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

Jill Wechsler

Just in case anyone suspected FDA of over-reacting to problems at this troubled vaccine production site—or that any poor-quality materials could be released—FDA officials have taken the unusual step of issuing the closeout report (Form 483) on its just-completed re-inspection of Emergent BioSolutions’ Baltimore manufacturing facility. The report cites multiple ongoing violations that undermine assurance of quality in products from this plant and the need for a continuing “pause” in production.

FDA Acting Commissioner Janet Woodcock and Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), issued a 

emphasizing the importance of thorough FDA inspections and review of quality procedures to ensure product quality. These FDA leaders aim to reassure the public that no vaccine will be released from the Emergent facility until FDA can assure it meets standards.

 that raise the risk of product cross-contamination and unsanitary conditions, specifically citing improper cleaning, lack of written procedures, faulty handling of raw materials and containers, and inadequate employee training to perform required job functions. And these are many of the same issues cited in by FDA inspectors in previous site visits, indicating that Emergent has failed to address multiple ongoing problems.

The situation now has drawn attention on Capitol Hill. Leaders of the House Oversight & Reform Committee and its Select Subcommittee on the Coronavirus Crisis have 

into how Emergent lobbying and political connections may have influenced continued funding for vaccine manufacturing, despite ongoing regulatory issues.

Woodcock and Marks emphasize that they are “doing everything we can” to ensure that COVID-19 vaccines for Americans meet FDA’s high standards for quality, safety, and effectiveness. The result, they hope, is that FDA will maintain the public’s trust in its operations.

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A FDA report cites multiple ongoing violations that undermine assurance of quality in products from this plant and the need for a continuing “pause” in production.

FDA Unveils Extensive Manufacturing Violations at Emergent

Just two weeks after instructing Johnson & Johnson (J&J) to take over operations at Emergent BioSolution’s noncompliant Baltimore manufacturing operation, FDA has called a halt in production of vaccine drug substance and to quarantine all remaining product at the Bayview plant. FDA initiated a “for cause” inspection of the facility last week to follow-up on violations found in an inspection last year, but requested the shutdown on April 16, 2021, according to an 

This latest enforcement action further muddies the supply outlook for J&J’s troubled COVID-19 vaccine, which separately is being reviewed by FDA and the Centers for Disease Control and Prevention (CDC) as to the cause of rare blood clots following vaccination. The feds had stopped distribution and use of the J&J vaccine pending further review of the safety issues. Meanwhile, Emergent evidently has produced more than 60 million doses of the J&J vaccine but cannot release the drug substance to a finish/fill operation until FDA certifies the Baltimore plant as meeting good manufacturing practices (GMPs).

FDA had cited serious quality concerns at Emergent’s Bayview plant in an inspection in April 2020, 

. That situation was disclosed when Emergent reported last month that it had to discard 15 million doses of the J&J vaccine drug substance due to possible cross-contamination of two vaccines. Journalists and investigators have further uncovered additional government reports and complaints about Emergent’s operations and practices, raising ongoing questions about how and why federal health officials continued to expand and extend contracts with the company.

The FDA form 483 inspection report issued a year ago described 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 (CGMPs) . A final observation cited deficient operations to prevent contamination or mix-ups of products by having separate or defined areas for holding rejected components before disposition. FDA and other government agencies 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 had to be discarded due to a mix-up with vaccine ingredient being produced for AstraZeneca.

Even though J&J assumed responsibility for manufacturing its vaccine drug substance at the Emergent facility two weeks ago, that apparently was not sufficient time to address the systemic manufacturing issues identified by FDA. At that time, 

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 and downplayed its quality control issues. Hopefully, those and other government funds will be used to resolve the vaccine quality issues in time to be useful.

FDA has called a halt in production of vaccine drug substance and to quarantine all remaining product at the Bayview plant. 

FDA Shuts Down Emergent Vaccine Facility

FDA is halting enforcement of a policy that limits prescribing and dispensing of Mifeprex (mifepristone), a widely used drug to induce a medical abortion in the very early stages of pregnancy. The revision allows doctors to authorize the pills via telemedicine and to make them available to patients through mail-order pharmacies while the pandemic continues, as a way to facilitate treatment while minimizing risky personal contact. And it puts FDA in the middle of the abortion debate.

Since approving Mifeprex for market in 2000, FDA has required women to obtain the drug directly from certified healthcare providers in certain clinics, medical offices, and hospitals. The shared risk evaluation and mitigation strategy (REMS) program for the drug and generic equivalents calls for patients to be evaluated by trained medical professionals and blocked product dispending by retail or mail-order pharmacies or over the Internet. While medical professionals and women’s health advocates have opposed these restrictions for years, the limitations appeared more egregious when the Trump administration dropped similar distribution restrictions for a number of high-risk medicines to ease patient access to treatment during the pandemic, but did not extend such flexibility to mifepristone, despite its strong record for being safe and effective.

Now FDA is modifying the requirement for in-person consultation, stating that the agency will exercise “enforcement discretion” regarding dispensing limitations during the public health emergency and will be flexible in 

permitting Mifepristone dispensing through the mail 

. FDA Acting Commissioner Janet Woodcock confirmed the change in letters to the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine.

, who sought and gained federal court approval in July 2020 for FDA to suspend its restriction on mifepristone dispensing directly to the patient in a clinic or medical office.  The judge cancelled the prescribing restrictions on the basis that requiring women to travel to clinics in person to obtain the pill put them at risk of COVID infection. However, the Trump administration appealed the ruling, and the Supreme Court overrode that decision in January 2021, restoring the requirement that individuals seeking medication abortions must obtain the pills in person.

Now FDA has moderated the in-person prescribing requirement, supported by evidence from continued review of adverse events related to Mifeprex during the six months last year when the more liberal dispensing policy was in effect. Woodcock explained in her letter that FDA reviewed studies related to mifepristone safety and adverse event reports from January 2020 to January 2021 and found no evidence that remote patient consults raised serious safety issues, such as sepsis infection, bleeding, or ectopic pregnancy.

The debate reflects how Mifeprex has become more widely used to halt unwanted pregnancies as state and federal policies have made surgical abortions more difficult to obtain. Abortion opponents seeking to limit access to mifepristone claim that a telemedicine appointment to discuss such treatment raises grave safety risks to patients. Several states are considering bills to ban the pills or make them even harder to obtain. However, state restrictions could become moot with more flexible video consultation policies that enable patients to obtain a prescription from a physician in another state and to receive the drug through the mail. Some women may be reluctant to take a pill that is banned in their home state for fear of arrest and charges, even though most doctors consider mifepristone safer than many common over-the-counter pain medications.

FDA announced its more flexible approach to Mifeprex prescribing as a deadline neared for a federal appeals court to decide a challenge to the Trump requirements upheld by the Supreme Court. A long list of leading medical societies, including the American Medical Association, the American Academy of Family Physicians, and ACOG, sent a letter March 1, 2021 to President Biden and Vice President Harris urging “swift action” to end the prior administration’s “unscientific and discriminatory policy” that forces patients prescribed mifepristone for pregnancy termination to pick up their medications at a health center. They point out that such requirements contradict actions by FDA and other federal agencies to promote the use of telemedicine during the pandemic to ensure access to health care while limiting unnecessary contact.

Separately, the Biden administration has moved to repeal regulations instituted by the Trump administration that bar family planning clinics that receive federal funds from offering abortion referrals and counseling. That move was widely hailed by women’s health advocates, but strongly opposed by anti-abortion forces.

FDA Lifts Restrictions on Access to Abortion Pill

FDA Acting Commissioner Janet Woodcock announced this week that Patrizia Cavazzoni will become the director of the Center for Drug Evaluation and Research (CDER), shifting from her role as acting director since spring 2020. While not a surprise, the move makes clear that Woodcock will not return to that position at CDER, which she had held for much of the past 30 years (1).

Instead, Woodcock remains in limbo as the temporary head of FDA, a situation that has been lamented on all sides. Several months ago, she was expected to get the top job until that move drew opposition from certain consumer activists who regard her as too cozy with industry and responsible for permitting deadly long-acting opioids on the market. The situation has led to inaction at the White House, leaving the leadership of FDA as one of the few unfilled top administration positions, a notable concern in this time of public health emergency. Woodcock’s long experience and strong leadership at FDA makes her a prime choice to lead the agency after a year of indecision and errors under Stephen Hahn, who came to the job with little knowledge of FDA or federal government operations. With the COVID-19 pandemic still raging across the United States and the world despite effective vaccines and therapeutics, FDA continues to face difficult decisions as it strives to shepherd new therapies to patients.

In only three years at FDA, Cavazzoni has impressed colleagues and FDA stakeholders for being a capable administrator and creative problem-solver. Woodcock brought her to CDER in 2018 as deputy center director for operations, and she briefly served in 2019 as acting principal deputy commissioner. Before coming to FDA, she held executive positions involving pharmacovigilance and drug safety at Pfizer, Sanofi, and Eli Lilly. In the past year, Cavazzoni kept the drug regulatory process running smoothly, as the pandemic placed added pressures on drug development and approvals, particularly with the halt to field inspections needed to vet product quality.

A main challenge for Cavazzoni will be to explain and reassure Congressional leaders of the strength of various CDER programs and decisions, as the agency continues to face sharp scrutiny for its handling of drug testing and product approvals during the pandemic. CDER will be in the spotlight as it seeks approval of new drug user fee agreements and sufficient resources in the coming months. And with a number of long-term FDA officials poised to retire, Cavazzoni will face the challenging task of recruiting and retaining capable staff under difficult circumstances.

Woodcock was named FDA acting commissioner in January 2021 when the Biden administration took office. In closing her announcement about Cavazzoni, Woodcock acknowledged that, in addition to serving temporarily as the agency head, her official FDA position now is principal medical advisor to the commissioner, the role she assumed when detailed last May 2020 to head therapeutics development at Operation Warp Speed. Under current law, she can serve as acting commissioner only until mid-August, unless she or another person is named to the commissioner’s job. Woodcock could remain at FDA in her medical advisory role under a new commissioner, but it won’t surprise anyone if the chooses to retire from the agency at that time.

1. J. Woodcock, A Message From the Acting Commissioner, Personnel Update–CDER Director, April 12, 2021.

Patrizia Cavazzoni will become the director of the Center for Drug Evaluation and Research, and Janet Woodcock remains in limbo as the temporary head of FDA.

Leadership Change at CDER Spotlights Imperative to Name New FDA Commissioner

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.

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. 