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by Tamar M. June

Think the Food and Drug Administration’s February withdrawal of its draft 21 CFR Part 11 guidance covering electronic record integrity means the agency doesn’t care about the quality of your records? Think again.

“FDA inspectors are human, and they have different approaches and styles,” says Ken Miles of the FDA’s Pacific Region. “But believe me, they’re still taking Part 11, quality system regulations, and corrective and preventive action plans quite seriously.”

“I’ve heard straight from dozens of key FDA personnel and leading consultants in the field that 21 CFR Part 11 is not going away, and neither is the agency’s demand for electronic record integrity,” adds Michael Causey, editor of the industry newsletter Part 11 Compliance Report.

As one consultant put it, “If you don’t care about the accuracy and efficiency of your electronic records, then you don’t have to worry about Part 11, quality assurance or computer system validation.”

The FDA is making no secret of the fact that it still cares very much about these issues. For example, at an industry seminar in May, John Murray, the primary adviser to the FDA’s office of software validation, policy, classification and Part 11 compliance, stated the agency actually assumes most computer systems will fail at some point. Murray suggested the real question firms should be asking themselves is how a system failure would affect the safety and efficacy of their product and their record integrity.

Sion Wyn, one of the authors working with the FDA on the Feb. 20 Part 11 guidance withdrawing the prior draft guidance, said in an interview with Part 11 Compliance Report: “It would be a mistake to regard Part 11 compliance as having a lower priority with the FDA. It’s a matter of a more appropriate focus. The FDA is looking at all the good manufacturing practices as part of its risk-based, science-based 21st century initiative. The agency’s objective, in my opinion, is to develop an approach to using electronic records and signatures that fits with that initiative. This balances the need for secure and accurate record keeping--and, of course, patient safety--with the potential benefits of innovative technology.”

Finally, Joe Famulare, director of the FDA’s Division of Manufacturing and Product Quality, recently said that industry must remember that the agency’s new risk-based and narrower interpretation of Part 11 does not mean the FDA won’t enforce the rule or has lost interest in it. “The importance of electronic record integrity is still there,” Famulare says.

“It frankly amazes me: the number of smart pharmaceutical executives who have told me since February that they don’t think they need to devote much time to Part 11 and its related issues now,” notes Causey. “They’re on the verge of making a big mistake.”

As if the FDA’s seriousness wasn’t enough, consider what can happen to your firm’s bottom line and its reputation if you fail to take quality and record integrity seriously. For example, take a look at the infamous November 1999 FDA Consent Decree with Abbott Laboratories. Hard lessons learned about the importance of rigorous quality assurance still ring true today.

Abbott signed a consent decree of permanent injunction in which it agreed to stop manufacturing and distributing many of its in-vitro diagnostic tests until it corrected manufacturing problems in its Diagnostics Division. In-vitro diagnostic tests are designed to be performed in laboratories on samples of patients’ blood, urine, mucous and other bodily fluids for use in diagnosing and treating diseases. “Over the past six years, Abbott has failed to comply with FDA’s good manufacturing practice and quality system regulation,” the agency reported. “Despite warnings from [the] FDA, Abbott has failed to correct its problems.”

The FDA hit the firm hard both in the pocketbook and on the production floor. Abbott agreed to comply with the FDA’s quality systems regulation for these products according to a schedule approved by the FDA. The firm also agreed to pay $15,000 per manufacturing process per day (up to $10 million) for failure to adhere to that schedule.

The firm agreed to pay $100 million to the U.S. Treasury within 10 days after the court entered the decree. The amount covered is described in the complaint filed by the court as the equitable remedy of disgorgement. It set a precedent as the largest amount of money ever paid by an FDA-regulated company for a civil violation of the Federal Food, Drug and Cosmetic Act.

In addition, the company agreed to pay 16 percent of the gross proceeds generated by the sales of medically necessary products not brought into compliance within one year after the court entered the decree, as determined by an independent financial auditor.

Abbott’s manufacturing practices first raised FDA concern in 1993, when GMP deficiencies were found during inspections of the firm’s Abbott Park, Illinois, and North Chicago manufacturing facilities. Violations were found in process validation, production and process control, and corrective and preventive action.

After these inspections, the FDA sent a warning letter to Abbott in March of 1994. Subsequent FDA inspections during 1995, 1996, 1997 and 1998 continued to find the same types of deficiencies. The FDA tried to work with Abbott to correct these problems without seeking relief from the courts. However, when the firm failed to meet promised completion dates and failed to correct problems adequately, the FDA sent another warning letter in March of 1999 and re-inspected the facilities during May, June and July. During that inspection, the FDA found continuing deficiencies and decided that a court order would be necessary to ensure that the firm’s processes were brought into compliance in a timely and orderly fashion.

In addition to the stiff financial penalties in the consent decree, Abbott also agreed to correct deficiencies in its manufacturing operations for all other diagnostic tests. The corrections had to be overseen by an outside expert, hired by Abbott, who certified to the FDA that the corrections were made. The FDA had the option to re-inspect Abbott’s facilities to verify that the products had been validated and that the manufacturing processes conformed to the QSR.

Once the corrective action was complete, Abbott was allowed to resume manufacturing and distribution. However, the company had to hire an independent auditor to conduct audit inspections of its in-vitro diagnostic device manufacturing operations at least twice a year for at least four years.

Results of these audit inspections are required to be reported directly to the FDA. If Abbott fails to comply with the QSR or the terms of the consent decree, the FDA may order the firm to again stop manufacturing and distributing, recall the products, or take other action.

With the seriousness of the Abbott case in mind, it’s worth looking at how some FDA-regulated life sciences and biotech firms are changing their approach to quality and validation since the FDA’s February Part 11 shift. In truth, they’re not changing much.

“We’re not changing our approach to Part 11 at all,” says Karen Maskell, principal software quality engineer at device firm Medtronic. Speaking at the Minnesota Quality Conference in April, Maskell said that Part 11 was “one of the most demanding regulations in FDA history.”

It’s also interesting to take a closer look at how other firms are tackling quality, validation and record integrity issues in the wake of the agency’s Part 11 shift. Understanding that compliance with Part 11, quality and efficiency are basic requirements in today’s marketplace, Galderma R&D quality assurance leader Herve Leroy knew that he had to update his managing audit reports and follow-up procedures that were based on paper and were frankly “not very efficient.”

Galderma R&D planned to acquire an electronic tool that would enable the company to build a master audit plan, schedule individual audits, record and report findings, get response from audit contacts, allow response delegation (one level), and monitor post-audit actions and/or other CAPA actions.

His new streamlined approach has improved operations at Galderma in several ways, including:

Management has access to the audit information as soon as the audit report is issued and can fully manage the audit contact’s response, which gives it a more active role as a manager.

The auditor can easily produce an electronic audit report and follow post-audit actions and due dates, which are dispositioned to the audit contact.

With one click, the audit contact can delegate each issue’s response to an assigned delegate and can simultaneously oversee and endorse the final response.

Quality assurance management can handle problem resolution and trigger CAPA when audit problems are residual.

Galderma is currently testing the application and expects to start the performance qualification process later this summer.

Shawn Gould, software compliance specialist for aaiPharma, a pharmaceutical company based in Wilmington, North Carolina, says he’s satisfied with the recent draft guidance. “We’re pleased the FDA narrowed its scope with the new draft guidance,” says Gould. “It gives us some breathing room for our legacy systems and allows us to make decisions based on our own risk analyses.”

There are numerous other systems at aaiPharma that are Part 11-compliant, and the company’s Part 11 team holds weekly meetings to discuss ongoing projects and requirements. It has now put into place a policy that requires all future purchases to be Part 11-compliant.

“No matter what the final outcome is, it just makes good business sense to be Part 11-compliant,” says Ken Miles of the FDA. “I can’t see how companies can continue to put information on paper when they have a golden opportunity to automate their processes and improve their productivity and bottom line.”

Even though numerous companies have invested a considerable amount of effort, time and money towards compliance with Part 11, their efforts aren’t wasted. There is a chance that the FDA will reinstate the guidelines, but more importantly, these companies will be ahead of the competitive game by having systems in place that maintain the integrity of their electronic records.

About the author

Tamar M. June is director of marketing at AssurX Inc., a provider of CAPA software systems to a variety of industries including medical device, pharmaceutical, semiconductor, aerospace and contact manufacturing. She has spent the past 16 years in both manufacturing and information technology. Letters to the editor regarding this article can be sent to letters@qualitydigest.com.