What Investigators Look For in GMP Inspections

Whether your next FDA inspection is a preapproval inspection or a routine surveillance inspection, will you be ready?

CDER plans to spread drug company inspections across three of its offices — the Office of Regulatory Affairs, Office of Pharmaceutical Quality and Office of Compliance — rather than conduct all inspections through OPQ, center officials have said.

According to Lawrence Yu, deputy director of OPQ, preapproval inspections will reside within OPQ, which will work with ORA to conduct them, OPQ will initiate routine surveillance inspections and OC will be in charge of for-cause inspections.

OPQ and ORA are developing an inspection protocol, which will include quality data gathering and semi-quantitative scoring to allow for comparisons within and between sites. The offices are making significant progress, Yu says, and they hope to begin conducting inspections using this approach this year.

The integrated team-based quality assessments that will be the central tenet of OPQ’s drug review process also are underway, Yu says.

All new NDAs and ANDAs received since Oct. 1, 2014, are being assessed using this approach, which involves a team of experts who take into account the drug product, the drug’s substances, manufacturing process and the applicant’s facilities before making a recommendation on whether to approve the drug.

Attendees at a recent cGMPs and FDA Inspections conference said noncompliance to GMPs, not having complete documentation and not having answers to FDA investigator questions were their top three concerns before investigators arrive.

Of the four major types of FDA GMP inspections — preapproval, postapproval, surveillance and for-cause inspections — for-cause are the most unscripted and harder to prepare for. Investigators may have specific assignments that are not publicly available, said Denise DiGuilio, facility reviewer, Office of Process and Facilities in CDER’s OPQ.

For more frequent preapproval inspections, investigators look for readiness to manufacture a new drug, and they will review investigations and trends, material handling, contamination, procedures and process feasibility.

Data Integrity Foundation of GMPs

Investigators will also look for data integrity issues and will examine all raw data, especially stability data.

“We are looking for integrity of your data, and the way we may check that is to look at audit trails to compare information provided in applications compared to on-site raw data,” she said, noting that inspectors are looking for tests that may not be accounted for.

A GMP inspection will cover two or more systems — production, laboratory, materials, facilities and equipment, or packaging and labeling — with mandatory coverage of the quality system.

The FDA investigator can conduct either a full inspection, which covers the quality system plus three other systems, or an abbreviated inspection, which covers the quality system plus one other system.

A history of noncompliance or significant changes such as new equipment or facilities would trigger a full inspection, DiGuilio said, as would a follow up to a warning letter.

“Be prepared for coverage of any system when you are getting ready for an inspection,” she said.

For-cause and directed inspections are usually triggered by a specific problem that has come to the FDA’s attention such as a field alert report, a recall, an adverse event cluster or other event.

The Investigator’s Inspection Plan

Before the investigator arrives, he or she will create an inspection plan based on previous establishment inspection reports and Form 483s and responses to Form 483s and warning letters. The investigator also will review a firm’s website, including recent press releases.

During the inspection, investigators will watch the manufacturing process and employee practices. They may watch the sterile process for more than an hour and will ask operators questions.

Investigators also look closely at documentation to support conclusions made in reports. For example, too many reports of “analyst error” is a red flag, DiGuilio said.

“I always like to visit the reject cage,” DiGuilio said. “Just like you can learn a lot going through your neighbor’s trash, we can learn a lot about a company by looking in the reject cage.”

“How you handle these key issues … gives us a lot of information about your quality system. If you have complete investigations and figure out root cause, you probably won’t have any problems,” she said.

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