PMs- How to Prepare for a Foreign FDA Audit During the COVID 19 Pandemic - Case Study

Every aspect of our lives is being affected by the COVID-19 global pandemic. The pharmaceutical industry is working hard to adapt to the new world order. It provides effective vaccines at the speed required to fight the international threat. The FDA was one of the first to announce that it would delay on-site inspections in 2021. However, the industry is working hard to provide effective vaccines at the speed needed to combat the international threat. It also reorganizes its business models to ensure that other medicines continue reaching patients in need. In the interim, information in inspection applications will determine if a foreign manufacturing facility can safely and adequately produce a drug product.

There is still so much to learn about COVID-19. This includes whether or not we will go back to pre-COVID days, or if we should be preparing for a new future where we live in a mix of both. It is also important to understand what regulators expect from you during this time. Also, how you can facilitate paper-based inspections instead of having to visit the site. It could make the difference between a successful audit or questions and concerns from regulators that cause costly delays to your program timeline.

What is "Mission Critical"? And What Does it Mean for Domestic Locations Versus Foreign Locations.

The FDA's guidance on COVID-19 inspections describes the criteria and rating system used to determine an "Advisory Level" for areas where prioritized domestic inspections (which generally includes surveillance and pre-approval inspections) are required. This advisory levels outlines the regulatory activities that can be carried out within the geographic area. The guidance states that there are major categories of regulatory activities that can be performed for priority domestic inspections.

Only mission-critical inspections

All inspections are subject to caveats in order to protect staff members who self-identify as being in a vulnerable group.

If a site is approved only for mission critical inspections, the agency will review each application individually to determine if a product meets that threshold. The criteria are based on "public health benefits" for U.S. citizens having access to the product. These include, but not limited to, whether products have been given breakthrough therapy or regenerative medicine advanced treatment designations, or if they are used to diagnose, treat or prevent serious diseases or conditions for which there is no alternative. Domestic drug manufacturers will need to prepare for an inspection on the spot just like they would normally, and take into consideration any safety precautions necessary to protect all parties.

Foreign locations will be subject to the same criteria as domestic. However, foreign mission critical inspections are the only ones that are required for pre-approval or for-cause inspection assignments. Each case is being evaluated individually. All other inspections will be temporarily canceled if this happens. What happens if your product does not meet mission-critical requirements and is not located in the U.S. These situations will require the agency to use all available tools and information to support regulatory decisions and make next steps based upon the information. They will provide a date for inspection of the facility if they determine that an application requires it. The FDA will issue a CRL if it is not safe to travel into the facility after the "action date". If the FDA is unable to decide whether the facility is acceptable, they may delay action. They will contact the applicant in these cases. 3

In either case, insufficient information could cause delays. Due to the unpredictable rise or fall of COVID-19 cases around the world, it could take months, if not years, before your area is safe enough for travel. This is a race to the market, where every second counts. Particularly for emerging and small drug companies that depend on investors funding to reach program milestones, this is time you can't afford to lose. It is important to understand how to prepare for an email-based paper-based audit. This will help you avoid any surprises and ensure that your interactions with FDA go as smoothly as possible.

What is the difference between a paper-based review and an on-site inspection?

Before COVID-19 restrictions were implemented, an FDA request was made for an inspection on-site. You then work with them in order to schedule a visit. This is usually around a month later for foreign inspection. This type of inspection does not require an agenda. Therefore, you must be ready to provide all records as soon as possible. Auditors do not like to wait long to receive requested documents. The audit must be managed by a designated team. An individual from regulatory assurance and quality should form an audit team to review the initial draft. You can also contact the agency to ask. You can find many useful documents and presentations online to help you prepare.

The FDA may send you a Pre-Inspection Records request (Form 4003) at this time. This is according to the FDA staff manual Guide 9004.1: Policy & Procedures for Requesting Records in Advance or In Lieu Of a Drug Inspection. The Federal Food, Drug, and Cosmetic Act states that if a company refuses, delays, or limits the results of a drug inspection, it will be deemed adulterated and may not allow the company to sell the product in the U.S. 6

The FDA may request many documents with this form. They are most commonly reviewed during an on-site inspection to assess facility GMP compliance. These documents can be requested again once they have been on-site (if deemed necessary). One example is the site master file. These forms are requested by the FDA. You have more time to prepare them, but your audit team should review them as if they were onsite.

You can expect that they will request proprietary information. Although you might feel uncomfortable about disclosing confidential information, remember that you are working alongside an organization that is just as concerned with the safety and integrity your product or process as you are. They will take all precautions necessary to protect your data. 5 Depending on the file size, the documentation can be sent by email. If either the manufacturer or the FDA has security concerns about the information being sent via email, the manufacturer would need to send a request to [email protected] for a license to send the information to the FDA in an encrypted message.

Preparing Information For A Paper-Based In Lieu of Inspection

The critical aspect of the paper-based review process is how you present the information in response to Form 4003. It is important to present the information in a clear and understandable manner. All documentation should be reviewed by the relevant SMEs to ensure accuracy and clarity. Be aware of differences in translations and the potential for confusion. A PowerPoint presentation can also be used to present the site master file in a summary and give an overview of the specific information within the file. Answer the questions in Form 4003 with exact detail. There could be confusion if they request too much or too little information. You can use the form to reference your presentation and highlight each piece of information they requested. Also, point out where it is located in the site master files.

The FDA may request information such as your organization chart, contact details, description of your establishment, size and other pertinent information. You can also break down each piece of information in your presentation by page number. You can give them more information on a particular standard operating procedure (SOP) if they ask. However, you should not just refer to the SOP. Instead, point out exactly where the answer is located in the procedure. This not only provides a checklist for inspectors to assist in what can be a slow and tedious task but also shows that you are ready to put the effort in to make it right the first time.

If you're a domestic manufacturer who works with a CDMO having facilities overseas, make sure to ask how they prepare for inspections under the COVID-19 restrictions. If they make mistakes in providing information about the manufacturing facility, it could lead to costly delays or even shutdowns. They should provide complete transparency throughout this process, including virtual access such as videos so that you can see how their facility and team are functioning.

We are all in this together

A paper-based review can be very different from a paper-based one. There is no personal interaction with FDA investigators, chemistry, microbiology and process/facility experts, so you should prepare accordingly. You and your subject matter specialists can give and explain details as the audit progresses on-site. It is a great advantage to be able look at someone and read their body language in any human-to–human interaction. This holds true for FDA inspections (for both the manufacturer and the investigator). It is possible to determine when someone is unhappy or confused by their facial expressions. It is possible that the recipient of documents sent via email may not understand the intended meaning. They may also make incorrect conclusions if they don't have the opportunity to interact with the receiver as they review it. You must avoid any misinterpretation of paper-based inspections that are conducted in lieu on-site.

It is important to also consider how the FDA investigators will manage this transition. They could do evaluations in their own cases, which allowed them to look at paperwork, inspect the facility and pose questions. They now have to go through multiple emails in order to view facility information such as SOPs and batch records on a computer screen. They will have to go through a lot of paperwork if they print the materials. This can lead to them having to do so quickly in order to avoid delays in delivering medication to patients around the world. A lack of organization could be disastrous, given the amount of information required to assess your facility's compliance with cGMP. A frustrated investigator could become overwhelmed and cause delays, frustration, and questions on both sides. An investigator may suspect that you are hiding something if you fail to prepare or delay in delivering materials.

Additionally, although immediate feedback can be provided during an on-site inspection, it is not common for paper-based evaluations to provide sufficient information. A reply could take several weeks. You must show patience and respond to their requests in a timely fashion. You may have additional questions or they might decide that an inspection on-site is required. One company's experience was that the requested information on Form 4003 was received promptly, but our team didn't receive a response for more than a month. This Sponsor was quick to comply with additional requests made by FDA. After submitting FDA Form 4003a, the agency confirmed receipt of records within a few days. This does not mean that the agency has received the records, but it does confirm that the records were received. If one has been produced, you can ask FDA for the Establishment Inspection Report.

While this may mean more work for you, remember that the FDA's workload is increasing. We are all stakeholders in the success and well-being of the pharmaceutical industry, but more importantly, we are all in it together. Therefore, it is important that we all do our part to reduce frustrations and misunderstandings that can further complicate an already complicated part of the compliance assessment process.

Conclusion

Some of the COVID-19-related changes in inspection techniques will likely be continued after normal operations resume. Remote records access for company audit, regulatory inspections and video will still be available. We will need to adapt to these new technologies and find ways to make auditors and virtual auditors more comfortable in an ever-evolving environment.