We’d be willing to bet your key collaborators aren’t all in the same building. Your team members, contract partners, clients, and suppliers are likely scattered across the globe. That makes collecting physical, “wet ink” signatures nearly impossible and turns digital approvals into a daily necessity.

But how you collect those electronic signatures matters, especially for GxP-regulated organizations.

The typical workaround of printing, signing, scanning, and emailing creates compliance risks and breaks the digital chain of custody. A dedicated e-signature tool is the smarter move, but not all platforms are created equal. Many standard business tools simply don’t meet the strict GxP compliance standards, leaving you exposed during an audit.

So, how do you get it right? Here’s what you need to know to make sure your e-signature process isn’t just efficient but provably compliant.

What makes an electronic signature GxP compliant?

The U.S. Food and Drug Administration (FDA) is clear about what makes an electronic signature 21 CFR Part 11 compliant. It’s more than just a digital image of your name; it’s a secure process built on several layers of identity verification and data integrity.

A compliant electronic signature process must include:

Two-component identification: Each user must have a unique identity that’s verified by the system. This typically requires at least two distinct identification components, like an identification code and a password.

Clear signature details: When the signature is displayed or printed, it must include key details, including the full name of the signer, the date and time it was applied (including the time zone), and the meaning of the signature (e.g., reviewer, approver).

An unbreakable link to the record: The signature must be permanently and securely linked to its specific electronic record, meaning it can’t be modified, copied to another document, or altered in any way. If a change is made to a signed record, it must clearly appear as unsigned.

Complete audit trails: If it isn’t documented, it didn’t happen. Your system must maintain a secure, time-stamped audit trail that independently records every action related to a signature. This log shows who did what, when, and why, and it can’t be altered.

A closer look at the planned Annex 11 updates

The EU’s Annex 11 is usually seen as the equivalent of 21 CFR Part 11. However, its guidance for electronic signatures is much shorter.

But that’s set to change. The European Commission recently released a draft of updates to Annex 11 that expands on the current guidance for electronic signatures. The heart of the guidance is the same, but the draft introduces much more detail, seeming to better harmonize it with 21 CFR Part 11.

Some updates include:

Greater specificity: The new draft explicitly requires that the meaning of a signature (e.g., reviewer, approver) be clear to the user during execution and that the system automatically logs the time zone where applicable.

Reauthentication: Users must perform a full reauthentication (such as with a password or biometrics) before applying a signature to ensure the right person is signing.

Detailed manifestation: When a signature is displayed or printed, the draft requires a full “manifestation” that includes the user’s name, role, the meaning of the signature, as well as the date, time, and time zone it was applied.

Addressing hybrid systems: For the first time, the guidance addresses “hybrid solutions” where a wet-ink signature is scanned into a computerized system. It requires that steps be taken to ensure that a signature is invalidated if there’s any change to the electronic record.

When is 21 CFR Part 11 and Annex 11 signature compliance required?

The rule of thumb is straightforward: If a document and its signature touch your GxP activities, the signature must be Part 11 and Annex 11 compliant. For example, when you work with a third-party vendor on a manufacturing plan and everyone needs to approve it, those signatures require full compliance.

On the other hand, some documents, like legal contracts or service agreements, don’t technically require this level of compliance to be valid.

However, many organizations find it’s far easier and more secure to route all signed documents through a single, compliant system. When your GxP-related approvals and your contracts are all managed in the same validated tool, you create a centralized source of truth. You never have to wonder if the right signature complies with the right regulation, and it makes finding any document during an audit much easier.

The real challenge: Validating 21 CFR Part 11 and Annex 11 compliant e-signature tools

Arguably the hardest part of 21 CFR Part 11 and Annex 11 compliance is validating the e-signature tools that make compliance possible.

While your team can easily verify surface-level compliance requirements (like the presence of a name and time stamp), it’s nearly impossible to validate back-end functions—like ensuring that a signature can’t be tampered with—without help from your software vendor.

Depending on your vendor, that could be quick and easy, or it could come with an extra unexpected cost. Some e-signature software vendors charge additional fees for access to their validation tools—but some, like ZenQMS, don’t.

That’s why it’s so important to ask about the validation process and any associated fees upfront before choosing a vendor. It’s the only way to get a complete picture of cost—and of the potential stress level.

Validation isn’t a minor detail; it’s a critical part of being audit-ready. In fact, it’s likely that one of the first questions an auditor will ask is, “How do you know this signature is Part 11 compliant?” Having the validation collateral from your vendor is the only way to confidently answer that question.

What’s the best tool for 21 CFR Part 11 and Annex 11 compliant signatures?

Docusign and Adobe Sign are big-name e-signature tools with 21 CFR Part 11 compliant options—but they come with a catch.

If you’re storing your documents in a GxP-compliant location, like an eQMS, using these tools to request and collect external signatures can create a tedious and potentially risky workflow. It requires you to:
• Download the document from your eQMS, creating a copy that now exists outside your validated system.
• Upload the copy into the separate e-signature platform to send to your external partner. Once it’s signed, download the document from the e-signature tool and then manually upload it back into your eQMS.
• Manually retire the original version.

This creates a disconnected process with two separate audit trails—one in your eQMS and one in the signature tool—that must be manually reconciled during an audit. Each step introduces the potential for human error and version control issues, adding risk where it doesn’t need to be.

Managing signatures—especially with external partners—shouldn’t force you to choose between compliance and convenience. That’s why we built ZenSign, a feature within ZenQMS that allows you to request and capture fully compliant electronic signatures from anyone, anywhere.

ZenSign is designed to streamline the collection of a single, global signature from one or more users on an entire document. This is perfect for when you need a contractor to approve a manufacturing plan, or a vendor to sign off on a waiver.

Here’s how it simplifies your workflow while tightening your compliance.

Documents never leave the system: The entire signature process happens within the security of your validated ZenQMS platform. Documents are never downloaded or sent to a third-party application, which eliminates compliance gaps.

No external accounts needed: Your external partner receives a secure link and verification request to view and sign the document directly. It’s a frictionless experience for them and a huge time-saver for you.

Seamless, compliant audit trails: Every action is captured in the document’s immutable audit trail, from the moment you send the request to the final signature. You get a single, unified record that’s always ready for an audit.

Simple, fast validation: As a ZenQMS user, you can leverage your initial eQMS validation to validate ZenSign. We also provide additional validation documentation at no extra cost.

Ultimately, ZenSign helps you enforce compliant workflows for your critical GxP documents while offering a centralized, easy-to-manage platform for all your signature needs.

E-signature tool validation guide: 10 questions to ask your vendor before you commit

Navigating the 21 CFR Part 11 compliant e-signature vendor selection process can be complex, but coming equipped with the right questions can help.

This guide provides 10 essential questions designed to cut through marketing claims and get to the heart of what matters for GxP-compliant signatures. Use them to vet potential vendors, uncover hidden fees, and select a partner that will truly support your compliance goals, not complicate them.

Get the e-signature guide here.

Published Aug. 8, 2025, by ZenQMS.