc1978Harvad Business School Lotus 1-2-31983IBM Excel1984Microsoft Corporation

23. VALIDATION STEPS FOR ELECTRONIC SPREADSHEET Preparation of test cases/test procedures for each functional element defined. Test case must challenge the operation and performance of the system especially for its most critical parameters Execution of the test cases and the results must be recorded Evaluate whether software has been validated for its intended use Documented evidence of all testing procedures, test input data, and test results must be retained

24. ANSWERS TO "HOW MUCH VALIDATION IS ENOUGH ?" "WHICH SYSTEMS DO WE HAVE TO VALIDATE ?“ “HOW TO COORDINATE THE VALIDATION EFFORTS ?” “HOW TO MAKE VALIDATION EFFORT WITHIN THE BUDGET ?”

25. ENTERPRISE RESOURCE PLANNING (ERP) Integrates planning, manufacturing, distribution, shipping, and accounting into a single system Designed to serve the needs of each different department within the enterprise Creates supply chain management An ERP implementation can cost millions of dollars to create, and may take several years to complete Implement ERP in a more incremental fashion Tremendous advantages: 1. Share information 2. Workflow becomes more automated 3. It can speed up the manufacturing process by automating processes and workflow 4. It also reduces the need to carry large inventories.

26. According to your view point, Why it is necessary to validate “Computer” ? [ 2 marks ] State the general principles of Software Validation. [ 5 marks ] What is OTS Software ? How the level of concern affect the documentation of OTS software validation ? [ 2 marks ] State the key principles of validating Electronic Records and Electronic Signatures. [ 5 marks ] How will you validate the Electronic Spreadsheet ? [ 2 marks ]

27. REFERENCESREFERENCES General Principles of Software Validation; Final Guidance for Industry and FDA Staff, January 11, 2002. (http://www.fda.gov/cdrh/comp/guidance/938.html)http://www.fda.gov/cdrh/comp/guidance/938.html Guidance for Industry, FDA Reviewers and Compliance on Off-The-Shelf Software Use in Medical Devices, September 9, 1999. (http://www.fda.gov/cdrh/ode/guidance/585.html)http://www.fda.gov/cdrh/ode/guidance/585.html Guidance for IndustryPart 11, Electronic Records; Electronic Signatures – Scope and Application, August 2003. (http://www.fda.gov/cder/guidance/5667fnl.htm)http://www.fda.gov/cder/guidance/5667fnl.htm Guidance for Industry 21 CFR Part 11; Electronic Records; Electronic Signatures Validation, August 2001. (http://www.fda.gov/ohrms/dockets/98fr/001538gd.pdf)http://www.fda.gov/ohrms/dockets/98fr/001538gd.pdf Guidance for Industry, Computerized Systems used in Clinical Trials, April 1999. (http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm)http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm

28. REFERENCESREFERENCES US Food and Drug Administration, Center for Devices and Radiological Health, Code of Federal Regulations, Title 21, Part 11, Volume 1, Electronic Records and Electronic Signatures, Revised as of April 1, 2005 (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? CFRPart=11&showFR=1)http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm? CFRPart=11&showFR=1 Computer Validation Guide, Final Draft, Version 2, December 2002. (http://apic.cefic.org/pub/compvalfinaldraftDecember2002.pdf)http://apic.cefic.org/pub/compvalfinaldraftDecember2002.pdf Technical Considerations for the Validation of Electronic Spreadsheets or Complying with 21 CFR Part 11 by Taun T. Phan, Pharmaceutical Technology, January 2003. (www.pharmtech.com)www.pharmtech.com Computer Validation Master Planning “Validation Strategies” by Michael Schousboe, Pharmaceutical Technology, November 1, 2005. (www.pharmtech.com)www.pharmtech.com Computers in Pharmaceutical Technology, Encyclopedia of Pharmaceutical Technology, Volume 3.