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21 CFR Part 11 Electronic Records & Electronic Signatures Svend Martin Fransen Principal Scientist, QS CRS Quality Services Novo Nordisk A/S.

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Presentation on theme: "21 CFR Part 11 Electronic Records & Electronic Signatures Svend Martin Fransen Principal Scientist, QS CRS Quality Services Novo Nordisk A/S."— Presentation transcript:

1 21 CFR Part 11 Electronic Records & Electronic Signatures Svend Martin Fransen Principal Scientist, QS CRS Quality Services Novo Nordisk A/S

2 Slide No. 2 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Contents 21CFR11 history The important aspects of 21CFR11 Equivalent requirements in EU legislation The Novo Nordisk 21 CFR11 compliance project Examples Experiences learned

3 Slide No. 3 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Contents 21CFR11 history The important aspects of 21CFR11 Equivalent requirements in EU legislation The Novo Nordisk 21 CFR11 compliance project Examples Experiences learned

4 Slide No. 4 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 It has gradually become common knowledge that knowledge is the most important resource in the business of the future. It is the ability to create new knowledge and the ability to utilize and organize existing knowledge that will be the primary source for obtaining lasting competitive advantages. Peter Holdt Christensen: Viden om – ledelse, viden og virksomheden Why do we have computers?

5 Slide No. 5 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 What is 21CFR11? 21CFR = FDA, Code of Federal Regulations 21CFR58= GLP 21CFR210 = GMP, Drugs (General) 21CFR211 = GMP, Drugs (Finished Pharmaceuticals) 21CFR312= Inv. New drug Application (GCP) 21CFR314 = FDA Approval of new drug (GCP) 21CFR6xx= GMP, biologics 21CFR820 = GMP, Devices 21CFR……= Food, nutrients and cosmetics 21CFR11 = Electronic Records; Electronic Signatures

6 Slide No. 6 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Historic overview A wish from the Industry (use of ES) FDA: Final Draft i 1994 Final Rule 20.March.1997, effective from 20.Aug draft guidelines, Glossary of Terms, Validation, Time stamps and Maintenance of ER GAMP Part 11 guide, published Nov (part 2) PDA GERM guide, published Sep (part 1) PDA GERM guide Models, expected 2003 (part 3)

7 Slide No. 7 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Contents 21CFR11 history The important aspects of 21CFR11 Equivalent requirements in EU legislation The Novo Nordisk 21 CFR11 compliance project Examples Experiences learned

8 Slide No. 8 QS CRS Quality Services / Svend Martin Fransen 03.Oct CFR11, Overview Substantive rule from 20 August 1997 Applies to any e-record in any FDA regulated work including legacy systems Criteria for e-records and e-signatures: Trustworthy and reliable E-signatures = hand-written signatures Minimum requirements / fraud prevention

9 Slide No. 9 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Systems not Applications All definitions and clauses in 21 CFR 11 refer to systems Application is not mentioned IT part of the GXP environment. Do they know? Working environment Computer based system Computer system Application -software Platform - hardware - system SW Controlled function Instructions, Manuals, etc. Equipment COMPUTER RELATED SYSTEM

10 Slide No. 10 QS CRS Quality Services / Svend Martin Fransen 03.Oct CFR Part 11, Basics Electronic records equivalent with paper records Storage, retrieval and copying in full retention period Submitting to FDA Protection of electronic records Security (physical and logical) Validation Audit trail (who did what, when including reason where req.) Permission to use of electronic signature Equivalent with handwritten signatures Name, date and meaning Linking of signature to record Unique for an individual

11 Slide No. 11 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 ORA, Compliance Policy Guide CPG (May 1999) Acknowledging not all older systems fully compliant by Aug 20, 1997 firms must take steps to achieve full compliance Regulatory actions based on case by case evaluation FDA auditors should intensify their scrutiny of e-recs Calls for firms to have a reasonable timetable promptly modify any system not in compliance be able to demonstrate progress have procedural controls in place by now

12 Slide No. 12 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 FDA 21CFR11 inspection questions (source: : 21CFR11 Compliance Report, Vol.2, No. 4). Who is allowed to input data? Who is allowed to change data? How can you tell who entered the data? How do you know which data had been changed? When do you lock down the data input? Can you do the following actions? Show me some data, show me you can see the history of the data, show me you control the data life cycle. Is the system validated and are the requirements met? Can you show me the results of the validation activities? Does the validation include: Pass/fail, signature, date/time stamp; and objective evidence - screen prints or page printouts with a link to the direction that generated the output.?

13 Slide No. 13 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Earlham College, Warning Letter In addition to the above listed violations, our Investigator noted that the laboratory is using an electronic record system for processing and storage of data from the atomic absorption and HPLC instruments that is not set up to control the security and data integrity in that the system is not password controlled, there is no systematic back-up provision, and there is no audit trail of the system capabilities. The system does not appear to be designed and controlled in compliance with the requirements of 21 CFR, Part 11, Electronic Records.

14 Slide No. 14 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Contents 21CFR11 history The important aspects of 21CFR11 Equivalent requirements in EU legislation The Novo Nordisk 21 CFR11 compliance project Examples Experiences learned

15 Slide No. 15 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 EU Annex 11, Computerised Systems Personnel Validation System Descriptions and SOPs Change control and configuration management Records; entry, storage, retrieval Audit trail Security and Disaster recovery etc.

16 Slide No. 16 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 PIC/S Draft Guidance Good Practices for Computerised Systems in regulated GXP environment Computer System Life cycle, incl. Electronic Records and Signatures Security, and Audit trail Checklists for Inspection Links ISO and IEEE standards, 21CFR11, APV guides, PDA Technical Reports together

17 Slide No. 17 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Quote from PIC/S Guide 21. ELECTRONIC RECORDS AND ELECTRONIC SIGNATURES 21.1 EC Directive 91/356 sets out the legal requirements for EU GMP. The GMP obligations include a requirement to maintain a system of documentation, (Article 9). The main requirements in Article 9.1 are that documents are clear, legible and up to date, that the system of documentation makes it possible to trace the history of manufacture (and testing) of each batch and that the records are retained for the required time. Article 9.2 envisages that this documentation may be electronic, photographic or in the form of another data processing system, rather than written. The main requirements here being that the regulated user has validated the system by proving that the system is able to store the data for the required time, that the data is made readily available in legible form and that the data is protected against loss or damage.

18 Slide No. 18 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Draft Proposal for a Commission Directive (30.Apr.2002) Amending Commission Directive 91/356/EEC, Laying Down the Principles and Guidelines of Good Manufacturing Practice for Medicinal Products for Human Use "When electronic, photographic or other data processing systems are used instead of written documents, the manufacturer or importer shall have validated the systems by proving that the data will be appropriately stored during the anticipated period of storage. Data stored by these systems shall be made readily available in legible form and shall be provided on demand to the competent authorities. For an investigational medicinal product when electronic, photographic or other data processing systems are used instead of written documents the manufacturer or importer shall have validated the systems to maintain the data during the required period of storage. Data stored by these systems shall be readily available in legible form and shall be provided on demand to the competent authorities."

19 Slide No. 19 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Contents 21CFR11 history The important aspects of 21CFR11 Equivalent requirements in EU legislation The Novo Nordisk 21 CFR11 compliance project Examples Experiences learned

20 Slide No. 20 QS CRS Quality Services / Svend Martin Fransen 03.Oct CFR11 Compliance Project Purpose Assist the units/system owners to prioritise the activities necessary to get in compliance over a limited period of time. Scope All Computer Systems within Novo Nordisk that generate electronic records covered by regulatory requirements from FDA, including the systems that utilise Electronic Signatures

21 Slide No. 21 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Overview of the 21CFR11 compliance project Product Supply Staffs, Quality, RA and other Development 21CFR11 project No. of systems today = 868 (PS) (Dev.) + 65 (others) = 1152 systems (..and more to come)

22 Slide No. 22 QS CRS Quality Services / Svend Martin Fransen 03.Oct CFR11 Compliance Project Tasks Secure cGxP for 21CFR11 at Novo Nordisk Maintain corporate policy and interpretations Responsible for project QAP reporting Participate in external groups as NN representatives Distribute knowledge to organisation through Training (short courses and Site specific) Knowledge and guidance database Project web page Guidelines

23 Slide No. 23 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Guidance database - web-enabled

24 Slide No. 24 QS CRS Quality Services / Svend Martin Fransen 03.Oct Identify and register systems (overview) 2. Prioritise systems 3. Evaluate high-risk systems 4. Evaluate medium- and low-risk systems 5. Evaluate corrections/solutions 6. Prepare implementation plan Quick fixes Full compliance, technical and procedural 7. Implement solutions Activities in relation to Part 11

25 Slide No. 25 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Prioritisation of systems Regulatory Risk Factor, based on: No. of records generated by the system, no. of users, frequency of use and system complexity High risk Low risk Medium risk Y X Non-GxP systems (17) Other GxP critical, systems (11) GxP, support systems (20)

26 Slide No. 26 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Gradual achievement of compliance Phase 1: Implement Site and system procedures Phase 2: Technology based solutions, etc. Phase 1 Phase 2

27 Slide No. 27 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Deliverables from common workgroups Evaluation of the system (gap-analysis) for technical issues Evaluation of possible solutions Recommendations and other input from supplier(s) Recommended solutions, including Draft or example of procedures Description of technical solution Estimated costs Suggested implementation plan

28 Slide No. 28 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Progress Follow Up = On track= Ensure no further delay= Take action to catch up Site System registration QA approved System evaluation on track Implementation plan preparation on track A B C D E F G H I J K L Example

29 Slide No. 29 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Kaye Validator SCADA (Fix32) Filter testing equipment (PALL) Instron (replacement for..) PE laboratory equipment (UV/VIS +..) incl. replacements for..) Usifroid freeze dryer BMS (building monitoring systems)...more to come (due to standardisation) Examples of Pilot projects in production area

30 Slide No. 30 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Contents 21CFR11 history The important aspects of 21CFR11 Equivalent requirements in EU legislation The Novo Nordisk 21 CFR11 compliance project Examples Experiences learned

31 Slide No. 31 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 What can go wrong, will... HPCE (High Pressure Capillary Electrophoresis) Scenario: Replacement of chromatography software to Millennium and setting up an archive installation 7 year old software HW requirements to PC Migration of ER from OS/2 to Win NT Indexation of migrated data ER on tape stored in safe Use of archive installation Training of users SOPs

32 Slide No. 32 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Further information: A hardware solution: Control power supply to individual physical entities in a PC including keyboard and mouse Solution is OS independent User access is controlled via Smart card: User profiles supported by pin code on the ZignX keyboard. Logging of access attempts Example for remediation

33 Slide No. 33 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Contents 21CFR11 history The important aspects of 21CFR11 Equivalent requirements in EU legislation The Novo Nordisk 21 CFR11 compliance project Examples Experiences learned

34 Slide No. 34 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Conclusions Management commitment pivotal Expensive and complex Requires highly skilled project management Risk-based prioritisation FDA enforcement becomes tougher and EU is on its way (DRAFT PIC/S Guidance) Just do it..!

35 Slide No. 35 QS CRS Quality Services / Svend Martin Fransen 03.Oct.2002 Problem areas Lack of knowledge in the organisation on Computer Validation 21 CFR Part 11 Maintenance of computer systems Purchase of non-compliant systems are ongoing Part 11 compliant systems do not exist Administrative controls (= Company policies) Procedural controls (= Company SOPs) Technical controls (= Supplier SW controls)


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