Susan Haigney

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On Feb. 5, 2024, FDA announced it has published a draft guidance, 

Notification of a Permanent Discontinuance or Interruption in Manufacturing Under Section 506C of the FD&C Act,

 to assist applicants and manufacturers in notifying the agency about changes in production of finished drug products, biological products, and APIs. The guidance is part of the agency’s efforts to prevent drug shortages. How FDA communicates with the public about drug shortages is also addressed in the document.

Notification of manufacturing interruptions are required under section 506C of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and FDA’s regulations. Applicants and manufacturers of certain finished drugs are required to notify FDA of permanent discontinuance of such drugs or an interruption in manufacturing that may lead to a disruption of the supply of the drug in the United States. The agency must also be notified of permanent discontinuance or a disruption of manufacture of certain APIs that may lead to a shortage of supply. Applicants and manufacturers should provide additional details with FDA and follow procedures to ensure the agency has the information needed to prevent a shortage.

The guidance document details who must notify FDA and which products are subject to the requirements. It also details when FDA should be notified and what information should be included in the notifications. It also provides information on how to notify the agency and what happens if the agency is not notified.

More information on the agency’s strategies for preventing drug shortages, including a drug shortages database, can be found on its website at 

https://www.fda.gov/drugs/drug-safety-and-availability/drug-shortages

Articles

The guidance discusses how to timely notify the agency of changes in production of APIs and finished products.

FDA Provides Guidance on Notifying the Agency of Manufacturing Interruptions

Communication between the manufacturing plant and retail stores. | Image Credit: © Cagkan - © Cagkan - stock.adobe.com

Biovian, a contract development and manufacturing organization (CDMO), announced on Feb. 1, 2024 that it was combining with CDMO 3P Biopharmaceuticals to form 3PBIOVIAN under the two companies’ common shareholder, Keensight Capital. The new group, 3PBIOVIAN, will offer end-to-end development and manufacturing services for protein expression systems and viral vectors for both drug substances and drug products from preclinical to commercial phases.

3PBIOVIAN will be a global CDMOoffering microbial and mammalian protein expression platforms, viral vector production for adenoviruses and adeno-associated viruses, cell therapy, and plasmid DNA production. It will also provide fill/finish services for recombinant proteins and viral vectors. The group has manufacturing sites in Pamplona-Noáin, Spain, and Turku, Finland.

“We are thrilled about this opportunity and the new chapter for our combined companies. The highly synergistic and comprehensive service offering allows 3PBIOVIAN to further enhance its competitiveness in the biologics CDMO market,” said Antti Nieminen, deputy CEO at 3PBIOVIAN, in a press release.

“The combination of technology, capabilities and most importantly, the quality of the human team, positions us a leader in the highly dynamic international market for the development and manufacturing of advanced therapies,” said Dámaso Molero Sánchez, CEO at 3PBIOVIAN, in the release.

“With a combined 40-year track record and a commitment to quality, both companies have always prioritized customer-centric service. The consolidation of these two technically and financially strong players creates a powerful global end-to-end service provider,” said Pierre Remy, managing partner at Keensight Capital, in the release.

The CDMOs are joining together to offer end-to-end development and manufacturing services for protein expression systems and viral vectors in Europe.

Biovian and 3P Biopharmaceuticals Combine to Form 3PBIOVIAN

cell culture at the laboratory of cell culture medical and medicine | Image Credit: ©murat - stock.adobe.com

The bio/pharmaceutical industry has seen the development of a variety of emerging therapies, such as messenger RNA (mRNA) vaccines and cell and gene therapies. These innovative modalities often require a need for new test methods, which has changed analytical testing requirements, says Jan Bekker, PhD, head of Global Commercial Operations at BioCina.

According to Milena Quaglia, PhD, senior associate principal scientist, RSSL, “the analytics required for these emerging therapies benefit from the knowledge and progress in the protein biopharmaceutical sector. Some of the chromatographic and biological methods have rapidly been adapted to the measurements of, for example, viral vectors. The increased opportunities, funding and industry needs have played a significant role in driving the enhanced robustness of analytical platforms, particularly those used in R&D (such as mass spectrometry) for routine analysis. The complexity of cell therapy and its production at a different scale render the analytical requirements and the location of the analytical physical sites challenging. Additionally, the development of potency cell bioassays for cell therapy has proven to be extremely complex due to the heterogenicity of the product.”

Cell and gene therapies, as well as mRNA, have developed alongside advancements in long-read technology to provide more holistic testing, says Andrea O’Hara, PhD, strategic technical specialist, Next-Generation Sequencing, GENEWIZ from Azenta Life Sciences. “A great example here is product characterization for AAV [adeno-associated virus] and mRNA therapeutics. While these two therapeutics are quite different, both require effective utilization of long-read technology to accurately characterize and confirm expected products,” says O’Hara. “For AAV, this option is necessary due to the intricacies of the product and its secondary structure around the inverted terminal repeats (ITRs), which are difficult to sequence with traditional approaches. For both AAV and mRNA therapeutics, the ability of long-read sequencing to effectively capture the full molecule is critical to ensure the purity and fidelity of these products.”

Currently, according to Bekker, technologies used in biopharma analysis include chromatography (e.g., high-performance liquid chromatography [HPLC] and ultra-high performance liquid chromatography [UHPLC]) with ultraviolet–visible spectroscopy (UV–Vis), fluorescence, MS, refractive index, evaporative light scattering, electrochemical, and charged aerosol detection. “BioCina uses different modes of chromatographic separation, such as [reversed phase]–HPLC, [ion chromatography]–HPLC and SE–HPLC [size-exclusion HPLC], coupled with UV–Vis, fluorescence, MS, or evaporative light scattering detection for purity analysis of in-process, release, and stability testing across the microbial, plasmid DNA, and mRNA product modalities,” says Bekker.

Other technologies include enzyme-linked immunosorbent assay (ELISA), capillary electrophoresis, gel electrophoresis, cell-based assays, microbiology test methods, coupled enzymatic assays, dynamic light scattering (DLS), among others, says Bekker. “[We use] DLS for the determination of particle sizes and analysis of particle size distribution for microbial products and lipid nanoparticles, including mRNA vaccines and other LNP-encapsulated products,” he states.

“Biopharmaceutical analytical workflows are currently well accepted in industry with an increasing confidence in mass spectrometry (particularly for host cell protein analysis and bi-specific antibodies) and bioassays including analytics supporting their development/validation,” says Quaglia.“While the development of bioassays for cell and gene therapy is still in its infancy, an increased appreciation of the data generated by mass spectrometry-based methods for AAV capsid characterisation, mRNA sequencing, purity determination is observed. The requirements for robust next generation sequencing are also increasing in the cell and gene therapy sector.”

Modern techniques are making analytical procedures more robust. According to Melissa El Khouri, head of Quality, BioCina, analytical development can be sped up and testing across multiple product modalities can be achieved by using modern analytical equipment and techniques compatible with high throughput testing. In addition, different types of analysis for multiple biologics modalities can be achieved by using sodium dodecyl sulfate capillary electrophoresis (CE–SDS), RNA, capillary isoelectric focusing (cIEF), and glycan analysis, according to El Khouri.

“While Sanger and short-read [next-generation] sequencing [NGS] have always been popular, long-read sequencing is on the rise,” says O’Hara. “Long-read sequencing has become more cost effective as the technology has advanced and offers insights that confirm or even surpass traditional Sanger and short-read NGS options.”

High-resolution analytical technologies, such as sensitive capillary electrophoresis sodium dodecyl sulfate (CE-SDS), are replacing older techniques, says El Khouri. “Modern capillary electrophoresis systems provide automated, quantitative, and highly repeatable sizing and purity analysis across multiple modalities. Operation is automated and sample preparation is kit-based, which minimizes processing time and reduces
processing errors,” she says.

 testing have been reduced by the increased use of cell-based bioassays; however, to ensure reliable data, analytical controls and standards are fundamental, says Quaglia. She stresses that regulatory requirements are not well-defined, which can cause confusion about which analytical procedure should be used for new modalities. “mRNA sequencing requires robust analytical and sample preparation platforms together with standards and standardized analytical workflows/guidelines. Availability of materials of good quality and at reasonable costs are often the main drawback for method development/improvement and implementation,” she says.

The development of assays for new modalities requires consideration of the potential product and possible pitfalls of that product, says O’Hara. “For example, with mRNA vaccines, we anticipate a full-length RNA with a specific length polyA tail. An assay to confirm this product needs to be extremely precise to confirm the exact sequence and length, down to the final nucleotide. However, we also need to consider what may go awry in the development process and test for that as well: partial or incomplete products, short or long polyA tail, missing tails, even alternative products. A robust assay will consider both the expected and the unexpected,” she states.

Bekker points to the following as considerations for developing assays for mRNA vaccines and other new modalities: sensitivity of equipment, investing in modern analytical equipment across multiple modalities, minimizing outsourcing of analytical testing to expedite batch release, regulatory expectations, and development of platform methods to streamline analytical development. “BioCina employs a platform approach to the manufacture of plasmid DNA and mRNA products, as well as the analytical testing of these products. A platform approach negates the need for extensive analytical development with each new plasmid DNA product, because methods only need to be verified. This approach speeds up development time and is more economical for our clients,” Bekker says.

‘Dry Lab Only’ using artificial intelligence (AI) and machine learning (ML) is a major trend developing in biopharma analysis, according to O’Hara, with companies moving from heavy onsite testing and analysis to computational analysis. “By utilizing these tools effectively, these companies can keep their labs lean and streamlined, outsourcing from third party wet lab workflow as needed to fill in the gaps,” she says.

“Big data [and] AI used to predict the 3D structure of proteins and molecular modeling for optimization of formulation, stability prediction, have the potential to revolutionize some of the current processes and analytical,” Quaglia agrees.

Primary testing of potential therapeutics has been revolutionized by AI and ML, according to O’Hara. “We can proactively predict aspects based on previous studies and models, including drug targeting, folding structures, and off-target interactions. Instead of testing a large variety of options, we can now utilize AI and ML to whittle down the list of candidates dramatically, and smartly, to a highly refined candidate list for downstream testing,” she says.

“Developing a strategy for analysis of biopharmaceuticals requires availability of skilled staff for sample handling, method development, and data analysis as well as appropriate equipment,” says Quaglia. “Instrumentation that is commonly used for small organic compounds needs to be biocompatible and able to deal with smaller amounts of sample. [The] [m]ain challenges for bioanalysis as analysis of small molecules/biopharmaceuticals in biological matrices (e.g., for bio-kinetic studies) are extraction, selection of appropriate standards/procedures, data analysis, and reporting. Bioanalysis laboratories are often GLP [good laboratory practice] accredited, contrary to analytical batch release laboratories that are GMP [good manufacturing
practice] accredited.”

Understanding the physiochemical characteristics of the bio/pharmaceutical product is important in order to analyze that product, says El Khouri. A bioanalytical strategy should incorporate quality-by-design, she stresses, including critical quality attributes, critical material attributes, critical process parameters, and control strategies to link these together with API and excipient specifications. “With the design of any bioanalytical strategy, it is important to build in product quality, safety, and efficacy,” says El Khouri.


Vol. 48, No. 2
February 2024
Pages 12-13, 17

When referring to this article, please cite it as Haigney, S. Emerging Therapies Drive Analytical Advancements

The emergence of mRNA vaccines and cell and gene therapies has pushed innovation in analytical methods. 

Emerging Therapies Drive Analytical Advancements

The European Medicines Agency (EMA) announced on Jan. 26, 2024 that the European Commission (EC) has given the agency a €10 million grant to support regulatory systems at a national and regional level in Africa. The agreement has been signed by the EC’s directorate-general for International Partnerships, marking the project’s official launch. The African Medicines Agency (AMA) treaty has been ratified by 27 countries with more African Union (AU) members expected to join.

EMA will collaborate with African, European, and international parties to set up the AMA. The AMA will be a specialized agency of the AU and will be dedicated to improving access to safe and effective medical products in Africa. Experts will be mobilized by EMA to support AMA, technical committees, and regulators. Training will also be provided by EMA to reinforce scientific and regulatory expertise.

“The creation of AMA is a unique opportunity to facilitate the regulation and oversight of key medicines at continental level, promoting collaboration among African countries and regions,” EMA stated in a press release. “By sharing its unique expertise and regulatory model, the EMRN [European medicines regulatory network] will share experience with AMA in pooling resources and coordinating work to regulate medicines efficiently and effectively, ensuring high-quality standards and use of the best available expertise, reducing administrative burden to allow medicines to reach patients faster and accelerating the exchange of information on critical issues such as medicines safety.”

“It will be exciting to see AMA build its own regulatory model and practices to increase availability of safe and affordable medicines in Africa. EMA will support this journey by sharing our learnings and experiences gained working together as a network of thousands of experts from across Europe,” said Emer Cooke, executive director of EMA, in the press release.

“As African Medicines Regulatory Harmonisation (AMRH) lays the foundation for the AMA, our collaboration with EMA marks a crucial stride towards the realization of AMA's mission. Together, AMRH and EMA will expedite the establishment of AMA, fostering greater collaboration among African nations. This partnership not only signifies a shared commitment but also accelerates AMA's journey to becoming a beacon for regulatory efficiency and healthcare advancement in Africa,” said Chimwemwe Chamdimba, head of the AMRH initiative at the African Union Development Agency-New Partnership for Africa’s Development, in the press release.

The agency will coordinate intra-regional medicines regulation to strengthen the African regulatory network.

EMA Given Grant to Support Establishment of African Medicines Agency

: The agency has made the webinar, conducted on March 7, 2024, 

FDA published final guidance on Jan. 30, 2024 that provides consideration for the development of chimeric antigen receptor (CAR) T-cell products. According to FDA, “[CAR T-cell] products are human gene therapy products in which the T cell specificity is genetically modified to enable recognition of a desired target antigen for therapeutic purposes.”

The guidance provides sponsors with information to help develop CAR T-cell products including specific recommendations regarding chemistry, manufacturing, and controls (CMC), pharmacology and toxicology, and clinical study design. Considerations for autologous or allogeneic CAR T-cell products are addressed as well as analytical comparability studies.

The provided recommendations are also applicable to other genetically modified lymphocyte products including CAR natural killer cells and T-cell receptor-modified T cells. FDA states that, to get considerations specific to these, highly specialized sponsors should communicate with the Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics Evaluation and Research (CBER) before submitting an investigational new drug application.

Specifically, the guidance discusses CAR-T cell design and development including CAR construct, vectors, cellular starting material, and fresh or cryopreserved final products. Vector manufacturing and testing as well as collection, handling, and testing of cellular starting material are addressed. Managing manufacturing changes and assessing comparability during the CAR T-cell product lifecycle and single-site or multi-site CAR T cell manufacturing are also discussed in the guidance document.

The Office of Therapeutic Products in FDA’s Center for Biologics Evaluation and Research is hosting a public webinar on the guidance on Thursday, March 7, 2024 at 1:00 PM ET. More information can be found on 

The final guidance provides specific recommendations for CMC, pharmacology, toxicology, and clinical study design for CAR-T cell products.

FDA Issues Guidance on CAR-T Cell Product Development

FDA published a final guidance document, 

Human Gene Therapy Products Incorporating Human Genome Editing,

 on Jan. 30, 2024. The document provides recommendations for developing gene therapy products incorporating genome editing (GE) of human somatic cells. Recommendations include information needed in an investigational new drug application for the assessment of the safety and quality of GE products. This information pertains to product design, manufacturing and testing, nonclinical safety assessment, and clinical trial design.

According to the agency, the use of human GE has increased, which has resulted in rapid development of gene therapy products that incorporate GE. FDA advises that the risks of these products is not well understood. The guidance document offers ways to assess the safety of these products. The agency states in the document that it may reevaluate its recommendations as the field evolves.

The guidance document defines human GE as, “a process by which DNA sequences are added, deleted, altered, or replaced at specified location(s) in the genome of human somatic cells, 

, using nuclease-dependent or nuclease-independent GE technologies. Human gene therapy products incorporating GE are referred to as human GE products throughout this guidance. FDA evaluates human GE products using a science-based approach weighing the benefits and risks of each product. The benefit-risk profile for each product depends on the proposed indication and patient population, the extent and duration of therapeutic benefit achieved, and the availability of alternative therapeutic options. Some of the specific risks associated with GE approaches include off-target editing, unintended consequences of on-target editing, and the unknown long-term effects of on- and off-target editing.”

Considerations addressed in the document include GE methods, type and degree of genomic modification, and GE component delivery method. Chemistry, manufacturing, and controls recommendations are also discussed.

The final guidance provides recommendations for developing gene therapy products incorporating genome editing of human somatic cells.