1. Meeting Regulatory Requirements for Electronic Signatures
Philadelphia , Pa
January 26, 1999
Presentation by Daniel Worden at the Validation Institute LIMS Electronic Signature/Validation Conference

2. 21 CFR Part 11 Electronic Records; Electronic Signature
Milestones
11/91 Project Launched
7/92 Advanced Notice
8/94 Proposed Rule
3/97 Final Rule
8/97 In Effect
Paul Motise

3. E - Record / E - Signature Acceptance
Reliable
Trustworthy
Part 11
Authentic & Legal

4. 21 CFR Part 11 Electronic Records: Electronic Signature
Overview 11
Summary of 21 CFR, Part 11
Subpart A: General Provisions
Subpart B: Electronic Records
Subpart C: Electronic Signatures
Potential Issues
Certification Statement
Advantages and Challenges
Critical Success Factors
Security and Control

5. 21 CFR Part 11 Electronic Records: Electronic Signature
AGENDA
Summary of 21 CFR, Part 11
Subpart A: General Provisions
Subpart B: Electronic Records
Subpart C: Electronic Signatures
Potential Issues
Advantages and Challenges
Critical Success Factors
Security and Control

6. 21 CFR Part 11 Electronic Records: Electronic Signature
Subpart A - General Provisions
Section 11.1 Scope
Regulations establish the criteria the FDA considers for electronic records and and electronic signature to be trustworthy, reliable, and generally equivalent to paper.
Applies to all records in electronic form under any records requirement within any FDA regulation.
Electronic records are considered equivalent to full handwritten signatures, initials, and other general signings.
Electronic records may be used in accordance with Part 11 unless paper records are specifically required.
Computer system (hardware and software), controls, and relevant documentation must be available for review during FDA inspections.

7. 21 CFR Part 11 Electronic Records: Electronic Signature
“Any combination of text, graphics, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system.”

8. 21 CFR Part 11 Electronic Records: Electronic Signature
“A computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.”

9. 21 CFR Part 11 Electronic Records: Electronic Signature
Handwritten Signature
“The scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form.”
“The act of signing with a writing or marking instrument such as a pen or stylus is preserved. The scripted name or legal mark, while conventionally applied to paper, may also be applied to other devices that capture the name or mark.”

10. 21 CFR Part 11 Electronic Records: Electronic Signature
Digital Signature
“An electronic signature based upon cryptographic methods of originator authentication, computed by using a set of rules and a set of parameters such that the identity of the signer and the integrity of the data can be verified.”
Biometrics
“A method of varifying an individual’s identity based on measurement of the individual’s physical feature(s) or repeatable action(s) where those features and/or actions are both unique to that individual and measurable.”

11. 21 CFR Part 11 Electronic Records: Electronic Signature
Closed System
“An environment in which system access is controlled by persons who are persons who are responsible for the content of electronic records that are on the system.”
Open System
“An environment in which system access is not controlled by persons who are responsible for the content of electronic records that are on the system.”

12. 21 CFR Part 11 Electronic Records: Electronic Signature
Subpart B - Electronic Records
Section Controls for Closed Systems
Must develop procedures and controls to ensure authenticity, integrity and confidentiality, and that signer cannot repudiate the signed record. The controls must:
Be validated
Maintain accurate and complete records
Limit the system to authorized persons
Protect records through retention period
Contain audit trails that are secure, operator independent, computer-generated, time-stamped, cover the creation , modification and deletion of records and do not obscure previous information

13. 21 CFR Part 11 Electronic Records: Electronic Signature
Section Controls for Closed Systems (cont.)
Allow for the performance of operational system checks, authority checks, and device checks to ensure system, record, and data integrity
Ensure appropriate personnel qualifications
Policies written and followed to hold personnel accountable for actions and to deter records falsification
Control over system documentation including distribution, access, use, revision and change control

14. 21 CFR Part 11 Electronic Records: Electronic Signature
Section Controls for Open Systems
Must develop procedures and controls that ensure authenticity, integrity, and confidentiality of electronic records and comply with all other parts of Section 11.10
Must use additional measures (e.g. document encryption, digital signature standards) to ensure authenticity, integrity, and confidentiality

15. 21 CFR Part 11 Electronic Records: Electronic Signature
Section Signature Manifestation
Signed electronic records must include the printed name of the signer, date and time of signature, and the purpose of the signature (e.g. review, approval etc.) Each of these must be readable by display or printout.
Section Signature/Record Linking
Electronic signature and handwritten signatures must be linked to ensure signatures cannot be excised, copied, transferred or falsified.

16. 21 CFR Part 11 Electronic Records: Electronic Signature
Subpart C-Electronic Signature
Section General Requirements
Must be unique to an individual and not reassigned
Identity of individual must be verified by organization
Must certify electronic signature system to the agency prior to or at the time of use of the system
Certification must be submitted in paper form and, upon agency request, provide certification that signature is legally binding

17. 21 CFR Part 11 Electronic Records: Electronic Signature
Section Electronic Signature Components and Controls
Non-Biometric signatures must:
Contain at least two different identification components (e.g. User ID and Password)
Single sign-on with multiple tasks: Use all identification components at first, with partial identification for each task thereafter
Multiple sign-on without continuous access requires all identification components to be used each time
Be used only by the owner
Ensure use by other individuals is precluded and does not occur without collaboration by at least two other individuals
Biometric signatures must ensure use by the owner

18. 21 CFR Part 11 Electronic Records: Electronic Signature
Section Controls for Identification Codes/Passwords
Persons using electronic signatures must use controls to ensure security and integrity and should include:
Assuring that no two individuals have the same combination of identification code and password
Periodic check, recall, or revision of identification code and password
Loss management and replacement procedures
Testing of devices (i.e. tokens or cards) that produce or maintain identification codes or passwords to ensure proper function and unaltered state.

19. 21 CFR Part 11 Electronic Records: Electronic Signature
Section Controls for ID codes/passwords
Unauthorized use safeguards
Report attempts in urgent & immediate manner to:
Security unit
Management, as appropriate

20. 21 CFR Part 11 Electronic Records: Electronic Signature
FDA’s View of What Industry Needs to Do
Learn Part 11
File (c) Certification
E-records maintained
ID formats FDA can audit/copy
Check with FDA auditors
Watch for guidance documents

21. 21 CFR Part 11 Electronic Records: Electronic Signature
FDA’s View of What Industry Needs to Do
E-records submitted to FDA
Check docket 92S-0251
Attn: logistics and guidance
file format/media
Transmission methods/archiving

22. 21 CFR Part 11 Electronic Records: Electronic Signature
Submit
Maintain
Signatures
Biometric
Nonbiometric

23. Part 11 Internet Web Site:
21 CFR Part 11 Electronic Records: Electronic Signature
Part 11 Internet Web Site:

24. 21 CFR Part 11 Electronic Records: Electronic Signature
7520 Standish Place
Rockville, MD 20855
Paul J. Motise
Consumer Safety Officer
Division of Manufacturing and Product Quality, HFD-320
Center for Drug Evaluation and Research
Phone: Fax:

25. Potential Issues
The final rule does not establish numerical standards for levels of security or validation (persons have the option of determining the frequency).
Wide spread implementation of time date stamped audit trails executed objectively and automatically and controls for limiting access to the database search software may change a company’s current practices.
The word “ensure” is used in the regulations. It is defined as “to make certain”. How will this be interpreted by a field inspector?
“Unique nature of passwords”. How is uniqueness determined and what are “good password practices”?
Part 11 does not apply to paper records that are or have been transmitted by electronic means but it does apply to records in electronic form that are created, modified, maintained, archived, retrieved under any record requirement regulated by FDA.
Record retention requirements for software and hardware used to create records that are retained in electronic form are subject to part 11.

26. Potential Issues (Cont’d)
“As the agency’s experience with part 11 increases certain records may need to be limited to paper if there are problems with the electronic versions of such records.”
“It may be necessary to inspect hardware and software used to generate and maintain electronic records to determine if the provisions of part 11 are being met.”
The assessment of adequacy of systems validation will include inspection of hardware to “determine if it matches the system documentation description of the hardware.”
For geographically dispersed systems, inspections would extend to operations, procedures and controls at one location and the agency would inspect other locations of the network in a separate but coordinated manner.
Is the implementation of an electronic system significant enough in manufacturing to require an NDA supplement prior to going live?
Dial-in access over public phone lines can be a closed system if access to the system is under the control of the persons responsible for the content of the record.

27. Potential Issues (Cont’d)
When an organization’s electronic records are stored on systems operated by third parties the agency would consider this to be an open system.
Electronic record is defined as “any combination of text, graphics, data, audio, pictorial or other information representation in digital form that is created, modified, maintained, archived, retrieved or distributed by a computer system.”
“The Agency believes that if it is important enough that a record be signed, human readable displays of such records must include the printed name of the signer, the date and time of signing, and the meaning of the signature”. Example: a message from a firm’s management to employees instructing them on a particular course of action may be critical in litigation.
“A single certification may be stated in broad terms that encompass electronic signatures of all current and future employees”.

28. Potential Issues (Cont’d)
21CFR11 applies only to those records required to be created, archived, and/or signed or initialed in accordance with another (predicate rule) FDA regulation. Failure to comply with Part 11 effectively invalidates the electronic record, thus placing the firm in violation of the predicate rule requiring the record.
The FDA is being lenient in enforcing the rule unless the investigator has reason to question the integrity of the data.
PhRMA feels that FDA’s interpretation of the electronic record portion of the rule is flawed since many computer systems in use in R&D, clinical and QC lack the capability of generating time-date audit trails (e.g.SAS and HPLC).
21CFR11 has evolved from an approach to facilitate a paperless system into an FDA enforcement tool .
PhRMA claims that the FDA definition of raw data has changed. Previous to the rule, raw data was considered to be paper documents with a handwritten signature. If the data were generated from a compuer, the printout was signed and archived as the official record.

29. Potential Issues (Cont’d)
FDA is considering additional guidance to try to create a procedure to ensure that electronic records can not be changed after a hardcopy has been signed.
FDA would like to obtain a copy of each electronic file, manipulate it, study it, and pick out trends.
The transition to paperless systems has proven to be gradual and potentially very expensive. Industry, therefore, has opted to maintain hybrid systems because many systems currently in use in R&D and Manufacturing are not able to comply with the electronic signature section of Part 11.
As of August 20, 1997 firms that used hybrid systems had the choice of maintaining the hybrids or converting to an electronic environment, in whole or in part, to meet FDA maintenance record requirements.
ID’s should not be reused even if the person using the ID leaves the company.
Passwords should consist of a minimum of six characters using a combination of letters and numbers.

30. Certification Statement
Pursuant to section of Title 21 of the code of Federal Regulations, this
is to certify that __________________ intends that all electronic signatures
Name of organization
executed by our employees, agents, or representatives, located anywhere in the
world, are the legally binding equivalent of traditional handwritten signatures.

31. Stringent Controls
“The agency believes that…it is vital to have stringent controls in place to prevent impersonation. Such controls include: (1) requiring an individual to remain in close proximity to the workstation throughout the signing session; (2) use of automatic inactivity disconnect measures that would “de-log” the first individual if no entries or actions were taken within a fixed short timeframe; and (3) requiring that the single component needed for subsequent signings be known to, and usable only by, the authorized individual

32. Electronic Signatures and Electronic Records
Advantages
Electronic Batch records can eliminate mountains of paper work, speed processing and allow for statistical and trend analyses.
NDA’s and other submissions can be submitted electronically in place of paper submission.
Increases the speed of information exchange.
Cost savings from reduced need for storage space.
Manufacturing process streamlining.
Job creation in industries involved in electronic record and electronic signature technologies.
Challenges
Firms planning on using electronic signatures in FDA regulated environments will be required to validate the computer related systems.
Design of systems must be well thought out and tested thoroughly.
Critical control points must be identified which can be monitored through electronic audit trails.
Adequate testing of security.
Fraud Detection

33. Electronic Signatures and Electronic Documents
Critical Success Factors
Validation activities in manufacturing, toxicology, clinical, regulatory and perhaps marketing (label approval) will need to be better process focussed, requiring definition of inputs and outputs with, procedural controls governing the process activities and standards dictating the format and content of inputs and outputs and well documented.
Configuration management, security management and periodic review and quality management must be a continual process.
Record retention and record disposal practices need to be revised to reflect company requirements to comply with new regulatory requirements.
Documentation standards and practices should be created that systematize the processes for creating and maintaining documents.
Planning will have to take into consideration re-engineering, replacement, or retirement of a computer system when operating costs increase or business process changes.
Requires effective change control.

34. ELECTRONIC BATCH RECORD SYSTEMS (EBRS)
EBRS are a critical part of an automated plant manufacturing/QC documentation system
A completely electronic environment may include:
- Computerized master and batch record documents
- Electronic routing and review
- Data collection
- On line documents (SOPs, forms, manufacturing instructions)
- Change control
- Automated batch release
- Retention and archival

35. ELECTRONIC BATCH RECORD SYSTEMS (EBRS)
Features may include:
Online Ad-hoc inquiries
Ability to select data to download to other systems
Batch status
Trend monitoring
Traceability
Review of quality actions
- Variences
- Corrections
- Rework
- Scrap
- Calibration
- Validation
Automatic batch document removal after retention period expiration

36. ELECTRONIC BATCH RECORD SYSTEMS (EBRS)
21 CFR (b) (11) requires documentation of each significant step in the manufacture, processing, packing or holding of a batch including identification of persons performing, supervising or checking each significant step.
When humans are replaced by computer it is necessary to:
1. Prepare documentation to demonstrate adequate checks and performance of the system
2. Validation of the performance of the computer program controlling execution of the execution of the steps
3. Recording specific checks in batch production and control records of the initial step, any branching step and the final step.
4. Demonstrating that the computer system examines the same conditions that a human being would look for, and that the degree of accuracy in the examination is at least equivalent.

37. ELECTRONIC BATCH RECORD SYSTEMS (EBRS)
Steps
1. Define system requirement
2. Identify documents
Types
Forms
Text
Graphics
Exceptions
Bill of materials
3. Routing and approvals
4. Change management
5. Distribution
6. Regulatory
GMPs
Validation
Electronic Signatures
Security
7. System administration
8. Hardware options
9. Vendors

38. Security and Control
Procedural
Physical
Logical

39. Procedural - Verification
Obtain and Review Corporate Security policy, security standards and procedures
Evaluate the effectiveness of the security organization
Evaluate the effectiveness of the process for requesting, granting and removing access.

40. An Enterprise-Wide Security Strategy Should ….
Identify risk, threats and potential vulnerabilities
Classify information based on sensitivity (sensitive, public, cGMP vs. non-cGMP, etc.)
Determine and implement appropriate controls based on risk assessment/classification
Ensure a consistent process to maintain an effective level of security and control
Document this approach in the form of an SOP

41. Physical Security Review Physical Access Policy
Identify sensitive areas (computer room, data rooms, wiring closets).
Determine process for granting, reviewing, monitoring and removing access.
Verify that process is operating effectively.

42. Logical Security Obtain and review data access policy
Identify access “Paths” to cGMP data
Dial-in
Internet
Local Area Network
Operating System
Database Security
Application Security

43. Logical Security For each access path, evaluate the following:
user security parameters
unique user ID/password combinations
password change intervals (90 days)
password composition (e.g., combination of numbers and letters required)
password length (minimum length of 6 characters)
access controls that enforce segregation of duties (read, write, delete)
monitoring functionality and audit trail

44. Logical Security - approach
Use automated tools to gather security-related information for dial-in, Internet, operating system, database, and Local Area Network.
Attempt to gain unauthorized access to sensitive cGMP data by exploiting “weak links” in the security chain.
Evaluate audit trail to ensure that activity was reported and followed up.

45. THE PATH FORWARD GAP ANALYSIS “As Is” processes Design Specs
Risk Exposure
SYSTEM CONTROLS
Security
Electronic Record Retention
Monitoring
FRAUD
MONITORING 483s