Complicated biomolecules call for alternative drug delivery strategies.

Next-Gen Technologies Tackle Drug Delivery Challenges

Data management strategy is important for generating successful analytical studies.

Increased Data Flow Demands Strategic Management

Early control architecture decisions impact a facility’s long-term capabilities.

Control Strategies for Single-Use Systems

Bioassay studies for biosimilars enables regulatory pathway.

Bioanalytical Studies Support Biosimilars Approval Pathway

Large-scale SUBs prove successful as limits are tested.

SUBs Prove Mettle Amid Growing Demand

Spectroscopy in Biopharmaceutical Analysis  2-Day Virtual Symposium

AstraZeneca’s AZD7442 Clinical Trial Meets Primary Endpoint

FDA Advisory Council Unanimously Supports Moderna COVID-19 Booster EUA

In conjunction with National Chemistry Week (Oct. 17- 23, 2021), Spectrum Chemical Mfg. Corp scientists compiled a list of their top 10 chemicals impacting quality of life, according to the company’s Oct. 2021 press release. This list is based on multiple factors, including contributions to saving lives, ending suffering, and enabling technological advancements that have provided more communication channels, improved access to information, and modernized the healthcare industry.

The “Top 10 Chemicals that Have Impacted Quality of Life”, as selected by Spectrum Chemical Mfg. Corp scientists, are as follows:

“Chemistry plays an essential role in improving the quality of life, as highlighted by the many chemists, scientists, and medical professionals playing a key role in the battle against COVID-19 and other diseases,” said Russell Kneipp, COO, Spectrum Chemical, in the press release.

National Chemistry Week is an annual event to build public awareness of the importance of chemistry to quality of life.

Articles

Spectrum Chemical scientists give a shout-out to 10 chemicals impacting quality of life in conjunction with National Chemistry Week.

Spectrum Chemical Names Top 10 Chemicals Impacting Quality of Life

Pfizer and BioNTech announced favorable results of a Phase III trial evaluating the efficacy of booster doses for their COVID-19 vaccine on Oct. 21, 2021. Participants who were given a booster vaccine in the trial had a disease reduction rate of 95.6% relative to those who did not receive a booster.

The trial included more than 10,000 participants aged 16 years or older. Participants—individuals who were administered the two-dose Pfizer-BioNTech COVID-19 vaccine—were randomized 1:1 to receive either a 30-µg booster dose or placebo. The median time between administration of the second dose and the booster was 11 months.

Symptomatic COVID-19 occurrence was measured from at least seven days after booster or placebo, with a median follow-up of 2.5 months. Five members of the group who received the booster dose contracted COVID-19, while 109 members of the non-boosted group contracted the virus.

“These important data add to the body of evidence suggesting that a booster dose of our vaccine can help protect a broad population of people from this virus and its variants,” said Ugur Sahin, CEO and co-founder of BioNTech, in a Pfizer press release. “Based on these findings we believe that, in addition to broad global access to vaccines for everyone, booster vaccinations could play an important role in sustaining pandemic containment and a return to normalcy.”

 received an Emergency Use Authorization (EUA) from FDA for the use of their COVID-19 vaccine as a booster among certain populations. This week, both 

 also received EUA’s permitting booster doses.

Pfizer and BioNTech’s Phase III trial demonstrated 95.6% booster efficacy relative to participants who received placebo.

Pfizer and BioNTech Release Phase III Trial Data Supporting Efficacy of Booster Doses

Bristol Myers Squibb (BMS) announced on Oct. 21, 2021, that the European Commission (EC) approved its drug Opdivo (nivolumab) as a complementary treatment to fluoropyrimidine- and platinum-based combination chemotherapy in adult patients with certain types of gastric or esophageal cancer. Nivolumab is a programmed death-1 immune checkpoint inhibitor that is designed to use one’s immune system to help restore the anti-tumor immune response.

According to a company press release, EC’s decision was made following a Phase III trial that evaluated nivolumab. The study found a clinically meaningful improvement in overall survival (OS) and progression-free survival (PFS) in patients given nivolumab who had unresectable advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. These results were found in patients whose tumors expressed a combined positive score greater than or equal to five.

The study evaluated OS and PFS rates among patients who received nivolumab and chemotherapy relative to patients who received only chemotherapy. According to BMS, median OS was 14.4 months in patients receiving nivolumab vs. 11.1 months in those receiving chemotherapy alone, while median PFS was 8.31 months in patients receiving nivolumab vs. 6.05 months chemotherapy alone.

“This approval marks a great achievement for many patients with gastric, gastroesophageal junction, and esophageal adenocarcinomas, who now have a new treatment option that has demonstrated superior overall survival compared to the long-standing standard of care,” said Ian M. Waxman, development lead, Gastrointestinal Cancers, BMS, in the press release. “With limited advances for [human epidermal growth factor receptor 2]-negative gastric cancers made in the past 10 years, we are especially pleased to move the field forward and introduce this [nivolumab]-based combination for patients in the European Union.”

The EC approved BMS’s Opdivo (nivolumab) as a complementary treatment to chemotherapy for adult patients with certain types of gastric or esophageal cancer.

Bristol Myers Squibb Receives European Commission Approval for Opdivo

Jennifer Markarian is manufacturing editor of BioPharm International.

Cellectis, an international, clinical-stage gene editing company, recently opened a manufacturing facility in Raleigh, NC. The new, 82,000-ft

 good manufacturing practice (GMP) facility is purpose-built for manufacturing allogeneic, universal chimeric antigen receptor T-cell (UCART) immunotherapies for oncology. UCART products are manufactured using the T-cells of a healthy donor to make off-the-shelf and ready-to-use gene-edited CAR T-cells. T-cells from one donor, used in one manufacturing batch of UCART, can make hundreds of doses of product, the company reports. 

 GMP facility in Paris, France was opened in 2020 and makes clinical and commercial critical starting materials including plasma DNA, messenger RNA (mRNA), and viral vectors that are used in UCART manufacturing. The two facilities give the company end-to-end in-house manufacturing capabilities for GMP manufacturing of all critical starting materials and cell products for clinical studies and, eventually, commercial distribution. 

The newly opened facility in Raleigh, NC, includes ambient GMP warehousing and cold-storage space, cryogenic storage for incoming white blood cells and for final products, manufacturing spaces, quality control laboratories, utility and maintenance areas, and office areas. Two UCART manufacturing suites each hold a custom designed, four-chamber isolator that encloses all parts of the manufacturing process, including Cellectis’ proprietary electroporation system that enables its TALEN gene editing technology.

“The manufacturing process includes manual steps that operators perform through glove ports in the isolators, which create a Grade A environment,” explains Steve Doares, senior vice-president of US manufacturing and Raleigh site head at Cellectis. “UCART processing can’t use in-process or terminal filter sterilization, so we must maintain an aseptic state from beginning to end. Rather than putting the process equipment inside biosafety cabinets, we chose to completely enclose them in isolators to give the best possible assurance of product quality for the patient.”

A separate filling suite contains a single-chamber isolator with a robotic filling system. Vials are filled, inspected, labeled, and frozen under highly controlled conditions. Doares notes that the manufacturing process uses single-use systems, which he says are most suitable for the scale of this process.

“Having control over the entire development, manufacturing, and production process helps eliminate setbacks in the product development timeline that could hinder delivery of medicines to patients, which is an issue biotech companies have struggled with during the COVID-19 pandemic,” notes Doares.

A new GMP facility in Raleigh, NC, and a starting materials facility in Paris, France, give Cellectis end-to-end, in-house manufacturing capacity for its UCART product candidates.  

Cellectis Opens GMP Manufacturing Facility

UK-based crystal and particle-engineering company, Crystec, and Argentinian company, Biosidus, have joined forces to enhance the delivery and performance of biotherapeutics, it was announced in an Oct. 19, 2021 press release.

Using Crystec’s proprietary modified supercritical antisolvent (mSAS) supercritical fluid particle engineering platform on selected Biosidus products, the companies hope to be able to generate a range of innovative, differentiated medicines. Initially, the partnership will focus on accelerating the development of a dry powder preparation of teriparatide for the treatment of osteoporosis.

Currently, teriparatide typically needs to be administered by daily injections over a two-year period. Crystec and Biosidus are hoping to be able to eliminate the need for daily injections by developing the dry preparation of the drug that can be used in formulations for administration via alternative routes, such as the nose.

“We are passionate about making our vital therapies accessible and convenient for those who require them. Our ultimate ambition is to eliminate the need for daily injections meaning that men, women, and children who suffer from long-term and chronic illnesses are not subjected to additional discomfort in the course of their treatment,” said Marcelo Criscuolo, scientific director at Biosidus, in the press release. “Working with Crystec’s innovative mSAS technology opens up the possibility of maximizing the therapeutic potential of these drugs through retaining improved biological activity levels and enabling ‘needle free’ delivery options for our patients.”

“We are delighted to work with Biosidus in this important area of drug delivery,” added Paul Thorning, CEO, Crystec, in the press release. “Our collaboration provides significant potential to demonstrate the power of the mSAS platform in simplifying biopharmaceutical processing, whilst facilitating the accelerated development of inhaled and nasal products that could be truly transformative for patients.”

Crystec and Biosidus have joined forces to enhance the delivery and performance of biotherapeutics.

Crystec, Biosidus Collaborate on Enhanced Delivery and Performance of Biotherapeutics 

The European Medicines Agency (EMA) has recommended the marketing authorization of a first-in-class medicine, Trodelvy (sacitusumab govitecan), to treat patients with an aggressive form of breast cancer.

More specifically, it was revealed in an Oct. 15, 2021 press release that the recommendation is for Trodelvy to be used in the treatment of adult patients with unresectable or metastatic triple-negative breast cancer who have already received two or more systemic therapies, with at least one of those treatments being for advanced disease. As patients with this aggressive form of breast cancer tend to be unresponsive to the standard treatment, chemotherapy, there is a high unmet medical need for new treatments in this area to improve patients’ outcomes.

Trodelvy combines a humanized antibody with a type of an antineoplastic agent called topoisomerase I inhibitor, which are intended to inhibit cancer growth, division, and spread. The marketing authorization application for the treatment has been evaluated under an accelerated process in efforts to speed up patient access to the medicine.

The regulatory authority’s recommendation was based on the data from a Phase III clinical trial that evaluated the safety and efficacy of Trodelvy in 529 patients. In the trial, it was found that the therapy helped to prolong the overall survival of patients by approximately five months and progression-free survival by approximately three months.

This recommendation will now be sent to the European Commission for a final decision on marketing authorization for the European Union. If a positive final decision is made, each European member state will make decisions on price and reimbursements for the medicine

EMA has recommended the marketing authorization of Trodelvy (sacitusumab govitecan) to treat patients with an aggressive form of breast cancer.

Trodelvy Gains EMA Nod for Treatment of Aggressive Form of Breast Cancer

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has approved two new manufacturing sites and a ready-to-use formulation of the BioNTech-Pfizer COVID-19 vaccine, Comirnaty.

Announced in an Oct. 18, 2021 press release, the two new manufacturing sites are both located in Italy—one in Monza, operated by Patheon, and the other in Anagni, operated by Catalent Anagni. Both sites are set to manufacture finished product and are expected to be able to produce up to 85 million addition doses of the COVID-19 vaccine to the European Union before the end of 2021.

The ready-to-use formulation that has been approved by CHMP does not require dilution prior to administration and will be available in a 10-vial (60 dose) pack size. The new formulation can be stored at 2–8 °C for up to 10 weeks. Currently, the concentrated formulation of Comirnaty needs to be diluted before use and can only be stored for up to one month at 2–8 °C. So, the new formulation should provide better storage, transport, and logistic options for distribution and administration.

According to the press release, the new formulation will be rolled out in a phased way commencing in early 2022.

EMA's CHMP has approved two new manufacturing sites and a ready-to-use formulation of Comirnaty.

EMA Approves Two New Manufacturing Sites and a New Formulation for Comirnaty

The European Medicines Agency (EMA) has commenced its evaluation of the BioNTech-Pfizer COVID-19 vaccine, Comirnaty, in children who are aged between five years and 11 years old, to determine if it can be authorized for further expanded use.

According to an Oct. 18, 2021 press release, EMA’s Committee for Medicinal Products for Human Use (CHMP) will review available data on the vaccine, which include results from a clinical study involving children between five and 11 years old that is ongoing. Once CHMP has formed a decision on whether or not an extension of the use of Comirnaty is appropriate it will forward all information onto the European Commission for a final decision.

EMA has specified in the press release that it will “communicate on the outcome of its evaluation, which is expected in a couple of months unless supplementary information is needed.”

EMA has started its evaluation of further expanded use of Comirnaty in children aged between five years and 11 years old.

EMA Starts Evaluation of Comirnaty in Children

The government of the United Kingdom has secured two new antiviral treatments for COVID-19, it was revealed in an Oct. 20, 2021 press release. The deals were made by the government’s Antivirals Taskforce and could be rolled out through a national clinical study before the end of 2021.

“I am delighted to confirm we may soon have a new defense in our arsenal with two new antiviral drugs that we have secured,” said Sajid Javid, health and social care secretary for the UK government, in the press release. “Our work is far from done though—and we’ll continue our tireless work to secure more innovative treatments so we can protect as many people as possible from the virus, its variants, and future diseases.”

Primarily, the antivirals—Molnupiravir (MSD) and PF-07321332/ritonavir (Pfizer)—will be used for the most vulnerable patients, including the elderly and those with weakened immune systems. Both treatments will need to be evaluated by the UK’s regulatory body the Medicines and Healthcare products Regulatory Agency (MHRA) before they are authorized.

“This is a very important development in our mission to find antivirals for those exposed to COVID-19, supporting the renowned vaccination program and the [National Health Service] over the coming months,” added Eddie Gray, chair of the Antivirals Taskforce, in the press release. “Should they be approved by the medicines regulator, we could see these treatments rolled out to patients this winter, providing them with vital protection.”

In response to the government’s announcement, Richard Torbett, chief executive of the Association of the British Pharmaceutical Industry commented in a press statement, “Vaccines have already done so much to help break the link between infections and hospitalizations. Antivirals are another line of defense for the most clinically vulnerable and patients who are seriously ill with COVID-19. This is good news, and another example of the pharmaceutical industry and government working together to make sure we have as many effective tools as possible to tackle this pandemic.”

UK government has secured two new antiviral treatments for COVID-19, which may be rolled out in a national clinical study before the end of 2021.

UK Government Announces Deal to Secure Two New COVID-19 Antivirals

FDA announced on Oct. 20, 2021, that it had amended its Emergency Use Authorization (EUA) for various COVID-19 vaccines. The Moderna and Johnson & Johnson (J&J) vaccines can both be administered as booster doses under certain conditions. Additionally, the amendment allows for heterologous booster shots, which use boosters of vaccines different from what the recipient received for their base vaccination.

Similar to Pfizer’s vaccine, which received limited booster approval 

, a booster of Moderna’s COVID-9 vaccine is authorized for the following populations six months after their original vaccination:

Individuals aged 18 through 64 at high risk of severe COVID-19

Individuals aged 18 through 64 with frequent institutional or occupational exposure to SARS-CoV-2.

J&J’s product, a single-shot vaccine, received more broad usage. Any individuals aged 18 or older can receive a booster dose of this vaccine two months after their first shot.

FDA also chose to allow for heterologous booster shots following a presentation of clinical trial data from the National Institute of Allergy and Infectious Diseases, the Vaccines and Related Biological Products Advisory Committee’s discussion of information submitted for consideration, and the agency’s own evaluation of available data. Eligibility requirements are the same as those authorized for the individual’s primary vaccination.

“The amendments to the [E]mergency [U]se [A]uthorizations to include a single booster dose in eligible populations are based on the available data and information and follows the input from the members of our advisory committee who were supportive of the use of a booster dose of these vaccines in eligible populations,” said Peter Marks, director of FDA’s Center for Biologics Evaluation and Research, in an agency press release. “We are also taking action today to include the use of mix and match boosters to address this public health need. We will work to accrue additional data as quickly as possible to further assess the benefits and risks of the use of booster doses in additional populations and plan to update the healthcare community and public with our determination in the coming weeks.”

In addition to allowing booster shots of the Moderna and J&J vaccines, FDA approved heterologous booster shots.

FDA Amends EUA to Allow Booster Shots for Moderna, J&J COVID-19 Vaccines

 Washington Editor, jillwechsler7@gmail.com.

In its ongoing campaign to encourage industry adoption of more efficient and reliable pharmaceutical production methods, FDA is expanding its Emerging Technology Program (ETP) and providing more support for new drug applications (NDAs) that present advanced manufacturing technologies. While these initiatives aim to limit drug shortages and recalls due to quality issues, the program also seeks to expand investment in domestic production to enhance access to critical therapies and vaccines for patients in the United States. At the same time, the agency is collaborating with foreign regulatory authorities to support international harmonization of policies designed to advance continuous manufacturing operations for drugs and biotech therapies around the world.

Congress is supporting these efforts, as seen in the recent House passage of legislation (HR 4369) to create national centers for excellence in continuous manufacturers at universities around the country. The measure benefitted from strong bipartisan support for authorizing $100 million to fund programs at several academic centers designed to improve drug quality and mitigate shortages.

The challenges of meeting urgent demands for more new medical products during the COVID-19 pandemic has highlighted the value of more responsive and flexible manufacturing methods, including manufacturing systems that can be scaled up more quickly and automated processes that can reduce in-plant staff and permit more flexible employee work schedules. These developments have increased collaboration and partnering among biopharma manufacturers over the past 18 months, as competitors have worked together to accelerate access to needed therapies by providing fill/finish services for vaccine makers and APIs for finished dosage forms, among other joint efforts.

These issues and opportunities will be discussed at an FDA conference on innovations in pharmaceutical manufacturing, as outlined in 

a report on the topic issued in March 2021

 by the National Academy of Sciences, Engineering and Medicine (NASEM). This review requested by for the Center for Drug Evaluation and Research (CDER) of the importance and challenges for advancing innovative biopharmaceutical manufacturing aims to reduce quality-related shortages that can limit patient access to safe and effective drugs. The virtual 

will discuss industry advances in manufacturing systems and policies and actions for moving forward.

CDER support for these initiatives appears to be having an impact, according to in a recent 

. CDER Director Patrizia Cavazzoni and Michael Kopcha, director of CDER’s Office of Pharmaceutical Quality (OPQ), note that the agency approved its first application for a drug produced by continuous manufacturing in 2015 and 10 more applications since then that utilize advanced approaches for finished dosage forms, APIs, and biological molecules. Now more than 100 proposals utilizing a range of innovative technologies have been presented to agency officials, necessitating an expansion in the ETP program to handle the workload.

FDA’s advanced manufacturing initiative also aims to enhance the competitiveness of US firms in the global pharmaceutical market by lowering costs and promoting quality. Acting Commissioner Janet Woodcock cites visible success in this area in a tweet posted Oct. 15, 2021, reporting that more than 80% of the drugs made using advanced manufacturing technologies are produced domestically. An FDA Center for Advancement of Manufacturing Pharmaceuticals and Biopharmaceuticals established in June 2021 is coordinating analysis related to such topics as end-to-end continuous manufacturing, portable and modular distributed manufacturing platforms, and use of artificial intelligence or advanced modeling approaches in manufacturing.

At the same time, FDA is promoting international coordination and agreement on the scientific issues and regulatory policies related to implementing and overseeing modern drug manufacturing, as seen in the 

new draft Q13 guidance developed through the International Council for Harmonisation (ICH)

. FDA recently posted the initial version of this standard for Continuous Manufacturing of Drug Substances and Drug Products, which applies to new drugs, generics, therapeutic proteins, and biosimilars. Manufacturers and other stakeholders should submit comments on the draft document to FDA by Dec. 13, 2021.

This ICH initiative aims to advance biopharmaceutical quality through operations that reduce manual handling that leads to human error, utilize online monitoring and controls, increase manufacturing speed and efficiency, and install smaller equipment that cuts costs.Ultimately advanced manufacturing systems would enable firms to respond “more nimbly” in the event of drug shortages and to adopt tailored systems that fit the needs of precision medicine.

Yet, FDA and industry face key challenges in advancing these initiatives. The agency’s traditional focus on ensuring the safety and efficacy of novel therapies has discouraged manufacturers from adopting less traditional production processes, especially when the evaluation of advanced manufacturing systems in an NDA might complicate or delay market approval. To move forward in this area, the NASEM report points out that FDA needs a program for evaluating innovative manufacturing processes and mechanisms outside the traditional NDA process, along with flexible and efficient procedures for processing post-approval changes to advance modern manufacturing methods for approved products. CDER leaders note that Congress has provided important funding to support advanced manufacturing, but that the agency will require added expertise and resources to progress further in building its capacity for assessing multiple novel technologies.

FDA is expanding its Emerging Technology Program and providing more support for new drug applications that present advanced manufacturing technologies. 

FDA Highlights Value and Challenges of Advanced Drug Manufacturing

FDA announced on Oct. 18, 2021, that it has approved Boehringer Ingelheim’s Cyltezo (adalimumab-adbm) as an interchangeable biosimilar for Humira (adalimumab). This designation indicates that adalimumab-adbm has no clinically meaningful differences from adalimumab.

Following this designation, adalimumab-adbm is approved for:

moderate to severe rheumatoid arthritis in adult patients

moderate to severe ulcerative colitis in adult patients

moderate to severe chronic plaque psoriasis in adult patients

severe polyarticular juvenile idiopathic arthritis in patients two years or older

Crohn's disease in patients six years or older.

Adalimumab-adbm is the second interchangeable biosimilar to be approved by FDA, and the first interchangeable monoclonal antibody. FDA has approved a total of 31 interchangeable products.

“The biosimilar and interchangeable approval pathway was created to help increase access to treatment options for patients with serious medical conditions,” said Janet Woodcock, acting FDA commissioner, in an agency press release. “We continue to be steadfast in our commitment to provide patients with alternative high-quality, affordable medications that are proven to be safe and effective.”

Boehringer Ingelheim’s Cyltezo (adalimumab-adbm) is the first FDA approved interchangeable biosimilar for Humira.