On July 16, 2015, U.S. Food and Drug Administration (FDA) Facility Reviewer Denise DiGuilio presented a seminar titled “What to Expect During a FDA Drug Manufacturing Inspection.” The seminar was part of a two-day regulatory education event held in Silver Spring, Maryland, USA. During her presentation, DiGuilio discussed the various types of FDA Current Good Manufacturing Practice (CGMP) inspections, how FDA investigators prepare for an inspection, and finally, what to expect during an inspection.
Types of FDA Drug Manufacturer Inspections
There are four types of FDA CGMP Inspections:
- Pre-approval – FDA conducts pre-approval inspections before a New Drug Application (NDA) is approved to ensure the listed establishment is capable of manufacturing the drug and that data submitted in the NDA is accurate. FDA will likely request data to support that the processes listed in the NDA are feasible and will confirm whether the manufacturer has contamination and hazard prevention in place.
- Post-approval – FDA usually conducts post-approval inspections between 6 and 24 months after an NDA is approved. Post-approval inspections are used to monitor changes in production and control practices. The extent of a post-approval inspection is determined by a manufacturer’s pre-approval inspection and compliance history.
- Surveillance/Routine – FDA conducts routine establishment inspections to ensure that drug manufacturers maintain compliance with CGMPs throughout their lifetime of operation.
- For-Cause/Directed – FDA conducts for-cause inspections to investigate specific problems brought to the agency’s attention. For-cause inspections are typically the result of compliance issues, such as NDA field alert reports, recalls, a cluster of adverse events, etc.
FDA can choose to conduct a full or an abbreviated inspection. During a full inspection, FDA will inspect a drug manufacturer’s quality system plus three other systems. During an abbreviated inspection, FDA will inspect the quality system and only one other system. FDA will always conduct a full inspection for a manufacturer’s initial inspection. Other reasons FDA may choose to conduct a full inspection include a history of non-compliance, significant changes to the company (new management, new equipment, etc.), or as a follow up to a warning letter.
How FDA Investigators Prepare for an Inspection
Before an inspection, FDA investigators review:
- The manufacturer’s NDA and/or Drug Master Files.
- Relevant FDA CGMPs, guidance documents, and the FFDCA.
- Relevant FDA Compliance Program Guidance Manuals.
- FDA’s Investigations Operations Manual (IOM), specifically Chapter 5: Establishment Inspections.
- Relevant FDA Inspection Guides.
DiGuilio strongly suggested that manufacturers familiarize themselves with these documents when preparing for an inspection, especially the IOM. She said the documents will help manufacturers understand FDA’s expectations, guide them to relevant regulations, and help them interpret what the regulations mean.
What to Expect
The following steps are indicative of the typical flow of FDA drug manufacturer inspections:
- FDA investigators are required by law to show credentials to the top management official of an establishment being inspected upon arrival. Management may examine the credentials and record the number and name, but FDA credentials may not be photocopied. Drug manufacturers located in the U.S. will also receive a Notice of Inspection upon FDA’s arrival.
- The lead investigator will state the purpose of the inspection and provide a general overview of the agenda.
- FDA investigators will tour the facility. They may ask if anything has changed since the manufacturer’s NDA was approved.
- After the tour, FDA investigators will look more critically at the establishment. They will likely examine incoming raw materials, as well as review equipment logs and other records. They may even question some employees about their daily work and watch as processes are executed. “Expect your investigators to stand there for an hour watching a sterile process,” DiGuilio said.
- DiGuilo suggested that manufacturers ask their investigators to participate in daily wrap up meetings so they can get an idea of how the inspection is going and what else may need to be inspected. Manufacturers should ask if there is anything they can prepare for the investigator for the next day.
- At the end of the inspection, FDA may collect samples, issue an affidavit, or issue an Inspectional Observations Report (FDA Form 483). At the end of a pre-approval inspection, FDA investigators will inform management of his or her initial recommendations before leaving. FDA will not provide recommendations at the end of post-approval inspections. Manufacturers can expect a copy of FDA’s inspection report within a month.
CGMP violations that FDA investigators typically look for include poorly trained employees, poorly maintained or contaminated equipment and facilities, lack of process controls, failure to conduct investigations or resolve CGMP issues and complaints, and more. FDA will want proof of claims. If a manufacturer claims to be conducting routine maintenance, FDA will want to see documentation. FDA will want scientific evidence to support conclusions made in various reports.
FDA generally classifies drug manufacturer inspections under one of three outcomes:
- Official Action Indicated (OAI) – This means FDA identified significant compliance issues during an inspection that require immediate corrective action.
- Voluntary Action Indicated (VAI) – This means FDA identified objectionable conditions or practices, but they do not warrant regulatory significance.
- No Action Indicated (NAI) – This means FDA did not identify objectionable conditions or practices.
It’s prudent for drug manufacturers to always be prepared for an FDA inspection. FDA investigators’ inspection plans are influenced by previous FDA inspection reports and manufacturers’ past responses to 483s and warning letters. The better the outcomes of a manufacturer’s first few FDA inspections, the more likely the manufacturer will endure shorter and more lenient inspections in the future.
Registrar Corp is a consulting firm that helps drug establishments comply with U.S. FDA regulations. Registrar Corp can help drug manufacturers:
- Register and list their products with FDA.
- Review their drug labels for FDA compliance.
- Submit DMFs to FDA.
- Handle FDA detentions and Import Alerts.
- Monitor their own company and suppliers for FDA compliance issues.
For assistance with U.S. FDA regulations for drug manufacturers, contact Registrar Corp at +1-757-224-0177 or chat with a Regulatory Advisor 24-hours a day at https://www.registrarcorp.com/livehelp.