Drug GMP violations lead plasma 483 items.

Violations of drug Good Manufacturing Practice (GMP) rules (21 CFR 211) continue to lead 483 citations to plasma derivative companies, FDA statistics show.

Susan Frantz-Bohn, a member of the Center for Biologics inspection task force, told a Feb. 24 Cambridge Healthtech conference on blood screening in McLean, VA, that "211 continues to be a major topic" in 483s for fractionators, as well as blood banks and plasma-collection centers.

She listed the following 10 violations, in order of prevalence, on 483s of 30 fractionators inspected in fiscal 1997 and fiscal 1998 to date:

1. Quality control/quality assurance. Lack of failure investigation, lack of documentation, incomplete corrective action investigation, lack of annual reviews and evaluations of batch records.

2. Lack of process validation and cleaning validation.

3. Failure to establish and follow standard operating procedures (SOPs) to prevent microbial contamination limits in media fills. Frantz-Bohn said FDA is concerned about filling conditions not "mimicking actual conditions because employees go on lunch breaks, or things go wrong."

4. Inadequate environmental monitoring, where monitoring is not done in actual use conditions

5. Lab controls, establishing controls with appropriate specifications. An example is a lack of data to support operating parameters for lyophilizers and pasteurizers, such as dry-heat ovens.

6. Incomplete training records. Frantz-Bohn said it was "common to find incomplete training SOPs, especially with virtual inspections and media fills."

7. Failure to establish cleaning procedures in aseptic processing.

8. Lack of SOPs for production process controls. Frantz-Bohn commented: "This is commonly cited and I thought it would be lower [on the list], but there are still processes where FDA investigators don't have the procedures. It's something that's so basic."

9. Failure to calibrate instruments and electronic equipment.

10. Viral inactivation. Inspections found discrepancies with viral inactivation data compared with SOPs, she said. "There were some cases where parameters were different in SOPs than how the validation of viral inactivations were done," Frantz-Bohn added. She said some SOPs were being conducted with invalidated parameters, while some involved temperature faults.

Frantz-Bohn said warning letters resulted from some of the 30 audits, but not all.

Dr. Thomas Lynch, Ph.D., senior staff fellow in the Division of Hematology, Office of Blood Research and Review, said in an interview that the agency - probably this month - will issue an addendum to its plasma compliance program regarding viral validation. He said the addendum becomes effective automatically. (See Next Page)

Lynch also said that how to handle out-of-specification results continues to be a problem for fractionators, "not in terms of designing SOPs, but following them." Due to the 1993 "Barr decision" on out-of-spec results, Lynch said: "A lot of SOPs seem to have been drafted by lawyers, which is why laboratories can't follow them."

Lynch said FDA will likely not issue guidance on out-of-spec results - which would require the concurrence of other product review centers - until the new drug GMPs become final. He added that guidance can be culled from the May 1996 proposed GMPs, but it is not binding.

FDA began enforcing the drug GMPs on the blood industry around 1991, said Eva Quinley, a trainer for Ortho Diagnostics. She told a Ortho-American Blood Resources Assn. training seminar in Herndon, VA, March 3, that because of FDA's inspection crackdown, plasma firms would be wise to organize quality assurance/quality control units that report to top management, rather than to the operations unit. She said this will minimize bias when conducting internal audits.

A former blood bank regulatory affairs/ quality assurance executive, Quinley also advised the adoption of an ISO 9000-style Total Quality Assurance System, which is centered on customer requirements, including FDA as a "customer."

Quinley said error management also will "give you the biggest bang for the buck in GMPs, by capturing errors and complaints and ensure corrective action is taken." She noted that inspec-tors are increasingly looking at error and accident reports during audits - in much same way inspec-tors of device firms go straight for the complaint file before doing anything else.

A special package containing plasma inspection guides addressing FDA and foreign audits, plus other important guidance, is available for a special rate of $30 plus retrieval. Doc. 108324M.