21 CFR Part 11

Electronic Records & Electronic

Signatures

Svend Martin Fransen

Principal Scientist,
QS CRS Quality Services
Novo Nordisk A/S
Contents

• 21CFR11 history
• The important aspects of 21CFR11
• Equivalent requirements in EU legislation
• The Novo Nordisk 21 CFR11 compliance
project
• Examples
• Experiences learned

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

Slide No. 3 • QS CRS Quality Services / Svend Martin Fransen • 03.Oct.2002

Why do we have computers?
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

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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

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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)

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Contents

• 21CFR11 history
• The important aspects of 21CFR11
• Equivalent requirements in EU legislation
• The Novo Nordisk 21 CFR11 compliance
project
• Examples
• Experiences learned

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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

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Systems not Applications

• All definitions and

clauses in 21 CFR
Application Instructions,
-software Manuals, etc. 11 refer to
systems
Platform
- hardware Equipment • Application is not
- system SW
mentioned
Computer system Controlled function
• IT part of the GXP
Computer based system
environment.
• Do they know?
Working environment

COMPUTER RELATED SYSTEM

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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

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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’

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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.”?

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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.

Slide No. 13 • 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

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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.

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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

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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.

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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."

Slide No. 18 • 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

Slide No. 19 • QS CRS Quality Services / Svend Martin Fransen • 03.Oct.2002

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

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Overview of the 21CFR11 compliance project

Development

Product
Supply
Staffs,
Quality, RA
and other

21CFR11 project

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

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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

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Guidance database -web-enabled

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Activities in relation to Part 11
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

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Prioritisation of systems
Regulatory Risk

• GxP, support systems (20)

Medium risk High risk
• Other GxP critical, systems (11)

Low risk Medium risk

• Non-GxP systems (17)
X
Factor, based on: No. of records generated by the system,
no. of users, frequency of use and system complexity

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 Gradual achievement of compliance

120

100

80 20 40
Interim solutions
60 20 Phase Technology
2
Procedures
40
20 Phase 60
1 50
20
20
0
Initial State State 2 State 3

Phase 1: Implement Site and system procedures

Phase 2: Technology based solutions, etc.
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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

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Progress Follow Up
System registration QA System evaluation on Implementation plan
Site
approved track preparation on track

A LL K L
B LL J J
C J J J
D J J K
E J K LLL
F J K K
G J LL L
H J J J
I J J J
J J K K
K LL J K
L LL J J
= On track = Ensure no further delay = Take action to catch up

Slide No. 28 • QS CRS Quality Services / Svend Martin Fransen • 03.Oct.2002

Examples of Pilot projects in
production area
• 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)

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Contents

• 21CFR11 history
• The important aspects of 21CFR11
• Equivalent requirements in EU legislation
• The Novo Nordisk 21 CFR11 compliance
project
• Examples
• Experiences learned

Slide No. 30 • 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

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Example for remediation
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
Further information: http://www.zignx.dk/

Slide No. 32 • 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

Slide No. 33 • 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 it’s way (DRAFT PIC/S Guidance)
• Just do it..!

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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)

Slide No. 35 • QS CRS Quality Services / Svend Martin Fransen • 03.Oct.2002