The Four Unsolvable Challenges of Part 11

Introduction

On March 20, 1997, the United States Food and Drug Administration (FDA) published 21 CFR Part 11, which became effective on August 20, 1997. This regulation established standards for managing electronic records and electronic signatures in the pharmaceutical industry. More than a quarter-century after its enactment, fundamental challenges persist that companies continue to face when implementing this regulation.

This article examines the “four unsolvable challenges” of Part 11 based on practical experience in the field. While these challenges may be technically solvable, they are recognized by the industry as problems that are difficult to resolve completely due to ambiguous regulatory interpretations, economic constraints, and organizational difficulties.

The Regulatory Environment Surrounding Part 11

The Importance of the 2003 Guidance

A critical document for understanding Part 11 is the guidance issued by the FDA in 2003, titled “Part 11, Electronic Records; Electronic Signatures — Scope and Application.”

In this guidance, the FDA exercised “enforcement discretion” for many Part 11 requirements, indicating that it would not routinely cite violations in these areas. Simultaneously, the agency shifted its focus to whether electronic records meet the requirements of the “predicate rule” and maintain data integrity. Predicate rules refer to existing regulatory requirements such as Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), and Good Clinical Practice (GCP) that existed before Part 11.

This policy shift clarified that Part 11 does not apply to “all electronic data” but only to “records required by predicate rules and maintained in electronic format in lieu of paper records.”

Recent Developments

In October 2024, the FDA issued its latest guidance document, “Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations: Questions and Answers (Revision 1),” providing additional clarification on the handling of electronic systems in clinical trials. This guidance addresses several key areas including:

• Clarification of Part 11 applicability to real-world data sources submitted to the FDA
• Guidance on Part 11 compliance for clinical investigations conducted outside the United States
• Risk-based approach recommendations for validation of electronic systems deployed in clinical investigations
• Recommendations for agreements between information technology service providers and regulated entities
• Guidance on data collection from digital health technologies (DHTs) used in clinical investigations
• Clarification on the use of electronic signatures in clinical investigations, including submission requirements for letters of non-repudiation

The regulatory environment continues to evolve, reflecting the ongoing digital transformation in healthcare and pharmaceutical development.

Data Integrity and ALCOA Principles

Modern regulatory expectations emphasize data integrity as a foundational element of quality systems. The ALCOA principles, originally articulated by FDA inspector Stan W. Woollen in the 1990s, have become the global standard for data integrity expectations. ALCOA stands for:

• Attributable: Data must be linked to the person or system that generated it
• Legible: Data must be readable and permanent
• Contemporaneous: Data must be recorded at the time the activity is performed
• Original: The original record or a certified true copy must be preserved
• Accurate: Data must be error-free and reflect true observations

These principles have evolved into ALCOA+ (adding Complete, Consistent, Enduring, and Available) and ALCOA++ (further adding principles such as Traceable, Transparent, and others), reflecting the increasing complexity of electronic systems and data management requirements.

According to FDA guidance, data integrity is defined as “the accuracy, completeness, and reliability of data.” Analysis of FDA enforcement actions shows that approximately 60-80% of warning letters in recent years have involved data integrity issues, highlighting the critical importance of these principles.

Challenge 1: Definition of Electronic Records — The “Typewriter Excuse” Problem

What is the Problem?

The preamble to Part 11 contains the following statement:

“The agency does not intend to apply Part 11 to records whose only connection to a computer system is that the record was generated by a computer and printed out on paper. In such a case, the computer system functions essentially as a manual typewriter or pen, and any signature would be a traditional handwritten signature.”

This statement spawned an interpretive controversy known in the industry as the “typewriter excuse.”

Pharmaceutical Company Arguments

Many pharmaceutical companies argued:

“We are merely using computers to create records. The true record is the paper record. For example, when we create documents for FDA submission using word processing software and print them out, the computer is being used just like a typewriter, and Part 11 should not apply.”

The background to this argument was the technical and economic burden of meeting Part 11 requirements such as audit trails, access controls, and validation.

FDA’s Counterargument

However, the FDA did not accept this interpretation. FDA staff countered:

“Part 11 applies only when the computer is truly being used like a typewriter, such as when no electronic record is created. Printouts cannot be inherently trusted because they do not contain the metadata information necessary to reconstruct or reproduce the data from the source.”

In other words, the FDA adopted a broad interpretation that “anything electronically recorded falls under Part 11.”

The FDA’s position is grounded in fundamental data integrity principles. Electronic systems create rich metadata—timestamps, user IDs, change histories, system configurations—that paper cannot capture. This metadata is essential for establishing the reliability and trustworthiness of records. When a document is created electronically, even if ultimately printed, the electronic version contains information critical to verifying the authenticity and integrity of the data. The absence of this metadata in paper printouts represents a loss of information that could be crucial during investigations, audits, or legal proceedings.

Response in Japan

Japan’s ER/ES Guidelines (Guidelines for Electronic Records and Electronic Signatures) address this issue as follows:

“When paper materials, which are materials and raw materials of applications, notifications, or reports for approval or licensing of drugs, quasi-drugs, cosmetics, and medical devices, and for registration of conformity certification bodies and other materials required to be retained according to the Pharmaceutical Affairs Law and related regulations, are created based on electromagnetic records and/or electronic signatures, it is also desirable to follow this guideline as well as possible.”

In other words, the “typewriter excuse” does not apply in Japan either. Even when created with word processing software and printed, proper management as electronic records is required.

Why This is an “Unsolvable Challenge”

This challenge remains “unsolvable” due to the ambiguity of regulatory interpretation. There is no clear boundary defining what constitutes “mere typewriter-like use” versus “creation of electronic records.”

In practice, any data stored electronically should be considered an electronic record. However, some companies continue to maintain that “paper is the original,” leading to ongoing disagreements with regulatory authorities.

This ambiguity is compounded by technological evolution. Modern software applications automatically create extensive metadata, version histories, and system logs, even for simple document creation. Cloud-based word processors maintain complete edit histories, multiple user contributions, and real-time synchronization across devices. The distinction between “using a computer like a typewriter” and “creating electronic records” has become increasingly artificial in the age of ubiquitous computing and cloud-based systems.

Furthermore, the regulatory landscape varies internationally. While the FDA and Japanese regulators have taken similar positions, other jurisdictions may have different interpretations, creating additional complexity for global pharmaceutical operations.

Challenge 2: Linking Records and Signatures — The “Hybrid System” Problem

What is a Hybrid System?

A hybrid system refers to an operational method where electronic records are printed on paper and hand-signed (or stamped). Many Japanese companies have adopted this approach.

At first glance, this seems like a reasonable way to balance electronic transformation with traditional paper-based operations. However, from a regulatory authority’s perspective, it presents serious problems.

Common Arguments and Their Flaws

Companies typically argue:

“In our company, the responsible person thoroughly reviews the records before signing (or stamping). Therefore, the paper is the original.”

However, this argument has a fatal flaw. Western regulatory authorities conduct inspections based on the premise that “in many cases, fraud is directed by the responsible person.” In other words, the fact that a responsible person has signed does not guarantee the reliability of the record.

This assumption is not mere cynicism but is grounded in real-world cases. Regulatory investigations have repeatedly uncovered situations where senior management directed or participated in data manipulation. The signature of an authority figure, rather than providing assurance, can sometimes be part of the problem. This is why regulatory systems emphasize technical controls, audit trails, and system validation—controls that function independently of human authority and cannot be easily circumvented by individuals in positions of power.

Specific Problems with Hybrid Systems

Hybrid systems present the following serious issues:

Fraud is Easy

A typical fraud scenario proceeds as follows:

1. Electronically alter problematic data
2. Reprint the altered data
3. Sign with a past date (backdating)

With electronic signatures, backdating is technically impossible because timestamps are automatically recorded. However, with handwritten signatures, there is no means to prevent date falsification.

The technical architecture of paper systems makes them inherently vulnerable to this type of manipulation. Unlike electronic systems where every modification creates an immutable audit trail entry, paper documents can be destroyed and reprinted without leaving evidence. The only record of the transaction is the document itself, which is under the control of the very people whose actions need to be verified.

The “Paper vs. Electronic” Contradiction

Hybrid systems create a fundamental question: “Which is the original?”

Even if you claim that paper is the original because it is signed, if the actual process is performed electronically, regulatory authorities will consider the electronic version as the original. This contradiction cannot be resolved while continuing operations in this manner.

This issue becomes particularly acute during regulatory inspections. Inspectors are trained to identify discrepancies between paper and electronic records. When found, such discrepancies raise immediate red flags about data integrity and can trigger expanded investigations. Companies often struggle to provide satisfactory explanations for why their “original” paper records differ from electronic files, or why metadata timestamps don’t align with paper signature dates.

Risk of Deleting Electronic Records

Some companies delete electronic records because “we approved them in paper format,” but this constitutes a serious violation. Even if you sign on paper, electronic records must be retained.

The regulatory requirement to maintain electronic records stems from their informational richness. Electronic records contain metadata, audit trails, and contextual information that cannot be captured on paper. Deleting these records destroys evidence that might be critical for investigations, recalls, or product liability cases. Furthermore, retention of electronic records is often explicitly required by regulatory guidance and company SOPs, making deletion a clear violation of established procedures.

Excel Management Problems

A typical example of a hybrid system involves entering data in Excel, printing it, and signing it. From a Part 11 perspective, Excel has the following problems:

• No audit trail capability
• Security issues (easy to edit)
• Electronic signatures cannot be used
• Inter-version compatibility issues
• Risk of macro virus infection

These technical limitations make Excel particularly problematic for GxP environments. Standard Excel workbooks lack the controls that Part 11 and data integrity principles require. Users can modify cells without leaving traces, formulas can be accidentally or deliberately altered, and there is no built-in mechanism to verify that the printed output accurately represents the electronic file at the time of signing.

Practical Considerations When Using Excel

If Excel must be used, the following precautions should be strictly observed:

1. Print immediately after input and sign with the current date (or convert to PDF and apply electronic signature)
2. Do not delete the input Excel file
3. Do not alter the timestamp (file date)
4. Manage in a security-protected environment (ideally write to CD-R or similar write-once media)

The timestamp is particularly important. For example, if an Excel file was created on March 31, 2022, and has a handwritten signature dated February 10, 2023, this shows some consistency because “the Excel timestamp is older than the signature date.”

However, if the signature is dated March 31, 2022, but the Excel timestamp shows February 10, 2023, this clearly suggests data falsification.

Modern approaches to Excel validation have evolved to address some of these concerns. Organizations can implement:

• Protected worksheets with locked formulas and defined input ranges
• Version control systems that track all modifications
• Add-in tools that provide audit trail functionality
• Automated conversion to PDF with embedded digital signatures
• Storage in validated document management systems with access controls

However, even with these controls, Excel remains a challenging tool for regulated environments. Many organizations are moving toward purpose-built applications or validated electronic data capture systems that provide comprehensive Part 11 compliance out of the box.

Why This is an “Unsolvable Challenge”

The hybrid system remains an “unsolvable challenge” due to organizational and cultural barriers.

In Japanese companies, “stamping paper” has long been the proof of decision-making. Transitioning to full electronic systems requires fundamental business process reviews, revision of internal regulations, and employee awareness reforms—challenges that go beyond mere technical responses.

Moreover, for companies that have maintained records using hybrid systems for decades, admitting that “actually, the electronic version was the original all along” means questioning the validity of past record-keeping practices.

As a result, many companies find themselves compelled to continue “halfway electronic transformation.”

This cultural dimension extends beyond Japan. In many organizations worldwide, paper documents with handwritten signatures carry psychological weight that electronic records lack. Decision-makers feel more comfortable with paper they can physically hold and review. Training programs must address not just technical procedures but also deeply ingrained attitudes about what constitutes a “real” document.

The cost of transition also creates barriers. Converting fully to electronic systems requires:

• Replacement or upgrade of legacy applications
• Integration with document management and quality systems
• Electronic signature infrastructure deployment
• User training and change management
• Validation of new computerized systems
• Migration or reconciliation of historical records

For large organizations with complex operations, these projects can require multi-year timelines and investments in the tens of millions of dollars.

Challenge 3: Long-Term Preservation of Electronic Records

Length of Retention Periods

The pharmaceutical industry must retain records for extended periods. Retention periods vary by record type:

Record Type	Retention Period
Manufacturing Records	Product shelf life + 1 year (approximately)
Clinical Trial Records	3 years after approval or trial completion (whichever is later); longer if required by sponsor (e.g., until post-marketing surveillance ends)
Specified Biological Products	30 years for marketing authorization holders; 20 years for medical institutions

Such long-term preservation presents challenges unique to electronic records that do not exist with paper records.

These retention requirements reflect the long product lifecycles in pharmaceuticals and the need to investigate issues that may emerge years after initial market authorization. Safety signals might appear a decade or more after approval, requiring access to original clinical trial data. Manufacturing investigations might need to trace back through years of batch records to identify the root cause of quality issues. The ability to retrieve and review these records, complete with their original metadata and audit trails, is essential for protecting public health.

Three Serious Problems

1. Will There Be Drives to Read the Media?

Imagine media that stored data 30 years ago. In the 1990s, floppy disks, MO (magneto-optical disks), and DAT tapes were used.

However, it is now extremely difficult to obtain drives that can read these media. Even if drives are found, there is no guarantee they can be connected to modern computers.

The obsolescence cycle for storage technology has actually accelerated in recent years. Technologies that were cutting-edge a decade ago are now legacy systems. Consider the progression: 5.25-inch floppy disks gave way to 3.5-inch disks, which were replaced by CD-ROMs, then DVDs, then USB drives, and now cloud storage. Each transition left behind vast archives of inaccessible data.

Even when drives are available, interface compatibility becomes an issue. Many legacy drives used SCSI, parallel port, or early USB connections that modern computers no longer support. Adapters and converters exist but add complexity and potential points of failure. The challenge compounds when dealing with proprietary formats or systems that required specific drivers that are no longer maintained.

2. Will There Be Software to Read the Electronic Records?

Even if files can be retrieved, software to open them may not exist.

For example, data recorded by HPLC and other analytical instruments 20 years ago cannot be opened in current systems. This is because the proprietary file formats used at the time have reached end-of-support.

Software obsolescence results from the mismatch between the pace of technological innovation and the length of retention period requirements. Twenty years represents several generations of technological evolution in the IT industry.

This problem is particularly acute for specialized scientific instruments. Instrument manufacturers may:

• Go out of business or be acquired, with legacy products no longer supported
• Discontinue software platforms in favor of new architectures
• Change file formats with each major version upgrade
• Require hardware dongles or license servers that no longer exist

Pharmaceutical companies have reported cases where they possess data files but cannot extract the analytical results they contain. The data exists, but it is effectively lost because the keys to unlock it—the software applications—are unavailable.

Some organizations have attempted to address this through:

• Maintaining “museum” installations of legacy software on virtual machines
• Developing custom file format converters
• Contracting with specialized data recovery services
• Implementing vendor-neutral data formats at the time of original creation

However, each of these approaches has limitations and costs.

3. Media Damage and Aging

Electronic media are vulnerable to physical damage. More seriously, there is no electronic medium (CD-R, hard disk, etc.) that can reliably store data for more than 10 years.

CD-Rs use optical read-write technology and may become unreadable within 5-10 years depending on storage conditions. Hard disks contain mechanical components and may malfunction if not used for extended periods. Semiconductor memory (USB drives, SSDs, etc.) may degrade within 10-20 years due to charge retention limits.

Part 11 §11.10(c) requires that records be “retrievable in accurate and complete form” throughout the retention period. However, media aging is an unavoidable physical phenomenon, and no complete countermeasure exists.

The physics of data storage creates fundamental limitations. Magnetic media deteriorate as magnetic domains gradually lose their orientation. Optical media degrade as dye layers break down under exposure to light, heat, and humidity. Solid-state storage loses charge over time through quantum tunneling effects. All physical storage media eventually fail—it is only a question of when.

Research on media longevity has produced sobering results:

• Consumer-grade CD-Rs may fail in 5-10 years under typical conditions
• Hard drives have mean time between failures (MTBF) of 3-5 years when actively used
• SSDs can lose data within 1-2 years if stored without power
• Magnetic tape, while more durable, still degrades over decades
• “Archival quality” media may extend these timelines but cannot eliminate the fundamental issues

Environmental conditions dramatically affect storage longevity. Temperature fluctuations, humidity, electromagnetic interference, and physical vibration all accelerate degradation. Professional archival storage facilities maintain controlled environments to extend media life, but at significant cost.

Two Approaches and Their Respective Difficulties

There are two contrasting approaches to long-term preservation:

1. Time Capsule Approach

This method maintains systems as they were when electronic records were created.

• Advantages: Data integrity is guaranteed
• Disadvantages: System obsolescence and vendor support termination will eventually make maintenance impossible

Keeping a 20-year-old system operational today is extremely difficult in practice.

This approach treats the entire computing environment as an artifact to be preserved. Organizations must maintain:

• Original hardware or functionally equivalent replacements
• Operating systems and all patches at specific versions
• Application software with appropriate licenses
• Network infrastructure compatible with legacy protocols
• Documentation of all system configurations
• Qualified personnel who understand the legacy technology

The cost of maintaining such environments grows over time as components fail and expertise becomes scarce. Hardware repair becomes increasingly difficult as replacement parts are no longer manufactured. Software bugs cannot be patched because vendors no longer support the platforms. Security vulnerabilities accumulate as systems age without updates.

Furthermore, the time capsule approach conflicts with modern IT management practices. Legacy systems cannot be integrated with current enterprise architecture. They present cybersecurity risks if connected to networks. They consume resources—both equipment and personnel—that could be deployed more productively elsewhere.

2. Migration Approach

This method migrates data from old systems to new systems.

• Advantages: Can be managed with current systems
• Disadvantages: Validation of migration programs, technical difficulties in migrating complete data including audit trails, ongoing costs

The particular problem is that complete migration may be impossible when the original system and new system represent data differently. In such cases, it becomes necessary to build separate search systems for legacy data.

Data migration projects face multiple technical challenges:

Schema Transformation: Old and new systems often use different data models. Converting from one schema to another without information loss requires careful mapping and validation.

Audit Trail Preservation: Migration typically creates new records with new timestamps and user IDs. Preserving the original audit trail information while adding migration metadata requires sophisticated data handling.

Format Compatibility: Different systems may use incompatible data types, precision levels, or encoding schemes. Scientific data with high precision requirements presents particular challenges.

Referential Integrity: Related records must maintain their relationships through migration. Lost linkages can render data meaningless.

Validation Requirements: Each migration must be validated to demonstrate that data transferred accurately and completely. Validation generates significant documentation burden.

Industry experience with migrations has been mixed. Successful projects share common characteristics:

• Early planning with clear data governance policies
• Phased approach with pilot migrations to identify issues
• Comprehensive validation protocols
• Involvement of subject matter experts who understand the scientific content
• Investment in data quality assessment and remediation before migration
• Post-migration reconciliation to verify accuracy

Failed or problematic migrations often result from:

• Inadequate understanding of source data complexity
• Rushed timelines without sufficient validation
• Lack of business user involvement in verification
• Poor project governance and change control
• Insufficient resources allocated to data remediation

Economic Dilemma

Furthermore, economic issues complicate the situation. The frequency with which preserved records are actually referenced is extremely low. Therefore, data migration projects tend to receive lower priority from a return-on-investment perspective.

However, the inability to retrieve records in the event of an inspection or lawsuit represents a critical risk for a company. This “low frequency but high risk” characteristic makes management decisions difficult.

The economics create a perverse incentive. Organizations must invest substantial resources in migration projects that may never provide tangible return, while failure to invest creates catastrophic but unlikely risk. CFOs and business leaders struggle to justify expenditures on what appears to be “insurance” against rare events.

This challenge is compounded by the difficulty of quantifying risk. How does one calculate the probability of needing a specific record from 15 years ago? What is the cost if that record cannot be produced during an FDA inspection? These questions defy precise analysis, yet the answers could mean the difference between continued market authorization and regulatory action.

Some organizations have attempted to address this through risk-based approaches:

• Tiering records by criticality and applying more rigorous preservation to high-risk records
• Accepting some risk of inaccessibility for low-value historical data
• Establishing recovery procedures that acknowledge some records may be irretrievable
• Purchasing insurance to offset potential regulatory or legal costs

However, regulatory authorities have shown limited acceptance of these pragmatic compromises. Their expectation remains that records must be retrievable in accurate and complete form throughout the required retention period.

Why This is an “Unsolvable Challenge”

Long-term preservation remains an “unsolvable challenge” because the pace of technological evolution fundamentally mismatches the length of retention periods.

It is impossible to predict the technological environment 20 or 30 years in the future, and there is no guarantee that today’s “best solution” will remain effective. As a result, companies have no choice but to “continue spending money on ongoing responses.” This is not a “solution” but a “continuous response.”

This challenge reflects a fundamental tension in regulated industries. Regulations are written to be technology-neutral and enduring, while technology itself changes rapidly. Requirements established in the 1990s must accommodate technologies that didn’t exist then—cloud computing, mobile devices, artificial intelligence—while still protecting data integrity principles that remain constant.

The industry has explored various approaches to address this challenge:

Standard Formats: Using non-proprietary, widely adopted formats (PDF/A, XML, CSV) can improve long-term accessibility. However, these formats often cannot capture all the metadata and functionality of specialized applications.

Emulation and Virtualization: Preserving entire computing environments in virtual machines allows old software to run on new hardware. However, this requires maintaining virtualization infrastructure and licensing for legacy operating systems.

Format Migration: Regularly converting data to current formats prevents obsolescence. However, each conversion risks information loss and requires validation.

Service Providers: Specialized vendors offer long-term data preservation services. However, this creates dependency on vendor viability and raises questions about data control and security.

Regulatory Engagement: Industry groups have sought clearer guidance from authorities on acceptable approaches. However, regulators are cautious about endorsing specific technologies or vendors.

None of these approaches provides a complete solution. Organizations typically implement combinations of strategies, accepting some residual risk while documenting their rationale and good faith efforts to comply.

Challenge 4: Responding to Legacy Systems

What Are Legacy Systems?

Systems that were in operation before Part 11 was enacted (1997) are called “legacy systems.” These systems were naturally not designed with Part 11 requirements in mind.

However, these systems continue to support critical operations in the pharmaceutical industry. Many core business systems, such as Manufacturing Execution Systems (MES), Quality Management Systems (QMS), and Laboratory Information Management Systems (LIMS), are legacy systems.

The term “legacy” can be somewhat misleading, as it suggests systems that are merely old. In practice, many legacy systems are the backbone of pharmaceutical operations, processing thousands of transactions daily and containing decades of institutional knowledge embedded in their configurations and workflows. They may have been updated and modified over the years, making them complex hybrids of old and new components.

Why the FDA Does Not Exempt Legacy Systems

In the 2003 guidance, the FDA stated it would exercise enforcement discretion for legacy systems. However, this does not mean “exemption.”

The FDA cites the following reasons for not exempting legacy systems:

1. The FDA May Be Denied Access to Electronic Data Systems for Inspection

Legacy systems often have inadequate external access functions. This creates situations where FDA inspectors cannot directly examine electronic records.

For regulatory authorities, inability to directly examine electronic records means inability to verify data integrity. Showing only paper printouts cannot confirm that underlying data has not been altered.

Modern inspection methodologies increasingly emphasize direct examination of electronic systems. Inspectors are trained in database queries, audit trail reviews, and system navigation. They expect to see data in its original electronic form, with full metadata and audit trail context. Legacy systems that cannot provide this visibility create inherent compliance risks.

The challenge is compounded by security concerns. Organizations rightfully worry about providing external access to systems containing confidential business information or controlling critical manufacturing processes. However, inspector access is a regulatory requirement. Finding the balance between security and transparency requires careful planning and potentially significant infrastructure investment.

2. Unauthorized Access to Systems is Permitted

Legacy systems often lack modern access control functions such as role-based access control and multi-factor authentication.

They may also permit ID or password reuse. For example, there may be cases where IDs of retired employees remain active, or multiple people share the same ID. This makes it impossible to identify “who” created or modified records.

Access control weaknesses in legacy systems reflect the security standards of their era. When many of these systems were designed, the threat landscape was different. Organizations had smaller, more stable workforces. Systems were often deployed on isolated networks. Security focused more on perimeter defense than granular user access controls.

Modern security frameworks emphasize:

• Unique user identification for all system users
• Role-based permissions aligned with job functions
• Multi-factor authentication for sensitive operations
• Regular access reviews and removal of unnecessary privileges
• Logging of all access attempts, successful and failed
• Integration with enterprise identity management systems

Legacy systems typically cannot support these capabilities without substantial modification or replacement. Even when technical controls can be retrofitted, the underlying architecture may not support them properly. Shared accounts embedded in automated processes, hard-coded credentials in scripts, and lack of API support for identity providers all create obstacles to modernization.

3. Systems Are Allowed to Become Unvalidated

Legacy systems may have been validated at the time of implementation, but subsequent changes and modifications are often not properly managed.

Due to inadequate change management, it becomes unclear “what state this system is currently in.” Documentation may be scattered, making it impossible to confirm validation status.

Validation state degradation is a subtle but serious problem. Each change to a validated system—whether software updates, configuration modifications, or hardware replacements—has the potential to affect system functionality and compliance. Proper change control requires:

• Assessment of change impact on validated state
• Testing appropriate to the change magnitude
• Documentation of change rationale and implementation
• Approval by appropriate authorities
• Update of validation documentation

Over years or decades, even minor changes accumulate. A system may have undergone hundreds of modifications since its initial validation. If change control was inconsistent, the cumulative effect becomes impossible to assess. Organizations find themselves unable to answer basic questions: What version of software is running? When was it last validated? What changes have been made since then? Are all modifications documented and justified?

This problem is exacerbated when organizational memory is lost. Knowledgeable personnel retire or move to other positions. Institutional knowledge about system configuration and modification history exists only in the minds of individuals who are no longer available. Documentation that should exist is incomplete or cannot be located.

4. Electronic Records Can Be Altered in Many Ways and Remain Undetected

The biggest problem with legacy systems is that audit trail functionality is absent or incomplete.

Without audit trails, detecting data alterations is impossible. If there is no record of who changed what and when, fraud cannot be discovered even if it occurs.

Furthermore, if system administrators can directly access the database, their operations may not be recorded. There is no means to prevent or detect fraud by system administrators themselves.

Audit trail deficiencies in legacy systems create fundamental barriers to data integrity assurance. The ALCOA principles require that data be attributable and traceable, but without comprehensive audit trails, these requirements cannot be met. Organizations face situations where:

• Changes to critical data leave no record
• Timestamp information can be manually edited
• Database administrators can modify records without detection
• System configurations can be altered without logging
• Failed login attempts and unauthorized access attempts go unrecorded

Modern Part 11-compliant systems create audit trail entries automatically whenever data is viewed, created, modified, or deleted. These entries typically include:

• User identification
• Date and time stamp
• Action performed
• Previous value (if modified)
• New value
• Reason for change (if required by business rule)

Furthermore, the audit trail itself must be protected from unauthorized modification and must be retained for the life of the record. Legacy systems rarely provide these capabilities at the necessary level of detail and reliability.

The absence of adequate audit trails doesn’t just create compliance issues—it fundamentally undermines an organization’s ability to investigate problems. When product defects occur, quality investigations require tracing actions and decisions through electronic records. Without audit trails, such investigations hit dead ends. Root causes cannot be identified, corrective actions cannot be properly targeted, and the organization cannot demonstrate that it has taken appropriate measures to prevent recurrence.

Why This is an “Unsolvable Challenge”

The fundamental difficulty of the legacy system problem lies in the dilemma of “not being able to stop systems that are running.”

Technical Difficulties

Replacing legacy systems presents the following challenges:

• Need to rebuild complex integration with other systems (ERP, PLM, QMS, etc.)
• Difficulty inheriting “tacit knowledge” accumulated over years of operation
• Establishing new operational methods and user training in the new system

Legacy systems typically sit at the center of complex ecosystems. They receive input from dozens of source systems, provide data to numerous downstream applications, and interface with external partners and regulatory authorities. Mapping all these touchpoints and ensuring continuity through a system replacement is a massive undertaking.

The challenge of transferring institutional knowledge is often underestimated. Legacy systems may contain thousands of business rules embedded in configurations, custom code, and operational procedures. Users have developed workarounds and practices that are never documented. The system may behave in ways that seem illogical to outsiders but actually reflect critical business requirements understood only by long-time users.

Replacement projects must somehow capture this knowledge, validate that the new system provides equivalent functionality, and train users on new procedures—all while maintaining continuous operations. The complexity can be overwhelming.

Economic Difficulties

System renewal requires investment ranging from hundreds of millions to billions of yen:

• Difficulty establishing prospects for return on investment (productivity improvements difficult to measure)
• Data migration projects tend to receive low priority
• Large implementation programs strain organizational resources and budgets

The business case for legacy system replacement is notoriously difficult to justify. The primary drivers are risk mitigation and compliance—benefits that are hard to quantify. Meanwhile, the costs are very tangible and immediate. Financial justification must rely on arguments like:

• Reduced risk of regulatory action and potential fines
• Improved operational efficiency (though often difficult to measure)
• Reduced maintenance costs for aging infrastructure
• Enabling digital transformation and new business capabilities
• Improved employee satisfaction with modern tools

These benefits are real but often spread across multiple years and difficult to attribute definitively to the system replacement. In budget negotiations, such projects frequently lose out to initiatives with clearer return on investment.

Furthermore, system replacement projects are capital-intensive, requiring substantial upfront investment before any benefits are realized. This cash flow profile is unattractive, particularly for organizations with limited capital availability or competing investment priorities.

Organizational Difficulties

• Pharmaceutical manufacturing operates 24/7/365, and extended manufacturing shutdowns directly impact revenue
• System changes may require amendments to manufacturing licenses in some jurisdictions
• Coordination among related departments (IT, Quality Assurance, Manufacturing, Regulatory, etc.) is complex
• Change management and user acceptance across large organizations is challenging

The organizational barriers to legacy system replacement often prove more daunting than technical challenges. Manufacturing operations cannot simply pause for system implementation. Extensive planning is required to:

• Phase implementations to maintain production continuity
• Develop detailed cutover plans with backout procedures
• Conduct extensive testing and simulation before go-live
• Provide comprehensive training to all affected users
• Establish support structures for post-implementation issues

In regulated environments, system changes may require regulatory notification or approval. The timing and requirements vary by jurisdiction and by the nature of the system and changes. Navigating these regulatory requirements adds months or years to project timelines.

Cross-functional coordination challenges are substantial. IT must work with operations to understand requirements, with quality to establish validation strategies, with manufacturing to plan cutover activities, and with regulatory to manage agency interactions. These departments often have different priorities, vocabularies, and perspectives. Achieving alignment requires strong program governance and executive sponsorship.

Change management—helping users adapt to new systems and processes—is often given insufficient attention but is critical to success. Users who have worked with legacy systems for years or decades may resist change, worry about their job security, or simply struggle with the learning curve. Without adequate change management support, even technically successful implementations can fail to achieve their objectives.

Modern Considerations for Legacy System Management

While full replacement may be the ultimate goal, organizations must manage legacy systems in the interim. Modern approaches include:

Risk-Based Assessment: Not all legacy systems present equal risk. Systems handling critical GxP records require more urgent attention than those supporting administrative functions. Risk-based assessment helps prioritize modernization efforts.

Compensating Controls: Where technical controls are lacking, procedural controls can provide some mitigation. Enhanced documentation, more frequent reviews, and restricted system access can partially offset technical deficiencies.

Hybrid Approaches: Rather than complete replacement, some organizations implement hybrid solutions where critical functions are migrated to modern systems while less critical functions continue on legacy platforms.

Phased Modernization: Breaking large replacement programs into manageable phases, delivering value incrementally while reducing implementation risk.

Cloud and SaaS Options: Modern cloud-based and software-as-a-service solutions can provide Part 11-compliant capabilities more quickly and with lower capital investment than traditional on-premise implementations.

Despite these approaches, the fundamental challenge persists. Legacy systems continue to operate, often far longer than originally intended, creating ongoing compliance risk and constraining organizational agility. This is why legacy system management remains one of the “four unsolvable challenges” of Part 11.

Conclusion

The four challenges discussed in this article—definition of electronic records, linking records and signatures, long-term preservation, and legacy systems—persist more than 25 years after Part 11’s enactment. While each challenge has technical solutions, practical resolution requires addressing regulatory ambiguity, economic constraints, and organizational barriers that extend beyond technology alone.

As the pharmaceutical industry continues its digital transformation, these challenges evolve but do not disappear. Cloud computing, artificial intelligence, and digital health technologies introduce new dimensions to old problems. The emergence of concepts like ALCOA++ reflects regulatory expectations adapting to technological change, but the fundamental tension between rapid technological evolution and long-term regulatory requirements persists.

Organizations must approach these challenges with realistic expectations. Perfect compliance may be unattainable, but continuous improvement, risk-based prioritization, and good faith efforts to meet regulatory expectations can position companies for success. The key is not waiting for perfect solutions but implementing pragmatic approaches that balance compliance, business needs, and available resources.

Regulatory authorities have shown increasing sophistication in their approach to electronic records compliance. Modern inspections focus on data integrity principles rather than prescriptive technical requirements. Organizations that embrace the spirit of Part 11—ensuring that electronic records are trustworthy, reliable, and equivalent to paper—generally fare better than those seeking loopholes or narrowly compliant technical solutions.

The landscape continues to evolve. Emerging technologies like blockchain for immutable audit trails, artificial intelligence for data integrity monitoring, and standardized data formats for interoperability may address some current challenges while creating new ones. International harmonization efforts through organizations like the Pharmaceutical Inspection Co-operation Scheme (PIC/S) and the International Council for Harmonisation (ICH) are working toward more consistent global expectations.

Ultimately, the “unsolvable” nature of these challenges reflects not technical impossibility but the complex intersection of regulatory requirements, technological change, economic reality, and organizational capability. Success requires not just technical solutions but strong quality culture, executive commitment, and continuous adaptation to changing circumstances. Organizations that recognize these challenges as permanent features of the regulatory landscape—to be managed rather than solved—position themselves for long-term success in an increasingly digital pharmaceutical industry.