Preparing for Pre-approval Inspection

Pre-approval inspection is a critical requirement to acquire commercial manufacturing  license for a new drug or a new manufacturing facility. If you fail to meet the standards during pre-approval inspection, it may lead you to legal difficulties and, worse, unanticipated delay in marketing of those products that can cost you millions of dollars.

FDA approves a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA) or Biological Licensing Application (BLA) only if the methods, facilities and procedures used at every step from raw materials to distribution of drugs are adequate to preserve the identity, quality, purity and strength of the drug.

Types of Pre-approval Inspection

The pre-approval inspections are of two types – priority and discretionary. Food and Drug Administration has established criteria to decide whether the inspection of your firm should be considered a priority or discretionary one.

If your firm has applied for the first time to FDA or EMA (European Medicines Agency) or your final product contains a New Molecular Entity (NME) or the product is manufactured by a completely different manufacturing process then FDA makes it a priority to carry out inspection at your site.

Certain situations can lead to discretionary inspection. These include:

  • Filing of multiple applications within a short period of time involving a single manufacturing facility

  • The investigator found significant deficiencies during previous pre-approval inspection or your company has a history of non-compliance.

Inspection Team and Schedule

The investigation team for PAI should normally consist of a district investigator and an analytical chemist. Sometimes, a microbiologist may also accompany depending upon requirements. Generally it is scheduled at the earliest opportunity possible for the district investigator. Inspection must be completed within 45 days (for domestic site) or 60 days (foreign site) of application.

Performing a Pre-Approval-Inspection Readiness Assessment

To have a successful outcome from the actual pre-approval inspection, you should conduct a mock PAI to assess the readiness of your facility. It should focus on the following three things:

  • Readiness for commercial manufacturing

  • Data integrity

  • Conformance to application

During actual PAI, one or more of the above listed objectives will be addressed. The degree of coverage should depend on whether the new profile classes are related to already inspected profile classes. A profile is said to be ‘related’ when the production process or dosage form is similar to that of a previously inspected product/process at the establishment.

If the findings of pre-PAI reveal anything that may withhold the actual PAI approval, you should fix the discrepancy at the earliest to avoid delays in licensing. These issues may include:

  • Substantial problems with data integrity. The data or other conditions related to submission batch may be misrepresented.

  • Grave cGMP concerns that may compel the FDA to question the formulation or processing.

  • Absence of manufacturing and control instructions, SOP, VMP or lack of data to support those instructions.

What if You Fail the Pre-approval Inspection?

Failing the PAI gives investigator an impression that the method of analysis and the way you claim to manufacture is not up to the cGMP standards. Though you’ll be given a chance to fix the issues, failing pre-approval inspections can lead to one or more of the following problems.

Increased Frequency of Inspections

FDA may schedule re-inspection at occasional intervals to verify the revised procedures, methods, and new supporting data. They will check everything all over again to ensure that you have made the required changes. Once they collect data during pre-approval inspection, they compare it with the information you have provided in the application.

Application Integrity Policy

The FDA inspectors may consider any repeated or severe discrepancies as a potential  attempt of fraud. If you have made even simple errors in recording and calculating data, you have made it unreliable for FDA. It can invoke the Application Integrity Policy forcing you to carry out your own internal audits and fix all the inconsistencies.

Delay in Product Launch

If inspectors witness faulty cGMP, VMP or any other discrepancy in the manufacturing facility or processes, they will not approve your NDA or ANDA.

Since the reports are regularly published, you can’t hide your failures from the public. So failing the pre-approval inspection can hamper your reputation, consumers’ trust and stock prices.