Documentation, SOP problems show up in GLP warning letters.

Dear Reader,

Failure to have adequate documentation and SOPs shows up frequently among FDA warning letters for Good Laboratory Practice (GLP) problems.

Addressing an April 29 GLP conference in Philadelphia, Barbara Patterson, directory of regulatory compliance for the discovery and development services at Charles River Laboratories in Wilmington, MA, shared a number of warning letters and 483s issued for inadequate documentation practices.

She told the meeting, sponsored by the Center for Pharmaceutical Training: "Poor documentation causes gaps which lead to incomplete information transfer and incorrect reporting, which could lead to inaccurate scientific conclusions. You can't take the risk of not having good documentation, especially if you're a small company with one product.

"Remember, FDA is not going to show up the day your study is finished; they're going to show up years later, and you need to have all the documents ready," Patterson added.

Responsibilities for personnel (management, study director/scientific personnel, technical/study personnel and QA) and their documentation are something FDA will look at closely.

"FDA expects QA to be looking at the whole study process and not just the final report." If they conclude lack of control or management that's a turbo 483," Patterson said.

She cited one warning letter, which targeted the "failure of management and QA to exercise their responsibilities and is a widespread consequence that adversely affect many areas of GLP compliance. QAU failed to assure that equipment, personnel, records and controls were in conformance with GLPs and facility SOPs."

Protocol and SOP documentation, which often leave gaps or lack details, are another hot spot. One warning letter states, "For protocol amendment #1 for the...study, the study director sent a facsimile to the sponsor on the...day asking that the sponsor's personnel falsely backdate their signatures to the...day when the study started. During the inspection, the non clinical laboratory personnel searched for protocols for studies; however, they were unable to find them or provide copies to FDA."

According to a warning letter for SOP problems, FDA noticed that "SOPs were not followed, and deviations were not authorized or documented... There were multiple instances of failures to review SOPs annually, as required by SOP...The first inspection found six SOPs that had not undergone annual review."

In an egregious example of poor documentation, another warning letter found that data was not only inadequate but also physically impossible. "The individual responsible for direct data input was not always identified at the time of data input into the automated data collection system...This violation was noted at both inspections."

Patterson said that in the first inspection, FDA found that documentation did not always reflect the individual identified as responsible for data input. In addition, during the second inspection, FDA found that the identification of the individual was not always correct. Five flow cytometer reports, one dated 8/10/00 and four dated 9/28/2000 contained the operator identification of an ex-employee who died 3/20/2000."

"FDA is going to look at facility records and then at traceability back to the study," she said. A 483 citation for facility equipment charges that "not all equipment was maintained and calibrated according to manufacturer's instructions, and you did not provide documentation that your procedures either met or exceeded the manufacturer's expectations. No written procedures for maintenance of the ...Analyzer, or for operation of an autoclave. No written procedures for documenting deviations in temperatures of refrigerators or freezers...the available records were inadequate to determine the identity of all equipment used for generation, measurement or assessment of data at the facility."

"People do things the right way routinely, but it is where things go wrong that things fall apart," according to Patterson, who advised being prepared for worst-case scenarios and testing contingency plans. "You may have a wonderful disaster plan, but did you test it?"

"We need to use critical thinking and take the mindset of an inspector. Sometimes we get caught up in minutia and don't see the bigger picture."

Sincerely,

The Editors