Jill Wechsler is Pharmaceutical Technology's Washington Editor, jillwechsler7@gmail.com.

Jill Wechsler

For anyone who was wondering in recent weeks what was holding up FDA Emergency Use Authorization for Johnson & Johnson (J&J) to distribute vaccine produced by the Emergent BioSolutions Bayview facility in Baltimore, the reason is clear from the multiple red flags and violations at the facility cited in an April 2020 field inspection report. Even before Emergent disclosed that it had to discard 15 million doses of the J&J vaccine drug substance, FDA inspectors had uncovered multiple deficiencies and quality control issues. Journalists and investigators have disclosed additional government reports and complaints about Emergent’s operations and practices, raising multiple questions about how and why federal health officials continued to ramp up contracts with the company.

A picture of wide manufacturing violations appears in a recently disclosed 

on a site visit to Emergent’s Baltimore vaccine plant conducted from April 9, 2020 to April 20, 2020. The report describes inadequate controls for computer and records systems, disregard of established test procedures and laboratory control mechanisms, failure to investigate deviations from test methods, unclear quality control unit responsibilities and procedures, and lack of employee training on current good manufacturing practices (cGMP) practices.

Most prescient is the last observation citing deficient operations to prevent contamination or mix-ups of products by having separate or defined areas for holding rejected components before disposition. The FDA investigator noted the absence of a report on a non-conforming material held in the “reject cage,” which was needed to explain the rejection and how the material was disposed. The year-old inspection report indicates that Trump administration officials and subsequently Biden staffers were aware of the serious quality control issues at the Emergent facility, even before the discovery that millions of doses of J&J vaccine doses were, in fact, discarded due to a mix-up with vaccine ingredient being produced for AstraZeneca. Despite the serious concerns raised by FDA and other analysts, pandemic preparedness officials continued to award ever-larger contracts to Emergent for vaccine ingredient production.

that it would assume full responsibility for manufacturing its vaccine drug substance at the Emergent facility. The company is shifting operations and quality experts to the site and “significantly increasing the number of manufacturing, quality, and technical operations personnel” to work with Emergent staffers. At the same time, Emergent was instructed by the Biden administration to halt production of the AstraZeneca vaccine, offering to assist the company in identifying other facilities to handle its production.

Even so, Emergent executives downplayed the situation, emphasizing in a press release that it was receiving an additional $23 million from the Biomedical Advanced Research and Development Authority (BARDA) to improve its manufacturing operations to expand J&J vaccine production. CEO Robert Kramer 

highlighted the company’s long-standing collaboration with the federal government

 in expanding vaccine production, and that the Bayview facility remains an Emergent property. This followed an 

that its quality control checks had identified only one single noncompliant batch, and that there was nothing unusual in having to discard some material in the complex vaccine production process.

The continued award of ever-larger manufacturing contracts to Emergent reflects its political connections in Washington as well as still limited US capacity for producing large quantities of critical vaccines. J&J has imported its vaccine substance from its plant in the Netherlands and also signed an agreement for Merck to produce its vaccine and has expanded its collaboration with Catalent to ramp up production of its vaccine at its Bloomington, Ind. facility.

One result of “uneven” production from the Emergent Baltimore plant is that federal health authorities now indicate that J&J will provide less than a million vaccine doses in the coming weeks, 85% less than the expected 5 million doses a week.

Articles

Even before Emergent disclosed that it had to discard 15 million doses of the J&J vaccine drug substance, FDA inspectors had uncovered multiple deficiencies and quality control issues.

FDA Inspectors Cited Critical Problems at Emergent Facility

For years now, US Congressional leaders and policy watchdogs have urged FDA to bolster its oversight of foreign drug manufacturing facilities to better ensure the quality and safety of the growing volume of medicines and ingredients imported to the United States. With the cancellation of most field site visits in 2020 due to the coronavirus pandemic, FDA now faces a serious backlog in inspections both in the US and abroad, raising the risk of shortages in vital medicines as well as access to needed treatments to counter new variants to the COVID-19 virus. Greater scrutiny of the vulnerability in the biopharmaceutical supply chain, moreover, as more drug manufacturing has shifted overseas, has increased pressure on FDA to renew site visits of facilities at home and around the world.

 This article was originally published online on March 10, 2021.

FDA Acting Commissioner Janet Woodcock responded to these concerns in a posting on March 18, 2021 that outlines a range of alternative methods the agency is using to verify the quality systems used to produce regulated products (1). She added that FDA is studying how to incorporate additional data sets and new technologies for facility oversight and will work with industry to expand the use of remote interactive evaluations, such as livestreaming video of operations, teleconferences, or screen sharing. Moreover, Woodcock indicated that as part of efforts to prepare for “resuming a more normal state of operations,” FDA is examining “how best to address inspectional activities that were paused due to the pandemic.”

Even before the COVID-19 pandemic, FDA faced significant challenges in conducting timely inspections of foreign facilities, namely a shortage of trained investigators, the need to pre-announce facility inspections, and language barriers that made site assessments more difficult and less reliable. The pandemic has made the situation even worse, according to the latest report from the Government Accountability Office (GAO), which finds that FDA failed to complete more than 1000 of planned surveillance inspections in 2020 due to travel restrictions and safety concerns imposed by the pandemic. FDA conducted only three foreign mission critical inspections and 52 domestic inspections between March and October 2020, compared to more than 600 foreign inspections during the same period in 2019 (2). FDA’s China office resumed some preapproval inspections in October 2020, but plans for surveillance inspections remain uncertain.

GAO predicts that continued postponement of planned surveillance inspections to ensure compliance with good manufacturing practices (GMPs) will greatly increase the number of facilities in high-risk categories (i.e., those never inspected or not visited for five years or previously cited for infractions). Such developments could undermine FDA’s risk-based inspection program, which aims to better target agency resources to operations most likely to raise pharmaceutical quality and safety issues.

This serious drop-off in manufacturing inspections comes after years of complaints from GAO and other analysts about inadequate FDA oversight of the growing number of foreign firms producing drugs and APIs for the US. At a hearing last month before the House Appropriations subcommittee that handles FDA funding, Mary Denigan-Macauley, GAO health care director, expressed fears that the mounting inspection backlog could take years to address (3).

As in several past reports, GAO criticizes certain FDA inspection practices as limiting the effectiveness of foreign site visits. A main target is the agency’s practice of providing up to 12 weeks advance notice of its plan to inspect a foreign facility, a timeframe FDA officials claim is necessary to ensure that a plant is open and operating before making costly arrangements to send an inspector. Greater use of FDA staff posted in China or India can reduce the pre-announcement timeframe to a few days, but these operations are limited. The practice of relying on foreign companies to select translators for inspections is also noted by GAO, which proposes that FDA adopt the European Union policy of providing a manufacturer with a list of approved translators for the company to select one and pay for the service. In the past year, more product sampling and testing at US borders led to FDA putting 54 foreign manufacturers on “import alert,” but that addresses only a fraction of potential problems and is “not a substitute for an inspection,” according to the GAO analysts.

FDA’s field inspection program continues to have difficulties in hiring and training investigators, particularly those able and willing to travel overseas. The legislators noted that Congress provided additional funds in 2020 to address problems with the foreign inspection program, but that the resources were used primarily to update and correct FDA’s inventory of active manufacturing sites to better identify those overseas facilities actually subject to inspection. It remains to be seen if FDA is able to address some of these issues with a portion of the $500 million in additional funding provided to bolster agency programs and initiatives to combat COVID-19.

Manufacturers and agency stakeholders maintain that inspections should resume, with investigators being vaccinated and provided protective gear. This raises the issue of whether inspections of pharmaceutical producers and research sites are considered “essential” under current guidelines and therefore should override travel restrictions and other limitations on federal agency programs.

In addition to the cancellation of most GMP inspections, GAO also notes a sharp decline in preapproval inspections usually conducted to support market approval of a new therapy. While this change did not delay approval of most new applications for much of last year, as many facilities had been assessed prior to the inspection shut-down, months of inactivity now appear to be taking a toll on the agency’s ability to confirm the capabilities of a facility not inspected in recent years (4).

Members of Congress charged with approving FDA’s annual budget will further address these issues in the coming months. Proposals on the table may seek to encourage more biopharmaceutical production in the US by authorizing “country of origin” labeling or public disclosure of a manufacturer’s compliance status, along with added FDA support for modern manufacturing systems that can better ensure product quality with less oversight.

1. J. Woodcock and J. McMeekin, “FDA’s Ongoing Use of Inspectional Tools for Ensuring Access to Safe, Quality Food and Medical Products During the COVID-19 Pandemic,” FDA Voices Blog, 

Drug Safety: FDA’s Future Inspection Plans Need to Address Issues Presented by COVID-19 Backlog

, March 4, 2021.
3. M. Denigan-Macauley, “

” testimony to House Committee on Appropriations (March 9, 2021).
4. J. Wechsler, 

When referring to this article, please cite it as J. Wechsler, “Pressure Mounts for FDA to Ramp Up Drug Inspections,” 

Concerns over vulnerability in the supply chain has increased pressure on FDA to renew site visits of domestic and foreign facilities. 

Pressure Mounts for FDA to Ramp Up Drug Inspections

 this week, presenting a host of strategies to strengthen the nation’s transportation, housing, jobs, education, and home healthcare, while also advancing research and science in multiple industries. The aim is to appeal broadly to Americans in all regions and across the political spectrum with the promise of better lives post-pandemic. With a cost of $2.3 trillion over eight years, and possibly up to $4 trillion over the next decade, the administration seeks to fund much of the tab with the hefty boost in the corporate tax rate over 15 years and to increase taxes on companies’ foreign earnings, changes that notably would affect biopharma companies.

The largest investments provide funds to modernize transportation infrastructure, expand affordable housing, bolster utilities, and expand home and community-based care for the elderly and disabled. Within these initiatives are multiple programs related to R&D and technology, such as funds for electric vehicle development, to expand high-speed broadband, and to improve the power grid. An emphasis on boosting support for research and development aims to make American industry more competitive with China and other advanced nations, while also creating more high-wage jobs and maintaining American global leadership in manufacturing and economic development.

A number of innovation and R&D programs fall under the $280 billion allotted for jobs creation and expanded research infrastructure to support the “technologies of the future” important to American competitiveness “on the global stage.” There’s $50 billion for the National Science Foundation to collaborate and build on high-tech programs in fields like biotechnology, semiconductors, advanced computing, and advanced energy technologies. There’s another $35 billion to address the climate crisis and advance clean energy technology. Efforts to retool and revitalize American manufacturing include a new office to monitor domestic industrial capacity and support production of critical goods such as semiconductors. And there’s more than $50 billion available for investment in US manufacturers and a plan for “regional innovation hubs” to spread new opportunities across the country.

Advancing American manufacturing also supports activities to “protect Americans from future pandemics.” That initiative provides $30 billion to invest in medical countermeasures manufacturing, shore up the strategic national stockpile, accelerate the timeline for R&D and testing of new therapeutics, and train personnel for epidemic and pandemic response. One notable proposal is to accelerate the nation’s ability to respond quickly to a medical emergency by developing prototype vaccines through Phase I and II trials. Biopharma manufacturing also would gain from investment in new technologies for rapid scale up of vaccine production, in expanded emergency production capacity and enhanced US infrastructure for biopreparedness, and in greater production onshore of APIs. 

The main source of funding for the massive program is to boost the corporate tax rate to 28%, up from the current 21% that was part of a major Trump administration tax cut. That’s still lower than the 35% corporate tax rate before the change in 2017, but still projected to provide up to $3 trillion to pay for the jobs and infrastructure package. President Biden explained that the plan aims to end “the race to the bottom on corporate tax rates” around the world. And reformers maintain that corporations actually pay only about a 16% tax rate, largely due to incentives for shifting production and jobs overseas.

Biden aims to fix that by revising current policies that exempt from US taxes most foreign assets and higher taxes paid overseas. A range of policy changes would discourage foreign based companies from shifting profits from US operations to avoid taxes, while also discouraging foreign takeovers of US firms. The global operations of most biopharma companies means that any changes in the international tax arena will have a significant impact on industry operations and business decisions.

Republicans already are loudly opposing the tax changes, and the package is slated to undergo significant changes to gain sufficient support for enactment.

The White House’s American Jobs Plan includes investment in new technologies for rapid scale up of vaccine production, in expanded emergency production capacity and enhanced US infrastructure for biopreparedness, and in greater production onshore of APIs.   

Biden Infrastructure Package Would Boost R&D and Corporate Taxes

With Senator Bernie Sanders (D-Vt) leading the charge on Capitol Hill, the campaign to limit US outlays for prescription drugs have accelerated, now aiming to include a number of cost-control measures in the massive economic development bill under development. Although such efforts have petered out in the past, the need for added revenues to fund billion-dollar infrastructure improvements has fueled challenges to industry pricing practices.

 hearing in March before the Senate Health, Education, Labor and Pensions (HELP) subcommittee

 chaired by Sanders. He and colleagues are sponsoring a 

 that would peg US drug prices to those in other industrialized nations, facilitate broader reimportation of prescription drugs from certain countries, and permit Medicare to negotiate prices paid by drug plans. 

Another popular proposal would require manufacturers to conduct comparative studies to justify “substantial” price increases related to product improvements. Debate continues over additional reforms involving rebates paid to Medicare drug plans and the role of patents in thwarting competition from low-cost generics and biosimilars. Broader disclosure of marketing expenditures and pricing decisions also have gained support.

None of these cost-cutting measures are new, and policy changes under the Trump administration already permit reimportation under certain circumstances. Industry and its Republican allies continue to push back with claims that limits on drug prices would stymie innovation and delay the development of critical new therapies. They prefer specific strategies for reducing patient out-of-pocket expenses through access to rebates and co-pay support programs. There is some agreement on policies to encourage biosimilar prescribing and the development of complex generic medications. Analysts acknowledge, moreover, that high-cost biotech therapies are driving cost trends, but that these can be life-saving treatments for seriously ill patients.

Despite concerns that price controls would block new drug development, the prospect that such reforms would create $450 billion in savings to offset trillion-dollar expenditures in economic development legislation may be sufficiently potent to drive reform forward. The House passed a broad drug pricing measure in 2019, but it never came up for a vote in the Republican-controlled Senate.

Now with public support growing for controlling medical costs, Senate moderates may join with progressives to lessen restrictions on the government’s role in limiting drug prices. They may be attracted by proposals to use some of those gains to fund new community health centers and further expand the Medicaid program to more low-income consumers. Moreover, Democrats may look to circumvent Republican opposition to pricing measures by including such reforms in budget reconciliation legislation, which requires only a majority to win Senate approval—and not 60 votes. Industry lobbyists will seek to foil that strategy, but there is concern that the rising outcry from individual patients hit by huge costs for vital medicines will sway Congressional action.

In addition to enacting legislation to challenge manufacturer pricing, reformers in Congress and consumer advocates are weighing a number of avenues to change. Biden administration officials are considering expanded use of Medicare demonstration programs and of the Center for Medicare and Medicaid Innovation (CMMI), as did the Trump administration, to test new payment models, discount drug vouchers, and other cost-cutting programs. The Department of Health and Human Services (HHS) also may propose new rules, payment policies, and waivers to alter current Medicare reimbursement and coverage requirements, as discussed in a white paper prepared by the 

Congressional reformers also want federal agencies to investigate pharma pricing practices. A group of House Democrats recently sent a letter to Federal Trade Commission acting chair Rebecca Slaughter urging a probe of possible collusion among leading insulin marketers. The request is similar to one made by Senator Sanders in 2016, but may get more attention from Slaughter, who recently announced increased scrutiny of drug industry mergers. The legislators cite reports on coordinated price hikes of insulins since 2012 by Eli Lilly, Sanofi, and Novo Nordisk, and note how the high cost of diabetes medicine is particularly harmful to minority patients [see 

(20) Rep. Katie Porter on Twitter: "Just 3 companies control nearly all of our insulin supply: Eli Lilly, Sanofi, and Novo Nordisk. Shocker: it turns out they raise prices in tandem—at least 13x in 10 years—while patients are rationing or starving themselves to try to cut costs. I want answers. https://t.co/AtkH3OonTs" / Twitter

Separately, consumer advocates are urging the National Institutes of Health (NIH) to “march in” and claim patent rights to medicines developed in collaboration with government-funded researchers. NIH scientists have been visibly involved in the research underlying the mRNA vaccines that have proven so effective in combatting COVID-19. A coalition of non-profit public interest organizations is urging NIH to ensure that the new vaccines, which advanced with notable support from the National Institute of Allergy and Infectious Diseases (NIAID), will be made available on an affordable basis to global health organizations for delivery to less developed nations around the world.

The great success of the biopharmaceutical industry in speeding to patients innovative vaccines and therapies able to combat COVID-19 has boosted public confidence in and regard for biopharma companies to notable highs. Industry leaders have highlighted the cutting-edge science and dedicated researchers that have produced these critical new therapies. This success has raised concerns about upsetting the underlying economic and scientific factors driving innovation, but that continues to be offset by vivid reports of patient hardship in accessing vital medicines.

The need for added revenues to fund billion-dollar infrastructure improvements has fueled challenges to industry pricing practices. 