FDA Revises Pre-Approval Inspection Compliance Program (7346.832)

Having been involved with the Concept of Operations for Integration of FDA Facility Evaluation and Inspection Program for Human Drugs  while at FDA, I am encouraged to see the release of a revised 7346.832 for pre-approval inspections (PAI) that will go into effect in September 2019.  

It is also important that the objectives, while elaborated on, will stay the same, as they are the cornerstone of the program for the evaluation of facilities that support drug applications submitted to FDA.  Sponsors and applicants need to take these objectives to heart, not just to pass the PAI and get their application approved, but more importantly to provide confidence to FDA and to the American public that they can consistently manufacture safe and effective medicines that will meet the patients or caregivers needs any time they use them.  

As mentioned, the PAI objectives have not changed.  They remain as follows:

Objective 1: Readiness for Commercial Manufacturing 

“Determine whether the establishment has a quality system that is designed to achieve sufficient control over the facility and commercial manufacturing operations.” Most importantly, can the sponsor ensure that they can produce a consistent, quality, commercial, product once the application is approved and over the product’s lifecycle (including process performance qualification and continued process verification programs found in the process validation guidance)?

Objective 2: Conformance to Application 

“Verify that the formulation, manufacturing or processing methods; analytical (or examination) methods; and batch records are consistent with descriptions contained in the CMC section of the application.”  Most importantly, will the on-site activities be in-line with what was submitted in the application that is under review by CDER?

Objective 3: Data Integrity Audit 

“Audit and verify raw data at the facility that are associated with the product. This information can, among other things, help to authenticate the data submitted in the CMC section of the application as relevant, accurate, complete, and reliable for CDER assessment.”  Most importantly, has the sponsor assured FDA that the assurance data used to support the application (including development data) are reliable so that an informed decision can be made when approving a product?

With respect to integration of facility inspections with submission assessment, FDA has made it clear in the revised PAI program that “Achieving a science-based approval decision about each application from a pharmaceutical quality perspective requires an integrated assessment of the application and associated facilities” and provides “specific examples of how quality risks could be addressed through integration of application assessments and PAIs.”  This does not mean that FDA did not consider both inspection decisions and assessment (review) decisions, prior to the 2017 Concept of Operations, but it does demonstrate a renewed emphasis on working as an integrated team across centers to make the best, science and risk based decision when considering approval of a drug; and whether or not a PAI is necessary.  

The Integrated Quality Assessment (IQA) team weighs both product and manufacturing (process and facility) risks; and the accuracy and reliability of the information provided in the application to make the decision to perform a PAI, waive a PAI or decide to follow-up on the specific product, post-approval (e.g., a product specific, post-approval inspection).

The last piece I would like to highlight are the inclusion of a clear delineation of roles and responsibilities by CDER and ORA when it comes to deciding on a PAI, performing a PAI, and post-inspection decision rights.  FDA’s integrated approach has caused some confusion in the recent past, but FDA has made this clear in the statement that “in general, FDA expects that the facility will resolve deficiencies identified on Form FDA 483 as they relate to ensuring compliance with CGMP, and the applicant will resolve any relevant application deficiencies resulting from inspection coverage.” This information should help to clarify for both the facilities and the sponsors on what to expect from FDA.  

I highly encourage reading the revised PAI program so that you may be ready for your next pre-approval inspection so that there are no delays on getting your product approved, launched, and available to patients.