FDA Identifies Multiple Violations at Emergent Facility; Vaccine deals announced

J&J COVID-19 Vaccinations Can Resume

Materials availability is a factor in vaccine production.

Supply Chain Hurdles for Vaccine Production

In-vitro and in-silico tools can help predict in-vivo outcomes.

Spray-Dried Dispersion Formulation

Intensified and distributed manufacturing approaches create flexible, local capacity.

Manufacturing Outside the Box

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

Efforts to return to a more consistent and timely federal field inspection program will take considerable time, as FDA expects to conduct only a small portion of scheduled facility visits in 2021 due to continued limitations on travel imposed by the COVID-19 pandemic. With a huge backlog built up since March 2020, it’s not clear when the agency’s inspection program for drugs and medical products will fully recover. These challenges are acknowledged in the recently issued “

Resiliency Roadmap for FDA Inspectional Oversight

,” which details how the pandemic has delayed all but the most important “mission critical” and high priority inspections this past year, leaving thousands of site visits that will need attention in the coming months—and years. 

The Roadmap reports that FDA was able to carry out approximately 1600 mission critical and high-priority inspections for all regulated products from March 2020 to March 2021, including 29 in foreign countries. However, that is far short of the more than 20,000 inspections normally conducted each year for food, tobacco, and medical products. About half of all the completed inspections (741) involve drugs and medical products. If one combines mission-critical and priority inspections, the totals come to 155 inspections of establishments producing human drugs, 80 for medical devices, and 63 for biologics; the largest portion of audits include more than 400 for clinical data and research sites.

One result is that 68 of more than 13,500 applications for new medical products had approvals delayed largely due to the agency’s inability to conduct inspections.

The prospects for catching up are dim because the agency must address all those site visits missed this past year, while striving to deal with continued growth in its oversight responsibilities. FDA should inspect more than 23,000 establishments across all commodities in the current fiscal year (ends Sept. 30, 2021), the number expanded by those rolled over from last year. About 4000 of these audits cover establishments producing drugs, biologics, and other medical products. But even with a return to standard operations by mid-summer, the agency expects to conduct only 851 mission critical and priority site visits for medical products. If all travel restrictions are lifted and no other emergencies occur, FDA’s best-case scenario calculates that it might be able to conduct 1600 domestic inspections this year—about half of the to-do list.

Moreover, there’s always the possibility the situation could get worse—if new variants emerge, travel remains restricted, or FDA staff appears at risk in visiting manufacturing facilities. Then the agency will have to revert to utilizing alternatives to on-site visits, such as virtual inspections, sample testing, and reliance on reports from trusted foreign regulatory partners—all considered less effective than real-time inspections.

FDA’s continued focus on mission-critical and high-priority inspections in the coming months means that it will postpone most routine surveillance activity. Mission-critical inspections include important products previously involved in recalls or serious adverse events, plus preapproval audits for breakthrough therapies, regenerative medicines, treatments for serious conditions, and products related to COVID-19. The ongoing delays in inspections for lower-risk facilities means that for some time there will be wider intervals of time between inspections for sites subject to routine post-approval surveillance, as compared to emergency use authorizations, emergency situations, or critical medicines.

For the longer term, FDA looks to modernize its inspection program as part of a multi-year effort to transform data enterprise platforms and enhance cross-program interoperability. This IT modernization initiative will review approaches to regulatory oversight using next-generation assessment technologies, while also reviewing the need for potential legislative action to enhance regulatory oversight. A new agency-wide Inspectional Affairs Council will plan and coordinate inspection activities.

Articles

FDA expects to conduct only a small portion of scheduled facility visits in 2021 due to continued limitations on travel imposed by the COVID-19 pandemic. 

FDA Inspection “Roadmap” Acknowledges Continued Delays and Challenges Ahead 

Biogen and Capsigen, a US-based adeno-associated virus (AAV) vector development company, announced on May 10, 2021 that they have entered into a strategic research collaboration to engineer novel AAV capsids to deliver gene therapies that address the underlying genetic causes of various central nervous system (CNS) and neuromuscular disorders for up to $1.37 billion.

Under the terms of the agreement, Capsigen will receive a $15 million upfront payment and is eligible to receive up to $42 million in potential research milestones, with an additional $1.25 billion in potential development and commercial payments, Biogen said in a company press release. Biogen will obtain an exclusive license under Capsigen’s proprietary technology for an undisclosed number of CNS and neuromuscular disease targets through the collaboration.

Additionally, as part of the agreement, Capsigen will utilize its TRADE platform and associated technologies to develop and classify novel AAV capsids designed to meet disease-specific transduction profiles.

“Through this collaboration, we aim to solve key technological challenges in the delivery of gene therapies to target tissues. One of our priorities for technology innovation is the discovery of AAV capsids with improved delivery profiles,” said Alfred Sandrock, Jr., MD, PhD, head of Research and Development at Biogen, in the press release. “We are investing for the long-term by building platform capabilities and advanced manufacturing technologies with the goal of accelerating our efforts in gene therapy.”

“At Capsigen, we believe the next revolution in gene therapy will be driven by engineered AAV capsids designed to meet disease-specific transduction profiles,” added John Bial, CEO, Capsigen, in the press release. “Biogen is a leader in neuroscience, and we are excited for the opportunity to work with them to potentially bring new treatments to patients. This collaboration is consistent with our strategy to work with world-class companies to develop the next generation of gene therapies.”

Biogen and Capsigen have entered into a strategic research collaboration to engineer novel AAV capsids to deliver gene therapies that address the underlying genetic causes of various central nervous system and neuromuscular disorders. 

Biogen and Capsigen to Develop Novel AAV Capsids for up to $1.37 Billion

On May 11, 2021, Fujifilm Irvine Scientific celebrated 50 years of providing cell culture media products and services.

Originally established in the 1970s as a fetal bovine serum supplier, the company continuously proved its strength in the cell culture solutions space by modernizing embryo culture with commercially available media for 

 fertilization clinics worldwide and by bringing chemically defined media to biotherapeutic manufacturers, Fujifilm Irvine Scientific said in a company press release. Recently, the company introduced products better suited for cell culture-based vaccine production, and advanced cell and gene therapy applications.

“We have reflected on our trailblazing history and many contributions over the last five decades. Our 50th year coincided with unprecedented challenges from the COVID-19 pandemic,” said Yutaka Yamaguchi, CEO and chairman of the board, Fujifilm Irvine Scientific, in the press release. “We are grateful for the dedication and commitment shown by our employees to uphold our standards of delivering the highest quality products and service under these difficult conditions. We are also humbled by the extraordinary efforts of the community we serve in the fight against the virus and honored that our customers trust Fujifilm Irvine Scientific to provide the critical cell culture media needed to manufacture lifesaving therapies and vaccines, and to support medical applications. We are inspired to continue our mission to improve health through innovation, partnership, and service for the next 50 years.”

Originally established in the 1970s as a fetal bovine serum supplier, Fujifilm Irvine Scientific continuously proved its strength in the cell culture solutions space.

Fujifilm Irvine Scientific Celebrates 50 Years of Providing Cell Culture Media Products and Services

The National Institutes of Health (NIH) reported on May 11, 2021 that research has found that an investigational gene therapy developed by researchers from the University of California, Los Angeles and Great Ormond Street Hospital in London can restore the immune systems of infants and children who have severe combined immunodeficiency due to adenosine deaminase deficiency (ADA–SCID), a rare, life-threatening inherited immunodeficiency disorder.

Caused by mutations in the ADA gene that impair the activity of the adenosine deaminase enzyme needed for healthy immune system function, ADA–SCID is often treated with enzyme replacement therapy, which does not reconstruct immune function, must be taken once or twice weekly, and requires a genetically matched donor, NIH said in a company press release. The new research evaluated the gene therapy by implanting a normal copy of the ADA gene into the patient’s own blood-forming stem cells. Then, a vector delivered the normal ADA gene to these cells in the laboratory and the genetically corrected stem cells are infused back into the patient, who has received a low dose of the chemotherapy medication busulfan to let the cells establish themselves in the bone marrow and begin producing new immune cells.

Phase I/II clinical trials conducted in the United States and the United Kingdom showed the gene therapy to be safe overall, with some participants experiencing mild or moderate side effects attributed to the chemotherapy they received.

“These findings suggest that this experimental gene therapy could serve as a potential treatment option for infants and older children with ADA–SCID,” said Anthony S. Fauci, MD, director of NIH’s National Institute of Allergy and Infectious Diseases, in the press release. “Importantly, gene therapy is a one-time procedure that offers patients the hope of developing a completely functional immune system and the chance to live a full, healthy life.”

NIH reported that an investigational gene therapy developed by researchers from the University of California, Los Angeles and Great Ormond Street Hospital in London can restore the immune systems of infants and children who have severe combined immunodeficiency due to adenosine deaminase deficiency. 

Research Shows Gene Therapy Restores the Immune Systems of Infants and Children with Rare Immunodeficiency

FDA expanded the emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 vaccine to include adolescents 12–15 years of age, according to a May 10, 2021 announcement. The vaccine will be administered in two doses, three weeks apart, using the same dosage and dosing regimen for people ages 16 and older.

In an ongoing clinical trial of 2260 participants, with half receiving the vaccine, the immune response measured in 190 participants, 12­–15 years of age, was at least as good as the immune response of 170 participants, 16 through 25 years of age.

An analysis of cases of COVID-19, conducted seven days after the second dose, showed no cases of COVID-19 occurred among 1005 vaccine recipients, demonstrating the vaccine was 100% effective in preventing COVID-19.

Side effects in adolescents were consistent with those reported in clinical trial participants 16 years of age and older.

FDA amended the EUA originally issued on Dec. 11, 2020 for administration in individuals 16 years of age and older. From March 1, 2020 through April 30, 2021, the Centers for Disease Control and Prevention (CDC) received reports of approximately 1.5 million COVID-19 cases in individuals 11–17 years old.

“The FDA’s expansion of the emergency use authorization for the Pfizer-BioNTech COVID-19 vaccine to include adolescents 12 through 15 years of age is a significant step in the fight against the COVID-19 pandemic,” said Acting FDA Commissioner Janet Woodcock. “Today’s action allows for a younger population to be protected from COVID-19, bringing us closer to returning to a sense of normalcy and to ending the pandemic. Parents and guardians can rest assured that the agency undertook a rigorous and thorough review of all available data, as we have with all of our COVID-19 vaccine emergency use authorizations.”

Adolescents are now eligible for the Pfizer-BioNTech COVID-29 vaccine under expanded EUA.

FDA OKs Pfizer-BioNTech Vaccine for Adolescents

Eli Lilly and Company (Lilly) and MiNA Therapeutics, a UK-based RNA activation therapeutics company, announced on May 11, 2021 that they are launching a global research collaboration to develop novel drug candidates using MiNA's proprietary small activating RNA (saRNA) technology platform.

Under the terms of the partnership, MiNA will receive a $25-million upfront payment and will be eligible to receive development and commercialization milestones of up to $245 million per target as well as tiered royalties from the low-single to low-double digits on product sales resulting from the collaboration, Lilly said in a company press release. Through the collaboration, MiNA will use its saRNA platform to research up to five targets selected by Lilly to address diseases across its key therapeutic focus areas, while Lilly will handle the preclinical and clinical development of the candidates and will maintain exclusive commercialization rights for any products resulting from the collaboration.

"Small activating RNAs are a promising new technology, which will expand the breadth of Lilly's RNA therapeutics platform and the targets we can pursue," said Andrew C. Adams, PhD, vice-president for new therapeutic modalities at Lilly, in the press release. "We are excited about the potential of combining MiNA's leading saRNA platform and our expertise in new modalities to accelerate development of RNA-based medicines in areas of high unmet medical need."

"This collaboration with Lilly is an important validation of our saRNA platform," added Robert Habib, CEO of MiNA Therapeutics, in the press release. "Lilly's expertise in the field of RNA therapeutics and clinical development will greatly enhance our efforts to realize the technology's full potential. Together, we aim to unlock new targets in multiple therapeutic areas and to ultimately move them towards clinical development and commercialization."

Through the collaboration, MiNA will use its saRNA platform to research up to five targets selected by Lilly to address diseases across Lilly's key therapeutic focus areas.

Lilly and MiNA Therapeutics to Collaborate on Novel Drug Development

Sterling Pharma Solutions and OncoTEX, an oncology company and member of the iQ Group Global bioscience investment enterprise, The iQ Group Global, announced on May 10, 2021 that they have entered into a clinical development agreement for the manufacturing of OncoTex’s novel platinum-resistant oncology drug candidate, OxaliTEX, for use in clinical trials.

Through the agreement, Sterling will produce clinical trial material at its current good manufacturing practice (CGMP) facility in Germantown, Wis., which can accommodate highly potent active pharmaceutical ingredients in fully contained manufacturing suites, Sterling said in a company press release. OxaliTEX has been developed using OncoTEX’s oncology drug platform, TEX Core, to address the clinical need for ovarian cancer diagnosis and treatment.

“The current prognosis for patients with platinum-resistant ovarian cancer is very poor, so the development of OxaliTEX is an important step in advancing the way ovarian cancer is treated,” said Jonathan F. Arambula, vice-president of Research at OncoTEX, in the press release. “The partnership with Sterling will allow us to make OxaliTEX that meets [FDA] regulatory requirements necessary for clinical use.”

“Our mission is to find, fund, and develop bioscience discoveries into life-changing medical innovations, and deliver them to the people who need them the most. Today’s announcement marks a momentous milestone for The iQ Group Global and our novel cancer-fighting drug, OxaliTEX. It brings us closer to our goal of giving the hundreds of thousands of women who are diagnosed with ovarian cancer each year access to a powerful new weapon,” said George Syrmalis, CEO and chairman of The iQ Group Global, in the press release.

“The challenges involved in the manufacture of this complex molecule was a perfect fit for the expertise and capabilities that our team in Germantown have,” added Andrew Henderson, chief commercial officer at Sterling Pharma Solutions, in the press release. “We have worked closely with the OncoTEX team to identify a suitable development and manufacturing strategy, and we look forward to continuing our partnership with them throughout the process to ensure the greatest chance of advancing this new therapy through clinical development.”

Sterling Pharma Solutions and OncoTEX have entered into a clinical development agreement for the manufacturing of OncoTex’s novel platinum-resistant oncology drug candidate, OxaliTEX, for use in clinical trials.

Sterling Pharma Solutions and OncoTEX to Develop Novel Treatment Against Ovarian Cancer

Syngene announced on April 26, 2021 that it has extended its research collaboration with Bristol Myers Squibb through the end of 2030.

The collaboration, which has been in place since 1998, will focus on drug discovery including chemistry, biology, drug metabolism, and pharmacokinetics, along with translational medicine research and pharmaceutical development, including chemical process development and analytical sciences, Sygene said in a company press release. The partnership extension will also include a 40% increase in the number of scientists and the addition of a new 50,000-ft2 dedicated laboratory space.

"For more than 20 years we have considered our work with Bristol Myers Squibb to set the benchmark for integrated research collaborations and are delighted with our joint commitment to extend this collaboration until at least the end of the decade, as well as expand our focus to new areas of science,” said Jonathan Hunt, MD, CEO, Syngene, in the press release. “I have every confidence that together we will continue to deliver science that will improve the lives of patients around the world."

"We greatly value our collaboration with Syngene International and are proud to extend and expand our work together,” added Gregory Vite, PhD, senior vice-president, Small Molecule Drug Discovery, Bristol Myers Squibb, in the press release. “The dedicated facilities and scientific team at Syngene play an important role in helping us realize our vision to transform patients’ lives through science.”

The collaboration, which has been in place since 1998, will focus on drug discovery, translational medicine research, and pharmaceutical development.

Sygene to Extend its Research Collaboration with Bristol Myers Squibb

BioNTech announced on May 10, 2021 that it plans to expand its global footprint by establishing its regional headquarters for southeast Asia and a new messenger RNA (mRNA) manufacturing facility in Singapore.

The fully integrated mRNA manufacturing facility will accommodate BioNTech’s pipeline of mRNA-based product candidates and capabilities for rapid response production for southeast Asia’s potential pandemic threats, BioNTech said in a company press release. The new facility, which is set to be operational by 2023, will feature mRNA production capabilities for drug substance, drug product, and fill/finish, and will supply an estimated annual capacity of several hundred million doses of mRNA-based vaccines.

“Having multiple nodes in our production network is an important strategic step in building out our global footprint and capabilities. With this planned mRNA production facility, we will increase our overall network capacity and expand our ability to manufacture and deliver our mRNA vaccines and therapies to people around the world,” said Ugur Sahin, MD, CEO and co-founder of BioNTech, in the press release. “Singapore provides an excellent business climate, growing biotechnology industry, and rich talent base. We would like to thank Singapore’s Economic Development Board who has been very supportive throughout our planning process and we look forward to contributing our technology and expertise to the development of the biotechnology industry in Singapore and this region.”

BioNTech plans to expand its global footprint by establishing its regional headquarters for southeast Asia and a new mRNA manufacturing facility in Singapore. 

BioNTech to Establish Regional Headquarters and mRNA Manufacturing Facility in Singapore

Pfizer and BioNTech announced on May 7, 2021 that they have initiated a rolling submission of a biologics license application (BLA) to FDA for the approval of their COVID-19 vaccine in individuals 16 years of age and older.

The companies initiated the BLA by submitting the nonclinical and clinical data needed to support licensure of the vaccine, Pfizer said in a company press release. The companies will continue to submit data on a rolling basis over the next few weeks, with a request for priority review from FDA.

Currently, the vaccine is available in the United States under an emergency use authorization granted by FDA on December 11, 2020.

“We are proud of the tremendous progress we’ve made since December in delivering vaccines to millions of Americans, in collaboration with the US Government,” said Albert Bourla, chairman and CEO, Pfizer, in the press release. “We look forward to working with the FDA to complete this rolling submission and support their review, with the goal of securing full regulatory approval of the vaccine in the coming months.”

“Following the successful delivery of more than 170 million doses to the US population in just a few months, the BLA submission is an important cornerstone of achieving long-term herd immunity and containing COVID-19 in the future,” added Ugur Sahin, MD, CEO and co-founder of BioNTech, in the press release. “We are pleased to work with US regulators to seek approval of our COVID-19 vaccine based on our pivotal Phase 3 trial and follow-up data.”

Pfizer and BioNTech have initiated a rolling submission of a biologics license application to FDA for the approval of their COVID-19 vaccine in individuals 16 years of age and older.

Featured Content

J&J COVID-19 Vaccinations Can Resume

Supply Chain Hurdles for Vaccine Production

Spray-Dried Dispersion Formulation

Manufacturing Outside the Box