21 cfr part 11 electronic records & electronic signatures svend martin fransen principal...

21 CFR Part 11Electronic Records &

Electronic Signatures

Svend Martin Fransen

Principal Scientist,

QS CRS Quality Services

Novo Nordisk A/S

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


Contents

• 21CFR11 history




• Examples



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?


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


Historic overview

• A wish from the Industry (use of ES)

• FDA:• Final Draft i 1994

• Final Rule 20.March.1997, effective from 20.Aug.1997

• 4 draft guidelines, ’Glossary of Terms’, ’Validation’, ’Time stamps’ and ’Maintenance of ER’

• GAMP Part 11 guide, published Nov. 2001 (part 2)

• PDA ”GERM” guide, published Sep. 2002 (part 1)

• PDA ”GERM” guide ’Models’, expected 2003 (part 3)


Contents

• 21CFR11 history




• Examples



21CFR11, 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


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


21 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


ORA, Compliance Policy Guide CPG 7153.17 (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’


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.”?


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.


Contents

• 21CFR11 history




• Examples



EU

• Annex 11, Computerised Systems• Personnel

• Validation

• System• Descriptions and SOP’s• Change control and configuration management• Records; entry, storage, retrieval• Audit trail• Security and Disaster recovery• etc.


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


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.


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."


Contents

• 21CFR11 history




• Examples



21CFR11 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


Overview of the 21CFR11 compliance project

Product Supply

Staffs, Quality, RA and other

Development

21CFR11 project

No. of systems today = 868 (PS) + 219 (Dev.) + 65 (others) = 1152 systems (..and more to come)


21CFR11 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


Guidance database -web-enabled


1. 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


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

Medium risk

Y

X

• Non-GxP systems (17)

• Other GxP critical, systems (11)

• GxP, support systems (20)


Gradual achievement of compliance

0

20

40

60

80

100

120

Initial State State 2 State 3

Interim solutions

Technology

Procedures

20

20

20

20

50

40

60

Phase 1: Implement Site and system proceduresPhase 2: Technology based solutions, etc.

Phase1

Phase2


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


Progress Follow Up

= On track = Ensure no further delay = Take action to catch up

SiteSystem registration QA

approvedSystem evaluation on

trackImplementation plan preparation on track

A B C D E F G H I J K L

Example


• 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


Contents

• 21CFR11 history




• Examples



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


Further information: http://www.zignx.dk/

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


Contents

• 21CFR11 history




• Examples



Conclusions

• Management commitment pivotal

• Expensive and complex

• Requires highly skilled project management

• Risk-based prioritisation

• FDA enforcement becomes tougher

• and EU is on it’s way (DRAFT PIC/S Guidance)

• Just do it..!


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 SOP’s)• Technical controls (= Supplier SW controls)

21 cfr part 11 electronic records & electronic signatures svend martin fransen principal...

Documents

individual slide

21cfr11 compliance report

cosmetics 21cfr11

electronic record system

contents 21cfr11 history

storage of data

data input

data life cycle