21 CFR Part 11

21 CFR Part 11 is a regulation established by the U.S. Food and Drug Administration (FDA) that sets the guidelines for the use of electronic records and electronic signatures in the pharmaceutical, biotechnology, medical device, and other FDA-regulated industries. 21 CFR Part 11 typically applies to companies operating in the United States.

This page offers a brief overview of technical functionalities that satisfy 21 CFR Part 11 requirements and support implementation within an organisation. It does not delve into comprehensive details of 21 CFR Part 11 or serve as legal counsel for achieving absolute compliance.

The page below summarises the relevant sections of 21 CFR Part 11 related to electronic systems and highlights how Seal implements these technical mandates.

Subpart B - Electronic Records

Section 11.10 Controls for closed systems

11.10 Persons who use closed systems to create, modify, maintain, or transmit electronic records shall employ procedures and controls designed to ensure the authenticity, integrity, and, when appropriate, the confidentiality of electronic records, and to ensure that the signer cannot readily repudiate the signed record as not genuine. Such procedures and controls shall include the following:

11.10a Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records.

According to the FDA classification above, Seal is a closed system because the use of the platform requires a login and password, both unique to the Seal system.

• Confidentiality: All records are by default only available to the authors, and authors can share them with other users within the closed system. Sharing rules and access rights can be set up within an organisation to further increase confidentiality.

• Authenticity: All records have only one unique/original author that cannot be changed during the entire lifecycle of a document.

• Integrity: Every single record as well as changes to a record are tracked in a full audit trail and obtain a timestamp provided by the server-system which cannot be manipulated by users. The deletion of documents is possible after authorization, and can be further controlled by organisational policy.

11.10b The ability to generate accurate and complete copies of records in both human readable and electronic form suitable for inspection, review, and copying by the agency. Persons should contact the agency if there are any questions regarding the ability of the agency to perform such review and copy of the electronic records.

Access to records in the closed system can be granted to any individual or organisation, and PDFs of records can be exported anytime. In both implementations, third parties can review records, authors, time stamps, audit trails, and electronic signatures.

11.10c Protection of records to enable their accurate and ready retrieval throughout the records retention period.

Records are stored for three years beyond the subscription period unless explicitly being deleted by the user. Thus, Seal complies with the standard “records retention period” of 21 CFR Part 11.

11.10d Limiting system access to authorised individuals.

Access to Seal requires authentication via a unique username and password. Access to records can be controlled, granted, and revoked anytime by the organisation which controls and owns these records.

11.10e Use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify, or delete electronic records. Record changes shall not obscure previously recorded information. Such audit trail documentation shall be retained for a period at least as long as that required for the subject electronic records and shall be available for agency review and copying.

All records and record changes are provided with a system-created time-stamp and recorded in an activity log which cannot be manipulated by any user of Seal. Deletion of records can be controlled and prohibited by organisational access rights and permissions.

11.10f Use of operational system checks to enforce permitted sequencing of steps and events, as appropriate.

If an organisation requires the sequence check of steps and events, they can implement these using steps in their protocols in Seal, as well as completing entire protocols in the workflow overview of an experiment record.

11.10g Use of authority checks to ensure that only authorised individuals can use the system, electronically sign a record, access the operation or computer system input or output device, alter a record, or perform the operation at hand.

Additional to the login, every user can be assigned administrative roles within an organisation. Read/edit access to records as well as the possibility to sign can be managed for every member of the organisation individually, allowing to enforce authority checks even within nested and branched organisational structures.

11.10h Use of device (e.g., terminal) checks to determine, as appropriate, the validity of the source of data input or operational instruction.

For manual inputs, the input is verified by the user and checks and warnings can be put in place to validate the record. For integration inputs checks and warnings can be established.

11.10i Determination that persons who develop, maintain, or use electronic record/electronic signature systems have the education, training, and experience to perform their assigned tasks.

The product development team is well trained in the field of software design, implementation of cryptographic methods and regulations.

11.10j The establishment of, and adherence to, written policies that hold individuals accountable and responsible for actions initiated under their electronic signatures, in order to deter record and signature falsification.

Seal can provide guidance to customers to develop an SOP for digital signatures.

11.10k Use of appropriate controls over systems documentation including: Adequate controls over the distribution of, access to, and use of documentation for system operation and maintenance; and Revision and change control procedures to maintain an audit trail that documents time-sequenced development and modification of systems documentation.

Documentation regarding the use of Seal can be accessed via the Seal website.

Section 11.30 Controls for open systems

Persons who use open systems to create, modify, maintain, or transmit electronic records shall employ procedures and controls designed to ensure the authenticity, integrity, and, as appropriate, the confidentiality of electronic records from the point of their creation to the point of their receipt. Such procedures and controls shall include those identified in 11.10, as appropriate, and additional measures such as document encryption and use of appropriate digital signature standards to ensure, as necessary under the circumstances, record authenticity, integrity, and confidentiality.

This section does not apply to Seal because seal is a ‘closed system’ according to FDA definition.

Section 11.50: Signature Manifestations

Signed electronic records shall contain information associated with the signing that clearly indicates all of the following:
    - The printed name of the signer;
    - The date and time when the signature was executed;
    - The meaning (such as review, approval, responsibility, or authorship) 
        associated with the signature.

Seal provides a digital signature which indicates the printed name of the signer, a time-stamp for the signature, and the meaning of the signature.

The items identified in paragraphs (a)(1), (a)(2), and (a)(3) of this section shall be subject to the same controls as for electronic records and shall be included as part of any human readable form of the electronic record (such as electronic display or printout).

Digital signatures in Seal as well as their authors and time-stamps are forever recorded in the activity log and can only be altered by persons with the appropriate authority. Digital signatures are displayed in the review section of each experiment entry and are exported as well during a PDF export.

Section 11.70 Signature/record linking

Electronic signatures and handwritten signatures executed to electronic records shall be linked to their respective electronic records to ensure that the signatures cannot be excised, copied, or otherwise transferred to falsify an electronic record by ordinary means.

By being electronically linked to each record, electronic signatures in Seal cannot be excised, copied, or transferred to another record.

Subpart C - Electronic Signatures

Section 11.100 General requirements

11.100a Each electronic signature shall be unique to one individual and shall not be reused by, or reassigned to, anyone else.

Any combination of username and password in Seal is unique. Since electronic signatures are linked to the username/password combination, they can be used only by one individual per signature.

11.100b Before an organisation establishes, assigns, certifies, or otherwise sanctions an individual’s electronic signature, or any element of such electronic signature, the organisation shall verify the identity of the individual.

Organisations can enforce Two Factor Authentication for all Electronic Signatures. If enabled, users will be asked to enter an authentication code before being able to sign.

11.100c Persons using electronic signatures shall, prior to or at the time of such use, certify to the agency that the electronic signatures in their system, used on or after August 20, 1997, are intended to be the legally binding equivalent of traditional handwritten signatures.
    - The certification shall be submitted in paper form and signed with a 
        traditional handwritten signature, to the Office of Regional 
        Operations
    - Persons using electronic signatures shall, upon agency request, provide     
        additional certification or testimony that a specific electronic         
        signature is the legally binding equivalent of the signer's 
        handwritten signature.

The submission of certifications to the FDA is beyond the scope of the software system provided by Seal and falls under the responsibility of the client.

Section 11.200 Electronic signature components and controls

11.200a Electronic signatures that are not based upon biometrics shall:

11.200a-1 Employ at least two distinct identification components such as an identification code and password.

11.200a-i When an individual executes a series of signings during a single, continuous period of controlled system access, the first signing shall be executed using all electronic signature components; subsequent signings shall be executed using at least one electronic signature component that is only executable by, and designed to be used only by, the individual.

11.200a-ii When an individual executes one or more signings not performed during a single, continuous period of controlled system access, each signing shall be executed using all of the electronic signature components.

11.200a-2 Be used only by their genuine owners;

11.200a-3 Be administered and executed to ensure that attempted use of an individual’s electronic signature by anyone other than its genuine owner requires collaboration of two or more individuals.

The first check whether a signature is executed by the authorised individual is provided by the system-login, which is unique for each individual Seal user. The second check is at the point of signing and is implemented using the Time-based One-time Password Algorithm linked to a specific device held by the user. (Note: Organizations must enable the Two-Factor Authentication feature to enforce this second check).

11.200b Electronic signatures based upon biometrics shall be designed to ensure that they cannot be used by anyone other than their genuine owners.

Electronic signatures based upon biometrics are not used on the platform.

Section 11.300 Controls for identification codes/passwords

11.300 Persons who use electronic signatures based upon use of identification codes in combination with passwords shall employ controls to ensure their security and integrity. Such controls shall include:

11.300a Maintaining the uniqueness of each combined identification code and password, such that no two individuals have the same combination of identification code and password.

The username and password combination which is required to authenticate to the system is unique for each individual Seal user.

11.300b Ensuring that identification code and password issues are periodically checked, recalled, or revised (e.g., to cover such events as password ageing). 

This feature is beyond the scope of the software system provided by Seal. During the implementation, Seal will liaise with the organisation’s IT department to adapt to the organisational policies regarding regular password change.

11.300c Following loss management procedures to electronically deauthorize lost, stolen, missing, or otherwise potentially compromised tokens, cards, and other devices that bear or generate identification code or password information, and to issue temporary or permanent replacements using suitable, rigorous controls.

After a report of a device being lost, stolen, missing or potentially compromised, Seal is able to remove that authorization method and issue a replacement.

11.300d Use of transaction safeguards to prevent unauthorised use of passwords and/or identification codes, and to detect and report in an immediate and urgent manner any attempts at their unauthorised use to the system security unit, and, as appropriate, to organisational management.

Seal has implemented security features that report suspicious behaviour. Unauthorised use can further be detected and prevented by monitoring and restricting IP addresses for system access.

11.300e Initial and periodic testing of devices, such as tokens or cards, that bear or generate identification code or password information to ensure that they function properly and have not been altered in an unauthorised manner.

There is an initial testing of the Two Factor Authentication device and a periodic testing of the same device. In case of failure, Seal is able to deactivate that device and change it to a replacement.