Imagine for a moment that this is your current situation…
You receive a frantic call from the receptionist at your facility. An Investigator from the Food and Drug Administration (FDA) has just arrived to inspect the site.
Now take a moment to think about the circumstances…
You knew it was a matter of time before an unannounced inspection occurred. Are you prepared? Will the Investigator's arrival cause panic, turning your firm's experience into a chaotic one, or have you appropriately prepared?
Whether it is for the approval of a new drug (announced) or a routine inspection (unannounced), an FDA inspection should not be too painful. Ensuring that any regulatory inspection is a positive experience starts with preparation and continues by creating a culture of compliance throughout the firm. Ongoing preparation and frequent inspection readiness practice are key to this continued culture of compliance.
Culture of Compliance
When it comes to preparing for an FDA inspection, the rubric "practice makes perfect" does not apply alone. It's a combination of practice and preparation that makes the difference. An organization that is routinely successful in FDA inspections incorporates all aspects of compliance into its company culture and has leadership that supports this culture daily.
As any company in this industry knows, living a life of cultural compliance provides the foundation for a successful FDA inspection. The likelihood that a firm will be successful during an FDA inspection diminishes greatly in companies where compliance is not a priority or not a daily practice. Although it is possible that an organization could get through one or two inspections in such a way, it is not likely to succeed in the long run if its day-to-day culture doesn't demand compliance.
A culture of compliance is also exemplified by knowing your job and doing it correctly each and every time. This is true for general compliance but also in preparation for inspections.
- Follow SOPs. If they are not correct or not clear, fix them.
- Remediate issues before they become inspection observations.
- Conducting routine walk-throughs of the facility is also beneficial in more ways than one. Look at the facility, whether it is the GMP portion of the facility or not, through the eyes of an Investigator will help set your firm up for success.
Inspection Preparedness
Does your firm have Standard Operating Procedures (SOPs) governing how to handle regulatory inspections? The answer should be, "Yes, there are procedures governing regulatory inspections, and all site personnel receive training on these procedures." Individuals who are most likely to interact with an FDA Investigator require more detailed training on the regulatory inspection process and appropriate interviewing skills, but it is also important that everyone on site understands what happens when an Investigator arrives for an inspection, including who should be contacted and how to interact with the Investigator.
The initial interaction with site personnel sets the tone for the rest of the inspection. An Investigator notices personnel who are confident in what they are expected to do, react calmly to the Investigator's arrival, and follow the site's procedure for handling an inspection. This illustrates that the site takes the inspection seriously and knows how to handle it. Demonstrating control and preparedness indicates that compliance is an ongoing management priority.
Your firm should have an Inspection Management Team (IMT) to handle all regulatory inspections. If you are a virtual firm, does your Contract Development and Manufacturing Organization (CDMO) have a dedicated IMT? If the answer is no, you should be concerned about the CDMO's ability to handle an inspection successfully.
The IMT should be comprised of individuals from several different functional areas. Each individual's roles and responsibilities should be documented (formally or informally), and the individuals should be trained and tested on their responsibilities. In addition, having a well-developed internal audit program is also a useful inspection readiness tool.
Members of IMT should include, but are not limited to:
- Inspection Lead (Typically the Site Head of Quality)
- Inspection Hosts (Front, Inspection Room) dedicated to each Investigator
- Audit Control Room (War Room) Leader (Typically QA Director or Manager)
- Subject Matter Experts (SME)
- Scribes (Note Takers)
- Runners (Escorts)
- Document Request Coordinator
- Administrative Personnel
Subject Matter Experts
One of the most critical members of the IMT is the Subject Matter Expert (SME). SMEs must be identified and selected based on their ability to completely and clearly answer questions from an Investigator on specific topics. It is important that they are not selected based on the length of time they have been at the facility or whether they are the department head.
SMEs must be knowledgeable, first and foremost. SMEs must answer concisely, confidently and intelligently, providing only the information requested. SMEs should also be well versed in answering questions about specific systems, issues, or challenges at the site, should the investigator ask them. Appropriately addressing challenges and risks at the facility is critical to a successful inspection.
The SME must also perform well in stressful situations. How will they handle a question they do not know the answer to? Will they make up an answer that they think the Investigator wants to hear? Or will they direct the question to the appropriate SME? It is important for the SME to realize that if they cannot answer a question that the Investigator asks, they must respond appropriately. In this type of situation, the SME should simply state that they are unsure of the answer but will either get the appropriate answer and provide it or find the individual who is able to answer the question.
Furthermore, Investigator questions should be answered using the facility's SOPs or appropriate documentation and data such as a report, a batch record, etc. A typical response would be, "I am unsure at this time, but I will verify that in the SOPs and provide an answer shortly." This shows that the SME understands how to use the SOPs, as well as their content and purpose.
Regardless of the criteria used to select SMEs, a firm does not want to choose the person that tends to say too much, volunteer information that wasn't asked for, complain constantly, lays blame, and/or does not act confidently and professionally when interacting with an Investigator. SMEs should be trained regularly, using simulated or mock inspections, to ensure they are ready for an actual inspection at a moment's notice.
Conducting Mock Inspections
It is essential that a War Room or Coordination Room, where all of the request responses are prepared and where the SMEs are prepared, be used efficiently to manage the inspection process. This is practiced by conducting several mock inspections in preparation. The War Room Coordinator must be someone familiar with all aspects of the site, organized, and good at documenting requests for information, data, procedures, documents, and other items that may be requested by the investigator.
It is important to test the War Room with a significant number of requests to prepare the team for the stress and volume of requests received during an inspection. In addition, it is critical to ensure that the documents going into the Inspection Room are correct, contain only the information requested, identify potential themes or the direction the Investigator is taking the inspection, and prepare for the next day.
The War Room Coordinator must maintain an accurate log of all requested items. Whether this is done electronically or paper-based, the War Room Coordinator must ensure copies are made of responses and are filed electronically in the request software used or are filed physically in an inspection binder, for example. Hence, it is clear what items were requested and what was provided. It is not uncommon for the same document to be asked more than once during an FDA inspection, especially if more than one FDA Investigator is involved. Handling a mock inspection the same way as an FDA inspection is a must.
Daily Inspection Close-Out and Next Day Preparation
Even when the Investigator leaves for the day, the inspection day is not complete. Once the Investigator(s) have indicated that they are getting ready to wrap things up for the day, the firm's management should request a daily close-out of the inspection. Items to focus on during these daily close outs, or request additional information on, include:
- Any potential concerns the Investigator has to date
- Items the Investigator desires to review or discuss upon their return to the facility
- Verification that everything that was requested to date has been provided
- Next day's logistics such as start and end times, potential tours, topics for review, etc.
If the Investigator mentions any potential concerns, the firm should work to address and correct the issue before the Investigator(s) return, if possible. If a quick fix is not possible, it is important not to rush corrective actions that may cause additional harm or non-compliance. If a quick fix is not possible, a Change Control, a CAPA, or a Deviation may be more appropriate.
Documents supporting any actions taken while the Investigator is gone should be reviewed and staged so they can be provided immediately upon the Investigator's return to site. Asking about items for discussion allows the firm to stage and review documents that might be requested, prepare SMEs for any discussion or questions, and provide the Investigator with information quickly, as it is asked for.
Verifying there are no outstanding requests allows the firm's inspection team to confirm what was provided and file or store documents that are no longer needed. The firm should also determine if the documents remaining in the Inspection Room are still needed and, if not, that they are immediately removed and refiled.
Successful Conclusion of an FDA Inspection
Hopefully, no substantial issues will be identified, and the Investigator will not issue a FDA Form 483 upon the inspection's completion. During the closeout, it is important to listen to everything the Investigator says regarding any observations and begin working to address them immediately.
If the firm believes any of the information contains errors, it is acceptable to ask for clarification of the observations; but it is not recommended that firms attempt to argue about the validity of the observations during the closeout. Instead, firms are advised to wait until the Form 483 is received, at which point they can compile a response that fully addresses each observation identified. Any applicable documentation or evidence regarding how the issues were addressed should be included in the response.
It is crucial that the response indicates what attachments apply to what observation. This can be done by linking the two items in an index. Firms should submit a response via certified mail within 15 business days of receipt of Form 483.
Should the FDA accept the response, the firm should receive the Establishment Inspection Report (EIR) upon closure. Receiving the EIR is official confirmation that the FDA has accepted the firm's response and agrees that the firm took the appropriate actions. The EIR is a valuable tool often overlooked when preparing for an FDA Inspection. It provides significant details regarding:
- What the Investigator(s) reviewed
- Concerns or questions they might have had that did not result in an observation
- Discussions about any refusals a firm might have received regarding providing information requested by the Investigator
The EIR should be filed with the response and reviewed as part of the inspection readiness program for the next inspection.
Get Expert Guidance to Stay FDA Compliant
Successful regulatory inspections do not just happen, they require a company culture built on sustaining compliance, significant training and preparation, and flawless execution during the inspection. Most firms have challenges or issues of some type. It is how they are handled and addressed during an inspection that can be the difference between a successful inspection and enforcement activity taken by the FDA or other regulatory agencies.
If your inspection yields a significant number of observations, or the observations are critical in nature, it is best to seek assistance from an outside firm specializing in quality and compliance issues.
Seeking support from a third party also indicates to the FDA that you take the issues seriously and are committed to addressing them in a timely fashion. Should your organization find yourselves in this position now or in the future, contact us right away, we can help.
Does your firm need assistance in preparing for an FDA or other regulatory agency inspection? ProPharma Group can help with GMP audits, Inspection Readiness, and beyond. Contact us today to learn how.
