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Jul 28, 2015

Three Keys to Successful FDA Inspections – Preparation, Management and Follow Up


Atlantic Validation

Successfully completing a FDA inspection is critical to cGMP operations and commercial success.  Implementing and maintaining robust quality systems is one element to accomplishing this goal.  However, it is not the only element.  Inspection preparation and management is another, equally important element to ensure a successful outcome.  In fact, proper Inspection management techniques can help mitigate the risk of receiving an observation for compliance gaps.  This article will provide insight on understanding the inspector, discuss how to prepare for and manage the actual Inspection, describe follow-up activities required for close-out, as well as describe real-life lessons learned.


Understanding the Inspector(s)

Patient safety is their number one concern, which means that they can be persuaded with good rationales and data.  This can take a lot of work, so pick your battles and have lots of data to support the decisions made.  With the 2011 Process Validation Guidance and ICH Q9, inspectors have become more science-based and more open to scientific justifications.  Remember that the inspector is not the bad guy.  They are professional skeptics who expect all claims, including risk assessments, to be backed up and supported with strong, data-based rationales.  

It is the responsibility of quality assurance management and subject matter experts (SMEs) to present the data in a way that persuades the inspector to conclude that the correct decisions were made.  It is important to note that it is possible to disagree with the inspector.  Of course, always be respectful and avoid heated battles.  The bottom line is that they need to be convinced that the manufacturing processes are well understood, how the quality management system is designed, and how the two work together to create a compliant system. 



This article is related to the Whitepaper: 21 CFR Part 11 Industry Overview: Ready for an FDA Inspection?.To get the full details, please download your free copy.
Instilling confidence in the inspector is a primary element for establishing a positive relationship and tone for the Inspection.  One way to instill this confidence is to present well- prepared packets of information with documentation that is consistently compliant with good documentation practices (GDP).  GDPs are the foundation of a robust quality system.  The adherence to GDPs will help the auditor have confidence in the data contained in the packet.  Furthermore, clearly labeled data packets (i.e. validations, summary reports, change controls, deviations, etc,) will help the inspector feel comfortable the information supplied is complete and accurate. In other words, “pretty counts.”

Additionally, demonstrating ongoing quality system improvements will illustrate to the Inspector the company’s commitment to maintaining cGMP compliance.  Examples of quality system improvements could be proved through periodic quality management review (QMR), CAPA records, and continuous improvement projects.

Remember, the inspectors have a limited amount of time to complete the inspection.  Do not waste their time.  It will not make them happy.  Instead, do what you can to make their jobs easier.


Inspection Preparation 

Preparation is worth its weight in gold!  Preparing for an inspection will help ensure a smoother, less stressful experience.  The first thing to do is to develop a “Managing Inspections” SOP.  The SOP should clearly state whom to contact when the FDA shows up at the facility.  First notifications should go to the site quality lead and the site operations lead and their backups.  This procedure should also describe a mechanism for alerting the entire facility that an inspector is in the building.  Do not forget to train everyone on this SOP and document that this training occurred.  This training must include the receptionist(s) and/or security personnel as they are typically the first people the inspector will encounter.  This SOP should cover the following topics:
  • Describe how to document FDA requests for information
  • Cover how to handle an Inspector’s request for photographs or video
    • FDA inspectors have the right to take pictures and video even if your SOP states otherwise.
    • Refer to Section 5.3 of the 2014 Investigations Operations Manual
  • Describe a method to respond to FDA requests that are in conflict with your quality procedures. 
  • For example, limited entry into cleanrooms during operations. Inspectors must be escorted at all times.
  • State the hours of operation.  
Developing an inspection readiness team (IRT) will help ensure that all preparation activities are identified and completed.  During the inspection, the IRT’s sole responsibility will be to support the inspection.  It is beneficial to have a cross-functional team with members from groups other than just the quality organization.

Adequate planning is the key to managing a less stressful Inspection.  Therefore, it is important to predetermine which conference room will be allocated for the inspectors and which conference room will be allocated to audit support (AKA “the War room”).  These two rooms should not be located too close to each other.  The War room can get busy and loud at times, especially when SMEs are strategizing an inspector’s request.   The conference room hosting the inspectors should be located away from heavy traffic areas.  Additionally, this room should (preferably) not be too close to the manufacturing floor or QC laboratories.                 

As part of the planning process, pre-determine who will be deemed SMEs and presenters of protocols and deviations.  Providing the opportunity to practice defending SOPs, deviations, trend reports, and validations is a great way to determine which personnel should be tasked with presenting to the inspectors.  More importantly, mock inspections afford the quality manager the opportunity to recognize who should NOT be present.  Presenting material to a regulatory inspector is a skill.  Not everyone has this skill.  Some people get way too nervous or tend to over talk an issue.  So practicing with the SMEs is an important element to successfully completing an inspection.

Not only should the presenters be knowledgeable and confident in the material they are presenting, the building’s interior and exterior should also be inspection-ready.  Think “curb appeal” in real estate terms.  If the outside of the facility appears well-maintained, it does provide some assurance the operation inside is in good condition as well. 

Along the same concept as facility curb appeal is the organization and visual presentation of documents. This is crucial to instilling a positive image to the inspector that cGMP documentation practices are implemented and followed.  Tables of contents and executive summaries are also good methods of organizing protocols and reports.  These documents can be very thick and since the inspector has limited time to review a lot of material, a well- written summary may be all that is reviewed.  Having a package that is complete with supporting documentation also helps the inspector avoid follow up requests for supporting documentation.  If a document such as a deviation or CAPA is referenced in a report, be prepared for that record to be reviewed as well.  Below is an example of a complete documentation package that stands up well to inspection scrutiny:
  • Summary Report
  • Executed Protocol
  • Deviations and Discrepancies
  • Supporting Exhibits
Quality managers should develop a list of “hot topics.”  These topics are the more difficult data packages to defend.  Whether it is a deviation with a justification that no longer seems robust enough or a validation protocol / report that has numerous deviations and discrepancies, every cGMP organization has them.  The key to mitigating risk during an inspection is to be aware of the more difficult conversations and develop a strategy to present and justify the decisions made.  Practicing this during a mock inspection is a good way to gain experience articulating the data and conclusions.

This is much more difficult to do in the moment.  Practicing can make this go more smoothly. 


Managing the Actual Inspection

First, ask the inspectors for their credentials and what type of Inspection is being conducted.  Immediately notify the quality head and operations head and their backups that regulatory inspectors are onsite. 

An important piece of information to obtain in the opening meeting is what type of inspection is being conducted.  This is important to know because an “inspection for cause” will be approached differently than a routine quality system surveillance inspection.  Once the credentials have been presented, escort the inspectors to the predetermined conference room.  Notify the entire site that an Inspection is in progress.  The inspection readiness team should automatically execute the predetermined back room set up plan.  Printers, computers, phones, Inspection request log, runners and scribes will be needed to support the inspection. 

An opening presentation can be delivered; however, keep it brief.  Show the organizational chart, headcount, hours of operation and facility layout.  The inspection will include a facility tour.  This usually occurs on the first day.  Ensure that any housekeeping that can occur prior to this tour happens.  Removing open cardboard boxes or general dust or debris could avoid questions about housekeeping procedures.  Prior to the tour, give the inspector a copy of the facility diagram.  Clearly illustrate personnel and equipment flow.

During the tour, the inspector will take note of equipment numbers and personnel names.  Once the tour is complete, this information will be used to request maintenance, calibration and training records.  All document requests should be logged and delivered to the audit support room.  Give the inspector realistic time frames for request delivery.  If inspectors have to continue asking for a document, they tend to get upset.  So reasonable turn-around times are expected.    

Make sure that each request is clear.  Feel free to ask the inspector to clarify the question or document request.  One inspection technique is to be deliberately vague in order to see what information is provided.  Always answer questions truthfully.  Any appearance of misdirection or dishonesty, intentionally or unintentionally, will certainly turn the inspector in a negative direction.  Always consider the inspector’s reaction when he uncovers the information himself. 

At the conclusion of each day, ask the inspector to debrief on the day’s observations.    Also, this is the time to see what direction the inspection will be going the next day.  This allows the staff time to stay after hours and obtain any documentation needed for the next morning.  It helps the inspection go smoother when documents are prepped and ready to go.  


Inspector Techniques

There are several techniques used by inspectors to obtain additional information during an inspection.  One technique previously discussed was intentional vagueness, so ask clarifying questions to ensure that the request is clearly understood. 

Another Inspection technique is prolonged silence.  People tend to talk more in order to fill the void.  Once the question has been answered, be comfortable sitting in silence until the next question is asked.  It is important to note that an inspector may ask questions about the data or the conclusions in order to hear the justification.  This line of questioning does not automatically mean they disagree with the approach, so defend the decisions made based on the supporting data.

Requesting a large amount of information in a short amount of time can happen.  The goal of this technique is to see how easily retrievable the documentation is, not to actually review all that paperwork. Provide turnaround times that are reasonable. 


Audit Follow Up

The goal of every quality manager is to obtain zero observations from an inspection.  However, if an observation is discovered, respond to the complete finding.  Ensure that all commitments are thoroughly considered and can be implemented in a timely manner.  Any deviations to the commitment that was submitted to the regulatory agency should be justified and communicated in a timely manner.  They understand that plans change, so make sure to communicate the plan. 


Conclusion

Developing and implementing an effective inspection readiness plan will help ensure better results, as well as a less stressful Inspection.  Planning ahead will reduce document turn-around time, improve presentation skills from SMEs and increase inspector confidence in the quality system.  



Kelly Thomas has 18 years of experience in the pharmaceutical, biotech, and medical device industries. Her area of expertise is in developing, implementing and managing all quality assurance and quality control activities impacting cGMP operations. This includes development and implementation of Quality Systems that ensure compliance strategies are consistent with the corporate strategic mission, customer expectations and regulatory requirements.

Ms. Thomas holds a Bachelor of Science in Biology from East Carolina University and a Master's of Business Administration from Meredith College. She also maintains several 
professional certifications from the American Society for Quality (ASQ).







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