As the COVID-19 pandemic continues and in-person activities and travel remain restricted, FDA has been making pharma inspection decisions using rules and policies that are not understood by the industry. The decisions can be a source of consternation for those hoping to be inspected—for example, as part of a new drug approval or for clearing an Official Action Indicated (OAI) status at a manufacturing site.

In some cases, the agency has let an action date lapse and taken no action. In other cases, it has chosen to schedule an inspection after approving a Biologic License Application (BLA) rather than as a prerequisite or to perform a “desk review” of documentation in lieu of an in-person inspection to approve a manufacturing site.

At FDLI’s Enforcement, Litigation, and Compliance Conference held virtually in December 2020, Parexel Technical Vice President Philip Crooker shared his company’s insights into the current inspection landscape, including details it has learned from its clients regarding FDA inspection alternatives they are experiencing.

“Along the spectrum of clients that we work with that range from very small biotech to what we would call sophisticated enterprise organizations—like Pfizer—a lot of this is determined on a very case-by-case specific basis that I think frustrates people,” Crooker commented. “But FDA is trying to develop a policy in the midst of a pandemic that is moving quickly, changing rapidly, and causing a variety of different situations.”

FDA Inspection Flexibility

Crooker explained that he has seen a continuum of flexibility regarding the different types of FDA inspections. Based on his experience, the agency’s inspections can be roughly categorized on a sliding scale from most to least flexible (Figure 1).

**FIGURE 1 | FDA Internal Guidance on Pharma Inspections**

“This slide shows a continuum of what we have noticed in terms of flexibility, with certain types of inspections, as you go from left to right,” Crooker said. “Preapproval or pre-license inspections are situations where we have seen more flexibility and the least amount of flexibility on routine surveillance. And I will put for-cause inspections to clear warning letters in that category as well.”

FDA’s Compliance Programs—some of which are cited in Figure 1 by program number—provide instructions to FDA personnel for conducting activities to evaluate industry compliance with the Federal Food, Drug, and Cosmetic Act (FD&C Act) and other laws administered by the agency.

FDA publishes Compliance Program Guidance Manuals (CPGMs) covering the following areas:

Biologics (CBER)
Bioresearch Monitoring (BIMO)
Devices/Radiological Health (CDRH)
Drugs (CDER)
Food and Cosmetics (CFSAN)
Veterinary Medicine (CVM)

The Field Management Directives (FMD) Manual is the primary vehicle for distributing procedural information/policy on the management of Office of Regulatory Affairs (ORA) field activities. The manual is issued on the authority of the Associate Commissioner for Regulatory Affairs (ACRA) and is intended as internal guidance directed to field managers.

The titles of the CPGM and FMD documents cited above are shown below. Links are provided at the end of this article. It is recommended that pharma manufacturing companies be familiar with the ones that are applicable to them.

FDA Inspection Alternatives Experienced

Pharma companies have experienced a variety of FDA inspection alternatives that range from taking no action on impending inspections/decisions to waiving a preapproval or pre-license inspection or choosing to inspect remotely. “There have been some very broad parameters that FDA has placed on what constitutes a mission-critical inspection or a mission-critical application or drug,” Crooker commented. Some of these scenarios are listed in Figure 2, with additional detail following.

Removing a site from a supply chain

If a supply chain is set up in a way such that it contains a problematic site—for example, one with an objectionable FDA site classification—and that site can be removed from the supply chain in the application, it can allow FDA to grant an approval with the remaining sites that have an acceptable FDA classification. “That is one of the simplest solutions that we have seen” to increase the chances of a successful inspection, Crooker commented.

Choosing to schedule a post-approval audit inspection

One publicly available example is illustrated by Biologic License Application (BLA) 761156 filed by Novo Nordisk for Sogroya (Somapacitan-beco, 10 mg/1.5 mL prefilled pen) for “replacement of endogenous growth hormone in adults with growth hormone deficiency.” The BLA “Summary Review” published by FDA’s Center for Drug Evaluation and Research (CDER) included the following (Figure 3):

Figure 3 Cross-Discipline Team Leader Review — **FIGURE 3 | Cross-Discipline Team Leader Review**

It is worth noting that the document is dated August 6, 2020, which is before the PDUFA Goal Date of 28 August 2020. It includes a recommendation for approval.

Included in the 51-page document are the following sections:

Benefit-Risk Assessment
Background
Product Quality
Nonclinical Pharmacology/Toxicology
Clinical Pharmacology
Clinical Microbiology
Clinical/Statistical Efficacy
Safety
Advisory Committee Meeting
(Section and name redacted using code (b)(4))
Other Relevant Regulatory Issues
Labeling
Postmarketing Recommendations
Recommended Comments to the Applicant

In the Product Quality section, it states (boldface added for emphasis), “During the review of the application, Dr. Ondeck noted that Novo Nordisk A/S, which is responsible for major activities related to the manufacturing and/or development of the final combination involving the device constituent part, has never been inspected. He indicates that the drug is not an emergency use product, the device is a typical pen injector, and it does not include vulnerable population, thus, the inspection is necessary. In addition, the Applicant already manufactures the identically designed device in other sites. However, the reviewer states the inspection can be done post-approval based ‘on given the risk of the product/user and lack of complexity of the device manufacturing processes.’ This issue should not affect approvability.”

Conducting a Desktop Assessment

The CDER Office of Pharmaceutical Quality (OPQ) made available NDA #213227 Product Quality Review, Integrated Quality Assessment document, an application for a new drug, Copper Cu-64 dotatate. It is a positron emitting isotope of copper to be manufactured by Curium US LLC at its Maryland Heights, MO site. The NDA was approved without an in-person inspection of the facility.

A preapproval inspection was requested by Curium US. However, in its place a “desk review” as permitted under the 2012 FDA Safety and Innovation Act (FDASIA) section 706, which allows the agency to obtain certain records and other information from a drug manufacturer in lieu of or in advance of an inspection, was conducted as shown in Figure 4 (taken directly from the NDA document):

Figure 4 Desk Review Pre-Approval Inspection — **FIGURE 4 | Desk Review**

Letting an action date lapse with no action

Crooker provided an example of a situation in which what appeared to be a promising new drug product was not acted on by FDA prior to its PDUFA action date.

In December 2019, Bristol-Myers Squibb (BMS) announced that the pivotal study of lisocabtagene maraleucel (liso-cel), an investigational CD19-directed CAR T-cell therapy for the treatment of adults with relapsed or refractory (R/R) large B-cell lymphoma after at least two prior therapies, “had met its primary and secondary endpoints while demonstrating durable responses.” The company said it planned to submit a BLA by the end of the year.

Nearly a year later, on November 16, 2020, BMS announced that FDA had informed it that agency review of the BLA for liso-cel will not be completed by the PDUFA action date of November 16, 2020.

FDA said that it was unable to conduct an inspection of a third-party manufacturing facility in Texas during the current review cycle due to travel restrictions related to the COVID-19 pandemic. Therefore, the agency is deferring action on the application until the inspection can be completed. The application remains under review. FDA did not provide a new anticipated action date.

“That was a product that seemed to have a significant number of mission critical indicia,” Crooker said, meaning that it had indications that matched what one would suppose would put it near the top of the agency’s list for priority approval. “Their application is now in a holding pattern until they have a domestic inspection that is completed for a facility in Texas.”

Recommendations for Manufacturers

Crooker provided some recommendations that his firm shares with clients to help guide them through the current inspection landscape and provide suggestions on how they might work with FDA to get their inspections accomplished (Figure 5).

“The first point here is important,” Crooker maintained. “It is early advocacy. We have seen applicants who get a communication from FDA during the review period of an application that essentially says, ‘We cannot inspect facility X, Y, or Z because of the travel restrictions. Please acknowledge.’”

He noted that there is a difference between acknowledging receipt of the letter and acknowledging that what it says is an acceptable posture from FDA. “Some of the receiving companies may not be as sophisticated—they may be foreign; they may be smaller; they may not be U.S.-based. Sometimes they get surprised by that. And that is when they contact us.”

“Your advocacy,” he stressed, is “extremely important,” particularly when it comes to pre-license or pre-approval inspections. “It should begin early, even prior to submission of the application, as a component of your discussions with FDA and your pre-submission meetings.”

“They may take a very neutral stance,” the Parexel Vice President said. “They may tell you there are a number of factors that have to be weighed. That does not stop the applicant from proposing a number of different approaches along a spectrum that can satisfy all parties so that the application is not delayed due to an inspection.”

There has been some correspondence from various trade groups such as PhRMA, BIO, AAM, and the PABO group on the inspection topic. “You can certainly align yourself with those,” Crooker said.

There are some constraints about records in advance or in lieu of inspection. “Stephanie [Haggerty] mentioned products that are prepared by aseptic processes. MHRA has had recent comments in public forums that it is their policy that a drug that is aseptically processed is just not going to be eligible for a remote inspection. That is where they have chosen to draw the boundaries for their policy, matching the mission-critical indicia.”

He pointed out that foreign agencies are developing their own guidelines around remote assessments. “If you are operating in a global environment, or if you want to align your approach and your thinking with agencies that are also communicating with FDA on this topic,” referring to the EMA Guidance related to Good Manufacturing Practice (GMP)/Good Distribution Practice (GDP) and Plasma Master File (PMF) distant assessments “can help align and draw some of the criteria more narrowly so that you have some more confidence in some of the proposals that you are submitting to FDA.”