FDA’s Pre-Approval Inspection Matrices Show Interesting Trends
[Posted on: Thursday, April 5, 2018] FDA recently published the time-lines for the pre-approval GMP inspections for drugs and medical devices and it shows some useful time-lines for regulatory actions that may be useful to all manufacturers planning for such inspections. Prior to approval of any new drug or medical device, FDA must conduct a GMP audit of the facility where the marketed product will be manufactured to verify its compliance with US regulations. Failure of the facility in the pre-approval inspection (PAI) would lead to delays in the market approval till such issues are addressed. For many such PAI issues, FDA and manufacturers may hold meetings to discuss measures to resolve such issues. Many of the facilities subject to the PAI may also be involved in manufacture of other FDA-approved products. In such cases, the findings of the PAI may turn into audit for other products as well and lead to 483s, and further regulatory actions such as Warning Letters and Import Alerts. Although the report from FDA does not include similar inspections for biologics and biosimilars, similar trends can be expected for those products as well. Almost all PAIs are conducted upon request by the reviewers of the market approval applications. Typically reviewers of the NDA, ANDA, 510(k) or PMA would wait for the “Acceptance for Review” decision for the application before asking the inspections division to conduct the PAI, as doing a PAI for an application that is not even accepted for review would be waste of resources. Typically, for new drugs it takes FDA inspectors about 102 calendar days to show up for the PAI from the day the reviewers request such inspection. It takes FDA inspectors about 7 days to issue the FDA 483 from the start of such inspections. The manufacturers almost always work to resolve the non-compliance issues listed in the 483 and may decide to meet with the regulators to discuss issues that require additional considerations or to get an agreement for alternate approaches. Such regulatory meetings are mostly held on Day 169 from the date 483 was issued. This could mean that the manufacturers must show reasonable effort in trying to address the findings before FDA would agree to meet with them. Warning Letters were mostly issued on Day 191 from 483 meaning that the resolutions offered by the manufacturer were not acceptable to the FDA. A total of 94 market approval applications (NDAs and ANDAs) were delayed due to the PAI issues last year. For medical devices, the PAI times are much shorter; 35 days for the inspectors to show up at the facilities and 5 days to issue a 483, and 5 medical device applications were delayed to failing the PAI. A PAI is an important event for any application so knowing when to expect the FDA inspectors is very useful information for applicants. The data is available only for one year but seems reasonable to expect similar trends this year.
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