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Focus on Regulation

FDA introduces new standardized inspection protocols for sterile drug manufacturers to modernize and strengthen oversight

On November 9, FDA Commissioner Scott Gottlieb, M.D., announced that the agency launched new inspection protocols for aseptic processing of sterile drugs to be used by FDA investigators during surveillance and pre-approval inspections.  The protocols were developed through the agency’s New Inspection Protocol Project (the “NIPP”), initially launched in 2014.  The NIPP is intended to develop standardized electronic inspection protocols to collect data in a structured manner; to reduce the variability in inspectional findings among investigators; and facilitate more efficient analysis of findings.  The NIPP is aimed at expanding the investigator’s focus beyond identifying specific current good manufacturing practice (CGMP) violations towards assessing the overall state of a facility’s quality systems and operations.

FDA has been focused on program alignment to better handle the increasing complexity of the pharmaceutical landscape and achieve better internal coordination. The NIPP’s objective is to develop a new inspection and reporting system to better assess and record the state of quality in manufacturing facilities.  “[T]here’s increasing need to more efficiently collect and analyze the information we gather during inspections to give us even better and timelier insight on the state of quality in drug manufacturing facilities promote the relevance of this information to our regulatory decisions,” Dr. Gottlieb recognized in his November 9 press release.

The significant patient safety risk and drug shortages involving sterile drugs are the primary reasons that FDA focused initially on aseptic processing.  The first phase of the NIPP included piloting a set of protocols for inspecting manufacturing facilities for sterile injectables, which included 10 pre-approval inspections and 10 surveillance inspections.  The facilities were scored based on specific “ratable elements” distinguishable from the traditional approach of preparing Establishment Inspection Reports that consist of narratives which may be difficult to analyze.  The agency intends that the protocols will allow investigators, compliance and review division staff to ascertain the level of manufacturing quality without a deep dive into the inspection report.  In addition, FDA intends that the protocols will facilitate quality assessments, including whether there has been improvement or decline,  and how facilities may compare.

The aseptic processing drug inspection protocols for sterile drugs are the first in a series of new inspectional protocols to be issued by the agency. FDA completed multiple pilots of the NIPP protocols, which led to their extensive revision and refinement to ensure they are consistent and can be integrated by investigators in the field.  New inspection protocols for inspections of manufacturers of solid oral dosage forms and active pharmaceutical ingredients are also expected.  The agency’s goal is to fully implement the new inspection protocols within the next two years.

Dr. Gottlieb offered assurances that the new protocols are not intended to change the role of the investigator to collect, evaluate, and document objective facts pertaining to the state of quality. Rather, the protocols establish a more structured approach to facilitate more thorough and efficient inspections.  While the protocols for aseptic processing drug inspections are not publicly available, we have learned the following from FDA statements made at industry conferences in terms of the structure of the protocols—

  • Investigators will use tablets uploaded with the protocols to rate facilities during domestic and international inspections.
  • The protocols will include 29 elements across the six systems that FDA inspections can cover. For pre-approval inspections, FDA investigators would score establishments on 24 elements in areas such as facility, equipment, personnel, processes, analytical, management of suppliers and contractors, data integrity, quality culture, process development program maturity, and lifecycle risk management. Investigators would score facilities on each of the 29 elements based on six performance levels during surveillance inspections.
  • There would be three levels of failure (critical, major, and minor), one acceptable level, and two levels of exceeding basic compliance. In addition, high-performing facilities may be rewarded with reduced surveillance inspection schedules. The rating scores are intended to provide more specific information to the inspected facility than the broader inspectional classification (NAI, OAI, or VAI).
  • Higher risk manufacturing sites will be identified through an algorithm that will integrate findings from historical data and product and facility risk factors. See our prior summary of FDA’s system for prioritizing surveillance inspections.  We believe that  it is likely that CDER will seek to integrate the data from the NIP into its risk-based site selection model.

The new protocols will provide “data-rich” reports that allow investigators to quickly assess the state of quality while maintaining flexibility to adapt inspections based on seriousness of violations and constraints such as time.  FDA has stated the agency will likely not make the new inspection protocols publicly available.  The purpose according to the agency is be to drive a company to focus on a constant state of quality, rather than demonstrating basic current good manufacturing practice (CGMP) compliance during an FDA inspection.

As the agency implements new structured protocols and investigators conduct more thorough inspections and obtain more data to provide their report, it is more important than ever that drug manufacturers and stakeholders ensure a robust and sustainable system for continual improvement of product and process quality has been implemented, which may include trending data and quality metrics programs, enhanced annual review and audit procedures, and comprehensive, objective pre-inspection assessments on a routine basis.

We will continue to closely monitor FDA’s implementation of new standardized inspection protocols and obtain more details on how these inspection initiatives may impact the regulatory enforcement landscape.