There are perennial, overarching questions the pharma industry has regarding FDA, such as:

  • What do they really want?
  • What are their hot button issues?
  • How do we develop a good relationship with them?
  • When we have a serious issue in our manufacturing plant, should we tell FDA about it to get their help and be transparent or just deal with it the best we can ourselves?
  • How do we decide which to do?

After nearly 28 years at FDA—in review, inspection, and compliance positions—David Doleski, now Compliance Head for Biologics Quality Operations at Sanofi, provided his perspectives on the questions posed above as well as his insight into how regulators think during his keynote presentation, “How Perspectives Change: From Regulator to Regulated” at the ISPE Aseptic Conference held in North Bethesda, Maryland, in early March 2020.

In the same presentation, Doleski also discussed the importance of the FDA’s emerging technology programs and the pros and cons of industry participation in them. That discussion is available here.

[RELATED: In addition to building a good relationship with FDA in general, it is also important to know how to interact with drug reviewers. Click here for a Checklist for Interacting with FDA During the Drug Review Process.]

Checklist: Interacting with FDA During Drug Review Process

What Does FDA Want?

In a pharma manufacturing organization, Doleski said, FDA would like to see:

  • A quality mindset
  • An empowered quality organization
  • Good understanding of manufacturing processes
  • Investment and modernization of facilities

Having a quality mindset at manufacturing facilities is extremely important to FDA, Doleski said.

“In particular, there is an emphasis right now on quality culture. Quality culture is clearly a part of the New Inspection Protocol Project (NIPP). FDA investigators are asking about quality culture, knowledge management, continual improvement, management reviews, and quality risk management.”

This “goes beyond the functions of quality” looking at the broad aspects of quality. “What is the quality mindset within the organization? What is the reporting structure for quality? How many resources are available?”

Doleski notes that he has had FDA investigators ask a lot of questions in this area – “things that previously would have surprised me”—for example, asking people in the quality group if they enjoy their job, if they have enough resources to properly do the job, and if they have management support.

FDA wants companies to understand their manufacturing processes well enough to have a level of control and be able to monitor their processes, their equipment, and their facilities. They should be looking for process drift and variations in the manufacturing process and be aware of developing problems over time, he said.

All of this is geared toward FDA pushing companies to invest in their facilities and to continue to modernize their facilities. FDA wants manufacturing sites to continue to improve.

“Investigators will ask what types of monitoring companies are doing of their processes,” Doleski pointed out. For example, they will look at maintenance orders for equipment and the state of environmental control. “All of this is geared toward FDA pushing companies to invest in their facilities and to continue to modernize their facilities. FDA wants manufacturing sites to continue to improve.”

There are a lot of aging facilities across the industry, Doleski said. “FDA wants not only to address the immediate problems with those facilities but to be sure the companies continue to improve their operations.”

FDA Hot Button Issues

“What are some of the things that trigger the FDA?” Doleski asked. “Throughout my time at FDA I have seen that there are issues that tend to antagonize or excite the agency in particular ways. I think you want to be aware of those situations and potentially avoid them.” These include:

  • Companies hiding information regarding problems
  • Revealing a partial story
  • Acceptance of poor quality
  • Defending the indefensible

Companies hiding information regarding problems, he said, “is a big trigger with FDA. There are diligent reviewers who spend time and effort reviewing applications and supplements. They take their jobs very seriously. There are times after the review is completed and approval is granted, they find out there are issues. That is very upsetting to the FDA.”

Similarly, during inspections, an investigator may spend a week or more at a facility, asking hundreds if not thousands of questions related to quality, investigations, deviations, change controls, CAPA (corrective actions, preventive actions). Then the inspection is closed out, potentially with form 483 findings, and some period of time later the agency finds out there was a critical issue at that company that has a severe impact on quality of production that was going on but not known during the course of the inspection.

“What I have noticed—as recently as a few weeks ago—is investigators asking broad questions, such as whether there are any critical issues that exist at the facility. The folks managing the inspection will come to me and ask what the question means. The purpose is they do not want to leave the inspection only to find out there is some critical issue that somehow was not covered during the inspection. As I said, that is a real trigger for FDA. I think it is important to have a level of transparency.”

Related to that is revealing a partial story, also a trigger for the agency. For example, a company has a critical issue and explains it to FDA, but tries to limit it, saying it is bracketed by a period of time for a subset of lots. “FDA then starts asking questions—pulling the string a little—and the problem expands, showing that it is actually bigger. Then more questions are asked, and the scope of the problem increases.”

FDA then starts asking questions—pulling the string a little—and the problem expands, showing that it is actually bigger. Then more questions are asked, and the scope of the problem increases.

Next on the list is acceptance of poor quality or defending the indefensible. For example, there is an ongoing inspection and someone at the company who is really aggressive and is trying hard to avoid a 483, who is pushing back and trying to defend a situation. What happens is the FDA investigator starts to think that there is not a good quality mindset at this company. “If it is clear that a problem exists and the company is not acknowledging it, it triggers FDA. Be mindful of that during an inspection. The way that you present to FDA is important.”

Suggestions for Developing a Good Relationship with FDA

As a starting point in developing a good relationship with FDA, Doleski suggested taking stock of interactions the company has had with FDA over the past few years, including inspections, application review, or meetings with the agency, and try to think about those interactions and any lessons learned. 

Was there any feedback from FDA?

Invest more time or money into a facility

There are times when the FDA will either directly or indirectly say that it thinks a company needs to invest more time or money into improving the state of a manufacturing facility, Doleski said. Perhaps it is an aging facility and it needs some investment. Or maybe during the review of an application, they saw some problems and you received information requests—for example, maybe all the pertinent manufacturing facilities were not listed. He pointed to new guidance that came out last year on this topic, “Identification of Manufacturing Establishments in Applications Submitted to CBER and CDER, Questions and Answers.”

Take stock of the situation and adjust course if necessary

Take stock of the situation and adjust course if necessary, Doleski advised. “If you think the advice or feedback is warranted, try to make the improvements or changes as a way to improve your relationship with FDA. Folks in FDA develop perceptions of companies based on their experiences, based on inspections, meetings, and applications. For every company, they have a mindset and perception of how that company is doing. It is important to be aware of that and adjust course.”

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He also suggested not focusing only on the immediate goal—for example, doing well in an inspection or an application review. Those are important, he said, but there are other issues surrounding those that are also important.

For example, if you have an issue with data integrity controls, it is important to go broadly and make global corrections rather than focus narrowly on a specific, immediate issue. “FDA is always thinking about the level of commitment a company shows to address any given situation.”

Display seriousness appropriate to the situation

Doleski emphasized the significance of displaying seriousness appropriate to the situation. For example, FDA will often have pre-meetings prior to meetings with companies. During a pre-meeting, FDA may ask who the company will be sending to the meeting. They will determine how serious you are regarding the issue by the level of the people representing the company—whether they are senior enough, and whether quality assurance be represented, he said.

“I am aware of meetings in which companies are discussing quality issues, but none of the representatives is from quality assurance. As strange as that sounds, I have seen that type of thing,” Doleski commented.

Do not overplay your cards 

“Do not overplay your cards—for example, in a shortage situation,” he emphasized. “Addressing and mitigating shortages are a high priority for FDA, including working with a company to alleviate the shortage in any way possible. That is an important goal from a public health perspective.”

The former FDA director recounted a situation he was involved in at FDA where companies were utilizing a shortage situation to try to extract some type of concessions —maybe expedited review for an application or some type of special treatment related to a quality situation. “FDA is not going to show what they are thinking or what they are feeling,” he said, “but they will remember.”

Do not diminish real problems for short term gains

“There have been sometimes when a company has overplayed its cards, perhaps exaggerated the situation a bit. FDA are smart folks and they know when this is going on. And it could have a negative impact on a company later on. Even if they work with you during that particular situation, they will certainly remember the details of what happened. It is important to be transparent and accurate. Do not diminish real problems for short term gains.”

Share timelines for products and projects

Lastly, Doleski said that “an easy thing to do” is to share timelines for products and projects. Some companies do this, but not a lot, he said. Some companies will approach FDA and give them a list of upcoming applications for supplements—things that may require a pre-approval inspection. “It is an easy thing to do, and FDA appreciates it, particularly in the biologics realm.”

“I experienced that both on the CBER and CDER side. It helps the agency prioritize and do some planning. This is probably not as important for NDAs. There are so many NDAs and ANDAs that it would not make sense to do this. But for biologics it is good to give the agency some advance notice.”

Proactive Information Sharing with FDA

Another way to develop a positive relationship with FDA is by proactively communicating certain types of situations to the agency—for example, potential product shortages, pervasive contamination of a manufacturing facility, or serious data integrity issues. Doleski said these were areas he saw companies proactively communicate with the agency on when he was there. He addressed the difficulty of deciding when to contact the agency with these kinds of issues and went through the pros and cons of telling or not telling the agency.

Product shortages “is a given,” he said. “If any of you are experiencing product shortages or see them coming, clearly it is important to go to FDA.”

Another situation is systemic contamination of a manufacturing facility—something that is pervasive and is hard to address. “You have been working on it, but it is something that is having impact on a lot of your product lots. That is something you may want to proactively identify FDA about.”

Another example is data integrity issues. That is a broad topic that can be anything from minor lack of controls of systems to much more serious situations involving product release testing. “If you find something that is more on the serious end of that spectrum—for example, a data integrity issue with testing that is performed for lot release—it may be a good idea to approach FDA,” Doleski advised.

‘If you find something that is more on the serious end of that spectrum—for example, a data integrity issue with testing that is performed for lot release—it may be a good idea to approach FDA,’ Doleski advised.

“I realize that this potentially is a huge issue that companies would not take lightly,” he said. “In some ways, you do not want to divulge some of your problems with a regulator. But I think it is worthwhile considering. I can say that more than a few companies have done this. Throughout my years at FDA, there were several companies that came forward to proactively notify us on serious problems they were having.”

Acknowledging that sharing some information is a big decision, Doleski discussed some of the advantages and disadvantages of sharing information.

What are the advantages of not telling FDA?

What are the advantages of not telling FDA? If you have a major problem and do not tell the agency, maybe they will never discover it. You can deal with it on your own terms. You can resolve it and hopefully everything will be good.

On the other hand, what would happen if you had a major problem with data integrity or contamination and FDA comes in, performs an inspection, and finds the problem. In that case, they are going to be aggressive with the inspection and with the 483.

“There could potentially be some kind of advisory action or warning letter or enforcement action. That can be very damaging. That is a risk. And you are living with the anxiety of thinking about when the agency will come and living with anticipation and dread of that situation being discovered.”

What if you proactively went to FDA and let them know about one of these situations?

What if you proactively went to FDA and let them know about one of these situations? “First, FDA would be very appreciative of the level of transparency, which creates a relatively more positive view of your company. They appreciate knowing about it.

And for you it is a good idea because you can frame the situation on your own terms. You can describe the situation, what investigation you have done and what corrective actions are underway. It allows you to control the message.”

Also, if FDA does decide to initiate an inspection to learn more about this, “the nature of the inspection will be different. If FDA already knows you have a situation because you have disclosed it to them, I think the tone and tenor of the inspection will be different.”

By letting them know before the inspection, you have taken away the psychological part of inspections where the investigator discovers something on their own and begins pulling that thread.

“Sure, they are going to look at the extent of the investigation and the extent of the corrective actions to make sure that everything that can be done is being done. But the tone is more confirmatory, to ensure that you have done all that you can do. By letting them know before the inspection, you have taken away the psychological part of inspections where the investigator discovers something on their own and begins pulling that thread.”

He noted that he has seen this from both the FDA side and industry side. “Since I have been in industry, we had a situation that we took to the agency and the outcome was very good,” he said. “It was well under control. We were dealing with it with a thorough investigation and escalation and a lot of corrective actions put in place. It can be a positive thing.”

What are the disadvantages of going to FDA? 

What are the disadvantages of going to FDA? You are potentially triggering an inspection sooner than one might have taken place. And then there is the time and effort to come up with a presentation to work through the talking points with FDA. It is a bit awkward to disclose some of your problems with FDA, Doleski commented.

“But overall, I would say if you have this type of situation, first, have an extremely aggressive response within your company. Do a thorough investigation and come up with corrective actions and inform the regulators. That is what I would recommend,” he said.

A Deeper Dive on Data Integrity

Doleski characterized data integrity as a “huge issue” with FDA. He described some of the history from his perspective when he was at the agency and provided some pointers on where to look in a pharma manufacturing firm for data integrity issues.

Over time there has been a waxing and waning of the interest in data integrity, he said. “When I was starting at the agency, there were a lot of issues with generic drugs. A lot of companies had falsified information. There were FDA inspections discovering falsification of data. Application reviews were being frozen under the Application Integrity Policy. Several applications were withdrawn. There were criminal prosecutions. There were a lot of serious issues with data integrity.”

After a while, that began to resolve, and it was no longer a prominent issue for many years, Doleski pointed out. Then over the past ten years the interest has ramped up again. FDA has developed a renewed interest and began doing data integrity audits. FDA investigators have had a lot of training in this area.

“When I was at FDA, there was a bit of frustration in that investigators were not well-equipped to perform data integrity audits. The agency subsequently invested a lot of time and money bringing in external experts and developing internal ones. Investigation techniques were shared. The level of awareness and the skill and capability of the investigators has really increased over time. It seems like the more they look, the more they find. There are quite a few warning letters mentioning data integrity issues.”

Data Integrity Audit Questions to Ask

As part of a data integrity audit in a pharma manufacturing facility, Doleski recommended some of the areas and systems that should be assessed, and questions to ask:

  • What are the levels of access to computer systems and are they appropriate? For example, you do not want to have a user with administrative access.
  • Are the audit trails—for example, on chromatography data system instruments—enabled? They should be.
  • Is there a routine review of the audit trails? There should be.
  • With what frequency do you back up data? Are there any vulnerabilities in the time that data goes from a local computer to a server? How is that data protected?

Many companies have been working on this for a long time and are in good shape, he said. At the same time, there are still vulnerabilities. “We are not 100%. I know this through talking with a lot of my colleagues in industry. There are still some gaps that exist. I would recommend looking through your gap assessment related to computerized systems and continue to work on this.”

This is a focus of the New Inspection Protocol Project, or NIPP. There are explicit objectives related to data integrity. So, looking for data integrity issues is becoming more consistent in the FDA inspection approach. All investigators will be looking at data integrity controls. (Read more on NIPP here.)

“If you are in a compliance role or in quality assurance or in a leadership role at a site, I would recommend having this as one of your top priorities,” Doleski concluded.

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