Health authorities rely on inspections of pharma manufacturing facilities as a critical element of the drug approval process and insurance of compliance to Good Manufacturing Practices (GMPs). However, during the COVID-19 pandemic, travel and in-person visitation have been restricted, creating challenging scenarios for health authority inspections and creative solutions.
Inspection alternatives used by the agencies include virtual inspections and document reviews in lieu of physical visits, which require a change in approach and logistics by the agencies and the companies being inspected.
Inspectorates outside the United States—including Australia’s Therapeutic Goods Administration (TGA), UK’s Medicines and Healthcare products Regulatory Agency (MHRA), the Russian State Institute of Drugs and Good Practices (SID&GP), Japan’s Pharmaceutical and Medical Device Agency (PMDA), and some EMA member states—have been using virtual inspections for pharma manufacturing facilities. The U.S. FDA, however, has not.
[Related: Read a special report by the author on the inspection landscape in mid-2020 plus more information on virtual inspections.]
At FDLI’s Enforcement, Litigation, and Compliance Conference held virtually in December 2020, Pfizer attorney Stephanie Haggerty—whose group supports manufacturing operations, pharmaceutical science teams, and pharmacovigilance teams—provided a look at Pfizer’s regulatory agency inspection experience during 2020 including the lessons learned.
Pfizer is the world’s largest pharmaceutical company with about 40 manufacturing sites worldwide, most of which are subject to FDA inspection. It markets products in more than 120 countries and generally hosts more than 20 FDA inspections each year.
Haggerty said that Pfizer had “a few inspections” in January and February of 2020, with the last inspection at a site outside the US in early February. Since then, “we have not seen FDA onsite at any of our facilities up until last week (December 2020). That was a one-day onsite inspection, related to the Pfizer COVID-19 vaccine candidate. It was very minimal.”
FDA Document Requests in Lieu of Inspections
Haggerty explained the FDA document request process her company has experienced is permitted in lieu of inspections under the 2012 FDA Safety and Innovation Act (FDASIA). The agency uses a form, number 4003, as a vehicle for official document requests.
“We have received a lot of FDA form 4003 document requests,” Haggerty said. “And for those of you who have gotten this type of document request, you know that it can be extensive.”
There are also requests that are much more extensive and take much more time to put together, she said. For sites outside the US, original documents in the local native language have been requested, and so have certified translations into English. “So, that essentially doubles the volume of the submission that needs to be made to FDA.”
Haggerty pointed out that there are size limitations for the documents that FDA can receive. “Our sites needed to break down the responses into 30 to 50 different documents and make the submissions that way to complete the document request,” she explained.
Inspection alternatives used by the agencies include virtual inspections and document reviews
Because it “is not necessarily value added time for someone to sit in front of a computer, breaking down PDFs into smaller chunks so that the documentation can be received by the FDA system,” she commented, Pfizer has reached out to FDA asking about the possibilities for different technologies that can be utilized.
“We want to get the agency the information it needs and we want to do it in a secure manner and in a streamlined fashion,” the Pfizer attorney emphasized. “If we are going to have more 4003 document requests and have remote inspections in the future, I think technology is going to be very key in that regard.”
She also pointed out that while the previous discussion is GMP related, “on the GCP side in the US all our clinical study site inspections have been performed in person in 2020. Outside the United States, however, those inspections have been canceled.”
Remote and Virtual Inspection Experience
Haggerty reported that Pfizer has not received a request from FDA to perform a virtual inspection at a Pfizer facility. It does, however, have experience with several other inspectorates including TGA, MHRA, SID&GP, PMDA, and some EMA member states such as FAGG in Belgium. “We have had many remote or virtual inspections with them, and a lot of learning has come out of those. We have some takeaways that I would like to share.” (Figure 1).
Importantly, we have found that having extensive pre-inspection discussions with the inspectors about logistics is especially important.
Time zone differences are important. “Right now, Japan’s PMDA is inspecting. Japan is 14 hours ahead of us. We needed to come to an agreement of when we would have in-person discussions versus when they would take their time away to review the documents.”
There are size limitations for the documents that FDA can receive
Regarding meetings via WebEx with an inspector, they may sit down and read company documents in real-time during the live meeting. “But when you are working with an inspectorate that is 14 hours ahead, or 10 hours ahead, a lot of times the document review happens offline. The interviews of the company personnel or the Subject Matter Experts (SMEs) take place during the in-person time.
“Ferreting out the logistics and figuring out when we can get the document to the inspectors for review and when are we going to have in-person interviews—the cadence of document submissions and reviews and coming to a meeting of the minds—has been very important for us,” Haggerty stressed.
Also, the development of an extensive agenda “has been important.” Not all inspectors want to do that. They may not want to tell you what they are going to look at or when they are going to look at it.
“We want to get the inspectors something in a timely manner, but our SMEs are working virtually,” she explained. “They are managing their jobs and their children, working at home—the reality of dealing with COVID and the pandemic. Coming up with an agenda of when people are expected to get on the phone and talk to an investigator to address a recall or a BPDR, or whatever topic comes up, is important, I think, for both sides. It works well. We have seen a lot of flexibility.”
Regarding live communication options, Pfizer largely uses WebEx, but not all inspectorates can use that platform. So, it is important to figure out what technology will work—maybe Zoom or something else—to enable meetings to take place.
In addition to in-person interaction, agreement is needed on a platform for document submissions. “Security is key,” Haggerty pointed out. “We want to provide the documents in a secure, streamlined fashion. Strong IT support is essential.”
Time zone differences are important
It is also important to ascertain the expectations for the timeliness of document requests, especially when dealing with different time zones.
“Working with Japan, for example, we needed to give them a lot of documents upfront to review,” she said. “Then they send document requests overnight for us to fulfill during the day. Getting that cadence correct is important.”
Regarding a virtual tour, Pfizer has seen a spectrum of requests. Photos are sufficient for some inspectors. Some have wanted pre-recorded walk-throughs of facilities. Others have wanted live tours with the ability to meet with someone and speak to them in real-time on the manufacturing line.
“As a pharma company, we have policies and procedures around recordings and live streaming and photography. We need to be able to talk to the inspector and come to a meeting of the minds on what they need to see and what we can do to fulfill their requests.”
Haggerty’s takeaways from Pfizer’s remote sessions, she said, “have been the importance of communication, flexibility, and technology.”
[Editor’s Note: For more on virtual inspections from this author, check out his earlier articles on the topic.]
Russian Inspectorate Weighs in on Remote Audits and International Harmonization
Preparing for a Virtual FDA Inspection: Advice from Former FDA Investigator and Investigations Director Ricki Chase
Hosting a Virtual FDA Inspection: Advice from Former FDA Investigator and Investigations Director Ricki Chase
[Related: Read a special report by the author on the inspection landscape in mid-2020 plus more information on virtual inspections.]
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