US FDA’S PRE-APPLICATION INSPECTIONS · 2020. 4. 15. · Karaiba Garden UBERLANDIA – 38411-186 Minas Gerais (MG) Telephone: (+55) 34-3235-1971

US FDA’S PRE-APPLICATION INSPECTIONS

22US FDA’s Pre-Application Inspections | www.globalregulatorypartners.com

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 IS PRE-APPROVAL INSPECTION?

WHAT SITES ARE INSPECTED BY FDA?

EXAMPLES OF SITES INSPECTED:

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).

¾ Finished dosage manufacturers ¾ API manufacturers ¾ Finished dosage and API testing sites ¾ Primary packaging and labeling sites ¾ For animal derived APIs, the facility thatperforms the crude extraction

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WHAT SITES ARE NOT INSPECTED BY FDA?

Intermediate Manufacturers ¾ On a case-by-case basis; evaluated only if the

intermediate is considered critical to quality of thedrug product.

Exhibit batch Manufacturers (if not proposed commercial site)

¾ Sites could be added on a for-cause basis if thereview identifies concerns

Component Manufacturers

¾ Includes syringe, vial, or stopper manufacturersand component-only sterilization sites

¾ Sites not generally evaluated unless for-causebasis

¾ It is the drug product manufacturer’s responsibilityto qualify their suppliers

Excipient Manufacturers ¾ Sites not generally evaluated unless it is a novel

excipient and/or the excipient manufacturingprocess is considered a critical step in the overall drug manufacturing process.

Secondary packager/labeler ¾ Site not generally evaluated



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:

1. Facility Risk

• Recent GMP issues and recalls• Many applications filed at once

2. Product Risk

• New Molecular Entity (NME)• First NDA or ANDA application• Drugs for serious conditions• Breakthrough therapy or shortage situation

3. Process Risk

• Narrow therapeutic range (95%-105%)• Incomplete development data• Batch records non-specific• Complicated process



WHAT DOES THE FDA CHECK DURING THE PAI?

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.



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.



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

Companies should have a proactive compliance approach:

1. Identify and fix quality issues and deficiencies thought due diligenceaudits before the PAI .

2. Open CAPAs for all identified deficiencies and have an appointmentplan for their resolution.

3. Qualify all supplies listed on NDA/BLA/ANDA application beforetheir usage.


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Global Regulatory Partners Inc, (GRP) provides regulatory affairs, clinical, quality and safety services to medical devices and pharmaceutical companies globally. As a qualified and licensed legal representative with offices in USA, China, Japan, Brazil, Mexico and Argentina, the company can represent life science companies in those countries and help them register their products in compliance with local regulations and in record time.

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US FDA’S PRE-APPLICATION INSPECTIONS · 2020. 4. 15. · Karaiba Garden UBERLANDIA – 38411-186 Minas Gerais (MG) Telephone: (+55) 34-3235-1971