FDA Expanding its Sterile Drug NIPP Inspection Pilot to Include Other Dosage Forms

FDA is expanding its New Inspection Protocol Project (NIPP) inspection methodology, initially piloted exclusively for sterile drug manufacturing facilities, to include other dosage forms, beginning this month. The agency also plans to use the information it continues to gather from NIPP to inform the model it uses to choose which drug manufacturing sites to inspect and how often.

End of Pilot Phase

At the Xavier Health AI Summit in Cincinnati in August 2019, Director of FDA Office of Regulatory Affairs Office of Pharmaceutical Quality Operations (OPQO) Alonza Cruse explained that the pilot phase for NIPP for inspections of sterile drug products has concluded, and FDA will be using the model for inspections of other drug product types.

“We have been using the inspection protocols in our sterile manufacturing inspections, and we are currently finalizing protocols for other dosage forms,” Cruse said. “When we first set this up, we decided to begin with the highest risk products – sterile products. However, the pool of available firms to get information from into the program was not very big.”

Cruse explained that the first version of the protocols – which includes a series of structured expert questions used during inspections – comprised 700+ questions. “That was way too many protocols for us to try to develop and conduct during an inspection. After extensive studies and a number of trial pilots we have reduced the number significantly. One of the key objectives is to develop consistent, comprehensive coverage of the critical areas.”

“We think we have nailed it down,” he commented. “We will have the protocols ready for piloting inspections of other dosage forms such as transdermal, oral dosage, and ointments and cremes, next month – sometime in September of this year.”

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What is NIPP?

When the Office of Pharmaceutical Quality (OPQ) was stood up in early 2015, the goal, according to the agency, was to create a “super office” in the Center for Drug Evaluation and Research (CDER) dedicated to product quality across all drug products CDER regulates (new, generic, and OTC), and all sites of manufacture, both domestic and foreign, with a goal of “one quality voice” oversight throughout the lifecycle of a drug product.

The intent was to integrate the review, inspection, surveillance, policy and research functions, spanning the pre- and post-approval lifecycle stages for new and generic drugs and strengthen pharmaceutical quality on a global scale.

The agency has long been aware that its traditional inspection paradigm is not a good predictor of product quality, but simply provided a generally limited snapshot in time of a manufacturing facility. As Cruse pointed out at the Xavier meeting, “In all our inspections – not just in the drug space – we look for things that are deviations. We look for things that are missing. We look for non-conformances. Rarely did we look for best practices. Rarely did we attempt during an inspection to understand the quality culture within a manufacturing facility. These are a few of the paradigm shifts we are planning to accomplish using the NIPP protocols.”

During the initial rollout, FDA spokespeople touted the program’s goal to recognize positive behaviors and reward companies when facilities exceed basic compliance goals. Whether that has taken place and to what extent remains unclear. It has been intimated by some agency personnel that only the individual companies being “rewarded” would know.

Cruse also commented on the site selection model the agency is using for surveillance inspections. “There are several factors that go into that model. CDER Office of Surveillance runs the model twice a year and shares that list with us. That is how we determine the order in which we conduct the surveillance inspections. If we can get a better sense of the state of quality that could certainly help inform the frequency of the inspections. I think that is a big plus we receive from using the new inspection protocols.”

Details are Sketchy

While the agency has made it clear that the protocols will not be made public, some aspects of the program and ways in which it might be used have been elucidated in public presentations by agency personnel.

At an FDA Quality Forum when NIPP was being rolled out, CDER OPQ Office of Process and Facilities (OPF) Division of Inspectional Assessment Acting Branch Chief Grace McNally provided insights into the project. In addition to what has already been discussed above, she said the inspection process focuses on measuring and describing the state of quality in the inspected facility and includes analyzable assessments designed to track and improve performance.

McNally noted that approach is a risk- and rule-based process using expert questions and a standardized inspection approach that differs somewhat depending on whether the inspection is a pre-approval inspection (PAI) or surveillance inspection. The process will run in parallel to normal inspection procedures and is not being used for compliance actions.

For PAIs, she pointed out, there are three objectives:

• Readiness for commercial manufacturing
• Conformance to application
• Data integrity

In addition to the coverage described in the existing FDA Pre-Approval Inspection Program, new areas assessed under the pilot include quality culture, maturity of the process development program, and lifecycle risk management and oversight.

Surveillance inspections will continue to focus on the six quality systems.  For the six systems, 29 “elements” were developed, each of which will be scored separately. While these elements were not disclosed, it was implied that they are areas typically covered during inspections. The scores will be “semi-quantitative” to allow comparison across sites.

Scoring for each element will consist of six performance levels as seen in Figure 1.

The scores aim to provide more specific information to the facility being inspected. The No Action Indicated (NAI), Voluntary Action Indicated (VAI), and Official Action Indicated (OAI) designations will still be used. The six performance levels are by element and would not translate directly to an action indicated status, which also considers historical and other information in addition to the inspection findings.

Statement from Former FDA Commissioner Scott Gottlieb

In late 2018, former FDA Commissioner Scott Gottlieb issued a statement on the agency’s manufacturing inspection efforts and the work the agency is doing to improve them. The statement reads in part:

“The New Inspection Protocol Project (NIPP) uses standardized electronic inspection protocols to collect data in a structured manner for more consistent oversight of facilities and faster and more efficient analysis of our findings. The protocols also include additional questions related to quality culture observed in facilities.

“The FDA conducted multiple pilots of the NIPP protocols to ensure that they would be consistent with current program objectives and integrate into the way investigators conduct inspections. Each new protocol version underwent extensive revision and refinement. Much of this work was based directly on feedback received from our investigators, compliance officers and reviewers who participated in the pilots.

“The result is protocols that promote consistent and comprehensive coverage of critical areas of sterile drug manufacturing and provide structured, data-rich reports that can be used to quickly assess the state of quality in drug manufacturing facilities while maintaining flexibility for investigators to adapt inspections based on constraints such as time or the seriousness of violations. The structured protocol also makes it easier to analyze data to find anomalies and inform decisions that can reduce risks to patients.”

AI and Future Developments

As noted above, since the time of the commissioner’s statement the sterile manufacturing pilot has been completed and the agency is now expanding NIPP to other dosage forms.

At the Xavier AI Summit, Cruse commented, “We are at a critical juncture. I think AI – artificial intelligence – can help us augment the information that we are already receiving. We use AI, but at some point, decisions will need to be made by a carbon-based life form. I can easily switch out ‘artificial intelligence’ with ‘augmented intelligence,’ which helps to form and shape data to provide information back to us that will help us make more informed decisions.”

He predicted that “augmented intelligence” along with natural language processing tools will eventually be used with the data from the NIPP project to produce “a good snapshot of the state of quality within the pharma space” that will, among other things, help the agency decide which manufacturing sites to inspect and how frequently.

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