FDA has halted most in-person manufacturing facility inspections during the COVID-19 pandemic, but some physical inspections are still being performed—for example, for-cause inspections where the public health could be at risk or pre-approval inspections for important new therapies. FDA can also perform virtual inspections or those based on records review.
How is the agency deciding which firms to inspect? What is the chance that your firm will be inspected?
In mid-June, the law firm Arnold & Porter sponsored a webinar, “FDA Inspection Alternatives During the COVID-19 Pandemic: Requesting, Preparing for and Responding to FDA Virtual Inspections,” featuring two speakers formerly with FDA, Howard Sklamberg and Ricki A. Chase.
Sklamberg is a partner at Arnold & Porter who spent seven years at FDA, most recently as Deputy Commissioner for Global Regulatory Operations and Policy when he left the agency for private practice three years ago. Ricki A. Chase is Executive Director, Compliance at Lachman Consultant Services, and spent 16 years with FDA, most recently as Director, Investigations Branch in Chicago before joining Lachman four years ago.
Sklamberg spoke about the current FDA inspection landscape and Chase addressed how firms can prepare for virtual inspections.
This article will be published in four parts:
Part 1: Sklamberg’s review of the current inspection landscape and what may trigger an inspection
Part 2: A review of a state-of-the-art virtual inspection platform using mixed reality technology developed by Thermo Fisher Scientific discussed at the ISPE Biopharmaceutical Manufacturing conference held virtually in early June
In his portion of the webinar, Sklamberg specifically addressed:
- FDA inspection status
- Preapproval inspections
- For cause, surveillance, and warning letter close out inspections
- Inspection alternatives
- Putting yourself in FDA’s shoes
- When physical inspections might resume
During the Q&A at the end, he answered questions regarding virtual inspections and warning letter issuance from a virtual inspection.
[RELATED: How does your inspection rate compare to that of your peers? If you want to find out, get your Free Benchmark Report.]
FDA Inspection Status
Sklamberg explained that most of FDA’s physical inspections have been suspended, but that “mission-critical” inspections will proceed. According to FDA, for cause inspections and preapproval inspections for important therapies or to address shortages will take place. “Anecdotally, some of those are occurring,” he said. “I know that a client of ours has gotten a surprise for cause inspection in the pharmaceutical area.”
There are also some preapproval inspections taking place. “Now that we know the pandemic will be around for a while, FDA is ramping up virtual inspections,” Sklamberg said. “FDA has said that it is working with the Center for Disease Control and Prevention (CDC) to develop a phased approach to resuming inspections, and that would be largely domestic.”
States and localities are at different stages in the process of reopening. FDA will send investigators in when the states’ and localities’ rules and laws permit it. That is going to vary geographically. If your company has a site in a state when it completely opens up, FDA will be able to perform an inspection there.
During the COVID-19 crisis FDA has talked about some inspection alternatives, “but they are really of limited benefit to the agency,” Sklamberg maintained. “They have talked about sampling, use of mutual recognition agreements, records review, virtual inspections, and import alerts.”
The limited benefit is that, for example, sampling as FDA has said, is not a substitute for an inspection. Mutual recognition agreements work. FDA has used its mutual recognition agreement with Europe, but Europe has limits on its inspections as well. “Records review and virtual inspections are areas that we all think FDA will ramp up in the coming months,” Sklamberg said.
In terms of preapproval inspections, FDA has broad discretion on when to inspect and how to inspect. It must find a manufacturing facility suitable. Compliance Program Guidance Manual (CPGM) 7346.832 lists the criteria for priority pre-approval inspections (Figure 1).
Figure 1: FDA Pre-Approval Inspections Criteria
Priority pre-approval inspections are based on risk, Sklamberg maintained. Risk increases when applicants have less experience, drugs are more difficult to manufacture, or have an Official Action Indicated (OAI) status, for example.
FDA has some more general criteria aside from priority preapproval inspections, “but they kind of mirror the criteria we just talked about. Again, risk for the product, risk for the facility, risk related to the compliance record of the company itself.”
Sklamberg pointed to the supply chain risk at the bottom of the list and noted that FDA has increasingly emphasized this at top levels in the agency, especially in the last year or so. And with the Covid-19 crisis, it is concerned about risks created by extended supply chains and supply chains that have problematic compliance records, particularly global supply chains, he pointed out.
For Cause, Surveillance, and Warning Letter Close Out Inspections
Surveillance inspections are the ones that are “the least mission-critical from FDA’s perspective, as they are not tied to cause,” Sklamberg maintained. “But they are nevertheless relevant because the CDER Manual of Policies and Procedures (MAPP) 5014.1 on this topic gives you a particularly good idea as to what FDA thinks is going to cause it to really want to inspect” (Figure 2).
Figure 2: For Cause, Surveillance, & Warning Letter Close Out Inspections Criteria
“When looking at those criteria, you can apply them to FDA thoughts about the need for a preapproval inspection and when it can waive inspection. If you look at these criteria, they are just like the CPGM ones that we talked about. They focus on risk from the facility, risk from the compliance history, risk related to the product, risk related to the company, and then specific instances of risk like patient exposure and hazard signals.”
“These would cause FDA to want to inspect or at least do a virtual inspection for an application rather than just waive the inspection. And there are also for cause inspections, which, as I indicated, FDA is doing domestically.”
According to Sklamberg, FDA has the extremely broad authority in the international realm to issue an import alert without an inspection. Oftentimes, when FDA gets a signal, it will quickly do an inspection and then issue an import alert afterwards. However, if there is a troublesome enough issue FDA might reach out to a company and ask for a recall. They also could just issue an import alert. The statutory standard is the appearance of a violation, which does not require an inspection to meet.
Regarding warning letter closeouts, “if you are thinking of instances where a firm wants an inspection, it would be to get their application approved or to close out a warning letter after remediation. The overwhelming majority of times the agency requires a physical inspection to close out a warning letter. But that is not required by statute. The whole warning letter process is something that is within FDA’s control. If FDA wanted to, it could rely on virtual inspections to close out warning letters.”
One alternative to performing an inspection is to waive the inspection. And for some particularly simple or less risky products, waiving inspection might be something FDA would do more frequently now than it would in the past, the Arnold & Porter partner said.
Figure 3: Inspection Alternatives
It is also important to understand that FDA is very aware of its user fee goals and user fee negotiations heading toward reauthorization of user fees a couple of years from now. “And they do not want to be missing a lot of goals. They are also probably aware that it would be hard for them to do physical inspections for all the products that are out there.”
As indicated, Europe has not been doing much inspecting outside of small areas. That is changing a bit as Europe is opening up. So, we may have increasing situations where European regulatory bodies can access European sites and that inspection report can be used by FDA for approvals.
The mutual recognition agreement with Europe only covers facilities in Europe and the US. There is an open question about if FDA wants to whether it could rely on European inspections outside of Europe—for example, if a European agency inspected a facility in India. “I think if this crisis goes on for a longer period, there will be more of an incentive for FDA to use that” he said.
FDASIA section 706 applies to pharmaceuticals and gives FDA the authority to get records in lieu of or advance of an inspection. The utility for a records inspection depends on what FDA is inspecting, Sklamberg pointed out.
“If they are looking at, for example, a follow up regarding investigation reports or out-of-specification (OOS) investigations, a lot of that work can be on paper. If it is something more physical where FDA is looking at an issue regarding equipment, obviously paper would not cut it nearly as much. And that is where a virtual inspection would be much more appropriate, where you can use live video interviews of personnel and look at some of the physical aspects of inspections.”
Sklamberg shared that FDA has reached out and informally told associations and some of his firm’s clients and others that “if you think your situation is one where it is appropriate to have a virtual inspection, make a proposal and make it specific. For example, if you have a warning letter close out and you think FDA can verify that without physically being there, tell them specifically how they could do it and how that would meet their needs. It would be the same thing for an application. How can FDA be satisfied that the company can make this product from this facility?”
Put Yourself in FDA’s Shoes
“As a former regulator,” Sklamberg said, “I would say to put yourself in FDA’s shoes.
- What does FDA want from that inspection?
- Why is FDA physically there normally?
- What are they looking at?
- And what can you provide them?
If there is an issue with equipment, then you would propose something visual. And I would be proactive with the agency in how specifically they can accomplish their goals. There are some concerns FDA would have, for example, if there is a big data integrity concern. FDA has said that would be extremely difficult to address remotely.”
“Spontaneous interviews, as you know, are an important part of an FDA inspection. From their perspective it is harder to do when it is not visual. When you have a video inspection, there can be other people in the room that FDA might not see, just like there will be other people in the room at FDA that you might not see. And that affects the spontaneity.”
He noted that some of his company’s clients have thought that a virtual inspection would be easier because the investigator is not there. “And I think it is just the opposite,” the former regulator said. “FDA is going to want to be sure that it is getting the information to satisfy itself. It knows it is being scrutinized. And you have the ability at FDA, instead of just having one or two investigators at a site, have a couple of them appearing on the computer screen but a whole bunch of people in the room.”
When Will Physical Inspections Begin Again?
“You hear lots of rumors from folks at FDA, at various levels of the agency about when they are going to restart their domestic or foreign inspection program,” Sklamberg noted. “But I can pretty much guarantee you that no one in the agency knows because it is an incredibly complex question.”
‘You hear lots of rumors from folks at FDA, at various levels of the agency about when they are going to restart their domestic or foreign inspection program,’ Sklamberg noted. ‘But I can pretty much guarantee you that no one in the agency knows because it is an incredibly complex question.’
It relates to not just what FDA wants to do, but the whole federal government and its policy. It relates to what foreign countries will permit as far as travel by folks from the US. “And even at FDA, it relates to labor issues, as most of FDA’s inspection force is in a union. And if there are going to be dangers to any of the investigators, that becomes a labor issue. FDA is a public health agency that is not looking to endanger its employees.”
“So, there are a lot of intangibles here. But I think one thing is for sure: There are going to be sharp limits on physical inspections for quite a while. And FDA is going to want to be able to approve important therapies and not miss a lot of its goals. So, they are going to be relying on virtual inspections, paper inspections, and other inspection alternatives.”
Q&A Focuses on Virtual Inspections and Warning Letter Issuance
In the Q&A at the end of the webinar, questions addressed to Sklamberg focused on the circumstances under which FDA might perform virtual inspections and on the agency’s ability to issue a warning letter based on a virtual inspection.
Several of the attendees wanted to know if a virtual inspection is possible for a site that has never been inspected by FDA before, and whether a virtual inspection could be used for an OAI site that wants to close out a warning letter.
Sklamberg replied, “the answer to both is yes. There is no legal limitation on FDA that requires it to do an in-person inspection, either for a warning letter close out or for new facility.”
“I think the way to look at it is the fact that a facility is OAI or that it is new makes it a higher inspection priority for FDA. What that means is it is much less likely the FDA is going to want to waive inspection for an application.”
“Whether it can do a virtual inspection or not I think it might depend on some other factors. For example, if it was an OAI site and the OAI issue was related to a big data integrity issue, I think it would be harder for FDA to do a non-physical inspection, as I mentioned earlier.”
“Some other types of warning letters are much more amenable to FDA following up without being there physically. As I mentioned before, if FDA is reviewing data, if they are reviewing a third party consultant evaluation of your OOS investigations, that can be done well with records remotely. There are certain types of issues in inspections that FDA can verify visually through video.”
For a new facility, which is a high risk for FDA, it is unlikely they are going to want to waive inspection, but they could do it virtually. In both those instances, if you are the entity that wants the inspection—maybe for preapproval or to close out a warning letter—be proactive with FDA and try to anticipate what FDA concerns would be and then try to address them.
“For a new facility, which is a high risk for FDA, it is unlikely they are going to want to waive inspection, but they could do it virtually. In both those instances, if you are the entity that wants the inspection—maybe for preapproval or to close out a warning letter—be proactive with FDA and try to anticipate what FDA concerns would be and then try to address them,” Sklamberg advised.
Another question directed to Sklamberg asked whether it will be possible for FDA to issue a warning letter or take other enforcement action because of a virtual inspection.
Sklamberg replied in the affirmative. “One way we know this is FDA issues warning letters based on illegal claims that are on the Internet without ever going to do an actual inspection. It can issue a warning letter based on FAQs on a firm’s website that make disease cure claims without going down to the firm, issuing a 482, and then looking at the computer system.”
“The thing about warning letters is they are quite formal in the way FDA has developed procedures, but the structure and details of a warning letter are not part of FDA’s statute,” he explained. “They are something that FDA came up with to get voluntary compliance. So, FDA has a lot of flexibility. It can issue a warning letter. It can withhold approval of applications. It can do an import alert. The thing that might get tricky is if it were to take judicial action. But judicial action is uncommon.”
This wraps up Part 1, Sklamberg’s review of the current inspection landscape and what may trigger an inspection.
Next time, we’ll dive into Part 2: A review of a state-of-the-art virtual inspection platform using mixed reality technology developed by Thermo Fisher Scientific discussed at the ISPE Biopharmaceutical Manufacturing conference held virtually in early June.
Editor’s Note: On July 10, 2020, FDA announced a plan to resume domestic inspections. Of particular interest is a statement that for the foreseeable future all FDA inspections (except undercover operations for tobacco) will be preannounced.
[RELATED: How does your inspection rate compare to that of your peers? If you want to find out, get your Free Benchmark Report.]
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