Pre-Approval Inspections (PAIs) are one of several significant milestones with an outsized impact on product approval and market entrance in FDA regulated industries.


Preparation should be a cross-functional project that incorporates training, compliance, organization, and validation.


The FDA conducts PAIs to assure that a manufacturing site named in a drug application can manufacture the product, and that the data submitted in the application is complete and accurate.


Any manufacturing site named for the first time in an NDA, ANDA, BLA, or PMA is subject to a PAI. 


These inspections are carried out at all kinds of facilties listed in applications, including API manufacturers, testing labs, and packagers, among others.


During a PAI, regulators will be looking to confirm the following:

  • The site conforms to the application
  • The site demonstrates manufacturing reliability
  • The site can scale its operations
  • The site is using suitable and adequate analytical methodologies
  • The site is producing authentic and accurate data
  • The site is in full cGMP compliance


The PAI has three stated objectives:

Objective 1: Readiness for Commercial Manufacturing: Determine whether the establishment(s) has a quality system that is designed to achieve sufficient control over the facility and commercial manufacturing operations.


Objective 2: Conformance to Application: Verify that the formulation, manufacturing or processing methods, and analytical (or examination) methods are consistent with descriptions contained in the CMC section of the application for the biobatch (and other pivotal clinical batches, when applicable), the proposed commercial scale batch, and the API(s).


Objective 3: Data Integrity Audit: Audit the raw data, hardcopy or electronic, to authenticate the data submitted in the CMC section of the application. Verify that all relevant data (e.g., stability, biobatch data) were submitted in the CMC section such that CDER product reviewers can rely on the submitted data as complete and accurate.


Preparing for a PAI is a process that should start at least a year before regulators are expected to walk through the door.

 

A Mock PAI planned and executed by a knowledgeable and experienced auditing professional is a critically important assurance activity. 


Following this assessment, any findings that require attention should be remediated through a diligent remediation project.


As part of any preparation plan, companies should designate a readiness team, identify and work with SME who will be involved, and ready their facility to receive regulators.


The FDA has broad discretion on when to inspect and how to inspect. Compliance Program Guidance Manual (CPGM) 7346.832 lists the criteria for priority Pre-Approval Inspections.


Source: Barbara Pirola