Strategies to Prevent Drug Shortages and Resolve Capacity Challenges

PharmTech’s Technology Forum Series

Pfizer vaccine has good results in adolescents; More vaccine capacity announced

Feds Direct J&J to Run Operations at Emergent Facility

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

On April 16, 2021, Sartorius, opened a new state-of-the-art manufacturing facility for downstream bioprocessing equipment in Havant, Hampshire, United Kingdom. The company announced that the opening marks the official relocation of more than 90 employees to the new facility from Sartorius’ former Portsmouth site, located a few miles away.

The new 58,000-ft2 site will bring together skilled engineers with biochemical, electrical, and mechanical backgrounds who will design and manufacture a range of systems for the biopharmaceutical market, including chromatography columns and filtration systems that will save time and costs. These systems are crucial elements for the manufacture of injectable drugs needed to treat cancer and diabetes and for the production of vaccines to prevent the spread of viruses, Sartorius reported in a company press release. In addition to a 28,000- ft2 production area, the center accommodates a 4000- ft2 customer test lab to demonstrate the functionality of Sartorius equipment.

The company will invest more than €400 million in 2021 to expand manufacturing capacities around the world to meet the growing demand in the biopharmaceuticals market. In line with these investments, Sartorius aims to expand its Havant site and is now offering positions for process engineers, project managers, and design engineers as well as several support functions, among other job vacancies. With the new facility in Havant, the company now has five locations in the UK, employing more than 900 staff members.

“The new facility in Havant will be an important part of our global operations network as it will enable our business to grow to meet the requirements of the expanding industry,” said Thorsten Peuker, head of operations, BPS Systems, at Sartorius in the press release. “The new facility increases Sartorius’ capacity to deliver support in all areas of our business and provide the highest quality equipment and services to our customers.”

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Sartorius has expanded in the United Kingdom with the relocation to a new facility in Havant, Hampshire, for downstream processing equipment.

Sartorius Opens New Downstream Center of Excellence Facility in UK

 on conducting remote inspections, or, as the agency is calling them, “voluntary remote interactive evaluations (VRIEs)” at pharmaceutical and biologics facilities, using videoconferencing software, 360-degree video inspection, and other tools. The agency had been criticized for failing to take a stand on the use of remote inspection technologies in light of a growing backlog of plant inspections and delays in new drug approvals due to concerns about putting inspection staffers at risk of contracting COVID-19.

The guidance’s wording makes it clear that the agency views use of these technologies as a temporary measure, only for as long as US health authorities continue to define the COVID-19 pandemic as a public health emergency. However, it also suggests that FDA may use remote technologies in the post-COVID-19 world, as a way to supplement inspections, gain additional insights into issues found during a traditional inspection, or clarify questions or support a new drug application. The guidance also hints that technology may be used as a preliminary step, to better define the scope, depth, and timing required for future in-person inspections.

The guidance was issued without the customary public comment period, although FDA’s conservative approach and silence on the subject of remote technology had been discussed widely in the press and at industry events. Remote interactive evaluations would be used for pre- and post-approval inspections, surveillance inspections, follow-up and compliance visits, and bioresearch monitoring inspections.

FDA will use risk-management tools to determine when to ask a facility to participate, and may requests records or ask the company to take part in a VRIE before an on-site inspection.The agency also emphasized that it will not accept requests from facilities to perform inspections remotely, but will notify the facility if it wishes to set up a VRIE. FDA will contact the company and ask for information required to plan the evaluation ahead of time.

In order to prepare for the evaluation, FDA will schedule a brief meeting with the company to discuss staffing, key contacts and roles, logistics, expectations, and to outline key responsibilities. It will also ascertain any time zone differences and needs for interpreters.

Among the issues to be examined would be the facility’s capacity to host such evaluations, specifically the host facility’s internet access and its ability to live stream video and audio during an actual inspection. Discussions will come to an end if it is found that there is insufficient bandwidth or that remote video will not give adequate visibility into the operations or segments of the facility being evaluated.

FDA also says that it will not issue a Form 482 for these evaluations and that it will use its own government-issued Microsoft Teams, Zoom, and Adobe Connect platforms. It also asks that facilities be sure to make electronic documents accessible for sharing.

FDA also asks that facilities that are still using paper documentation ensure that it is scanned into PDFs when possible.

The agency will use technology for “voluntary remote interactive evaluations” for pre- and post-approval and other types of inspections.

FDA Weighs in on Remote Inspections

ILC Dover’s soloPure flexible, single-use aseptic isolator is a cost-effective, closed-barrier system for sterile pharmaceutical drug product manufacturing. The isolator creates a closed, Grade-A, aseptic environment for fill/finish activities requiring positive and negative pressures, and is an alternative to conventional barrier systems.

The disposable chamber allows rapid changeover. The efficient design has a small footprint, enhances operator access with double-sided entry, and mitigates risk with integrity testing throughout its lifecycle. The system is beneficial for handling sterile potent powders and other challenging products that require containment and has options to sterilize in-place with vaporized hydrogen peroxide or operate with a single-use, disposable, gamma-irradiated chamber.

ILC Dover’s soloPure flexible aseptic isolator creates a closed environment for sterile filling. 

Single-Use Isolator Chamber for Sterile Manufacturing

Bristol Myers Squibb (BMS) has announced, in an April 14, 2021 press release, that the European Commission (EC) has approved Opdivo (nivolumab) in combination with Cabometyx (cabozantinib) for the first-line treatment of adults with advanced renal cell carcinoma (RCC).

EC’s decision was based on Phase III trial results demonstrating superior efficacy of the combination treatment versus sunitinib in progression-free survival, objective response rate, and overall survival. Additionally, the combination treatment was found to be well-tolerated with a low rate of treatment related adverse events leading to discontinuation.

“With this approval, we can now offer patients two different Opdivo-based combinations that have demonstrated significant survival benefits versus sunitinib,” said Dana Walker, vice-president, development program lead, genitourinary cancers, BMS, in the press release. “Today’s milestone builds on our heritage of developing and delivering novel treatments for patients with advanced RCC, first with the only dual immunotherapy option, Opdivo plus Yervoy, and now with a new immunotherapy and tyrosine kinase inhibitor regimen.”

“The combination of nivolumab and cabozantinib pairs two proven agents for advanced RCC that together have shown superior efficacy across key endpoints and subgroups of patients compared to sunitinib in the CheckMate -9ER trial. Additionally, the combination’s safety profile was manageable with known protocols, leading to a low rate of treatment-related discontinuations,” added Marc-Oliver Grimm, professor of medicine and urology department head, Jena University Hospital, in the press release. “With today’s approval, clinicians in the EU will be able to offer patients with advanced RCC an additional combination therapy that may help them achieve early control of their disease and improve survival outcomes.”

The European approval is for a flexible dosing regimen of the combination therapy—either using Opdivo 240 mg intravenously every two-weeks or 480 mg intravenously every four-weeks in combination with Cabometyx 40 mg, administered orally once a day. The combination therapy was approved by the US FDA in January 2021, further applications are under review with other regulatory bodies worldwide.

BMS has announced that the EC has approved Opdivo in combination with Cabometyx for the first-line treatment of adults with advanced renal cell carcinoma.



EC Approves BMS’ Opdivo in Combination with Cabometyx for Advanced RCC

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) is continuing its review of very rare cases of unusual blood clots in the US, following administration of Janssen’s COVID-19 vaccine.

According to an April 14, 2021 press release, as a result of six reported cases in the US of cerebral venous sinus thrombosis (CVST), which mostly occurred in instances where there were low levels of blood platelets (thrombocytopenia), Janssen has decided to delay the European rollout of its vaccine while investigations are performed. Janssen’s vaccine was authorized for use in the European Union (EU) on March 11, 2021, but widespread use of the vaccine has not yet started in the region.

EMA is working with the US FDA and other international regulators on the matter and will decide on whether regulatory action is necessary. The evaluation of all reported cases is being expedited and EMA expects recommendation on the matter to be issued within a seven-day period.

While the review is ongoing, EMA maintains that the benefits of the vaccine outweigh the risks of side effects.

EMA's Pharmacovigilance Risk Assessment Committee is reviewing very rare cases of unusual blood clots in the US, following administration of Janssen’s COVID-19 vaccine.

Safety Review of Janssen COVID-19 Vaccine Continues in Europe

The European Medicines Agency (EMA) has confirmed, in an April 14, 2021 press release, that it is continuing to monitor the incidences of very rare blood clots with low blood platelets occurring after vaccination with the AstraZeneca COVID-19 vaccine (Vaxzevria).

A continuation of the safety review is in line with a request from the European Union’s (EU’s) Commissioner for Health and Food Safety following a meeting of EU Health Ministers. Vaccination data and data on epidemiology will be reviewed by EMA.

Through the review, which will be performed by EMA’s Committee for Medicinal Products for Human Use (CHMP), the potential risks of Vaxzevria will be put into context of the benefits for ongoing vaccination campaigns. Additionally, considerations over whether or not recommendations for a second dose of the vaccine will be considered by CHMP.

Overall, EMA considers the benefits of Vaxzevria continue to outweigh any potential risks, the agency stated in the press release. Safety and effectiveness will continue to be monitored and any updates will be provided to the public by EMA.

EMA is continuing to monitor the incidences of very rare blood clots with low blood platelets occurring after vaccination with the AstraZeneca COVID-19 vaccine (Vaxzevria).



Further Context on AstraZeneca COVID-19 Vaccine Risks to be Provided by EMA

According to an April 15, 2021 press release, the European Medicines Agency (EMA) has started its review of monoclonal antibody VIR-7831 (also known as GSK4182136) as a treatment for patients with COVID-19.

VIR-7831 is an investigational dual action SARS-CoV-2 monoclonal antibody that has been developed through collaborative work by GlaxoSmithKline and Vir Biotechnology. The treatment is currently undergoing clinical trials to assess its efficacy and safety in the treatment of adults and adolescents (aged 12 years and older and weighing at least 40 kg) with mild-to-moderate COVID-19, who are at high risk of progressing to more severe COVID-19.

EMA’s review will include data from an interim analysis of the Phase III study, COMET-ICE (COVID-19 Monoclonal antibody Efficacy Trial—Intent to Care Early). The preliminary results indicate that VIR-7831 reduced the risk of hospitalization in patients studied by 85% when compared with placebo.

A more comprehensive rolling review of available data is expected to start prior to a possible application for marketing authorization, although the initial review will provide European Union-wide recommendations. EMA has revealed that it will provide communication on the outcome of the current review once it has been concluded.

EMA has started its review of monoclonal antibody VIR-7831 (also known as GSK4182136) as a treatment for patients with COVID-19.

EMA Review of VIR-7831 for COVID-19 Underway

HTL Biotechnology and Echelon Biosciences have formed a strategic partnership for the distribution of high-quality hyaluronic acid (HA) and glycosaminoglycan (GAG), and the co-development of novel GAG products. The partnership was revealed in an April 14, 2021 press release.

The partnership will enable academic research and pharmaceutical development laboratories to gain expanded access to good manufacturing practice (GMP)-grade, kit-packaged HA and GAG products. The goal of the partnership, and the provision of clinical grade products to early-stage researchers, is to bridge the gap between lab-based research, development, and commercialization.

“Innovation is at the heart of HTL’s DNA,” said Yvon Bastard, CEO, HTL, in the press release. “This growth opportunity reinforces our mission and vision to apply science for increased bio-compatibility and improved health outcomes around the world.”

“This new partnership offers scientists and researchers the key technologies to develop innovative biopolymer solutions for new medical applications in aesthetics, ophthalmology, rheumatology, tissue engineering, and drug delivery,” added Charles Ruban, deputy CEO, HTL, in the press release.

“Echelon has been granted the opportunity to expand its market-leading HA assays and extra cellular matrix product line with the supply of HTL’s HA and other GAG-derived products. HTL is recognized internationally for producing biopolymers of premium quality,” stated Bert Israelsen, president of Echelon Biosciences, in the press release.

HTL Biotechnology and Echelon Biosciences have formed a strategic partnership for the distribution of high-quality HA and GAG, and the co-development of novel GAG products. 

HTL Biotechnology, Echelon Biosciences Announce Strategic Partnership

Biogen UK has announced, in an April 15, 2021 press release, that the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Commission (EC) have granted marketing authorization for the subcutaneous (SC) formulation of Tysabri (natalizumab).

Both regulatory bodies’ approvals mean that adults patients living with highly active relapsing-remitting multiple sclerosis (MS) across the European Union (EU), in the United Kingdom, and Ireland now have access to natalizumab SC. Data from the DELIVER (Phase I) and REFINE (Phase II) trials were used in the regulatory review processes. In the clinical trials, the efficacy and safety of the SC formulation of natalizumab were found to be generally consistent with the intravenous (IV) formulation.

“People have such varied experiences of living with MS, which is why patient choice is a key factor. This treatment option offers flexibility and minimizes the time spent receiving treatment, while still providing continuity of care through access to MS healthcare teams,” said David Martin, CEO, MS Trust, in the press release.

Similarly, as with the IV formulation, the SC formulation of natalizumab is administered once every four weeks by a healthcare professional in a clinical setting. The nature of the SC route of administration means that the clinical setting for the new formulation of natalizumab can be expanded out beyond clinical centers, allowing for the potential of care closer to home.

“This unprecedented year has put the NHS [National Health Service] under significant resource pressures and created new challenges for those living with long-term conditions, like MS, when accessing vital, life impacting treatments,” added Dr Mihaela Vlaicu, head of Medical Affairs UK and Ireland, Biogen UK and Ireland, in the press release. “As our healthcare and everyday environment evolves, we must continue to provide solutions to address capacity and resource concerns within the health service, whilst addressing patient needs. Reinforced by nearly 15 years of real-world evidence and post marketing experience with natalizumab IV, SC offers a new method of delivery that can help to reduce patient time in a hospital setting and increase convenience in clinical practice.”

Biogen UK has announced that the UK’s MHRA and the EC have granted marketing authorization for the subcutaneous (SC) formulation of Tysabri (natalizumab).

MHRA and EC Grant Marketing Authorization for Biogen’s MS Treatment

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

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.

Featured Content

PharmTech’s Technology Forum Series

Feds Direct J&J to Run Operations at Emergent Facility

Supply Chain Hurdles for Vaccine Production

Spray-Dried Dispersion Formulation

Manufacturing Outside the Box