Improving Aseptic Processing and Manufacturing Needs

Drug Digest

Laboratories are focusing on more automated processes while also trying to maintain quality with each analytical test.

Testing Innovative Analytical Waters

Quality Quartets may be used to achieve knowledge-driven, risk-based approaches to commissioning and qualification that are consistent with ICH Q9(R1) principles.

Quality Quartets in Risk-Based Qualification: ICH Q9(R1) Considerations

The biggest hurdle is developing palatable formulations that are efficacious and patient friendly.

Overcoming Challenges to Formulation Development for Pediatric Medicines

A comprehensive understanding of what makes mRNA vaccines tick is crucial in charting the future of the market.

Charting the Future of Vaccines

Interoperability difficulties resulting from discrepancies in preferred programming languages can be resolved via statistical computing environments.

Exploring the Skills Gap in Statistical Programming Organizations

Drug Solutions

FUJIFILM Diosynth Biotechnologies has completed its new facility in Darlington, United Kingdom, which is now operational and can carry out current good manufacturing practice (CGMP) manufacturing of viral vector-based gene therapies, oncolytic viruses, and viral vaccines for clinical trials. The completion of this facility is part of the company’s investment strategy to address the increased demand for production of early stage clinical trial (first-in-human) investigational viral vector products, the company stated in a Sept. 14, 2023 press release.

The new CGMP site houses dedicated high containment clean rooms for viral vector manufacturing and segregated viral and non-viral suites. The facility holds a cell culture capacity of up to 200 L. The addition of the Darlington facility adds to the company’s global locations, which include College Station, Texas, and Watertown, Mass., in the United States (1).

“We are excited to continue working with our biopharmaceutical partners, including early-stage companies, to help them bring new gene therapies to market, which hold tremendous promise in revolutionizing treatment options for patients,” said Jonathan Haigh, head of UK site at FUJIFILM Diosynth Biotechnologies, in the press release. “Our advanced therapy integrated network, including an ongoing commercial viral gene therapy expansion in nearby Billingham, UK, allows customers to benefit from our end-to-end cell and gene therapy services provided by our highly skilled workforce.”

“In addition to providing increased manufacturing capacity for our early stage customers, we look forward to helping them efficiently navigate preclinical and Phase I hurdles by offering complementary services for fast, yet flexible drug candidate screening as well as feasibility studies,” Haigh added in the release. “This additional support will help biopharmaceutical customers create a simple, modular path to cGMP manufacturing, minimizing risk and streamlining drug substance and drug product manufacture for the clinic.”

1. FUJIFILM Diosynth Biotechnologies, Globally Integrated CGMP Production. 

Articles

FUJIFILM Diosynth Biotechnologies has finished its new viral vector gene therapy manufacturing facility in Darlington, United Kingdom.

FUJIFILM Diosynth Biotechnologies Completes New Viral Vector Gene Therapy Manufacturing Facility in UK

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On Sept. 20, 2023, Alexion, AstraZeneca’s rare disease group, completed the purchase and license agreement for a portfolio of preclinical rare disease gene therapy programs and enabling technologies from Pfizer. The acquisition cost AstraZeneca up to $1 billion, with the addition of tiered royalties on sales.Alexion hopes to create new genetic therapies, improving their safety and efficacy; the portfolio will bolster Alexion and AstraZeneca’s current work on genomic medicine.

Alexion entered into the agreement with Pfizer near the end of July 2023. The profile included sever novel adeno-associated virus (AAV) capsids, which have demonstrated to be effective for delivering therapeutic gene cargos for gene therapy and gene editing. Alexion reported that several Pfizer employees associated with the portfolio will join Alexion’s team as employees.

Alexion was formed as a group within AstraZeneca that focuses on rare diseases, following AstraZeneca’s acquisition of Alexion Pharmaceuticals in 2021. Alexion centers its research on novel molecules, focusing on the complement cascade and its development efforts on hematology, nephrology, neurology, metabolic disorders, cardiology, and ophthalmology.

, Marc Dunoyer, chef executive office at Alexion, said, “Today’s announcement represents another major step forward in Alexion and AstraZeneca’s ambition to be an industry leader in genomic medicine, which has potential to be transformative and even curative for patients with devastating diseases. We look forward to continuing our work to develop enhanced platforms and technologies with broad therapeutic application while integrating best-in-class expertise to accelerate promising therapeutics into the clinic.”

The AstraZeneca rare disease group hopes to use these new gene therapy programs to bolster its work on genomic medicine.

Alexion Completes Purchase and License Agreement of Rare Disease Gene Therapy Portfolio from Pfizer

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On Sept. 19, 2023, Pfizer announced that the European Commission (EC) granted marketing authorization for LITFULO (ritlecitinib) as a treatment for patients 12 years and older with severe alopecia areata. LITFULO is a daily oral capsule, and according to Pfizer it is the first medicine authorized by the EC to treat patients as young as 12 with severe alopecia areata. Pfizer also stated that LITFULO is “the first and only treatment to selectively inhibit Janus kinase 3 (JAK3) and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) family of kinases.”

The marketing authorization extends to all EU member states, as well as Liechtenstein, Iceland, and Norway. It follows approvals by FDA and the Japanese Ministry of Health, Labor and Welfare in June 2023. The EC approval was based on results from Pfizer’s ALLEGRO clinical trial program, which studied LITFULO in individuals 12 years and older with alopecia areata with 50% or more hair loss on the scalp. The study included those with total hair loss (alopecia totalis) and total body hair loss (alopecia universalis). The study reported that at 24 weeks of treatment, 13.4% patients receiving treatment with LITFULO 50 mg saw 90% or more scalp hair coverage as compared to 1.5% with placebo. Almost half of participants (49.2% ) receiving LITFULO reported “moderate” to “great” improvement in their alopecia areata as compared to 9.2% with placebo.

As of the publishing date of this article, Pfizer is conducting an open-label, long-term Phase III study, ALLEGRO-LT. This study is collecting data for adults with alopecia areata with 25% or greater scalp hair loss and adolescents with alopecia areata with 50% or greater scalp hair loss. Data from this study was included in the submission for approval to the EC.

Pfizer reports ritlecitinib is the first and only treatment for alopecia areata to selectively inhibit Janus kinase 3, and to treat patients as young as 12.

The European Commission Approves Severe Alopecia Areata Treatment

In part of the session "Continuous Manufacturing and Publication of ICH Q13" at the PDA/FDA Joint Regulatory Conference, Kelley Burridge, PhD, Product Quality Team Leader, OBP, OPQ, CDER, U.S. FDA, discusses the importance of continuous manufacturing for the future. 

Continuous manufacturing is here. An evolution of pharmaceutical quality over the last several decades started with adoption of risk based approaches, as this analytical Technology and Quality by design have set the stage for adoption of continuous manufacturing. What's needed for approval of continuous manufacturing packages is the same as what's needed for batch processes. A demonstration of pharmaceutical quality demonstrate that you understand your product and your process and that you have the capability to operate a well controlled process, consistent with manufacturer's quality guide.

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Kelley Burridge, PhD, Product Quality Team Leader, OBP, OPQ, CDER, U.S. FDA, discusses the importance of continuous manufacturing for the future. 

Continuous Manufacturing is Here to Stay (PDA/FDA Joint Regulatory Conference 2023)

Editor of Pharmaceutical Technology Europe

The European Commission (EC) has approved a novel oral fixed-dose combination treatment—INAQOVI (oral decitabine and cedazuridine)—for use in adult patients with newly diagnosed acute myeloid leukemia (AML) who cannot have standard induction chemotherapy.

According to a Sep. 19, 2023 press release, Otsuka Pharmaceutical Europe and Astex Pharmaceuticals’ INAQOVI’s commission approval was based on the results from a Phase III clinical trial (ASCERTAIN), which investigated the pharmacokinetic exposure equivalence of the therapy against intravenous (IV) decitabine in AML patients. The Phase III trial, which included 89 AML patients, successfully met its primary endpoint, demonstrating that the orally administered therapy achieved equivalent pharmacokinetic exposure to that achieved with IV decitabine and both with similar pharmacodynamic activity. The safety of the oral treatment option was considered to be consistent with that of the IV decitabine.

INAQOVI is an oral treatment combining decitabine (35 mg)—an approved hypomethylating agent (HMA)—with cedazuridine (100 mg)—an inhibitor of cytidine deaminase. The therapy works through inhibiting cytidine deaminase in the gut and liver, which allows for systemic exposure to decitabine through oral administration that is comparable to that achieved intravenously over a five-day period. With the EC’s approval, INAQOVI is the first oral therapy that incorporates a hypomethylating agent (decitabine) licensed within the European Economic Area for the treatment of AML patients.

Currently, AML patients are either administered IV chemotherapy infusions in a hospital setting, or administered hypomethylating agents parenterally when chemotherapy is not applicable. An oral option for the treatment of AML can help to improve quality of life for this patient population.

Furthermore, the European Medicines Agency agreed to a Paediatric Investigation Plan for the oral fixed-dose combination in June 2022, which has the potential to lead to clinical trials for the use of this therapy in children with AML.

Otsuka Pharmaceutical Europe and Astex Pharmaceuticals have announced the approval of INAQOVI by the European Commission.

EC Approves Fixed-Dose Oral Combination Treatment for AML 

A major revision of the International Council for Harmonisation’s (ICH) Q9 (R1) was published earlier in 2023, and the updates help to gain an understanding of lifecycle management, training materials, and other insights important to the industry, according to a session at the 2023 PDA/FDA Joint Regulatory Conference in Washington, DC (1).

In the session “The New ICH Q9 Guideline: The Next Generation of Quality Risk Management,” Alex M. Viehmann, division director, Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA, and Denise M. DiGiulio, head of Global Audit and Inspection Management, Genentech, both gave an overview of the changes to ICH Q9 (R1) and the lifecycle management of risks to ensure an ongoing state of control.

https://www.pharmtech.com/view/quality-quartets-in-risk-based-qualification-ich-q9-r1-considerations

https://www.pharmtech.com/view/navigating-the-formality-spectrum-in-ich-q9-r1-

https://www.pharmtech.com/view/knowledge-as-the-currency-of-managing-risk-a-smart-investment-for-patients 

Viehmann dived into the milestones of ICH Q9 R1, including the revision topics of subjectivity in quality risk management (QRM), product availability risks, formality in QRM, risk-based decision making, risk review, and hazard identification. As for the topic of subjectivity, Viehmann said how high levels of subjectivity in risk assessments and in QRM are problematic and are not aligned with the 1st QRM principle of Q9. Although this cannot be fully eliminated, it can be controlled by addressing bias and assumption with the proper use of QRM tools and use of relevant data.

Another example of a revision Viehmann went over is formality, in which many of those in the industry, including regulators, have a lack of understanding and uncertainty surrounding the topic. “This was a big revision topic because we wanted to get rid of the concept of formality, like there is informal versus formal,” he said. The ICH Q9 R1 addresses this issue with the inputs of complexity, importance, and uncertainty, which should lead to the proper resources for QRM activity to be used more efficiently.

According to DiGuilio, QRM includes taking into account new knowledge and experience and certain lifecycle events that can impact the original quality risk management decision. This may trigger risk review, as processes need to be reevaluated to continue to be improved, and the knowledge we gain through experience after initial launch and commercial manufacturing can help the improvements align with ICH Q10.

In a case study example, DiGuilio described the role of QRM in an aging facility, as it downgraded from an initial qualification site with highly formal QRM experts and knowledge in a state of control to facility deterioration, with no upgrades to technology or any upkeeping due to a lack of knowledge in 10 year’s time. This also impacted the long-term cost and product availability, which needed a resolution. DiGuilio explained how a critical senior management role to maintain ongoing oversight to ensure sustainability of operational design, control, maintenance, repairs, and more can be beneficial.

There are also early warning signals, such as increase in equipment issues, higher levels of deviations, and a reactive management, because these concepts cannot ensure quality performance. As for implementing ICH Q9 (R1) in the industry and not in the case study, DiGuilio said how QRM is not a one-time activity, it is what the industry does on a daily basis. “I think it’s about creating a culture regulatory compliance and following risk awareness, and understanding that QRM isn’t really a one-time activity,” she said.

DiGuilio, D; Viehmann, A. The New ICH Q9 Guideline: The Next Generation of Quality Risk Management. Presentation at the 2023 PDA/FDA Joint Regulatory Conference, Washington, DC, Sept. 18–20, 2023.

As for the topic of subjectivity, Viehmann said how high levels of subjectivity in risk assessments and in QRM are problematic and are not aligned with the 1st QRM principle of Q9.

ICH Q9 R1 Hits Major Milestones for the Pharmaceutical Industry

Feliza Mirasol is the science editor for 

On Sept. 20, 2023, Orionis Biosciences, a privately held US-based life sciences company with an integrated drug discovery and chemical biology platform, announced that it has entered into a multi-year collaboration with Genentech, a member of the Roche Group, under which the companies will discover novel small-molecule therapeutics for challenging disease targets, including oncology and neurodegeneration.

Under the agreement, Orionis will discover and optimize molecular glues using its Allo-Glue platform. The molecular glues will be used for Genentech’s designated targets. For its part, Genentech will take care of subsequent later-stage preclinical, clinical development, regulatory filing, and commercialization of such small molecules discovered through the collaboration. Orionis will get an upfront payment of $47 million and will also be eligible to receive development milestone payments, including commercial and net sales milestone payments, that may exceed $2 billion. The company can also receive a tiered royalty upon sale of collaboration products.

Orionis’s Allo-Glue platform works by using multiple unique approaches to discover drug-like small molecules against disease targets, particularly targets that have remained elusive to traditional discovery approaches. The platform is built on the integration of a suite of proprietary chemical biology technologies, including biological assays, computational analyses, chemical libraries, and automated processes. The platform allows for high throughput discovery, rational design, and optimization of small molecules that promote or induce interactions of proteins in living cells. Such molecules include molecular glues which have been shown to promote interactions that lead to either target degradation (via a ligase) or modulation of target function (via either direct or allosteric mechanisms), according to a company press release.

“Molecular glues represent one of the most exciting recent developments in small-molecule drug discovery. We are thrilled to collaborate with Genentech, a company long known for its world-class science and trailblazing medicines, to make use of technological innovations that we have systematically evolved over the past years to unlock novel target space with such drug modalities,” said Nikolai Kley, co-founder and CEO of Orionis Biosciences, in the press release. “We could not be more excited about the potential for this pioneering collaboration to lead to impactful new treatment paradigms.”

“Molecular glue degraders are an exciting modality to target disease-related proteins that have proven challenging with more traditional treatment modalities,” said James Sabry, global head, Roche Pharma Partnering, in the press release. “For patients with unmet needs, this offers a new therapeutic approach to modulate major disease drivers. This collaboration enables us to apply the concept of targeted protein degradation to discover and develop medicines for patients with serious and life-threatening diseases.”

Under the collaboration, Orionis will receive $47 million upfront to leverage its Allo-Glue platform to discover small-molecule monovalent glues.

Genentech Partners with Orionis Biosciences to Discover and Develop Molecular Glue Class Medicines

Korean contract development and manufacturing organization (CDMO), Samsung Biologics, has announced, in a Sep. 18, 2023 press release, a new agreement for the large-scale manufacturing of an antibody cancer drug substance with global biopharma company Bristol Myers Squibb.

This new agreement between the two companies adds to their long-standing strategic relationship, originally formed in 

. According to the terms of this latest arrangement, Samsung Biologics will be responsible for the drug substance manufacturing of a Bristol Myers Squibb antibody cancer drug at its biomanufacturing facility, Plant 4, located in Songdo, South Korea.

“Our relationship with Bristol Myers Squibb spans over a decade, and we are proud and excited to help bring important medicines to patients around the world,” said John Rim, president and CEO of Samsung Biologics, in the press release. “This collaboration with Bristol Myers Squibb underscores our commitment to expediting the delivery and ensuring the continuous supply of client pipelines, enabled by our commitment to manufacturing quality, innovation, and capacity.”

, voluntarily disclosed by Samsung Biologics, this new deal is contracted run until the end of December 2030—subject to change depending on contract terms—and is worth a little under $242 million.

This expanded agreement with Bristol Myers Squibb is another boost to Samsung Biologics’ relationship with Big Pharma. In 

, the CDMO also announced a collaboration with Pfizer, focusing on long-term biosimilars manufacturing. Under the terms of this agreement, Samsung Biologics is using its Plant 4 facility to provide Pfizer with additional large-scale manufacturing capacity for a multi-product biosimilars portfolio covering oncology, inflammation, and immunology.

Furthermore, earlier in the year (March 2023), Samsung Biologics revealed that its plans to 

 at the Songdo site (Plant 5) in response to increased market demand. Operations at this plant are expected to start in 2025.

Samsung Biologics and Bristol Myers Squibb have further expanded their strategic manufacturing agreement to include the large-scale manufacture of an antibody cancer drug substance. 

Samsung Biologics Expands Strategic Manufacturing Agreement with Bristol Myers Squibb

CN Bio, a organ-on-a-chip (OOC) company specializing in the design and manufacture of single-and multi-organ microphysiological systems (MPS), has partnered with LifeNet Health LifeSciences (LifeNet Health), a non-profit provider of all-human research solutions, to supply validated primary human cells. The cells will be used with CN Bio’s PhysioMimix OOC range of MPS.

Under the agreement, LifeNet Health’s MPS-validated, hepatic cells will be made available either within CN Bio’s non-alcoholic steatohepatitis (NASH) “in-a-box” kit or directly from LifeNet Health. The companies expect that this partnership will provide a streamlined solution for the recreation of CN Bio’s advanced 

 liver models and that the combination will maximize assay success.

According to a Sept. 6, 2023 company press release, CN Bio will use a stringent process to pre-qualify select hepatocyte, stellate, and Kupffer cells that are proven to thrive in extended 3D MPS culture. These cells will have to show that they maintain function and phenotype for a minimum of two weeks. It is known that lot validation in standard static 2D or 3D cell cultures does not guarantee the performance of primary cells in perfused MPS cultures. CN Bio carried out an analysis over a five-year period where it demonstrated that greater than 60% of hepatocyte cell lots across various suppliers failed to meet acceptable performance criteria for MPS assays. Thus, pre-validating cell lots for use in MPS assays is necessary, and it ensures that robust and reliable human-relevant data can be generated, according to the company press release. However, the validation process itself requires that additional resource, time, and budget be factored in.

“LifeNet Health and CN Bio share a commitment to helping researchers bring safer, more effective therapies to patients sooner, with no unnecessary animal testing,” said Tomasz Kostrzewski, chief scientific officer, CN Bio, in the press release. “In our studies, LifeNet Health’s cells have consistently shown high success rates, and we are confident this will lead to more reliable, reproducible results. Our partnership represents an important milestone for existing customers, alongside those looking to adopt OOC technology into their own labs. Validation of cells is a costly and laborious process, but one that is imperative for assay success. Harnessing our combined technical expertise and customer support, we can offer researchers a more complete solution to easily recreate our industry-leading liver models, removing the risk of failed experiments due to untested cells and the burden of in-house quality control testing—so that they can focus their efforts on new discoveries.”

“This partnership represents a joint investment to set a new standard for cell quality across the industry, enabling customers across a broad range of market segments to realize the potential of OOC, without the need for costly in-house validation,” said Ed LeCluyse, chief scientist, LifeNet Health LifeSciences, in the release. “Our cells are fully characterized for quality and performance, to ensure they can perform within advanced platforms, to more effectively mimic 

CN Bio and LifeNet Health LifeSciences have teamed up to provide direct access to a portfolio of highly characterized hepatic cells for the creation of advanced liver-on-a-chip assays.

CN Bio and LifeNet Health LifeSciences Partner to Supply Pre-Validated Cells

In part of the session "Continuous Manufacturing and Publication of ICH Q13" at the PDA/FDA Joint Regulatory Conference, Kelley Burridge, PhD, Product Quality Team Leader, OBP, OPQ, CDER, U.S. FDA, discusses the highlights of her ICH Q13 session that she wants others to be aware of.

Fundamental concepts of continuous manufacturing and Q13 are new to many in the pharmaceutical industry. Continuous manufacturing generates a lot of data that can be transformed into product and process knowledge. Building widespread knowledge experience in covert with continuous manufacturing for pharmaceuticals in industry and among regulators will take some time. To introduce [fleeing leisure]: A pharmaceutical development and manufacturing requires communication and collaboration among people with training in different fields, chemists, biologists, pharmaceutical scientists, and engineers, especially chemical engineers. If you don't know any chemical engineers, get to know them, as their core undergraduate training is rooted in the continuous manufacturing fundamentals highlighted in Q13. We build cross disciplinary teams and help them to really facilitate that knowledge sharing especially among teams that have similar job functions. Knowledge of chemical engineering fundamentals, plus experience with the aspects that are particular to the pharmaceutical industry will be a powerful force for modernization in pharmaceutical manufacturing. We also need to determine the best ways to present new types of information for industry and regulators to communicate effectively. conferences such as this one are a great way to share best practices.

 The words in the [bracket] are an assumption of what is being said, as it is not clearly picked up in our audio.

Kelley Burridge, PhD, Product Quality Team Leader, OBP, OPQ, CDER, U.S. FDA, discusses the highlights of her ICH Q13 session that she wants others to be aware of.