A Brave New World of Data Integrity

It’s a good time to be a contract manufacturing organization (CMO). Pharmaceutical and biotechnology companies, in a race to stay competitive and impact more patients, are choosing to focus heavily on research and development activities, with little left over for on-premise manufacturing. This means that CMOs are in high demand, and the products they’re manufacturing are more diverse and complex than ever.

This wave of opportunity has ushered with it an era of heightened regulatory scrutiny, particularly in relation to data integrity. The manual record-keeping practices that once satisfied regulators simply aren’t keeping up. Today’s auditors, sensitive to a recent uptick in infractions, expect broader access and more transparency from CMOs, with a particular emphasis on changes made in temporary memory.

In order to withstand this intensifying pressure while improving operational efficiencies, CMOs large and small are sunsetting their traditional data management workflows in favor of digital tools specially designed to ensure that data are complete, consistent, enduring, and available.

The pressure is on
In 2016, after reporting an overall increase in offenses related to poor data management practices and inconsistent documentation, the U.S. Food and Drug Administration (FDA) issued its Data Integrity and Compliance with CGMP Guidance for Industry. The European Medicines Agency (EMA), the UK Medicines and Healthcare Products Regulatory Agency (MHRA), and the World Health Organization (WHO) also issued new or updated guidelines during this period. Under the auspices of 21 CFR 11 and Annex 11, these updates reflect a notably higher standard of quality for the practices governing data integrity in QC and manufacturing labs.

In order to meet this elevated standard, CMOs around the world are rallying behind the principle that all data should be attributable, legible, contemporaneous, original, and accurate (qualities known by the acronym ALCOA), as well as consistent, available, enduring, and complete (ALCOA+). The concepts captured by that appended “plus” symbol are about giving a datum context, especially during future reviews and audits. In other words, ALCOA+ sets an expectation that CMOs can and will disclose a complete picture of data throughout its entire lifecycle.

As part of this expectation, the FDA has swung its spotlight toward a concept that, until relatively recently, had been widely accepted in the industry: the idea that data isn’t really data until and unless it’s saved. That moment—an analyst clicks “Save,” committing a datum to durable media—is the bright line dividing “temporary” from “enduring.” In its temporary state, data can be manipulated multiple times, either accidentally or (in rare cases) intentionally, since it has not been committed to durable media. A mistype can be fixed, a value corrected, or, as regulators fear, a noncompliant result deliberately changed in order to meet specifications, all without detection. As long as an audit only reveals the “enduring” state, regulators worry that an important piece of the story—a piece that could reveal bad behavior or a dangerous oversight—is missing. In order to strengthen the audit trail and encourage the retention of all necessary information, the FDA and other agencies around the world now recommend that CMOs capture all data, including data that has been entered but not saved.

This principle of dynamic auditing—that is, tracking changes to temporary data—has become a cornerstone theme of modern integrity standards, and it’s driving significant change in the way that CMOs manage their data.

What’s at stake for the CMO?
This world of greater data integrity, in which all activity in a dataset is subject to inspection, brings with it the possibility of severe consequences for those who are unable or unwilling to adapt.

When an infraction is discovered, regulators typically begin by issuing warning letters and Form 483 citations. If caught in the cross-hairs of such a warning, CMOs, already under pressure to narrow their margins as much as possible, can face costly fines with devastating consequences to their bottom line. They may even be placed under a consent decree, which could prohibit them from manufacturing, holding or distributing products until they achieve regulatory compliance. Rebounding from such an injunction can be very difficult.

Consent decrees are rare. But even a warning letter can trigger a negative spiral for CMOs, who operate in a competitive world where new business is often won and lost on the strength of reputation. A CMO carrying a data integrity infraction on its record is a CMO with diminished hope of survival.

Even in scenarios where data management is sub-par but not subject to official sanctions, CMOs face expensive consequences. For example, if the amount of product in a bottle relies on potency, an incorrect potency value could cost the company money when a bottle is overfilled (contributing to a reduced yield) or not filled enough (making it necessary to reprocess products). These mistakes accumulate quickly, often with significant financial fallout.

Staying out of trouble and maintaining a polished reputation are, of course, important. But for all responsible CMOs, protecting consumer health is what matters most of all, and intensified data integrity standards are, after all, designed to service the safety, efficacy, and quality of the world’s pharmaceutical supply. By maintaining compliance, CMOs aren’t just ensuring their own longevity in the marketplace; they’re also preserving product quality and availability for the patients who rely on their output.  

In order to maintain compliance while preserving this level of supreme quality and product consistency, many CMOs are modernizing their data-related practices with the introduction of advanced laboratory information management systems (LIMS).

What the modern CMO knows about LIMS
Manual, paper-based record-keeping, once the mainstay of CMOs, is facing obsolescence. More and more labs are migrating away from the porous nature of this traditional approach, in which integrity is lost with each transcription error, each small deviation in standard procedure, each frog-leap from one siloed system to another.

Efficiency is lost in traditional systems, too. Each manual task takes time. Time, especially in a market defined by tight margins and close competition, is money. Without improvements to their operational efficiency—and with their data subject to the errors and inconsistencies of manual record-keeping—CMOs risk falling behind their competitors. To avoid this fate, many CMOs are embracing an advanced generation of software-enabled electronic platforms to govern their data collection practices.

CMOs aren’t alone in their mass migration away from manual tasks. In all areas of manufacturing, from pharmaceutical labs to car assembly plants, companies are using programmable software to take over the tasks that humans aren’t especially good at (or inclined to do). The result is a tech-enabled workflow that’s many times as efficient, and far more consistent, than a manual approach. Think of industrial automation, for example: guided by software that never deviates from its preconfigured objective, a robotic arm can screw eight thousand nuts onto eight thousand bolts with total consistency. Each nut will be turned the same number of revolutions, with the same torque, producing the same verifiable result every time. Not so in the hands of even the most diligent human worker.

In a CMO, this level of stability and consistency begins with the adoption of a LIMS platform. The robotic arm that never stops working on the factory floor becomes the database that never stops refreshing itself in the LIMS-enabled CMO. This allows analysts to displace the burden of diligent, consistent record-keeping onto a system far more suited to its granularity and complexity, and far more resistant to error.

LIMS pull in data automatically, through mobile devices, hand-held scanners and lab instrumentation that interfaces directly with the software, signaling the end of a problematic era in which analysts transcribed data by hand from instrument readouts, or observed and recorded test results themselves. It also introduces a new layer of impartiality in a CMO’s record-keeping system, because LIMS possess none of the complicated moral ambiguity that, in humans, can very occasionally lead to “creative” record-keeping. By contrast, a LIMS platform is neutral, inexhaustible, and fanatically consistent.

How LIMS improves overall data management
Purpose-built to meet specific lab functions, a LIMS platform offers what manual systems never could: a way to capture, organize, and analyze data consistently, automatically, and across multiple sites. Every activity benefits from this level of automation. Undertaking a routine workflow, for example, would once have required lab workers to interpret and follow paper-based protocols. Like 10 different chefs following the same recipe in 10 different kitchens, this would naturally lead to inconsistencies in execution—10 different cakes.

Not so with a LIMS platform in place, which enforces consistency, and even interfaces directly with lab instrumentation to ensure it’s precisely configured according to specific assay parameters. The result is a consistent and reproducible workflow, with a predictable result, time after time.

In an era when many CMOs are growing their global footprint through acquisition, this enforced consistency is especially valuable. Centrally hosted and globally accessible to authorized users, a LIMS platform offers the secure accessibility that geographically diverse sites need. It enforces process. It upholds standardization. And because it can pull data directly from connected instruments without relying on the accuracy of manual transcription, it provides continuous protection against quality-related risks.

The ubiquity of a well-deployed LIMS platform helps not just in connecting remote sites, but in connecting diverse functions, too. Some advanced LIMS allow users to turn on Electronic Laboratory Notebook (ELN) and Laboratory Execution System (LES) functionality. In a traditional workflow, data would have to jump between these different systems via a paper-based chain of custody. Each jump would introduce a new possibility for error. In a modern LIMS platform, which integrates ELN and LES functions in a single uninterrupted workflow, each datum is stored exactly once and shared across the whole system. Fewer jumps, fewer opportunities for error.

Such a high degree of integration also introduces new and in-depth searchability across complex CMO networks. With fewer siloes barricading data in fragmented clusters, and greater transparency throughout every step in a workflow, CMOs can locate and recall a detailed history of each event, whether from last month or last year. And because users interact with the LIMS platform under unique and authenticated identifiers, lab managers know with precision who entered what datum, and when. This means that they can track any irregular activities—like multiple repetitions of the same test—with a high degree of transparency, further ensuring regulatory compliance.

Ensuring no data is forgotten
While one of the greatest advantages of the LIMS platform is its ability to interface directly with instrumentation, every CMO still requires some degree of manual data capture, depending on the interoperability of a lab’s incumbent systems and instruments. In this case, too, the LIMS platform is invaluable as a vigilant partner for the human worker. For example, CMOs can configure their LIMS to recognize an accidental keystroke or a dropped digit. This means that users will get a prompt if, say, they’ve entered an “impossible” datum, like a pH value of 15 or a negative value for weight. Before they can proceed to their next step, they must correct that error, which helps to protect the database from inconsistencies.

Such manual corrections are, of course, the stuff of temporary data, now within the purview of regulatory oversight. The most advanced LIMS platforms play a crucial role here, too. They’re designed to automatically capture any datum entered but not saved, and to require a reason for any changes made in temporary memory. Some LIMS even include a visual flag in the permanent data trail, signalling the presence of underlying temporary data available for review.

The result is a clean, transparent, GxP-compliant audit trail based on the full history of a test.

Conclusions
As the pharmaceutical and biotechnology industries race to develop ever more advanced and complex chemical entities, pressure is growing on individual CMOs to operate more productively, cost-effectively, and safely than the next competitor. Watching over this crowded landscape is the ever-widening aperture of the industry’s regulatory alphabet: the FDA, the EMA, the MHRA, and the WHO. Their guidelines for data integrity, newly refreshed for the modern world of data collection, demand more transparency and accuracy than ever before.
As these pressures accumulate, modern CMOs must abandon their traditional, paper-based record-keeping practices in favor of preconfigured, pre-validated LIMS built specifically for the needs of today’s pharmaceutical manufacturers.