'E-Sig' letter faults more common than once thought: but FDA focus seen more on 211 than part 11.

Dear Reader,

The more-innocuous electronic signature facet of FDA's electronic records regulation (21 CFR Part 11) is apparently more common in FDA inspections and warning letters than one would think.

Ron Tetzlaff, Ph.D., president of KMI/Parexel in Alpharetta, GA, and a former FDA national expert on parenteral drugs and sterilization, cited excerpts from 27 warning letters containing Part 11 violations at a Barnett/Parexel meeting in Philadelphia June 25-27 to drive home his point.

The letters that Tetzlaff presented date back to 1997, but most were issued in 2000 and 2001. They included 12 to human and animal drug makers--including one medical gas company--10 to device manufacturers, three to biologics establishments and two to the sponsor/monitor of device clinical trials.

Among companies receiving letters included Ansell, Aventis Bio-Services, Baxter, Cardinal Health, Johnson Matthey, Meridian Bioscience, Purepac, Schering, Schein/Marsam, Synthes and Zeus Scientific.

It is not easy to discern from the letters that they contain violations of the "E-Sig Rule," as FDAers commonly call the regulations. That's because it has been agency policy since Part 11 became effective in August 1997 to not cite the rule itself, but "predicate regulations" that require firms to keep records in the first place. Hence, most of the warning letters Tetzlaff found make no specific mention of Part 11, but to other applicable FDA rules.

According to Tetzlaff, some companies did not have proper password control or appropriate written procedures addressing employee responsibility for electronic signatures.

Some of the letters described firms that could not replicate accurate copies of forms in human readable and electronic form. Thus, FDA could not audit electronic records through electronic copies.

Tetzlaff said another common theme in the warnings he examined was companies providing inadequate responses to FDA concerns.

Once a deviation is found, he said, it is the manufacturer's responsibility to act accordingly and appropriately, addressing the concern head on. Tetzlaff said FDA expects companies to promptly correct compliance issues, including any legacy systems, within a reasonable timetable. The agency does, however, recognize that new controls may take longer to install in older systems.

In order to avoid regulatory sanctions, Tetzlaff recommended companies perform a "gap analysis," including a risk assessment, an inventory of all sys-tems, and measuring results against emerging trends.

Next, firms should devise a corrective action plan with written SOPs. He said the plan should delineate responsibilities, estimate costs, place tracking systems and progress reports, and provide any necessary training to personnel.

Finally, the ex-FDA staffer covered imple-menting remediation activities and preparing ac-complishment reports.

Ultimately, preparation for and anticipation of the FDA's concerns is tantamount. "Many compa-nies know beforehand that they are not compliant," said Tetzlaff. "But, if they have a good plan, it gets them out of trouble."

However, Tetzlaff argued "FDA is not really inspecting for 21 CFR Part 11, more so these days for Part 211," referring to the drug GMPs, which could be translated easily into device or biologics GMPs.

"Currently the FDA does not have an inspec-tion program specifically for Part 11, and they are unlikely to conduct inspections solely for checking compliance with Part 11."

Tetzlaff argued FDA might only inspect spe-cifically for Part 11 under certain conditions if, for example, there are data integrity issues, complaints or a history of GMP non-compliance.

He said a new section of the agency's Investi-gators Operations Manual requires investigators to carry laptops. Investigators will want all their data electronically, he said, but in a file form that can be copied. The FDA will want to look at electronic databases, electronic summaries and reports and the trending of electronic data.

In the process of accessing such data, FDA will likely discover if there are Part 11 discrepan-cies at the company.

Tetzlaff said companies should be aware of FDA's stress on "time stamps," because a new guidance was only published in February. He said this document, though a draft, urges firms to have time stamps to ensure authenticity and synchronic-ity of documentation.

Sincerely,

The Editors

The entire batch of warning letters with Part 11-related citations covered by Tetzlaff, including summaries of each letter with highlights of the "E-Sig" observations is available from RECORD-RETRIEVE for a special packaged rate of $35 plus retrieval. Doc. 11788W