Video & Article: How To Handle Regulatory Authority Warning Letters

The second online seminar in the First Wednesday series looks at what you need to do after receiving a warning letter from a regulatory authority, such as the U.S. FDA. This edited transcript looks at:

• Best practice in your GMP remediation program
• The warning letter
• Inspection readiness
• Managing difficult questions

The period after an FDA inspection can be a time of joy or pain. However, if your FDA Form 483 is lengthy, you can assume that you will receive an FDA warning letter.

In baseball parlance, an FDA warning letter feels like strike two. The good news is that it is something you can recover from, so you can avoid strike three and out. This online seminar will highlight how to respond properly, thoroughly, and professionally to the issues highlighted in the warning letter. We will look at the typical life cycle when you receive a warning letter and the types of warning letters. We will also discuss the immediate actions to take after the inspection and before receiving the warning letter.

Receiving an FDA 483 in a final meeting is tough for any company to experience. It can demoralize people. The first reactions, in our experience, vary wildly: Disbelief, blame, denial and disappointment abound.

As people move away from disbelief, denial, and anger, we often find a period of stasis. They do not know what to do. They have a sense of shock. They know there is now not just a facility to run and customers to service; there is a GMP remediation program, or business transformation program, needed. That can sometimes overwhelm companies, and this period of stasis can be troublesome. You must move from stasis to acceptance as quickly as possible and be objective and open in your communications. Then it would be best if you started assembling a team of subject matter experts. What is important at this stage is to build a team with diverse experiences to help ensure that all the warning letter issues are dealt with comprehensively.

Companies often utilize their corporate QA teams and independent GMP consultants (such as NSF). However, the subject matter experts must own the response to this crisis.

Engaging with the FDA is a crucial step in confronting the issue. This meeting needs to show the agency that your company is committed to addressing the GMP concerns in full. A face-to-face meeting with the FDA can be useful in assuring them that your company is utilizing the right resources and that your glide path of GMP compliance is credible.

We always advise companies at this stage to sit with a corporate QA expert or an independent reviewer to make sure they are achieving what they set out to do. This is a critical step many companies fail to take, but it can give them peace of mind so they can welcome the FDA back for a reinspection.

The first type is the general warning letter. In a general warning letter, companies have listed against them some significant violations of the cGMPs, which are related primarily to other systemic or repeat issues, and to issues that undermine their ability to make a properly branded product that is free from adulteration. If a warning letter is required in this situation, you know you will have to respond to the FDA 483 report and the warning letter that is coming. A point to note here is that the FDA is not required to issue a warning letter if enforcement action, such as a consent decree, is needed.

However, they will provide a warning letter as a precursor to that market action in most cases. The other warning letter comes from either inaccurate or misleading marketing and advertising claims; however, today we will focus on the general warning letter for pharmaceutical facilities. Once you have sight of your GMP deficiency, either during or after the FDA inspection, the first thing you want to be sure about is: Does your team have the GMP knowledge to tackle this issue?

• Do they realize that this issue is a cGMP violation?
• Do they understand what “GMP compliance” and “best practice” looks like?

Often, companies will do a detailed review of the expertise and experience within the team to make sure they understand the issue correctly. Secondly, it is important to make sure you can properly define the problem.

Ensuring that you understand the true root causes of each GMP violation is important. If you can recognize all the steps that led to that GMP violation — all the contributions from engineering, QC, microbiology, operations, production, and QA — you will have a much better idea of how to resolve it. It is worth taking the time to fully understand how you got here, why you got here and the scale of the issue causing so much concern with the FDA.

Once you have an idea of root causes, you can structure a CAPA plan. The preventative nature of the CAPA plan is essential in eliminating or minimizing the degree of recurrence and making any violation much easier to detect. The CAPA plan should also reduce severity and frequency and improve detectability. That aligns nicely with ICH Q9 quality risk management.

When the inspectors have left the facility, you need to assemble your cross-functional team of experts from various groups: engineering, QC, facilities development, corporate quality groups, and (possibly) clients or license holders. It is especially important to make sure everybody knows what has happened. At a time like this, transparency is critical, and people need to commit to ensuring that work gets done and issues get sorted out. Often, particularly if the FDA 483 is lengthy, you are under pressure to achieve.

You only have 15 business days to write a detailed written response and get back to the FDA. Then there is a very intense period in which you designate an owner for each observation. You will need to investigate the observation and propose some CAPA plans with realistic and credible target completion dates. You will need to assess the impact on patient safety and product quality against every single violation so that you are sure each CAPA is addressing the issue in full.

In our experience at NSF, we find that companies will put together a project team that will have daily meetings to get this response together. Our experience has shown us that having an efficient meeting secretary/note taker will add value by helping ensure that actions are followed up on. Often, an emergency remediation budget is needed, and therefore the finance department must be in the loop to see that the project is supported effectively.

What should you include in your response when you write back to the FDA?

• Did you fully understand the finding and seek out the true root causes? It is important to consider all the root causes and even consider human error factors and what significant impact human error may have had on your GMP violation. So that, for example, you’re thinking very hard not just about upgrading master manufacturing records or SOPs or GMP records, but also about training, competency, proficiency testing, quality, culture, quality mindset, management style and ensuring that whatever you’ve done to fix the issue will keep it fixed for the long term.
• Did you respond to all the findings? It is amazing how many times we check people’s responses and discover that there are errors or omissions.

A very good tip, particularly if you are a quality director of a network of facilities, is to make sure you share your FDA 483 report and your responses with all the other relevant facilities in your network so that they can benefit from this. They can put their own CAPA plan in place ahead of their GMP inspection from the FDA.

We have seen this from various sources on the internet through freedom of information. One facility in a network suffers from some GMP violations, and the FDA gives them a warning letter. Then the agency moves on to the next facility in the network and the next and finds repeated issues. This repeat violation highlights a dysfunctional corporate quality and knowledge management system across the network. You must also see if the issues are systemic across your complete network and then respond accordingly.

Often, firms can feel somewhat overwhelmed with all these tasks. You must be sure that they are in the right order in a project plan, that they are realistic and that all of the relationships between the tasks are properly defined so that you are doing everything well just once without wasting time reworking solutions. Having a detailed project plan and using some project management tools, such as GANTT charts, can be extremely helpful.

It is acceptable, in exceptional circumstances, to add into your response a challenge to the findings in your Form 483. This is an opportunity to demonstrate how you feel that the finding may or may not be a fair reflection of reality. The next step is to show that you have undertaken a detailed further review across the site and other systems and have looked to see where else the problem might lie. Here you need to explain to the agency that you have defined, I, at what point the issue started and at what point the issue ended.

This is called bracketing. You must be certain that everything outside that bracket is unaffected by the observation. Everything within that bracket must be addressed and resolved in full. Of course, the agency expects you to give details of the root causes, the product impact, and the patient safety impact, ensuring that you set your CAPA to help prevent recurrence or severity or make the issue more detectable. The next stage of the response is to demonstrate what you did to contain the issue immediately. Finally, you need to prove that you have verified that the CAPA has prevented the reoccurrence of the issue.

• How is this affecting me?
• Am I going to be on import alert?
• Are my products going to be frozen at the dock?
• Am I allowed to release any more products?
• How is this going to affect the supply of my product?
• Is this going to cause a drug shortage within the territories we supply?

You need to notify your investors and finance professionals because the warning letter is a very visible and accessible document often easily identified through freedom of information. Furthermore, at a time like this, companies will need to consider the cost of a GMP remediation program and, potentially, the impact of that warning letter on their stock.

Nevertheless, you must take the time to read the warning letter in detail to help ensure that you understand everything outlined within it.

U.S.-based companies need to be aware that any license applications the FDA would have reviewed will not be approved until they are proven to comply. Typically, when we measure our lead times or program times for a GMP remediation program, they are measured in months. Often, they can take up to 24 months. That time frame aligns with a visit from an FDA inspector to ensure that your facility has returned to compliance.

If you are a foreign company sending products into the U.S. market overseas, your products will be placed under an import alert. The FDA will assess whether those impacts are also appropriate and relevant to the other products you supply. Having your products on import alert, potentially for up to 24 months, can significantly impact your facility.

• Did we respond to all the findings?
• Did we look at them holistically?
• Did we look at them as a systemic problem?
• Did we look at the other sites in the network?
• Did we provide time frames that are realistic, credible, and based on good science and good program management?
• Did we provide in the cover letter to the FDA some assurance that the corporate and senior management of our organization acknowledge and take this issue very seriously and are willing to resource properly or budget for the types of changes and transformation that are required?

The FDA expects to see a written commitment from your senior management in that cover letter that they are engaged in this and are willing to address it. Of course, it makes perfect sense to request a meeting with the FDA to be able to lay out your intent to fix the issues.

It is important to be completely transparent and unambiguous about the issues. You must have an open-book process with the FDA to enable everybody to make the right decisions for the right reasons. Remember that you will be expected to provide quarterly updates to the FDA. In some cases, these could be as frequent as monthly.

Everybody on your team needs to understand the impact of the warning letter on the organization. Individuals need to understand the effect it can have on their employment and the priorities they might have for the near future. Everybody needs to play their part in remediating the issue, and everybody needs to own it. It is important to be realistic about the workload people can take on.

Make sure everything you do can be proven. When you generate your CAPA plan and your body-of-evidence folder, which explains what you did and what evidence you’ve provided for each task, make sure you have something you can show that proves the transformation you’ve made.

The body-of-evidence folder needs to show the changes made, demonstrate that they comply with the Code of Federal Regulations or cGMP, and illustrate that the changes are in effect.

Are the operators adhering to the change? Are the analysts? Does everybody understand it? Can you verify that the improvement you made is in use? And then, of course, the last thing is to verify that the tasks you completed work in practice.

Focus on the concerns raised by the FDA. Yet this is also an opportunity to be expansive and consider the totality of what happens in the facility, and to bring into the fold people who may not previously have been in the spotlight in your business. These unsung staff members could in this instance prove to be pivotal members of the team.

NSF expert Maxine Fritz, herself a former FDA inspector, says that companies need the right culture and the right set of communication methods, and that teams need to collaborate up and down the organization.

Taking inspiration from Maxine Fritz’s observations, you need to ask:

• Do you have the right people in the right positions, at the right levels, at the right stages in their careers?
• Do you have the expertise and experience to communicate key information and risks in a way management can act on?

Collaboration will be essential, and building these professional relationships is important. There must be a degree of trust within your organization, but there also must be a degree of verification. If someone checks to make sure one of their colleagues has done something to a standard it should be done to, that is not a terrible thing. Why? Because they are looking out for their colleague by supporting and coaching them while carrying out the check.

Verification is good, but once verification shows that a process or a facility is in good order, you can begin to develop the levels of trust you need in an organization for decisions to be made quickly. The balance between trust and verification is especially important because everybody wants to run facilities, create revenue and make products for patients, and we want to foster ways of working that are enduring and that work for all. So when you think of a remediation plan, also consider the chain of risk.

The uppermost priority in all of this is patient safety, because you must help ensure that the risks associated with products, adulteration and misbranding are minimized. Your first thought on seeing the FDA 483 nonconformance should be: Is this issue leading to either product adulteration or product misbranding? If not, was the issue in contravention of our product license or in noncompliance with the pharmaceutical compendia? Or did we fail to comply with the quality technical agreement with our clients?

As you go through your remediation program, you should begin to think about getting ready for reinspection. A reinspection might take place anywhere from nine to 24 months after your warning letter. The evidence file, as referenced earlier, should show the FDA exactly what has been done to remedy the identified problems.

However, suppose there was a litany of small GMP issues and nonconformances in your FDA 483, pointing to a dysfunctional internal audit program. In that case, you need to consider why these were not identified before the FDA inspection. Internal auditors should have identified them. It might be the right time to set up a proficiency test if they were not. Likewise, problems around deviation investigation, customer complaints and out-of-specification results may point to shortcomings in the skills of the company’s investigation team. Again, this might present a chance to evaluate proficiency. In both instances, shortcomings could be addressed by relevant training.

Many companies opt for a mock inspection before having the FDA come back on-site. The benefit of a mock inspection with ex-regulators and industry experts is that their report gives you time to address any last-minute issues before the FDA returns.

On the day of the FDA meeting, be careful that you do not undermine all the good work you have done by trying to defend something that is just not defendable. Be focused on the three Cs. Like Maxine Fritz often tells us, company culture, communication and collaboration are key. Verify the effectiveness of those commitments and get yourself ready for reinspection.

If you need assistance with a project like this, NSF would be delighted to advise you. We collaborate with companies worldwide to help ensure that they are completing their remediation projects in a timely and effective manner. We also assist them with mock inspections before their reinspection by the FDA. Contact us today by completing the form below if you would like to start a conversation with us about any of the issues in this article.