A new inspection protocol project FDA officials have been discussing at recent conferences could help the agency discern differences in the state of quality among pharmaceutical manufacturing facilities and reward the better ones with reduced oversight.

The project, a collaboration between the agency’s Center for Drug Evaluation and Research and its field organization, the Office of Regulatory Affairs, also could reduce the variability in inspection findings among investigators.

The project will enable the agency to acknowledge quality when it sees it and get away from what the center’s director, Janet Woodcock, calls a “traffic ticket approach” to assessing manufacturing facilities ([A#08141030004]).

A year into the project, details remain fuzzy – and it looks like another year or two could go by before it all becomes clear.

“This is a significant change,” Lawrence Yu, deputy director of the center’s new Office of Pharmaceutical Quality, told the International Forum and Exhibition on Process Analytical Technology (Process Analysis & Control), known as the IFPAC conference, in Arlington, Va., Jan. 26. “I’m hoping within the year or within a couple of years we’ll … provide you more information with this project.”

Yu said that FDA will apply the new protocols to pre-approval, surveillance and for-cause inspections.

The project was nearing the end of its first year when Ellen Morrison, assistant commissioner for operations in the agency’s Office of Regulatory Affairs, discussed it Dec. 3 at the Parenteral Drug Association’s quality metrics workshop in Washington.

The project “is going to be a sea change, not only for our staffs, but for the companies that we’re inspecting, first obviously, on a pilot basis,” said Morrison, who co-chairs the project with Theresa Mullin, the head of OPQ’s new surveillance office.

Under the new approach, investigators won’t just be looking for problems to describe in Form 483 reports, Mullin said: They’ll be observing the overall state of quality.

Mullin said the thinking is that:

There will be a scale for gauging the state of quality that investigators observe, and the scale will be standardized, “so that there are more consistent findings and observations made and recorded across investigators as they go into the facility.”
There will be a more efficient way to capture the information post-inspection and add it to the agency’s information systems.
The scale will include a positive range for favorable observations and findings.

A six-systems approach

FDA is looking at building the protocols around the six-system approach that’s already at the heart of its inspection process. “The approach we’re taking may sound pretty basic,” Mullin explained, “but you’ve got to start somewhere.”

The agency is developing a scale for rating each of the systems – quality, facilities and equipment, materials, production, packaging and labeling, and laboratory control – as well as factors within each system.

The scale includes, on the negative side, extreme failure, substantial failure and unacceptable, and on the positive side, acceptable, enhanced and superior.

A way to share experience

If all goes well, the new inspection protocols will institutionalize the knowledge of experienced investigators.

Mullin said project deliverables include “trying to develop this risk-based, rule-based approach that takes experienced investigators in sites and what they look for – we’ll call it the signs and symptoms of good quality management and quality culture – and building that into the prompts and the information and how you would train investigators so that people are consistently using those kinds of signs and symptoms to make their assessment.”

Additionally, investigators would use new electronic tools during inspections to support more consistent recording of their findings, she said. This would yield “a more structured and streamlined inspection report that’s more accessible and usable downstream.”

Mullin added that this will involve giving the ORA field organization access to the same systems that CDER uses “so that we’re able to work and collaborate much more closely through the same platforms – and that’s a big advance for us.”

Who will set the schedule?

It’s too early, however, to say whether the task of scheduling inspections based on the new ratings will fall to CDER or the ORA district offices, Mullin said in response to a question. She added, however, that “we are moving to having the centers make the overall assessment [and] the schedule.”

She emphasized the effort’s collaborative nature: saying that the center and the field collaborated in developing the ratings and that they will pilot them together.

When asked, Mullin said that the agency would eventually share the site rating methodology it develops. . However, she noted, it won’t disclose the full details of the site prioritization model already in use.

FDA is taking a question-based approach to the new methodology, she said. “When we get to the point where we’ve tested this and it’s become something that we’re going to make part of our internal protocols and procedures, and it becomes part of our formal procedures that we have, it will become public just as any other documents do when they reach that stage of maturity.”

Asked whether FDA will continue to classify inspection outcomes into the three severity categories of “no action indicated,” “voluntary action indicated” and “official action indicated,” Mullin said the agency is not sure yet.

The focus is on adding a range of positive observations, she said. “Do we map all that into the three categories we’ve used historically or do we consider something else? It’s a good question.”

No scoring of facilities

FDA’s Neil Stiber, who is co-chairing one of the groups involved in the inspection protocol project, told the PDA quality metrics workshop Dec. 4 that the goal is not to score facilities, which in his view would be neither appropriate nor helpful.

Stiber, director of the CDER OPQ surveillance office’s Division of Quality Intelligence, Rich Analysis and Modeling (DQIRAM), spoke instead about using the protocols to develop indicators of quality.

Investigators would evaluate key attributes within each of the six systems that Mullin described, yielding “semi-quantitative assessments on the state of quality at inspected facilities.”

Scores might result from that process, but FDA would not use them as ratings. Rather, Stiber said, “It would be an input into that process of determining what should be the classification of the inspection.”

Inspection classification would depend on many factors, he explained, including prior compliance issues, drug availability, other public health needs, and how the facility responded to problems in the past.

He added that investigators will delve into the realm of quality culture as well. “Some of the questions we’ll be asking will be directed more at the staff, more at the personnel who are conducting the processes, to better understand how engaged they are in the process.”

This is going to be a difficult adjustment for the investigators. “It’s a real challenge for us to try to think about these questions, to think about an investigator's role slightly differently,” Stiber said.

Finding cGMP deficiencies will remain the foundation of inspections, “but there will be other things that the investigator needs to think about, needs to ask about and look for.”

Stiber concluded his remarks with a plea for feedback. “We don’t have a guidance or a draft rule on this,” he noted. “It’s something that we’re moving forward on, and we’re interested to hear your comments and feedback while this is moving forward, because we want it to be something that is effective and meaningful for everyone, and that it really does result in higher quality pharmaceutical product for the consumer.”

Inspection consistency

ORA’s Morrison underscored in the Dec. 4 discussion the promise of greater consistency that the new inspection protocols could deliver.

“We have some of our best talent, our best folks working closely with CDER to develop protocols,” she said. Once in place, the protocols would standardize the inspection process and benefit all investigators with the

Morrison added that the initiative should benefit her ongoing efforts to increase operational excellence, “which includes a lot of consistency in how we do inspections, and I think these kinds of protocols will actually help that a great deal.”

Pharmaceutical manufacturers take different approaches to deal with inconsistency among investigators. Discussions during an interest group session on inspection preparation at the March 16-18 PDA annual meeting in Las Vegas and in “The Gold Sheet” LinkedIn group revealed two main approaches. Many do their best to find out which investigator will conduct the inspection so they can prepare for that investigator’s individual quirks and biases and favorite questions. Others just focus on understanding their manufacturing processes.

An April 15 white paper about FDA’s new Office of Pharmaceutical Quality devoted three paragraphs to the new inspection protocol project. Here is what it said:

“Inspections have traditionally focused on facility compliance with current good manufacturing practices (CGMPs), with particular attention to process deviations and system failures. Such inspections have not been a reliable predictor of the state of product quality. Consequently, FDA is working to develop a new inspection and reporting paradigm to better assess and record the state of quality in manufacturing facilities; this new paradigm is embodied within an initiative referred to as the new inspection protocol project (NIPP). NIPP is expected to provide a more quality-focused, semi-quantitative approach with streamlined and structured inspection reports.

“The NIPP protocols utilize expert investigator questions and assessment approaches. NIPP is expected to increase the quality focus of investigator assessments, so that facilities and behaviors found to exceed basic compliance can be recognized as such.

“Following successful piloting, NIPP-developed protocols will be incorporated into new mobile technology to capture investigator findings and assessments and better support investigators while traveling and during facility inspections.”

FDA Aims for State of Quality with New Inspection Protocol Project

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