The FDA has recently updated two compliance program guides addressing PAI inspections (7346.832) and routine GMP surveillance inspections (7356.002). This new guidance updates the criteria that the FDA uses to decide whether to conduct a PAI, in addition to now incorporating the ICH Q9 guideline on quality risk management, the ICH Q10 guideline on pharmaceutical quality systems, and the ICH Q12 guideline on post-approval changes. The updates also formalize the agency’s practice of using alternative tools to conduct PAIs, including the use of inspection reports from trusted foreign regulatory partners through mutual recognition agreements, and the use of remote assessments, through either record requests or remote virtual conferencing systems. You can read the guidance documents for PAI inspections here and GMP surveillance inspections here. You can also connect with one of our quality assurance experts for more information when preparing for an FDA inspection.

When your company is moving from clinical stage to approval of your first commercial product, one of the key milestones is preparing for an FDA inspection. Once your application is submitted for approval, the FDA can plan a PAI or BIMO Inspection at any time. You may or may not be notified prior to the FDA arriving to conduct an inspection. As such, it’s critical that you begin preparing for an inspection long before the FDA shows up at your door! 

What are BIMO and PAI? 

The two main types of FDA inspections you may be subject to are known as BIMO and PAI. 

BIMO 

The FDA’s Bioresearch Monitoring Program (BIMO) is defined by the FDA as “a comprehensive program of on-site inspections and data audits designed to monitor all aspects of the conduct and reporting of FDA regulated research.”  The scope of the BIMO inspection includes verification of: 

• Protection of the rights, safety, and welfare of subjects involved in FDA-regulated clinical trials 
• Verification of the accuracy and reliability of the clinical trial data submitted to FDA in support of research or marketing applications 
• Compliance with FDA’s regulations governing the conduct of clinical trials, such as   
• Electronic Records / Electronic Signatures 
• Protection of Human Subjects 
• Financial Disclosure by Clinical Investigators 
• Institutional Review Boards 
• Investigational New Drug Application 

PAI 

An FDA Pre-Approval Inspection (PAI) is conducted to assure that a manufacturing site named in a drug application is capable of manufacturing a drug and that the supporting data submitted are accurate and complete. 

These inspections are carried out at all types of sites, including API manufacturers, testing labs, finished dosage manufacturers, and packaging facilities, among others. The scope of the PAI includes verification of: 

• Readiness for commercial manufacture to determine if the facility has a quality system in place and appropriate to maintain sufficient control over the operations 
• Sponsor oversight to assure that the site is using qualified suppliers and vendors and has appropriate quality agreements and contracts in place 
• Conformance to the application to verify that the processing methods and analytics are consistent with the descriptions contained in the application 
• Data integrity to audit the raw data to authenticate the data submitted in the application and to ensure that the submitted data is complete and accurate and can be used to perform the evaluation for approval 

Preparing for an FDA Inspection

Once your application is submitted for approval, the FDA can plan a PAI or BIMO inspection at their convenience. The inspection may be scheduled and announced in advance, or the FDA may simply show up at your door. Either way, it’s important to be prepared. 

Learn more about our Inspection Readiness Consulting Services

1. Put the IR team together. The first priority in preparation is to put an Inspection Readiness (IR) team together. This should be led by a Project Manager and include Subject Matter Experts (SMEs) in each of the areas that may be inspected, as well as members of the Quality team that will lead the inspection. This team will identify the potential scope of the inspection, develop a readiness plan and timeline, identify resources, and execute the project to prepare for the upcoming inspections.  

The IR team will compile a list of all open items and tasks that need to be completed in order to become inspection ready. They will prioritize these tasks and create a timeline to ensure completion prior to expected arrival of the FDA. The team will identify who will fill several key roles, including who will be in the front room, directly interacting with the inspector, and who will be in the back room, supporting the inspection behind the scenes. 

2. Conduct a gap analysis. The IR team will begin by conducting a gap analysis of current systems to identify any potential gaps and develop a remediation plan to resolve any identified issues prior to the arrival of the FDA. It is very helpful to review the FDA Compliance Guides for Inspectors to become familiar with what the FDA is looking for when they conduct an inspection.  

As potential issues are identified, compile a list of additional tasks that are needed in order to become fully inspection ready. The team will need to prioritize and schedule these in addition to the previously identified tasks.  

You may also identify added ‘hot topics’ for discussion and decide to prepare storyboards to address each potential topic. Storyboards are extremely useful to summarize how a potential issue was identified and remediated, to capture the history of the issue, and document the current thinking around decisions that were made. These can be used for an SME refresher prior to the inspection and as a reference during the inspection, as well as provide a historical record for any future questions.  

3. Provide Inspection Readiness (IR) training. Another key activity to preparing for an FDA inspection is to provide Inspection Readiness training for all SMEs and the inspection team. This training should cover the purpose of the FDA inspections, what the FDA is looking for, inspection behavior, and how to interact with an inspector when you’re being interviewed.  

It’s recommended that you also provide Inspection Readiness training for all personnel at the site, even if they’re not directly involved in the inspection. This training should address a brief overview of why the FDA is coming to the site, acceptable behaviors while the FDA Inspectors are on-site, how to interact with the inspectors during tours, and individual preparation of workspaces. And, because you may or may not be notified prior to the arrival of an FDA Inspector, all receptionists and anyone who may open the door to an inspector must be trained in what to do if an inspector arrives. 

Additionally, training will be needed for those who will fulfill specific roles in the Front and Back Rooms during the inspection. The QA Host is the Front Room lead and is responsible for everything in the Front Room, where the actual inspection takes place. The FDA Inspector, a scribe, and any SME being interviewed will be in the front room as well.  A Front Room coordinator is often included to provide support for the QA host by documenting all inspection requests for documents or interviews and communicating them to the Back Room. No one should enter the Front Room without being specifically invited.  

The Back Room Manager is responsible for all activities in the Back Room, also known as the “war room.” This is where all the preparations and behind the scenes action takes place. The Back Room handles all requests for documents and ensures that the SMEs are prepped to be interviewed. All people and documents must be cleared through the Back Room prior to entering the Front Room.  

The Back Room Manager is responsible for prioritizing requests, reviewing completed requests to ensure they accurately fulfill the request, and communicating with the Front Room as needed. A Back Room Request Tracker manages fulfillment of the inspection requests by contacting appropriate SMEs to request documents or for interviews, tracking and updating the request status, and providing completed requests to the Back Room Manager for communication to the Front Room. SMEs provide support for the Back Room by identifying, obtaining, and reviewing requested documents. SMEs may also be called into the Front Room to speak with the inspector directly.  

4. Conduct a mock inspection. The next important step is to participate in one or more mock inspections as a dry run for the FDA inspection. A mock inspection is a key opportunity to have the inspection team walk through their roles and the inspection process to identify any weak areas or needs for improvement in order to fine tune the process.  You can plan for an announced or unannounced mock inspection.  

It will start with the mock inspector arriving at your facility. An FDA inspector is required to present their credentials and sign in. The first step when an inspector arrives is to contact the identified QA lead to receive the inspector. The QA lead will verify the credentials and accept the FDA notice of inspection and the inspection agenda from the inspector.  

At the same time, the QA lead will notify the inspection readiness team to begin executing the inspection management plan. This includes notifying all personnel that an FDA inspector is on site and setting up the Front and Back Rooms. In the case of a pre-announced inspection, the required personnel and rooms will already be set up.  Identified personnel will assemble as planned to fulfill their specific roles.  

The inspection usually begins with the Inspector stating the purpose and scope of the inspection. They may provide an agenda of topics to be covered, but it is not required. The QA host will introduce key players and provide an opening presentation to share a brief background on the company and the specific product being reviewed. 

As the inspector asks about various topics, the appropriate documentation and/or SMEs will be requested from the Back Room. The inspector will review documents, and SMEs may be called into the room to answer questions. The scribe will take notes on topics discussed, SMEs interviewed, and any activities happening in the room. The scribe notes are shared electronically with the Back Room to provide awareness of progress and status. Any observations or potential observations will be noted by the Front Room support.  

At the end of the day, the inspector will have a daily wrap up to review any potential observations and address any open questions for the next day. After the inspector leaves for the day, the inspection team will stay to meet and address any open questions and document requests, try to resolve any potential observations, and prepare for the next day. At the end of the inspection, an inspection close-out meeting will be held, and a preliminary inspection summary report will be shared with the team. The company must then respond to the observations within an agreed-upon timeframe.  

5. Remediate the Inspection Findings. The summary report for the inspection will call out any observations that would have been noted if this had been a real FDA inspection. Any items identified will need to be added to your task list and resolved.  

Additionally, a mock inspection will provide you with the opportunity to detect areas in your inspection process and materials that may need more attention. You may have observed that you were unable to answer questions posed by the inspector about a specific topic. Those topics might need to be added to the hot topics list and additional storyboards created.  

You may not have been efficient at pulling requested documents. This can indicate that you need to have a better organization of pre-staged documents and files so that requested information can be easily found. The SMEs may not have been comfortable or professional when speaking with the inspector. Perhaps they provided too much information in their responses or were not clear. Their answers might have had the potential to open the door to other topics to be addressed. This can be resolved with additional training and practice interviews.  

Additional gaps such as not having necessary procedures or documentation may be identified. These can be added to your task list to ensure they are completed prior to an FDA inspection.  

Potential FDA Inspection Outcomes 

When you undergo an actual FDA inspection, there are three possible outcomes: 

• NAI – No Action Indicated: this means that you are in compliance and will help you on the path to approval. 
• VAI – Voluntary Action Indicated: this happens when there are minor deviations from the regulations, and voluntary correction is requested. This result will typically not keep your product from being approved, providing corrections are made as promised. 
• OAI – Official Action Indicated: this is the result when there is serious non-compliance requiring further action by the FDA. This can stop approval of your product.  

In the case of a real FDA inspection, an initial response must be provided to the FDA within 15 days of the inspection. The response must include any corrective actions already taken, along with plans and timelines for root cause investigations and CAPA plans to be conducted to fully address all observations. You will then need to follow-up regularly with the FDA until all action items are completed.  

Thoroughly preparing for an FDA inspection is a critical part of preparing for product approval and may feel overwhelming. Clarkston Consulting can help by providing project managers to manage your Inspection Readiness activities, supplying SMEs to help identify hot topics and assist with development of appropriate procedures and documentation, and supporting your remediation efforts.  Learn more about how we helped our biotech client  to manage and prepare for a PAI and BIMO inspection below.

PAI and BIMO Inspection Readiness Case Study