Keeping FDA Happy: Proactive and Reactive Best Practices

It’s common wisdom that there has been more FDA enforcement action within the drug industry in the past few years. Has the Agency raised the bar? There are a number of things going on, said Patti Gupta, former consultant and current VP of Compliance for J&J's Janssen supply group, speaking at the PDA Annual Meeting on April 12 in San Antonio. For one thing, the Democrats are in the White House, she said, which tends to "ratchet up enforcement" within the Agency. Also, FDA has hired 700 new investigators in the past few years, so "you have a lot of senior people doing good investigations, and a lot of junior people doing not-so-good investigations," she said, but regardless, more investigations are taking place.Whatever the reasons, the compliance bar, she said, is constantly being raised—"keeping the little 'c' in cGMPs." Sometimes, she said, major companies actually play one-upsmanship, taking compliance activities further than before, "and when an FDA investigator sees that, it then becomes the 'bar' in their mind."GMP SurveillanceIn response, Gupta said, manufacturers should start their own GMP Surveillance Program, which involves some of the following:

• Joining industry organizations and benchmarking groups
• monitoring FDA, EMA and other regulatory websites, as well as other media outlets
• designating at least one person in your company to develop and perform GMP Surveillance activities
• hiring consultants to do benchmarking, and hiring new employees (that is, "new blood" with experience at other companies) for key positions
• submitting FOI requests for 483’s and other documents from companies similar to yours
• developing in-house communication to update employees on regulatory changes and to provide routine updates (at least quarterly) to senior management

Gupta then provided tips for how manufacturers can prepare for the various inspections and communications with FDA that may arise:Prepping for a PAI or Routine InspectionMost of Gupta's suggestions for PAI prep were straightforward:

• Perform a data verification audit.
• Identify documents relevant to the product and its submission.
• Review the product development/history report with the appropriate scientists.
• Print out all deviations, investigations, CAPA's and change requests associated with exhibit and validation batches.
• Perform a gap analysis per FDA requirements.

A few ideas manufacturers may not consider, however: Identify significant issues, problems, questions and prepare a 3-4 slide PowerPoint presentation to describe events and subsequent CA's. Also, she said, provide printouts of the manufacturing process for inspectors—make it easy for them to get the information they need.Identify your tour route to be used during site inspection. Make sure workers along that route understand what’s expected of them and are prepared to speak, Gupta said. If the product under review is not being manufactured at the time of inspection, rehearse manufacturing personnel to be able to discuss the new product.Finally, she said, it makes sense to hire auditors, or use qualified internal personnel, to do a mock PAI in advance of the real thing.For routine inspections, Gupta recommends:

• Perform periodic, comprehensive audits of each potential FDA-inspected site.
• Ensure that your external audit program includes service providers and that the information is up to date.
• Perform regular, comprehensive audits of your Quality Systems, and ensure site management is doing likewise.
• Do surprise walk-throughs of your facilities.
• Do periodic audits of your manufacturing records against training documentation. (There is frequently incompatibility between the two, she noted, and workers performing certain tasks may not be adequately trained to do them.)
• Perform Gap Analysis using FDA compliance programs.

Responding to a 483For manufacturers, the occasional 483 is unavoidable. Gupta’s suggestions for how to address them include:

• Read, and re-read, each 483 observation to make sure you understand what issues have been raised by the Agency.
• Incorporate a "SWAT Team" approach to writing and revising responses—that is, she said, make sure that your best people and subject matter experts participate.
• Include copies of specific SOP's, policies, and documentation that have been revised due to the 483.
• Include specific timeframes for your corrective actions. "FDA doesn’t want lengthy CAPA's . . . make sure to keep your timeframes very tight, especially for simple things."
• Responses should be sent so that FDA receives them within 15 days. Even though responses to 483's, technically, are not required, they should be done as a matter of practice, Gupta said.

In regards to responding to a Warning Letter, Gupta recommended:

• Remember that a response is required within 15 days.
• Responses must be comprehensive and global.
• Read and understand underlying issues, and address all of the systems that may need correction.
• Describe both immediate Corrective Actions as well as Preventive Actions

Perhaps most importantly, Gupta cautioned not to be combative regarding the Agency's assertions. "Do not make any excuses," she said. "Fix underlying causes and identify proactive CAPA’s."Gupta finished her talk by providing suggestions on how to handle the unlikely event of a regulatory injunction. However, she noted with humor, if a Consent Decree is issued, "you're in a world of hurt" and probably need advice far beyond what she is able to provide in a brief conference presentation.