The Office of Pharmaceutical Quality (OPQ) was launched in early 2015 with a slogan of “One Quality Voice”. With Michael Kopcha, Ph.D., R.Ph. as the Director of the Office of Pharmaceutical Quality at CDER, and with approximately 1000 personnel in his group, OPQ’s objectives are as follows: a) streamline the regulatory processes and integrate major functional areas to facilitate a lifecycle approach to quality starting from pre-approval to post-product approval for branded and generic drug products; b) establish consistent quality standards and set clear expectations for industry; c) anticipate problems related to quality before they escalate to drug shortages; d) use quantitative metrics and surveillance techniques to help monitor quality across manufacturing facilities, and e) promote the adoption of more efficient pharmaceutical technologies that improve product quality.
In looking at the way inspections have historically been conducted, FDA has acknowledged that, although significant resources (human and financial) have been spent on inspections, such inspections have not been a good predictor of product quality. FDA’s internal analysis of approximately 5000 inspections showed that most inspections were conducted in 20-200 investigator hours with a mean of 80 investigator hours. The analysis also showed that more time has been spent on inspections with OAI results than those with VAI outcomes; and more time spent on those with VAI outcomes than those with NAI results. To this end, FDA implemented a two-year plan in 2015 to devise a new inspection approach that describes and assesses a company’s state of quality, the New Inspection Protocol Project (NIPP). NIPP’s goal is to use informatics, predictive analytics, and internal analysis to prepare for and guide inspections. NIPP, aims to provide a more quality focused, standardized, semi-quantitative approach to drug quality surveillance and inspection resulting in more streamlined and structured inspection reports; identify manufacturing excellence, practices and behaviors that exceed basic compliance, and identify industry-wide trends in quality. Additionally, based on the knowledge garnered from the NIPP inspections, the Agency can make more informed decisions on frequency of inspections, prioritization of inspections, and more effective pre-inspection planning.
Clearly, NIPP is of great interest to regulated industry. However, other than laying out the objectives of NIPP and a general overview of the initiative, FDA has not provided much detail on the conduct of the new inspectional protocol. However, at one of the breakfast sessions during the 2016 PDA/FDA Joint Regulatory Conference on September 14, 2016, Neil Stiber, Co-chair of NIPP/Surveillance, FDA/CDER, provided an update on the current status and future plans for NIPP. Protocols for each of the NIPP subgroups (Pre-approval Inspections [PAI], Surveillance Inspections and the For Cause Inspections) that have been prepared by FDA.
There are 24 elements that represent areas of coverage for the PAI and include broad categories, including the usual areas, such as equipment, processes, analytical, facility, data integrity, etc. New elements never seen before during an inspection have been added and include pre-approval quality culture, overall maturity of the process development program, and lifecycle risk management and oversight. Importantly, the new current PAI protocol only applies to sterile drug process inspections.
For the Surveillance Inspections, 29 elements culled from the six systems have been identified and similar to the PAI above, also currently focus on sterile drug process inspections.
Mr. Stiber did not elaborate on the elements, but stated these are coverage areas typically evaluated in the traditional inspections.
At the conclusion of an inspection, the investigator will give the inspected facility the Form FDA 483 observations. Under NIPP, there will be six performance levels that will be used to grade the respective elements of the protocol, and consequently, the facility’s state of quality. There will be three levels of failure (critical, major, and minor), one acceptable level and two levels of practices/behaviors exceeding basic compliance. The scores are intended to provide more specific information to the inspected facility than the broad classifications, and will not hamper the process for the issuance of Form 483s, nor would they directly translate to NAI, OAI, or VAI as these classifications are based on a number of factors, such as availablity of the drugs, the inspected facility’s prior issues, and the quality of its responses to prior issues.
An algorithm is intended to integrate the findings from the historical data and, along with product and facility risk factors, a site ranking will be determined, which can be used in the future for identifying higher-risk manufacturing sites for inspection. Consequently, the data can also help reduce investigator hours, while improving overall inspection value.
The second stage of a NIPP pilot program is in effect, but no further details were provided. Next steps include continuation of the pilot inspections; evaluation of the outcomes from the pilot inspections, improve NIPP protocols based on lessons learned, enhance IT capabilities to align with the NIPP protocols, and expand NIPP to other dosage forms.
As FDA inspections become more transparent to drug makers relative to the elements of the protocols, specific findings of the facility, and as the process becomes more semi-quantitative, it is bound to be mutually beneficial to both the Agency and the pharmaceutical industry.
