Feliza Mirasol is the science editor for 

Feliza Mirasol

Merck, known as MSD outside of the United States and Canada, entered into a definitive agreement earlier this month with Curon Biopharmaceutical (Curon), a privately held biotechnology companyunder. With the agreement, Merck, through one of its subsidiaries, will acquire full global rights to CN201, Curon's novel investigational clinical-stage bispecific antibody for treating B-cell associated diseases.

The deal is worth potentially up to $1.3 billion, comprising an upfront payment by Merck of $700 million in cash and up to $600 million in milestone payments for which Curon is eligible, contingent upon the development and regulatory approval of CN201, according to an Aug. 9, 2024 company press release. The transaction is expected to close in the third quarter of 2024, subject to customary closing conditions.

“We continue to identify opportunities to expand and diversify our pipeline,” said Dean Y. Li, MD, PhD, president, Merck Research Laboratories, in the press release. “Early clinical data have provided robust evidence for the potential of CN201 to target and deplete circulating and tissue B cells with the potential to treat a range of malignant and autoimmune diseases.”

CN201, a novel CD3xCD19-targeting T-cell-engager bispecific antibody, is designed to target B cells for elimination by T cells. It is currently being evaluated in a Phase I clinical trial for treating relapsed or refractory non-Hodgkin’s lymphoma and in a Phase Ib/II clinical trial for treating relapsed or refractory acute lymphocytic leukemia. According to preliminary data, CN201 demonstrated activity in patients with relapsed or refractory B-cell hematologic malignancies and has been shown to be well tolerated. It has demonstrated the potential to induce significant and sustained reductions in B-cell populations. Merck aims to evaluate CN201 as a treatment for B-cell malignancies and investigate its potential to provide treatment for autoimmune diseases.

“This agreement reflects the drive and dedication of the Curon team,” said Zhihong Chen, president and CEO, Curon, in the press release. “As a pioneer in immuno-oncology, Merck is well positioned to build upon the work done to-date and investigate the wide-ranging, first-in-class potential of CN201.”

Also in August, Merck expanded its existing co-development and co-commercialization agreement with Daiichi Sankyo for three investigational derivatives of exatecan (DXd) antibody-drug conjugates (ADCs). Under the expanded agreement, Merck’s investigational delta-like ligand 3 (DLL3) targeting T-cell engager, MK-6070, was added, and the companies will jointly develop and commercialized the drug candidate worldwide, except in Japan where Merck will retain exclusive rights, according to an Aug. 6, 2024 company press release. Merck will have sole responsibility for manufacturing and supply for MK-6070.

Under this expanded agreement, Merck gets an upfront payment of $170 million in cash; it has also satisfied a contingent quid obligation from the original collaboration agreement with Daiichi Sankyo. Meanwhile, both companies will share R&D and commercialization expenses and profits worldwide, excluding Japan. For Japan, while Merck retains exclusive rights, Daiichi Sankyo will receive sales-based royalties. Furthermore, R&D expenses related to MK-6070 in combination with ifinatamab deruxtecan will be shared between the companies according to their original agreement for ifinatamab deruxtecan.

MK-6070 is currently being evaluated in a Phase I/II clinical trial as a monotherapy in certain patients with advanced cancers associated with the expression of DLL3 and in combination therapy with atezolizumab for treating certain patients with small cell lung cancer (SCLC). In March 2022, FDA granted MK-6070 orphan drug designation for treating SCLC.

1. Merck. Daiichi Sankyo and Merck Enter into Global Development and Commercialization Agreement for MK-6070. Press Release, Aug. 6, 2024.

Merck, known as MSD outside of the United States and Canada

Articles

Merck, known as MSD outside of the United States and Canada, will gain CN201, a next-generation bispecific antibody, from Curon Biopharmaceutical in a  deal potentially worth up to $1.3 billion. 

Merck to Gain Investigational Bispecific Antibody in $1.3 Billion Curon Biopharmaceutical Deal

Andelyn Biosciences, a patient-focused cell and gene therapy contract development and manufacturing organization, announced on Aug. 6, 2024 that it has entered into a license agreement with the Broad Institute of MIT to include MyoAAV plasmids in its AAV Curator Platform, which expands the platform’s offerings.

Under the agreement, Andelyn will have use of the MyoAAV plasmids to perform research and development services for clients who are developing gene therapies. Andelyn will screen potential candidates and perform scale-up and pre-clinical development work to prepare for investigational new drug-enabling studies. The agreement also gives Andelyn permission to sublicense the MyoAAV plasmids to its clients for internal research purposes.

The MyoAAV plasmids were developed by researchers at the Broad Institute of MIT and Harvard. They are a new family of plasmids that produce adeno-associated viruses (AAVs) ten times more efficient in reaching muscle tissue and targeting the liver than wild-type vectors, according to a company press release. “With more precise targeting of muscle tissue, research shows MyoAAV-delivered therapies may require lower dosing,” Andelyn stated in the press release.

Andelyn will utilize its expertise in translational drug development to bring Broad's new class of engineered AAVs to biotech organizations as they target diseases in therapeutic areas with significant unmet need. The company expects that the new AAVs will ultimately reduce the effective dose demand while improving product safety.

“Our license from the Broad Institute furthers our goal of providing the industry access to critical tools and capabilities that facilitate the development of innovative therapies to bring more treatments to more patients. With access to the increased specificity of MyoAAVs, our clients now have the opportunity to maximize efficiency in their gene therapy processes and drive down the cost per patient,” said Matt Niloff, chief commercial officer of Andelyn, in the press release.

In May 2023, Andelyn was selected to manufacture AAV therapies using its Curator Platform under the California Institute for Regenerative Medicine (CIRM) Accelerating Medicines Partnership (AMP) Bespoke Gene Therapy Consortium (BGTC) (1).

CIRM established a partnership with Andelyn to advance BGTC’s goal of developing platforms and standards that will drive the development and delivery of customized or “bespoke” gene therapies for rare diseases. BGTC is focused on developing cures for eight such rare diseases. Andelyn’s role will be to optimize and scale the AAV gene therapy processes for treating congenital hereditary endothelial dystrophy–type 1.

“As a long-standing pioneer in AAV gene therapies and historical connection to the clinic, we have great synergies with the CIRM/BGTC. Andelyn is privileged to work with the CIRM/BGTC on its first AMP established specifically for rare disease and leverage our AAV Curator Platform to help overcome the major obstacles related to developing gene therapies,” Niloff stated in a company press release (1).

1. Andelyn Biosciences. Andelyn Biosciences Selected as Viral Vector Manufacturing Partner for the California Institute for Regenerative Medicine (CIRM) Accelerating Medicines Partnership (AMP) Bespoke Gene Therapy Consortium (BGTC). Press Release, May 23, 2024.

With the agreement, Andelyin Biosciences will add MyoAAV plasmids developed by Broad Institute of MIT and Harvard to its AAV Curator Platform.

Andelyn Biosciences and Broad Institute of MIT Enter into License Agreement to include MyoAAV Plasmids in AAV Platform

US Specialty Formulations (USSF), a provider of pharmaceutical solutions for healthcare, diagnostics, and new drug developers, has begun a $15 million initiative to expand biopharma operations at its Allentown, Pa., facility, according to a July 31, 2024 press release.

USSF has already secured $4.7 million of its $15 million goal. Under the expansion, the company plans to bring in new facility cleanroom suites and state-of-the-art automated packaging and product inspection equipment. The expansion is expected to increase the company’s cleanroom production capacity by more than 2.5 times. The expansion is expected to be completed at the end of 2025. Once done, the company will have the capability to take on substantially larger projects to support growth for new and current clients.

“This expansion is a transformative step for USSF,” said Kyle Flanigan, CEO of USSF, in the press release. “By investing in cutting-edge technology and streamlining our manufacturing processes, we are raising the bar for ourselves and reaffirming our commitment to delivering innovative pharmaceutical solutions that reduce the risk profile of new drug development or contract manufacturing and ultimately improve patient lives. This expansion empowers our dedicated team to serve our partners and clients worldwide more effectively.”

In addition to raising USSF’s cleanroom capacity, the expansion is also expected to significantly boost the local economy by creating jobs and increasing revenue for the Greater Philadelphia region. When completed, USSF will seek to employ more than 100 staff to support the facility.

The company stated in its press release that cleanrooms are required to meet most pharmaceutical manufacturing standards. “They provide a highly controlled environment essential for product quality, safety, and compliance with CGMP [current good manufacturing practice] standards. These rooms provide a sterile environment for the production of injectables, including small molecules, botanicals, and vaccines.”

USSF offers a range of services, including drug R&D, contract manufacturing, private label formulations and packaging, and small-molecule pharmaceuticals. The company has developed the oral vaccine platform, QYNDR, and a self-administered drinkable vaccine, the first, according to the company. This drinkable vaccine completed a Phase I clinical trial in 2023 (1).

QYNDR is a next-generation protein-based oral vaccine (mucosal vaccine) developed to addresses the challenges seen with the current COVID-19 vaccines. According to a company press release, the results of the Phase I clinical trial showed that the vaccine demonstrated longevity and cross-variant protection from multiple COVID-19 strains. In addition, the study may possibly have identified a correlation of protection against the virus and other strains, which is to be further investigated in a Phase II clinical trial (1).

“The [P]hase I clinical data showed strong evidence that this oral platform and vaccine is a revolutionary industry disruptor and will become the preferred method of vaccination in the future,” Flanigan said in a press release issued at the time that the Phase I trial was completed. “As we proceed into Phase II and III, we are confident this next-generation vaccine will be more effective than other mucosal vaccines in current development and testing.”

1. US Specialty Formulations. US Specialty Formulations Completes Phase I of Clinical Trials for the Qyndr Vaccine. Press Release, Sept. 7, 2023.

 US Specialty Formulations plans to invest $15 million to expand biopharma operations at its Allentown, Pa.,facility.

US Specialty Formulations to Modernize Biopharma Operations with $15 Million Investment

BioIVT has launched new cleanroom manufacturing space in Winchester, Va. A research partner and biospecimen solutions provider for drug and diagnostic development, the company partnered with Germfree, a provider of modular cleanroom infrastructure and services, to build the space, according to an Aug. 1, 2024 company press release.

The cleanroom comprises design and solutions from Germfree that boost BioIVT’s capabilities in cell and gene therapy (CGT) development. The integration of cleanroom processes will include BioIVT’s good manufacturing practice (GMP)-compliant raw materials for supporting CGTs, including Human AB serum.

“This facility will play a significant role in our expanding portfolio of GMP-compliant products,” said Parijat Jain, vice-president of Cell & Gene Therapy at BioIVT, in a company press release. “The cleanroom was designed in collaboration with Germfree, relying on their extensive expertise to build a facility that will support client-specific manufacturing requirements and configured for high-volume production enabling product use in late-stage clinical and commercial manufacturing. We continue to evolve and strengthen our support for the development of CGT research, and our future-ready cleanroom will provide expanded capabilities and access to developers.”

The new space is purpose built to support workflows for excipient and ancillary material bioprocessing. The cleanroom ensures quality and regulatory compliance and includes the following features:

qualified in accordance with FDA requirements

FDA-current GMP, International Organization for Standardization, ion selective electrode, Center for Disease Control–Biosafety in Microbiological and Biomedical Laboratories, and American Society for Testing and Materials tested

heating, ventilation, and air conditioning controls systems

high efficiency particulate air filtration.

"We at Germfree are honored to contribute to BioIVT's groundbreaking manufacturing space by providing our modular cleanroom technology,” said Kevin Kyle, CEO, Germfree, in the press release. “This new facility reflects BioIVT's dedication to advancing biospecimen solutions and scientific research, and the company’s deep experience in helping manufacturers build cutting-edge facilities. We are excited to support their mission and look forward to the innovative achievements that will benefit the life sciences and pharmaceutical industries, fostering advancements in research and development."

The cleanroom addition is the latest in a series of expansions BioIVT has pushed forward. In February 2024, the company increased its capacity for delivering readily available fresh, standard, and mobilized human leukopaks (1). The additional capacity further builds the company’s ability to scale its network of diverse and highly characterized cell donors. Earlier in October 2023, BioIVT expanded its biospecimen portfolio with the launch of its new Center for NeuroExcellence. Through this center, BioIVT can offer neurology researchers a single source from which they can obtain supplies, from controls to difficult-to-collect biofluid samples from populations with neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (2).

1. BioIVT. BioIVT Announces Expansive Fresh Leukopak Capability in Europe. Press Release, Feb. 22, 2024.
2. BioIVT. BioIVT Expands its Biospecimen Portfolio in Support of Neuroscience Research. Press Release, Oct. 27, 2023.

BioIVT opened new cleanroom manufacturing space, using Germfree’s technology to boost its capabilities for cell and gene therapy development.

Partners BioIVT and Germfree Open New Cleanroom Manufacturing Space at US Site

Finished pharma product inspection requires stringent oversight that may be lacking in systems that rely on manual or only semi-automated processes. With the rise of automation technologies applied to biomanufacturing systems, having an automated finished product inspection system in place can make up for gaps where a lack of trained personnel may persist.

Finished product inspection starts with an evaluation of the inspection process to determine if it is able to detect defects in a pharmaceutical presentation. Once that determination is made, it is important that the inspection method is established, whether manual, semi-automatic, or fully automated. There are cases where a semi-automated or automated inspection system is not an option, which leaves manual inspection; however, if semi-automated or automated inspection options are available, then an inspection method should be determined based on lot size. In one example, lot sizes under 5000 are likely to utilize manual inspection, while lot sizes between 5000 and 15,000 would likely require a semi-automatic inspection. Above a 15,000-lot size, a fully automated inspection system is the better choice (1).

Mike Pipe, head of Global Sales & Product Management at Mettler-Toledo, points to X-ray technology as one solution in product inspection, noting that there are three main quality control issues that X-ray technology can solve in the packaging area: detection of foreign body contaminants, identifying incomplete or missing medicines, and identifying damaged packaging.

“As any responsible manufacturer knows, there can be no trade-offs in quality standards when it comes to the manufacture of pharmaceutical products. Whether the medicine is in liquid or tablet form, it is essential that foreign body contaminants are detected and removed,” Pipe states. He emphasizes that the dosage or fill levels must be correct, and that the integrity of both the packaging and the product must not have been compromised.

Pipe explains that it is now commonplace for product inspection equipment to be used in the pharma sector to overcome these challenges. “Metal detection systems can be used before tablets are pressed or packed to detect ferrous, non-ferrous, and stainless-steel metal contaminants. Vision systems and checkweighers also play a vital role in ensuring that products are complete, labeled correctly, and are at the correct weight,” he says.

Pipe points out, however, that with tablets being increasingly packaged in aluminum foil-based blister packs, metal detection systems may have a difficult time identifying if metal contaminants are present if the pharma products are inspected after packaging. “This is where X-ray technology can help. [X-ray] can detect a wide range of foreign body contaminants, including metal, both before and during packaging. It can also deliver several further quality assurance benefits,” he states.

Pipe highlights five key areas where X-ray inspection can make an important contribution in pharma production and packaging:

 As pipe points out, foreign body detection is a critical aspect of any pharma manufacturer’s product inspection operation. While metal detection is a robust inspection technology for detecting metal contaminants, including stainless steel, in the preparation or tableting process, X-ray inspection can complete contamination checks early in the production process. Using X-ray can also allow for inspection of contaminants at the final packaging stage following the blister-packing process. X-ray measures differences in absorption between low and high-density matter and can provide exceptional detection not only metal contaminants, but also glass and certain plastics and rubbers, regardless of the contaminant’s shape, size, or location within the product.

Help ensure product and packaging integrity.

 X-ray inspection can carry out a range of additional quality control (QC) tasks while simultaneously detecting foreign body contaminants, including:

Product completeness checks, including counting components and identifying damaged components—with comparison to the known number of items that should be in a pack

Identifying damaged packaging, inspecting seal quality to detect product trapped in the seal, and identifying missing components such as screw caps

Measuring product mass and comparing it to a known mass value for a reference pack

Checking fill levels—X-ray inspection images show clear discrepancies in fill levels between packs, where, for example, one pack may be under-filled and another pack may be over-filled, which can make the overall pack weight seemingly correct.

 Product recalls represent a twin-headed peril for pharma manufacturers, says Pipe. On the one hand, a product recall is costly because of wasted products and production time; on the other hand, a recall causes damage to the pharma manufacturer’s good name. “While the costs of the former are often quickly absorbed, the negative effects on brand reputation can be much more long lasting,” he notes. Therefore, implementing a well-designed X-ray inspection program can cut the risks and the costs involved in product recalls. X-ray “run codes” are assigned to each product run and can be compared to checkweigher batch data, which potentially helps isolate smaller contaminated batches that need to be recalled, instead of an entire production run.

 The absence of good product inspection can endanger patient health and safety. Such incidents can lead to major legal action being taken. Even without a worst-case scenario such as major legal action being taken; however, there is still danger posed to a pharma brand. For example, in the United States, says Pipe, pharma producers that fall foul of FDA 21 

) Part 210 (Current Good Manufacturing Practice in Manufacturing Processing, Packing, or Holding of Drugs) (2) and 21 

 Part 211 (Current Good Manufacturing Practice for Finished Pharmaceuticals) (3) are issued warning letters that are publicly available. The issuance of a warning letter can impact public trust in the brand and the brand’s reputation in the industry as well as cause extra delays and costs in bringing products to market.

 Because the pharmaceutical industry is highly regulated, compliance is critical for both patient safety and the furtherance of responsible drug supply. Quality assurance programs should therefore be robust and comprehensive, with risks identified and mitigated, Pipe says. The requirements specified in FDA’s 21 

 Parts 210 and 211 include that pharma producers must take steps to protect against contaminants getting into products and protect against damaged or compromised products reaching the market. “X-ray technology can play a key part in helping to ensure compliance, for the reasons already listed above. In addition, modern X-ray inspection systems keep digitalized records of activity, helping producers to meet the demands of 21 

 Part 11 (i.e., audit trails and digital signatures) (4),” Pipe adds.

The advantages offered by automated visual inspection include speed, precision, and consistency. An automated system can quickly process large volumes while at the same time detecting small defects, which can be missed in a manual inspection (5).

It is important to note that automated vision inspection systems have their own limitations, namely that the system’s performance is only as good as its programming. For instance, if the system has been programmed to account for every possible variation in inspection conditions, then there is a risk that it may erroneously flag safe products as defective (6). Meanwhile, there are practical considerations that may hinder widespread implementation of automated vision inspection systems across all operational scenarios. Contract development and manufacturing organizations may encounter challenges, for example, when justifying the capital investments needed (significant capital investments) and associated validation processes for implemented automated inspection. Justifying implementation could be particularly difficult when dealing with products manufactured in small batches or products that have infrequent production cycles (7).

1. Grand River Aseptic Manufacturing. Finished Product Inspection: Automation, Complex Therapeutics, and Quality Standards. 

 (Government Printing Office, Washington, DC).
3. 

 (Government Printing Office, Washington, DC).
4. 

 (Government Printing Office, Washington, DC).
5. Marsale, T. Balancing Act: Human vs. Machine Inspection in Pharmaceutical Manufacturing. 

 online, Oct. 18, 2023.
6. Yadav, V.; Kennedy, C. Vision Inspection Using Machine Learning/Artificial Intelligence. 

. November/December 2020.
7. Melchore, J. A. Sound Practices for Consistent Human Visual Inspection. 

 (1), 215–221. DOI: 10.1208/s12249-010-9577-7

®
Vol. 48, No. 8
August 2024
Pages: 29–30

When referring to this article, please cite it has Mirasol, F. Considerations for Finished Product Inspection Systems. 

Manual and automated inspection technologies have their own advantages and limitations.

Considerations for Finished Product Inspection Systems

On Aug. 1, 2024, Freudenberg Medical announced  an expansion to its biopharma product portfolio, which now includes custom single-use assemblies. The assemblies will be combined with the company’s expertise in silicone extrusion and molding. Included in the new offerings are single-use Y-connector manifolds, tubing assemblies, and bottle cap assemblies with multiple inlets/outlets. Both labs and current good manufacturing practice (CGMP) bioprocesses commonly use bottlecap assemblies with Y-connector tubing for critical fluid transfer applications, according to the company in a press release.

The assemblies are cleanroom manufactured according to customer specifications. Among the advantages, Y-connector overmolds offer unobstructed flow within a critical fluid path and can prevent leaks from occurring. Leaks are commonly seen with standard fluid couplings, fittings, and connectors, according to Freudenberg. “Validated production processes with proven process capabilities will continuously ensure consistent overmolding of Y-manifolds on customer-specified tube ends,” the company stated in the press release.

The expanded biopharma portfolio complements the company’s existing PharmaFocus Premium product line containing high purity, platinum-cured silicone tubing and sanitary ends for single-use systems. The company’s tubing, molded components, and systems are used in bioprocessing, biotechnology, lab processes, GMP manufacturing, small batch processes, and cell and gene therapy as well as for the production of messenger RNA, biosimilars, and regenerative proteins.

The company’s other expansion activities include a $50 million investment in a new Hemoteq AG production facility in Aachen, Germany, to expand its coatings business (1) and a $25 million investment to establish a manufacturing site in Costa Rica (2). The expansion in Germany, which Freudenberg announced in June 2024 will triple its manufacturing footprint with a new 130,000-ft

 facility in Alsdorf, near the existing site. The new facility houses ISO Class 7 cleanrooms, laboratories, and offices and will serve as a hub for R&D and production as well as drive innovation in medical coatings (1).

The new Costa Rica facility, announced in February 2024, is slated to come online in the beginning of 2025 and will be dedicated to assembling high-volume minimally invasive catheters for electrophysiology, vascular and structural heart therapies, and other medical devices requiring high-precision manual assembly. The first phase of construction comprises a build on 50,000 ft

 and the facility will house three ISO 7 cleanrooms. The company also expects to add another 50,000 ft

 to the site within three years of its opening. This added construction will quadruple Freudenberg’s total footprint in Costa Rica (2).

Of the Germany site expansion, Mark Ostwald, CEO of Freudenberg Medical, said in a company press release issued at the time, "The convergence of medical devices and drugs is inspiring a new generation of innovative products that fundamentally improve patients’ outcomes. With this innovation driven investment, we are strengthening our position as a strategic partner to our customers, offering vertically integrated solutions along the entire supply chain" (1).

Meanwhile, Róger Gómez, vice-president/general manager of Freudenberg Medical in Costa Rica, said of the Costa Rica facility expansion at the time it was announced, “The investment in this new site underlines Freudenberg Medical’s confidence in Costa Rica as an integral part of our global growth strategy. In the next three years, we will triple the number of employees from the current 300 to over 900 team members. Committed to diversity and inclusion, we offer equal opportunities to all” (2).

1. Freudenberg Medical. Freudenberg Medical Expands Coatings Business with New Production Facility. Press Release, June 11, 2024.
2. Freudenberg Medical. Freudenberg Medical Establishes Second Production Facility in Costa Rica. Press Release, Feb. 14, 2024.

Freudenberg Medical has introduced custom single-use assemblies for silicone extrusion and molding for biopharma applications.