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US FDA’s Pre-Approval Inspections
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What is Pre-approval Inspection?
A pre-approval inspection (PAI) is performed to contribute to FDA’s assurance that a manufacturing establishment named in a drug application is capable of manufacturing a drug, and that submitted data are accurate and complete.
What sites are inspected by FDA?
FDA inspects the sites that are named in the Chemistry, Manufacturing, and Controls (CMC) section of a New Drug Application (NDA), Abbreviated New Drug Application (ANDA) or Biologic License Application (BLA).
Examples of Sites Inspected:
• Finished dosage manufacturers• API manufacturers• Finished dosage and API testing sites• Primary packaging and labeling sites• For animal derived APIs, the facility that
performs the crude extraction
US FDA’s Pre-Application Inspections
What sites are Not inspected by FDA?
Intermediate Manufacturers
• On a case-by-case basis; evaluated only if the intermediate is considered critical to quality of the drug product.
Exhibit batch manufactures (if not proposed commercial site)
• Sites could be added on a for-cause basis if the review identifies concerns
Component manufactures
• Includes syringe, vial, or stopper manufacturers and component-only sterilization sites
• Sites not generally evaluated unless for-cause basis
• It is the drug product manufacturer’s responsibility to qualify their suppliers
Excipient manufacturers
• Sites not generally evaluated unless it is a novel excipient and/or the excipient manufacturing process is considered a critical step in the overall drug manufacturing process.
Secondary packager/labeler • Site not generally evaluated
US FDA’s Pre-Approval Inspections
US FDA’s Pre-Approval Inspections
How does the FDA select sites for inspection ?
FDA uses risk-based Priority Inspection Criteria to make the decision for PAI. There are 3 categories of risk:
Facility Risk
• Recent GMP issues and recalls • Many applications filed at once.
Product Risk
• New Molecular Entity (NME) • First NDA or ANDA application • Drugs for serious conditions • Breakthrough therapy or shortage situation
Process Risk
• Narrow therapeutic range (95%-105%) • Incomplete development data • Batch records non-specific • Complicated process
What does the FDA check during the PAI?
US FDA’s Pre-Approval Inspections
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.
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 bio-batch (and other pivotal clinical batches, when applicable), the proposed commercial scale batch, and the API(s).
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, bio-batch data) were submitted in the CMC section such that CDER product reviewers can rely on the submitted data as complete and accurate.
US FDA’s Pre-Approval Inspections
What are the PAI outcomes?
1. Recommend Approval
Occurs when investigators didn’t find any significant issues during the inspection. However, it is important to respond to their observations.
2. Recommend Withholding of Approval
Occurs when investigators observed that the site is not GMP compliant, information in CMC is not consistent with site records, or information submitted in the NDA /ANDA/ BLA is not accurate and complete. Responding to their observations is critical and must be performed.
US FDA’s Pre-Approval Inspections
Companies should have a proactive compliance approach:
1. Identify and fix quality issues and deficiencies thought duediligence audits before the PAI .
2. Open CAPAs for all identified deficiencies and have anappointment plan for their resolution.
3. Qualify all supplies listed on NDA/BLA/ANDA applicationbefore their usage.
Best Practices for a Successful PAI
Once the NDA/BLA/ANDA is submitted for review the FDA considers the company and all its’ facilities listed on the application ready for PAI
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US FDA’s Pre-Approval Inspections
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