As Vaccines Near the Possible-Approval Line, New Challenges Await
Eight months after it began developing its Covid-19 vaccine, Pfizer formally filed for emergency use authorization from the US Food and Drug Administration on Friday. https://www.npr.org/2020/11/20/937026003/pfizer-asks-fda-to-approve-its-covid-19-vaccine-for-emergency-use
“Filing for Emergency Use Authorization in the U.S. is a critical step in making our vaccine candidate available to the global population as quickly as possible,” BioNTech CEO Ugur Sahin, MD, said in a joint statement released by the companies, NPR reported. “We intend to continue to work with regulatory agencies worldwide to enable the rapid distribution of our vaccine globally.”
Pfizer Chairman and CEO Albert Bourla, DVM, told NPR on Thursday that the company anticipates producing enough vaccine to inoculate 25 million people by year’s end. About 12.5 million of the initial doses will be earmarked for the US with the remaining half going to the rest of the world.
Also this week, Moderna announced that its vaccine candidate, in preliminary results, has shown to be more than 90% effective against the coronavirus. Both the Pfizer and Moderna vaccines are two doses per patient and must be refrigerated, Pfizer’s vaccine at minus 70 degrees Celsius, or colder than winter in Antarctica. Moderna’s vaccine requires refrigeration at minus 20 degrees Celsius, about the same temperature as a regular freezer.
Other vaccine hopefuls that have reached the final phase of its trials include Janssen Pharmaceutical Companies of Johnson & Johnson, and Oxford University-AstraZeneca. Interim data from the Oxford vaccine showed that it produced an immune response in older and younger adults.
As welcome as the Pfizer and Moderna news is, a large swath of Americans still remained unsure about the vaccines’ safety. Health officials estimate that 70% of the population would have to be vaccinated to stop the rampant spread of Covid-19. A recent Gallup poll found that only 58% of Americans were willing to get vaccinated. People are worried that a vaccine developed so quickly was done by cutting corners.
APIs no longer in our midst
Historically medicine manufacturing has been US based. But in the last few decades that has changed. Most drug ingredients are made overseas. They are called active pharmaceutical ingredients, or APIs. APIs are the actual drugs that are formulated into the tablets, capsules, and injections
Pfizer, based in New York, said it plans to manufacture its vaccine at three sites in the US and Europe. Moderna has said it will make its vaccine, and the ingredients, in the US and Switzerland where its partner, Lonza, is located.
AstraZeneca has its manufacturing agreement with Catalent. Catalent has said manufacturing will occur in Maryland and the AstraZeneca site in Italy. Catalent is also helping out Johnson & Johnson and Moderna with their manufacturing needs.
Regardless of where APIs or finished drugs originate, they must meet all FDA statutory and regulatory standards for safety, quality, and effectiveness for manufacturing processes for over-the-counter and prescription drugs. While not a mandate for approval of a new drug, inspections of the manufacturing facility by the FDA often are made before drug approval. The purpose of these inspections “is to contribute to FDA’s assurance that a manufacturing establishment named in a drug application is capable of manufacturing a drug, and that submitted data are accurate and complete.”
In its August guidance on the temporary suspension of facility inspections during the pandemic, the FDA said it would use other “tools,” “such as reviewing a firm’s previous compliance history, [and] using information sharing from trusted foreign regulatory partners through mutual recognition.”
US drugs, everywhere
In her October 2019 testimony before the House of Representatives Subcommittee on Health, Janet Woodcock, MD, director of the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration told the subcommittee that only 28% of the manufacturing facilities that made APIs to supply the US market were domestic.
“By contrast, the remaining 72% of the API manufacturers supplying the U.S. market were overseas, and 13% are in China,” Dr. Woodcock said..
Along with China, 28% of APIs come from the European Union (26%), India (18%), Canada (2%) and the 13% from the rest of the world. Dr. Woodcock said the number of Chinese companies making APIs for the American market has increased over the last decade. But the FDA has not been able to calculate the amount of APIs being used for US-marketed drugs from China or India or what percentage of US drug consumption it represents.
“W e do not know whether Chinese facilities are actually producing APIs, how much they are producing, or where the APIs they are producing are being distributed worldwide, including in the United States,” she told the subcommittee.
Testifying before the Senate Finance Committee in June 2020, Director of Health Care for the GAO Mary Denigan-Macauley said that Covid-19 had called greater attention to America’s reliance on foreign drug manufacturers and the pharmaceutical supply chain.
“Like the majority of other drugs manufactured for the U.S. market, much of the manufacturing of drugs for treating COVID-19 occurs overseas,” she told the committee.
Ms. Denigan-Macauley said that FDA data showed that 70% of companies manufacturing APIs and 50% of those manufacturing finished drugs for the US market were located overseas. Of all the foreign companies shipping drugs to the US, India and China were responsible for 40%.
According to her testimony, FDA inspectors faced several challenges conducting foreign inspections. In America, the FDA inspections almost always arrive unannounced. Overseas, however, foreign manufacturers know about an impending inspection as much as three months in advance, giving them plenty of time to clean up quality control issues and fix production problems.
Ms. Denigan-Macauley acknowledged that since the GAO started examining the issue in 2009, the FDA had made important changes in adapting to the globalization of the pharmaceutical supply chain. Still, the agency faces many challenges overseeing foreign drug manufacturers.
“Since then, the outbreak of COVID-19 has added a layer of complexity,” she concluded. “It also further highlights the global nature of our pharmaceutical supply chain.”