The playbook for truly paperless validation in pharma

Presented by ValGenesis. Published by FiercePharma.

Both the United States and the European Union require validation of the manufacturing process of drug and biological products. Both also allow for the submission of electronic records through the Food and Drug Administration’s Part 11 regulation and the European Commission’s equivalent known as Annex 11, though neither agency requires it.

With no mandate for digitization and amid resistance to change, paper-based validation and auditing processes have remained the norm for decades, even though it’s an inefficient and inconsistent bottleneck prone to human error.

However, a transition to virtual or remote audits and inspections, coupled with increased FDA advocacy for the use of digital tools, is increasingly showing pharmaceutical companies that digital workflows for validation are not only possible but preferable to paper-based processes. Firms that complete this shift to digital validation workflows are positioned to cut the time and cost of product development by 10% and lay the groundwork for automating validation and supporting enterprisewide digital transformation initiatives.

5 reasons paper-based validation is a bottleneck

For decades, paper-based workflows have been the industry standard for validating systems and processes. Quality assurance teams and auditors are used to a printed record they can hold in their hands. Unfortunately, the largely manual process is a bottleneck in pharmaceutical manufacturing for five important reasons.

It’s inefficient. Printing, copying, and scanning documents take time, especially if they’re inches thick like the typical validation submission. Only one person can review a hard copy of a document at a time, and they must provide handwritten feedback that’s legible. Documents then must be signed by hand and faxed or emailed to the next reviewer. All in all, it’s a process that forces highly skilled employees to focus significant time and energy on low-value, paper-pushing tasks.

It’s unreliable. The only way to back up a printed document is to make a copy of it. But how do you know which version is the original and which is the copy, especially if you’ve made a copy so two people can review a validation submission simultaneously? Manual workflows also don’t lend themselves to a reliable way to track changes; reviewers must reread one page at a time and look for updates.

It’s error-prone. Even seasoned reviewers make mistakes when scrutinizing a document. Unfortunately, most reviewers don’t have time on their side, and skimming a document compounds the odds they’ll overlook something. Errors also plague documents that have been converted to Excel, as formulas must be constantly maintained and updated. Creating Excel records at the end of the project, when information is likely out of date, doesn’t help the cause, either.

It’s inconsistent. Without a reliable way to track changes, the terminology will likely vary significantly from one document version to another. Even if templates or other standards are in place, there’s no way to ensure they’re followed consistently. Beyond adversely impacting the appearance and quality of the document, this lack of consistency increases the likelihood of data integrity risks.

It’s costly. Maintaining stacks of paper requires physical space and security, especially if it’s stored off-site with a third-party vendor. The manual review process also contributes to additional costs, delays to the FDA new drug submission process as software corrections are made or, worse, fines and sanctions (and the reputational damage that goes along with it) due to errors that aren’t corrected. Companies that outsource the validation process also must contend with the cost and challenge of working with subcontractors.

Resistance has been strong…

Despite the clear disadvantages of paper-based validation, many pharmaceutical companies have been reluctant to transition to a modern, digital process. Paper-based validation has been baked into standard operating procedures for decades. Plus, change doesn’t come easily in pharma, especially if regulatory agencies in the U.S. and the EU don’t require it outright.

A big part of this resistance to change stems from how quality assurance teams view paper:

• A paper document is regarded as tangible and valid, as something that can be easily seen and touched. On the other hand, a digital document is virtual and uncertain, especially if it’s stored in the cloud.
• It’s easy to look at a large stack of paper and assume that a validation submission has been documented thoroughly. The same can’t be said for a digital document that doesn’t sit on a shelf and is represented by an icon in a file folder.
• When an organization hands a printed validation package to an auditor, they know exactly what the auditor is looking at. It is assumed they have less control over the process when an auditor works with electronic documents or digital systems.

…but change is coming along

Validation is increasingly moving toward a digital world as artificial intelligence technologies make remote audits and inspections possible. This is better for the safety of auditors and inspectors, who aren’t at risk of exposure to highly infectious diseases either at the manufacturing plant or in the process of traveling to the plant. It also means that paper documents can’t be contaminated on-site. Virtual inspections streamline the process as well, as travel time is significantly reduced if not eliminated.

In addition, the FDA is increasingly advocating for the use of digital tools for computer system validation. The agency intends to publish draft guidance on computer software assurance (CSA) for production and quality system software.¹ This guidance is part of the FDA’s larger effort to accelerate the adoption of advanced manufacturing technologies to modernize industry best practices, expedite quality and safety reviews and bring much-needed medical products to market faster.²

The cornerstone of CSA is a risk-based, least-burdensome approach to validation that takes advantage of technology that was unavailable in 1997, when Part 11 was written, and in 2002, when Part 11 was updated. This includes technology with decision-tree logic, unscripted testing methods, and automated validation planning, which collectively ensure that the right level of validation is applied to each computer system based on the level of risk it may pose. Industry trends and FDA advocacy suggest that the validation process is ready, willing and able to support digital workflows. Better yet, validation benefits from going digital.

12 reasons to transition to a digital validation process

Create, route, and enforce validation documents electronically. Validation documents created manually must be routed via email (or inter-office mail). Depending on where the most recent version of a document resides, it may not be available for reference for reviewers or software developers. Delays in the routing process are not uncommon and only lead to delays in the development process. Since documents created and routed through electronic workflows are much easier to share, teams can enforce requirements throughout the development lifecycle instead of scrambling to do so at the end.

Expend less effort recording data. Paper-based workflows require manual transcription of data that is then entered into a word processing or spreadsheet application and then printed, collated, put in a binder, and archived. This is a significant amount of low-skill work for highly skilled QA staff. Digitizing data collection eliminates these unnecessary steps, giving reviewers more time to focus on high-value work such as risk assessment.

Spend less time analyzing data. Manual analysis of validation documents, poring over paper or searching through word processing documents and spreadsheets, is time-consuming. Even the most seasoned reviewers will miss something. Machine learning algorithms can be deployed not only to search, sort, and analyze the data in digital documents but also to identify trends, all in a matter of minutes. This allows reviewers to use their expertise to address anything that looks amiss, from a glaring error to an empty row in a spreadsheet.

Let multiple people author and review documents. Only one reviewer at a time can work with a paper document. For effective version control, the original reviewer’s comments should be incorporated before the document is passed to the next reviewer. Putting more than one copy of the document out for review at the same time only complicates the process. With digital validation, multiple reviewers can author and edit a document simultaneously, and version controls indicate who made which changes at which times. This expedites the review process while automatically creating an audit trail.

Reviewers receive alerts when action is required. The paper-based review process is largely passive, as reviewers must wait for a document to arrive in their mailbox or inbox. Digital validation workflows provide real-time alerts, indicating not just that a document is ready for review but also highlighting the necessary tasks the reviewer is required to complete. Reviewers who can’t complete a task can decline the work in real time, allowing those managing the review process to transfer those tasks to another reviewer and avoid costly delays.

Maintain requirements and traceability matrices electronically. In paper-based workflows, requirements and traceability matrices are treated as an afterthought, often assigned to junior-level staffers toward the end of a project. This poses a significant risk that something will be missed given the complexity of the work coupled with its time-sensitive nature. Digital workflows maintain these important resources as a validation document is completed, making the review and the software testing processes more efficient and accurate.

Embed review of exceptions and deviations into workflows. Handling deviations and exceptions manually requires a paper-based documentation process that’s separate from the review itself. This is time-consuming, and it quickly becomes difficult to track. Digital workflows can help reviewers manage deviations concurrently, speeding up the execution process. Digitization also makes it possible to trace each deviation activity and identify the impact of each validation, further ensuring that issues don’t go unaddressed and companies produce a compliant, high-quality product.

Control who can review what information. In paper-based workflows, reviewers can’t do their work if they don’t have a physical copy of a document. At the same time, a manually created document can easily get lost in the mail or emailed to the wrong person, creating immediate security concerns. Through digital validation, documents become a secure, single source of truth with role-based access controls that restrict who can view, edit, or sign. When access becomes virtual, untethered to physical locations, companies can adopt a “follow the sun” collaboration model that saves even more time.

Improve periodic review and revalidation schedules. Review and revalidation are critical steps, but manual workflows make it difficult to keep these processes on a tight schedule. Not only are companies working with paper documents that are typically generated as a one-off for each project, but there’s rarely a common calendar indicating when review and revalidation work must take place. By combining a dynamically generated calendar with real-time alerts, digital validation workflows ensure that companies don’t miss upcoming reviews and revalidations, and can staff for them accordingly.

Resolve business continuity and disaster recovery issues. Paper documents are easily misplaced or destroyed. Additionally, the lack of version control makes it difficult to determine which document stored at which site, or sitting on which desk, is the “version of truth.” Digital documents that are backed up frequently, stored in the cloud, dispersed geographically, and used within highly fault-tolerant systems resolve the easily preventable business continuity and disaster recovery concerns of paper-based validation workflows.

Improve compliance through standardized workflows and digitized audit trails. Maintaining consistent document templates, collecting feedback from multiple reviewers, and locating physical documents for auditors are some of the biggest challenges of manual validation workflows. Digitization supports workflow standardization from document creation to submission, while digital audit trails indicate when changes were made, and by whom. This ensures compliance throughout validation, as digital workflows match both the development process and the finished product with the necessary regulatory requirements.

Make better use of reviewers’ time and expertise. Regulatory compliance is certainly important, but so is software quality. Given the significant investment of time and resources for gathering paper-based evidence for auditors, the pharmaceutical industry has tended to put compliance first. The focus on quality and risk management has been lost in the process. Streamlining the validation process through digitization and automation gives reviewers more time to apply their critical thinking expertise to validation, ensuring that products are not just compliant but also safe and effective.

Four conversations to help overcome common hurdles to digital validation

Change doesn’t come easily to pharma; it’s an industry that takes pride in the high degree of scientific rigor applied to both medical research and the practice of medicine. As a result, it may take some effort to convince key internal stakeholders to transition to digital validation workflows. The conversations outlined here will help companies overcome some of the most common hurdles to digital validation and make a compelling case for a transition away from paper.

1. How to obtain a commitment from leadership

Getting executive buy-in is obviously essential for any IT investment, especially something as large-scale and transformative as a shift from paper to digital validation. Focus on these three points when engaging with corporate leadership to make the case that digital validation is worth the allocation of time and resources.

Better decision-making. It’s too easy for companies to print validation documentation, store it, and forget about it until it’s time for an audit. Automating validation through digitization allows for the creation of a living document that empowers business leaders to identify and remove bottlenecks in real time. More importantly, this access to data and insight enables more informed decision-making through the product development lifecycle, allowing business leaders to take proactive steps instead of reacting to a document based on data that’s weeks (or months) old.

Fast ROI. Companies can expect efficiency gains of 50% or more throughout the validation lifecycle. Activities that support validation, such as tracking status, planning for audits, and allocating validation resources see a 70% efficiency improvement³, and sometimes even more. All told, digital workflows cut the timeline for validation processes in half. As validation makes up 20% of product development, digital validation cuts the timeline and cost of product development by 10%. The return on investment will compound, project after project.

Support the move to Pharma 4.0. As described by the International Society for Pharmaceutical Engineering, the Pharma 4.0 operating model represents the push to embed digitization and automation into pharmaceutical product development in a similar manner to traditional manufacturing processes.⁴ If pharma companies aim to transition to Pharma 4.0, and gain a significant competitive advantage, they can’t do so with a paper-based validation process.

2. How to articulate benefits to business lines

While executives want to know how digital validation affects the company as a whole, business unit leaders will benefit from knowing how their workflows will improve for the teams they manage. Use discussion points such as the following to lead conversations with department heads.

Validation teams gain access to a traceability matrix that’s generated and maintained in real time. This allows validation to happen in a much more agile manner throughout the product development lifecycle. It also enables teams to identify and mitigate issues before they pose a substantial risk to the product.

Quality assurance benefits from a standardized process, which results in more consistent reviews regardless of which internal and external stakeholders contribute to the effort. QA teams also can spend less time on the minutia and more time reviewing the technical controls that impact product quality and compliance.

Manufacturing and IT dramatically improve efficiency through digitization. Electronic workflows for creating and approving validation plans, generating traceability matrices, executing validation protocols, conducting risk assessments, maintaining revalidation schedules, and other tasks can lead to efficiency gains of 50% or more.

3. How to emphasize the existing precedent for automation

One of the most common causes of pushback for digital validation is the notion that it represents a significant change for pharma companies. While this is true, it’s also true that many other business units within pharma companies have embraced automation. Highlight how these departments have benefited from agile and digital workflows to show that the learning curve doesn’t need to be so steep.

DevOps leverages autonomous maintenance and monitoring to enable continuous delivery and incremental improvement of software products. Manual processes for maintenance and monitoring negatively impact productivity, making agile software development nearly impossible.

Security takes advantage of continuous threat monitoring and automated remediation to identify and respond to far more cybersecurity threats than individual security analysts could find using manual workflows.

Quality assurance automates the software testing process so it can be routinely done throughout the development lifecycle. This allows bugs and other flaws to be fixed in real time, long before they impact additional features downstream.

4. How to demonstrate the potential for proactive decision-making

It’s difficult for decision-making based on paper documentation to be anything but reactive. In the mere minutes it takes to print a validation document, an engineering team can easily make large-scale changes to the application being validated, rendering the printed document obsolete. One of the biggest benefits of digitization is that it enables validation to shift from a retrospective process to one that’s more proactive and prescriptive.

Continuous validation. With traditional validation, a large amount of effort is spent on the initial project. Revalidation is resisted because the initial validation required too much time and effort. Automation allows validation to occur continuously throughout the development lifecycle, in minutes instead of months.

Up-to-date traceability. Automation lets companies build traceability matrices throughout software development and validation. Along with allowing companies to update matrices in real time, instead of creating them at the end of the manual validation workflow, automation helps companies ensure that matrices are readily available during an audit.

Issue resolution. Real-time validation identifies and prioritizes issues with a software product. One benefit is fixing bugs as they arise. Another is the ability to flag issues that are likely to cause trouble downstream. This lets engineers address these problems in the moment, before they require significant and time-consuming rewrites to the application.

Process transformation

One of the biggest dangers of digitizing a manual process is bringing along the inefficiencies of working with paper, whether it’s data entry, version control, or communication with reviewers. Automating these aspects of validation transforms them into highly streamlined processes that occur in the background so reviewers can focus on tasks that require their full attention.

New standard operating procedures

Paper-based validation workflows have remained in place for so long because they’ve been the de facto standard operating procedure. The efficiencies and savings associated with digitized validation, from planning and tracking to execution and maintenance, allow pharma companies to rewrite the SOPs for validation once and for all.

Conclusion

The pharmaceutical industry has embraced digitization in many business lines, but validation has been one of the few processes to remain manual. Paper-based validation processes pose a clear challenge to any company aiming to gain a competitive advantage through digital transformation and the Pharma 4.0 operating model.

Fortunately, the industry is increasingly realizing that digitization is preferable to time-consuming and error-prone manual workflows that depend on literal stacks of paper. Pharma companies experience many core benefits, from improved efficiency to greater technical controls over validation documents.

As digital validation matures, companies can take a critical step forward and automate much of the process. This leaves reviewers to focus on high-level problem solving instead of low-skilled administrative tasks. In addition, it supports proactive data-driven decision-making during validation and throughout the product lifecycle.

Overall, digitization and automation cut the time and money spent on validation in half. As validation represents 20% of the product development cycle, this means pharma companies can go to market 10% faster, boosting revenue while putting more life-changing therapies in patients’ hands in less time.

ValGenesis, Inc. is the creator of an innovative software platform that serves as a foundation for managing compliance-based validation activities in life science companies. ValGenesis, Inc is the provider of the first enterprise application that manages the corporate validation lifecycle process. This solution is fully compliant with U.S. FDA 21 CFR Part 11 and Annex 11 requirements.

References (preserve URLs)

1. CDRH Proposed Guidances for Fiscal Year 2022. U.S. Food & Drug Administration (FDA). Content current as of Oct. 26, 2021.
2. Accelerating the Adoption of Advanced Manufacturing Technologies to Strengthen Our Public Health Infrastructure. FDA. Content current as of Jan. 15, 2021.
3. Digitizing Validation Yields 50% Overall Efficiency Gain According to ROI Study, ValGenesis. March 22, 2022.
4. Pharma 4.0. International Society for Pharmaceutical Engineering. Accessed July 17, 2022.
5. www.valgenesis.com