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People around the world rely on medicines to improve—and often save—their lives. These therapies must not only be effective, but also safe for people to use. Regulatory bodies offer guidelines and regulations to ensure medicines are properly developed and manufactured. These guidelines are commonly referred to as good manufacturing practices (GMPs), among other ‘good practices’, in the United States and are outlined in the 

) and ensured by FDA (1). In Europe, GMPs are coordinated by the European Medicines Agency (EMA) and compiled in the 

 (2,3). Knowledge and proper implementation of these guidelines is key to the production of safe and effective medicines.

For patients, a lack of quality in a therapeutic product can have a dire impact. From a business perspective, a lack of training can result in delays getting product to market, product recalls, and regulatory scrutiny. Regulators want the assurance that a company’s training is adequate. “Regulators consistently review training programs during quality inspections,” says Peter Phillips, vice president, Quality Operations, BioVectra (a part of Agilent). “This is typically examined in two contexts: either as part of an investigation into specific incidents or as a standalone area of focus. Inspectors also assess how well the training aligns with employees’ job descriptions and actual responsibilities, ensuring that staff are properly trained to perform their tasks in compliance with regulatory requirements.”

The development and manufacture of medicines, however, is a complex process that involves early development scientists, pre-marketing analysts, manufacturing engineers, quality control personnel, contract organizations, and a variety of other personnel. If these many and varied individuals are not properly trained in their individual tasks, there may be a negative impact on the final drug product.

In an example of poor training impacting drug quality, Lara Ionescu Silverman, principal consultant at LIS BioConsulting, shares the story of a company’s quality department tracking results from a new analytical method that showed a decreasing trend in one value across all evaluated materials. “After an investigation, it was determined that the operator was slowly morphing the method and did not recognize the change, which resulted in the shift in values. Due to the criticality of the test, many contract projects had to be notified and retested at great expense. This could have been avoided through more frequent retraining, operator observation, and the use of multiple operators (to more quickly reveal any issues from a single operator),” says Silverman.

Training should be a constant, living element in a bio/pharmaceutical organization to prevent these kinds of problems. “Consistent, repeatable processes are critical to ensuring a robust product and process, and these processes rely on thorough and appropriate training. This includes not only technical and equipment operation training, but also safety protocol training and regulatory requirements,” says Phillips. “If personnel are not adequately trained … and a well-structured training program put in place, it can lead to process variability, safety risks, and non-compliance,” he warns.

Development of a drug is the first step in getting a therapy into the hands of patients. This step involves choosing the building blocks of the drug, from ingredients to delivery method to process development.

“It is critical to ensure that the research and development staff understand the future activities required to get a novel biologic or small-molecule drug approved,” says Silverman. “These scientists are doing incredible work to uncover novel mechanisms, drugs, and treatments. But, if they don’t keep the end in mind, issues can arise down the road. Providing basic training on the regulatory, manufacturing, and commercialization requirements can help scientists understand future activities and drive their present-day work.”

A lack of training in those individuals involved in the development of a drug can impact the quality of that drug in a variety of ways, according to Tony Cucinella, vice president, head of Quality and Regulatory Affairs at Selkirk Pharma. He points to poor aseptic techniques as a risk factor for contamination. “This [factor] is particularly critical for biologics, which are highly sensitive to microbial contamination,” says Cucinella. Improper training of processes can lead to variability, which can lead to inconsistencies in batches of product, he reports. Proper handling and storage of materials and the final product is also essential. “Improper training can result in mishandling, degrading the drug’s efficacy and safety,” Cucinella says. Lastly, he stresses that accurate documentation is key to drug quality. “Poor training can lead to errors in data recording, which can compromise the integrity of the development process and regulatory submissions.”

Utilizing reagents and equipment properly in a GMP setting with good controls and consistency is essential, specifies Silverman. “These materials and equipment should come from reputable manufacturers and allow for large-scale production, enabling the company to meet their market size goals to achieve ultimate commercial success. Also, it is important to gather (and organize!) analytical data from the ancillary materials, the process, and the final drug substances/products to allow for future comparability as well as the development of suitable control strategies to enable efficient GMP manufacturing,” she stresses.

Errors such as choice of delivery technology can happen when a development scientist is not properly trained, according to Chris Moreton of FinnBrit Consulting. “From my own experience, such a failure can cause a delay of about two years in the time to get to a reliable Phase I clinical trial result. This would be a fatal delay for many biotech start-up companies,” Moreton says.

Cucinella stresses that a comprehensive and ongoing training program for all those involved in drug development is essential for quality. “Trained personnel are better equipped to identify and troubleshoot issues during development. Without proper training, problems may go unnoticed or unresolved, affecting the drug’s quality,” he states.

A variety of unexpected events can happen during drug manufacturing, warns Michael Pinaud, senior vice president of Operations at Ascend Advanced Therapies, that can result in a final product that is unsuitable for use. “Without proper training on how to deal with the unexpected, the result can have detrimental impact on the quality and the ability to release drug product, says Pinaud. “Training operators to follow the appropriate procedures and keep good batch records should be considered the bare minimum expectation. Capturing all the relevant information and keeping a thorough timeline of events (through investigations and real time interviews) also helps to ensure that if/when something happens, it is clear if/how the quality of final drug product might be impacted because you have a detailed record of what actually occurred to refer to.”

Drug products are manufactured under strict quality requirements, especially biologics, according to Phillip Hernandez, head of Quality, Andelyn Biosciences; therefore, personnel working in these areas must be thoroughly trained in processes, gowning, the flow of the facility, aseptic techniques, contamination control, and documentation. “Improper training can lead to breaches in contamination control, introducing harmful microorganisms or particles into the drug product, which can have serious implications for patient safety. Proper training in documentation practices is crucial for maintaining compliance and traceability,” Hernandez stresses. “Manufacturing processes require precise execution of protocols and batch records. Variability in execution can result in batches that do not meet established quality standards, affecting efficacy and safety.”

Hernandez points to the example of a vaccine manufacturing facility that received an FDA Form 483 for multiple quality control deficiencies that resulted from poor training. “As a result of these findings, the company faced regulatory action and had to implement multiple corrective actions, including enhancing their training programs and reinforcing SOP [standard operating procedure] compliance among all personnel,” Hernandez warns. “This incident highlights the critical importance of effective training in ensuring product quality and regulatory compliance, particularly in high-stakes environments like vaccine manufacturing.”

While training is obviously not new in the pharma industry, Pinaud stresses that teaching the ‘how’ of an operation isn’t the only thing that matters. Personnel should also be taught the ‘why’ of what they are doing. “Training has been a focus for years now, so the actual execution of manufacturing is covered for the manufacturing operators. What we can tend to see is a focus on how to perform each operation and less of a focus on why each unit operation matters and what each step is accomplishing. Understanding the why is just as important as the how when taking a holistic approach to quality training,” he says.

Often, it’s the method of training that is lacking and/or how the training is conducted, according to Siegfried Schmitt, vice president, Technical at Parexel, often relying on great amounts of SOPs to be read and remembered. “If the training of the SOP were conducted in conjunction with performing the tasks, then this is much more efficient as visual experience is much better remembered than pure text, especially when unrelated to practical experience,” says Schmitt. “Training on the job beats mere theoretical training hands down.”

When training lapses or fails, it’s often up to training programs that have not been updated to include new technologies and changing regulatory expectations, according to Phillips. Management skills, especially, can be undervalued. “This area of training is critical, as poor management can lead to issues such as employee retention problems, insufficient follow-up on corrective actions, and decreased overall team performance,” says Phillips.

“I think the biggest area lacking training is around regulatory requirements,” says Silverman. “This area is particularly important because so much of the activities that occur at GMP facilities are a direct result of FDA requirements. Implementing such training is challenging because FDA regularly releases updated guidance documents and information; however, ensuring that staff are aware of regulatory topics can lead to smoother operations overall.”

Cucinella agrees that rapid advancements in technology are a challenge, with automation, artificial intelligence, and machine learning requiring continuous learning. In addition, Cucinella says, “With the increasing reliance on digital systems, ensuring data integrity and cybersecurity is paramount. Training on how to handle, store, and protect data is often lacking.”

“Pharmaceutical companies and contract manufacturers often lack robust and continuous training programs in GMP compliance and in the nuances of understanding analytical testing methods and interpreting data,” says Shailesh Vengurlekar, senior vice president Quality and Regulatory Affairs, LGM Pharma. “Personnel may lack training in data integrity and the importance of accurate and traceable data in manufacturing, especially with electronic record-keeping systems. Many contract manufacturers ignore the importance of instrument maintenance programs, which could lead to several product quality issues including contamination.”

Lee McKinley, director, Organizational Development, BioVectra (a part of Agilent) points to personnel not being able to fully observe processes and often not having full access to equipment for training. “Providing a safe environment for hands-on training, where employees can practice without disrupting ongoing operations, is crucial. Without this, ramp-up times can be significantly delayed, affecting overall efficiency and performance.”

How can training be conducted to ensure the quality of bio/pharmaceuticals? Moreton suggests the appointment of a ‘training officer’ who’s job and authority is to ensure proper training is taking place for both new and existing staff. “The training officer must also monitor the quality of training and keep records of attendees and also monitor individual training records. In the event of an error or incident that compromises quality, the training officer should be part of the investigation team,” says Moreton.

A comprehensive onboarding program that focuses on GMP training is essential, remarks Cucinella, as are detailed SOPs. Training for the role is also important, he says, to be sure the employee is trained on their specific roles and responsibilities. Creating a quality culture that fosters continuous improvement is also key, notes Cucinella.

Cyrill Kellerhals, COO at Andelyn Biosciences takes onboarding of personnel seriously by going “well above-and-beyond” when it comes to minimum requirements. The company also has a partnership with a university for new staff training and incorporates on-site training before a new operator begins. “[We also have] on the job training to ensure more experienced operators are working with new staff members while they build up their comfort level and ability to execute,” says Kellerhals.

After onboarding, Diem Hoang, director of Quality, LGM Pharma recommends that a training timeline be established to set training expectations going forward, then follow up with documentation to track the employee’s progress. Recertification should be scheduled if needed.

McKinley stresses that training should incorporate diverse learning styles and backgrounds, with clear lay-person language, in-person sessions, e-learning, hands-on practice, interactive elements, and feedback.

An electronic data management system (eDMS) should be implemented, according to Hernandez. “An effective eDMS provides up-to-date, dynamic reporting on the training records of every staff member and serves as a repository for the version history and current revisions of all SOPs and quality documentation,” he says.

The effectiveness of training should be measured with pre- and post-assessments, according to McKinley. Assessments enable one to identify where improvements in the training program are needed. “Additionally, incorporating refresher training later in the onboarding process helps reinforce key concepts. Repetition is vital to ensure that staff internalize GMP standards and consistently follow quality procedures. All of this contributes to a successful training program,” says McKinley.

Industry groups offer expert training. Utilizing industry groups is a tool bio/pharmaceutical companies can use to ensure a robust training program, specifically for GMPs, according to Phillips. These groups are usually knowledgeable of current regulations and often offer their own training programs that can be tailored to group members. “In addition, participating in these networks creates opportunities for knowledge sharing, adding insights to courses, and accessing further training resources,” says Phillips. “However, it’s equally important to have an effective mechanism for integrating this training into the organization. Often, employees attend external training sessions but fail to share their learnings with the broader team, which represents a missed opportunity for company-wide improvement. Establishing a system for disseminating and reinforcing acquired knowledge can enhance the overall impact of training,” he stresses.

“Such [professional] training can be used to augment any in-house training. They can also be used to audit company in-house training and overall training. In-house trainers must also be properly trained in training techniques and methods of instruction,” agrees Moreton. “Not everyone can train, but even good trainers can improve their effectiveness with proper training.”

With the global biologics market expected to reach US$1,374.51 billion by 2033 (4), it would suggest that this growth would create a demand for experience in the development and manufacture of these products. But how can bio/pharma companies and contract organizations keep up with the training their employees will need to meet this demand?

Moreton suggests that training in new modalities not be left to non-technical staff and that information available in the scientific literature be reviewed. “This can be achieved in several ways; one of the most effective is to engage the scientific and technical staff and ask them to review literature sources and add any noteworthy information to a central repository that is reviewed and discussed at regular meetings of the technical and scientific staff for relevance and importance,” he says.

“Maintaining effective training in the evolving field of biologics requires active engagement with industry groups and networking with other companies, as mentioned above,” says Phillips. “By staying connected to what is currently happening in the industry and understanding emerging standards, companies can continuously adapt their training programs to meet new challenges and requirements.”

The trainer also needs training to keep up with these new modalities, explains McKinley. “It is crucial to ensure that trainers possess the necessary expertise to effectively deliver training. This includes staying up to date on best practices by regularly participating in ‘train the trainer’ programs and professional development sessions,” he says. “These sessions should focus on emerging training technologies, innovative learning modalities, and adult learning principles, which are essential for adapting to the rapidly changing environment of biologics manufacturing.”

Quality in the bio/pharmaceutical is the responsibility of everyone involved in the development and manufacture of drugs. But if those individuals are not properly trained, mistakes can happen, resulting in either unsafe and/or ineffective drugs. Therefore, training should be an important part of a pharmaceutical company’s and/or contract organization’s procedures.

“While the quality department is ultimately responsible, it is critical for individuals in manufacturing, supply chain, and other functions to also understand what might impact quality, so that investigations can be initiated if concerns arise,” stresses Silverman. “Such inquiries can be especially important in highly complex drug products such cell and gene therapies, where the product characteristics can be hard to understand.”

FDA. Current Good Manufacturing Practice (CGMP) Regulations. 

https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations (accessed, Nov. 1, 2024).

 https://www.ema.europa.eu/en/human-regulatory-overview/research-development/compliance-research-development/good-manufacturing-practice (accessed, Nov. 1, 2024).

. https://health.ec.europa.eu/medicinal-products/eudralex_en (accessed, Nov. 1, 2024).

Biologics Market Size, Share & Trends Analysis Report by Source (Microbial, Mammalian), By Product (MABs, Recombinant Proteins, Antisense & RNAi), By Disease Category, By Manufacturing, By Region, And Segment)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2024–2033.

®
Vol. 48, No. 12
December 2024
Pages: 10–15

When referring to this article, please cite it has Haigney, S. Enhancing Quality Through Training. 

Articles

With so many personnel involved in the development and manufacture of pharmaceuticals, proper training of all staff is key to ensuring a quality product.

Enhancing Quality Through Training

Feliza Mirasol is the science editor for 

Novo Holdings has received approval from the European Commission (EC) for its acquisition of Catalent and the subsequent related sale of three Catalent manufacturing sites to Novo Nordisk, Novo Nordisk announced on Dec. 6, 2024 (1). Novo Holdings is a holding and investment company responsible for managing the assets and the wealth of the Novo Nordisk Foundation. In earlier related news, Novavax announced on Dec. 4, 2024, that it signed a definitive agreement to sell its manufacturing facility in Bohumil, Czech Republic, to Novo Nordisk for $200 million (2).

Novo Nordisk had announced on Feb. 5, 2024 that it will acquire the three Catalent manufacturing sites from Novo Holdings upon completion of the Catalent transaction (3). These three sites are located in Anagni, Italy; Brussels, Belgium; and Bloomington, Ind., United States. The sites specialize in the sterile filling of drugs and employ more than 3000 personnel, all with ongoing collaborations with Novo Nordisk. Under the transaction, Novo Nordisk pays $11 billion upfront.

The acquisition of the three sites will be completed immediately following the merger of Catalent and a Novo Holdings subsidiary, which is expected towards the end of 2024. Until the close of the Catalent acquisition, Catalent will continue to operate independently and separately from Novo Holdings and Novo Nordisk. Following the close, Novo Nordisk will honor all customer obligations at the three Catalent sites it is acquiring (2).

Meanwhile Novo Holdings’ acquisition of Catalent is expected to be completed near the end of 2024, pending customary closing conditions, including regulatory approvals in other jurisdictions (1).

“We are very pleased with the agreement to acquire the three Catalent manufacturing sites which will enable us to serve significantly more people living with diabetes and obesity in the future,” said Lars Fruergaard Jørgensen, president and chief executive officer at Novo Nordisk, in a company press release issued at the time of the sites acquisition announcement (3). “The acquisition complements the significant investments we are already doing in active pharmaceutical ingredients facilities, and the sites will provide strategic flexibility to our existing supply network.”

The acquisition of these three Catalent sties will enable an expansion of Novo Nordisk’s manufacturing capacity at scale and speed and provides future options and flexibility for the company’s existing supply network. Novo Nordisk expects to gradually increase its filling capacity from 2026 and onwards through the acquisition of these sites.

Under the Novavax transaction, Novo Nordisk will gain that company’s Bohumil manufacturing site, which includes a transfer of assets such as a 150,000-square-foot state-of-the-art recombinant protein manufacturing facility, support buildings, and the existing workforce as well as all related and required infrastructure, for $200 million (2). This transaction is expected to close by Dec. 30, 2024, at which time Novo Nordisk will take over full responsibility for the manufacturing facility.

"The decision to sell the Czech Republic manufacturing facility aligns with our previously announced commitment to evolve Novavax into a more lean and agile organization focused on partnering our pipeline assets and technology platform," said John C. Jacobs, president and chief executive officer, Novavax, in that company’s press release (2). "We are thankful to our dedicated colleagues in the Czech Republic who have contributed to Novavax's mission of delivering our technology to address unmet needs. We look forward to working with Novo Nordisk to ensure a successful transition."

1. Novo Nordisk. The European Commission Approves the Acquisition of Catalent by Novo Holdings and the Related Acquisition by Novo Nordisk of Three Manufacturing Sites from Novo Holdings. Press Release. Dec. 6, 2024.
2. Novavax. Novavax Announces Sale of Czech Republic Manufacturing Site to Novo Nordisk for $200 Million. Press Release. Dec. 4, 2024.
3. Novo Nordisk. Novo Nordisk to Acquire Three Fill-Finish Sites from Novo Holdings A/S in Connection with the Catalent, Inc. Transaction. Press Release. Feb. 5, 2024.

The European Commission has approved Novo Holdings' acquisition of Catalent, which includes the related sale of three manufacturing sites to Novo Nordisk, which is also acquiring the Czech Republic manufacturing site of Novavax for $200 million.

Novo Nordisk Gains Manufacturing Sites from Novo Holdings and Novavax while EC Approves Catalent Acquisition

Enzene on New Technologies and New Jersey Site Capabilities

Shilpa Gadgil, PhD, from Enzene, discusses the company's Fully-Connected Continuous Manufacturing™ (FCCM™) platform and EnzeneX™ 2.0 for commercial biologics supply, as well as which large molecules have been successfully produced using the platforms. She also covers Enzene's new biologics site in New Jersey and the bottlenecks the company has overcome regarding transfer and scale-up.

Videos

Shilpa Gadgil, PhD (VP, Head of Process and Analytical Development, Head of CDMO Development) discusses Enzene's new technologies and the New Jersey site capabilities.



Breaking barriers: EnzeneX™ to EnzeneX™ 2.0

Gary Ritchie, InfraTrac gritchie@infratrac.com, is director of Scientific Affairs at InfraTrac.

Sharon Flank, PhD, sflank@infratrac.com, is CEO at InfraTrac.

Before industrialization, pills were formulated by compounding, mixing, rolling, cutting, and finishing for a particular patient. This process remains useful when mass production fails to create a version that works for an individual, whether because the dose is incorrect or an unacceptable ingredient such as an allergen must be avoided. Compounding for a single individual is regulated differently from mass production (1) in every jurisdiction; although, it is worth noting that even trituration via mortar and pestle must be performed using gloved hands, in a clean environment, free of vermin, standing water, and the like (2). Three-dimensional printing (3DP) offers many advantages, particularly for personalized medicine, but, from a legal and regulatory perspective, regardless of specific print technique, it is neither exactly compounding, nor is it exactly mass production. The technology can be used to develop novel drug delivery options, potentially manufactured at scale and thus falling under existing FDA manufacturing regulations. It can be employed for distributed manufacturing, introducing issues of portability that FDA is addressing in its Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) discussions (3). Here the focus is more on point-of-care production, either for a single patient or, potentially, for a small group as in a children’s hospital. Wise regulatory choices can allow 3DP to flourish to patients’ advantage, building on its strengths and, crucially, adding options for better patient care. A focus on the intersection of areas of need (dose customization, polypills, allergen avoidance) with relative simplicity will lead to earlier success.

Compositional changes affect bioavailability and cannot be implemented at the point of care, but shape and size variations can be pre-tested, bounded, and made available for the dispensing pharmacist to control. One approach to such bounding is the creation of so-called pharma-inks, pre-formulated but with dosing to be controlled at the point of care; another is the use of cartridges. Neither of these approaches offers allergen avoidance, but it is possible that there will be other intermediate-based offerings that allow limited customization (e.g., from a list of APIs according to a validated formulary). While it is unlikely that 3DP will be as fast as industrial-scale manufacturing such as tableting and capsule-filling, the ease of variation offers advantages whenever changeability is a positive attribute. This paper addresses the interplay of positive variation (e.g., for personalized medicine) and negative variation (i.e., repeatability failure).

The variety of 3DP technologies has been discussed in depth, including for drug printing (4). All share several basic commonalities. First, raw materials can be placed in a particular location in a dose form, with the result that geometric features are available to manipulate drug delivery parameters. In conventional manufacturing, coating offers this option, but only in a limited fashion. Second, the raw materials are utilized first in a flowable form (powder, liquid, gel), and then, depending on the method, one or more techniques are used to solidify the resulting dose. In the case of filament-based printing, this is a two-step process, in which a coil of thin filament is first created, generally via hot-melt extrusion, and then fed through a printer so that the shape can be manipulated.

Submitted: July 1, 2024
Accepted: July 15, 2024

 Title 21, 225.1 (Government Printing Office, Washington, DC). 

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=225.1

Guidance for Industry, on Pharmacy Compounding of Human Drug Products Under Section 503A of the Federal Food, Drug and Cosmetic Act

CDER Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) Initiative, Distributed Manufacturing and Point-of-Care Manufacturing of Drugs, 

Gary Ritchie, InfraTrac gritchie@infratrac.com, is director of Scientific Affairs at InfraTrac. Sharon Flank

, PhD, sflank@infratrac.com, is CEO at InfraTrac.

To whom all correspondence should be addressed.

®
Vol. 48, No. 12
December 2024
Pages: 22–25

When referring to this article, please cite it Ritchie, G.; Flank, S. Legal and Regulatory Perspectives on 3D Printing: Drug Compounding Applications. 

This paper explores the legal and regulatory framework around 3D drug printing, particularly for personalized medicine, considering regulatory compliance, business concerns, and intellectual property rights.

Legal and Regulatory Perspectives on 3D Printing: Drug Compounding Applications

Novartis has entered into a global license and collaboration agreement with PTC Therapeutics (PTC) under which Novartis gets access to PTC’s PTC518 Huntington's disease program, which includes related molecules, the two companies announced on Dec. 2, 2024 (1,2). PTC518 is a huntingtin (HTT) messenger RNA (mRNA) splice modulator. It has the potential to become the first oral disease-modifying therapy for Huntington's disease, according to the Novartis press release (1).

Under the agreement, Novartis will pay an upfront payment of $1 billion and up to $1.9 billion in development, regulatory, and sales milestones. Both companies will share in profits and losses in the United States on a 40/60 basis (40% PTC and 60% Novartis) (2). Novartis will also pay PTC tiered royalties on sales outside the US (1). The transaction is subject to customary closing conditions, including regulatory clearance, and is expected to close in the first quarter of 2025 (2).

Novartis will assume responsibility for the development, manufacturing, and commercialization of PTC518 following completion of the placebo-controlled portion of an ongoing Phase II study (PIVOT-HD), which is expected in the first half of 2025. The agreement bolsters Novartis’ neuroscience pipeline and as the company focuses its efforts on neurodegenerative diseases with high unmet needs.

"PTC518 is the leading oral disease-modifying therapy in development for Huntington's disease and the economics of this agreement are consistent with the promise of this treatment," said Matthew B. Klein, MD, chief executive officer, PTC Therapeutics, in that company’s press release (2). "This collaboration combines PTC's expertise in developing small-molecule splicing therapies with Novartis's expertise in global development and commercialization of neuroscience therapies. We are excited to collaborate with Novartis to accelerate the potential of PTC518 for the hundreds of thousands of HD patients worldwide in need of a therapy designed to be well-tolerated and an effective disease-modifying therapy. PTC will use the proceeds of this transaction to expand our splicing platform as well as to support commercial and development portfolio activities."

PTC discovered PTC518 through its validated splicing platform. Interim results reported in June 2024 (3) from the ongoing Phase II study demonstrated that treatment with PTC518 resulted in durable, dose-dependent reduction in blood and cerebrospinal fluid mutant HTT levels. The interim results also showed early signals of a dose-dependent benefit on key clinical measurements at 12 months. More importantly, according to PTC, PTC518 has continued to demonstrate a favorable safety and tolerability profile (3).

"Huntington's [d]isease is a devastating, fatal, familial disease. This agreement with PTC is intended to bolster our neuroscience pipeline and reflects our strategic focus and commitment to explore new and potentially transformative approaches for neurodegenerative diseases with high unmet needs," said Vas Narasimhan, CEO of Novartis, in PTC’s company press release (2). "We look forward to building on our expertise in neurodegenerative diseases and experience in [Huntington's disease] with the intention to advance this potential first-in-class oral therapy for the [Huntington's disease] community."

1. Novartis. Novartis Bolsters Neuroscience Pipeline with In-Licensing of PTC518 for Huntington’s Disease. Press Release. Dec. 2, 2024.
2. PTC Therapeutics. PTC Therapeutics Enters into a Global License and Collaboration Agreement with Novartis for PTC518 Huntington's Disease Program. Press Release. Dec. 2, 2024.
3. PTC Therapeutics. Interim PIVOT-HD Results Demonstrate Evidence of Favorable CNS Biomarker and Clinical Effects at Month 12 in Huntington's Disease Patients. Press Release. June 20, 2024.

Novartis will in-license PTC's PTC518 program, which has the potential become the first oral disease-modifying therapy for Huntington's disease.

Novartis Enters $2.9 Billion License Agreement with PTC Therapeutics for Huntington’s Disease Development Program

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The first CPHI Middle East event, to be held Dec. 10–12, 2024 at the Riyadh Front Exhibition & Convention Center Riyadh in Saudi Arabia, is expected to be host to 30,000 pharma professionals, according to the event’s planners. According to CPHI, the region is planning to expand its domestic manufacturing capabilities as new technology investments are poured into the market.

Indian contract development and manufacturing organizations are expected to invest in the region as they support emerging biotechs that have product development in India, according to CPHI, with more than 80 Indian companies exhibiting at the event. There are a total of 400 companies exhibiting, with more than 65 from Europe and 90 from China.

“The event is held under the patronage of the Saudi Ministry of Health, who will be among more than 160 experts presenting at the event,” CPHI stated in a press release (1). “A Ministerial Panel on 10 December will outline the Kingdom’s strategy to develop a biopharma ecosystem, in alignment with the Kingdom’s vision to be the leading biotech hub in MENA [Middle East and Northern Africa] by 2030 and globally by 2040. The Kingdom has ambitious plans to reduce its reliance on imported drugs. In fact, currently, Saudi Arabia imports over 81% of its generic medicines and 94% of its medical devices, however, by 2030, the Kingdom aims to produce 40% of its drug needs domestically.”

Hala Audi, CEO of UNIZIMA—which specializes in partnerships for bioproduction facilities in emerging market—is a keynote speaker at the event and will discuss building biologics capabilities in emerging markets.

“The event’s success is just another indicator of the significant investment underway in the region,” said Audi in the press release (1). “The rate of change is only accelerating, and the Kingdom is building pharma infrastructure at pace. The [g]overnment is rightly driving the momentum, by focusing on its strengths—a sizeable domestic market, growing scientific and medical talent, and financing power. I believe that with the right technology partnerships, the region is poised to build a biotech ecosystem that will compete with the best globally. Next generation technologies for vaccines and therapeutics including, for instance, RNA based treatments offer an opportunity for KSA [Kingdom of Saudi Arabia] and the region to leapfrog and lead the way in biotech.”

The conference agenda will include a variety of topics related to the future of pharmaceutical development in the Middle East and will span four show-floor theaters. Panel discussions will include talks on the expansion of Saudi Arabia’s domestic manufacturing hub.

“CPHI Middle East is set to be the portfolio’s most successful launch to date – with incredibly impressive attendee and exhibitor numbers,” April Hung, brand manager for CPHI Middle East, stated in the release. “This level of interest reflects the region’s ambitions and strong demand for partnerships. The public–private collaboration here is impressive, and by bringing CPHI to Saudi Arabia, we’re helping accelerate the development of partnerships and supply ecosystems that will fuel growth over the next five years. We’re thrilled to launch the show and play a role in building a new ‘heart of pharma’ in the Middle East.”

1.	CPHI. Saudi Arabia Poised to Expand Domestic Manufacturing Eco-system as 30,000 Attendees join Inaugural CPHI Middle East. Press Release. Dec. 9, 2024.

The first CPHI Middle East event will be held Dec. 10–12, 2024 at the Riyadh Front Exhibition & Convention Center Riyadh in Saudi Arabia and is expected to be host to 30,000 pharma professionals.

CPHI Middle East Sees Domestic Manufacturing Expansion in Saudi Arabia

Cheryl Barton is director of PharmaVision, 

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Over the past decade, researchers have developed a greater understanding of the relative contributions of the environment, genetic, and epigenetic influences on the onset and progression of Parkinson’s disease (PD). New strategies have emerged that seek to modulate inflammatory cellular mediators, mitochondrial function, and/or halt the accumulation of synuclein and neuromelanin (1–3).

In August 2024, German-based Centogene NV released new data from the landmark Rostock International Parkinson’s Disease (ROPAD) Consortium Study which aimed to characterize the genetics of PD to better understand disease progression, diagnosis, and treatment for patients (4). The study identified that approximately 15% of 12,580 patients studied harboured genetic variants that present new opportunities for genetic testing and the development of innovative therapies such as cell and gene therapies (CGTs) (5).

New formulations and novel non-biological drugs

More than 10 million people worldwide are living with PD, and it is now classed as the fastest-growing neurological condition in the world (6,7). Several companies such as NeuroDerm (a Tanabe Pharma company), Cerevel (an AbbVie company), and Swiss-based Contera Pharma A/S are working on non-biological agents with immediate or long-duration action to improve the symptoms of PD (8–10) (

). In October 2024, the US Food and Drug Administration (FDA) finally approved AbbVie’s Vyalev (foscarbidopa and foslevodopa), the first 24-hour infusion of levodopa-based therapy for motor fluctuations in adults with advanced PD (11). This single infusion helps reduce the pill burden whereby PD patients may take more than 20 tablets a day to control their symptoms. AbbVie gained approval for the drug, under the trade name Produodopa, from the European Commission (EC) in January 2024 (12). In May 2024, Portuguese BIAL Holding S/A launched a novel sublingual film formulation Kynmobi (apomorphine hydrochloride) in Germany, for the intermittent treatment of off episodes in adult patients with PD who are not sufficiently controlled by oral anti-Parkinson medication (13).

Pharma companies are actively pursuing the development of drugs that target novel pathways involved in the underlying mechanism of PD (

). These include BIAL’s BIA 28-6156, a small-molecule activator of glucocerebrosidase (GCase), a lysosomal enzyme involved in the breakdown of glycosphingolipids and UK-based Neurolixis’ NLX-112 (befiradol), a novel 5-HTA1A receptor agonist that has completed a Phase IIa proof-of-concept trial for dyskinesia in PD (14–16).

Innovative non-biological drugs under clinical development for Parkinson’s disease (PD).

Innovative biological therapies are progressing through trials

Several companies are looking to harness biologics to halt the accumulation of detrimental proteins such as alpha-synuclein (a-syn), which has been implicated in the pathology of PD (

). US-based AC Immune is evaluating ACI-7104 in Phase II, a monoclonal antibody (mAb) that has been shown to inhibit the accumulation of a-syn aggregates in preclinical animal models and the brain tissue of PD patients (17). An alternative approach is the use of adeno-associated virus (AVV) vectors to deliver genes that selectively modulate the production of proteins such as glutamic acid decarboxylase (GAD) to increase gamma-aminobutyric acid (GABA) levels, or glial cell line-derived neurotrophic factor (GDNF) to boost dopamine levels. In January 2024, Asklepios BioPharmaceuticals (AskBio, a subsidiary of Bayer AG) released positive data with its AAV2-GDNF showing that the one-time bilateral delivery of AB-1005 gene therapy was well-tolerated, and no serious adverse events (AEs) were observed (18). In October 2024, US-based MeiraGTx Holdings released positive top-line data from its clinical bridging study with MGT-GAD-025, an AAV-GAD, resulted in a significant and clinically meaningful improvement in Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) from baseline to Week 26 in patients with idiopathic PD (IPD) (19).

Cell and gene therapies under clinical development for the treatment of Parkinson’s disease (PD).

Cell-based therapy is expected to provide an alternative route to treat PD through the surgical injection of autologous induced pluripotent stem cell (iPSC)-derived dopamine neurons into the putamen, the brain region affected in PD. Denmark/China-based iRegene is evaluating chemically induced human dopaminergic neuron precursors derived from iPSCs to treat moderate to severe PD; the company entered clinical development with its gene therapy NouvNeu001 in the second half of 2023 (20). Similarly, Massachusetts-based BlueRock Therapeutics (a subsidiary of Bayer AG) has released promising Phase I follow-up data from its safety trial with its cell-based therapy bemdaneprocel (MSK-DA01) (21). Alternatively, Australia-based Living Cell Technologies (LCT) is developing an alginate-coated capsule containing clusters of neonatal porcine choroid plexus cells that contains a range of factors that support nerve cell functions and protective enzymes that are crucial for nerve growth and healthy functioning in PD patients (22).

Since 2019, the number of active clinical trials for PD has remained relatively consistent, with more than 136 trials per year. However, the proportion of disease-modifying to symptomatic therapies has been increasing during the past five years, and the diversity of drug targets across both symptomatic and disease-modifying drugs has also increased. Interestingly, the number of trials investigating drugs aiming to improve non-motor symptoms has expanded and several drugs are now being developed to target inflammation, a key driver of PD progression (23). But despite these significant advances, many drugs still fail to transition from Phase II to Phase III.

National and international organizations and foundations, such as Cure Parkinson’s, the American and European Parkinson’s Disease Association, Michael J. Fox Foundation, National Parkinson’s Foundation, and Parkinson’s UK, have an important role in raising awareness, supporting patients, and funding PD research. Pharma companies including Bayer, Biogen, Genzyme, GlaxoSmithKline, Sanofi, and Pfizer have made multi-million-dollar strategic investment investments, and several life-changing therapies, including CGTs, are steadily progressing through the clinic. If successful, these therapies could help rewire the PD brain circuits and fundamentally change the way patients are treated over the next decade (24).

1. Elsworth, J.D. Parkinson’s Disease Treatment: Past, Present, and Future. 

 May;127(5):785-791.
2. Pajares. M.; Rojo, A.I.; Manda, G.; Boscá, L.; Cuadrado, A. Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications. 

 Jul 14;9(7):1687.
3. Abeliovich, A.; Hefti, F.; Sevigny, J. Gene Therapy for Parkinson‘s Disease Associated with GBA1 Mutations. 

 11(s2): S183-S188.
4. Westenberger, A.; Skrahina, V.; Usnich, T.; et al. Relevance of Genetic Testing in the Gene-targeted Trial Era: The Rostock Parkinson’s Disease study. 

. 147(8) 2652-2667.
5. Centogene. Introducing the ROPAD Consortium: Unlocking Real-world Genetic Insights to Accelerate Treatment Access for Parkinson’s Disease. Webinar. October 2024.
6. Parkinson’s Foundation. Statistics. 

 (accessed 30 Oct. 2024).
7. BBC News. New Parkinson’s Drug Produodopa to be Available on NHS. 16 Feb. 2024.
8. NeuroDerm Ltd. ND0612 (accessed 30 Oct. 2024).
9. Cerevel Therapeutics. Cerevel Therapeutics Announces Positive Topline Results for Tavapadon in Phase 3 Adjunctive Trial for People Living with Parkinson’s Disease | Cerevel Therapeutics. News Release. 18 Apr. 2024.
10. Contera Pharma A/S. Contera Pharma Reports Topline Results from its Phase IIb Clinical Trial ASTORIA, evaluating JM-010 for the Treatment of Parkinson’s Disease Dyskinesia. News Release. 21 May 2024.
11. AbbVie. U.S. FDA Approves VYALEV (foscarbidopa and foslevodopa) for Adults Living with Advanced Parkinson’s Disease. News Release. 17 Oct. 2024.
12. AbbVie. AbbVie Launches PRODUODOPA (foslevodopa/foscarbidopa) for People Living with Advanced Parkinson’s Disease in the European Union. News Release. 9 Jan. 2024.
13. Bial. Bial launches Kynmobi in Germany. News Release. 3 May 2024.
14. Bial. BIA 28-6156. 

. (accessed 30 Oct. 2024).
15. Cavion. Cavion to Present Results of Phase 2 Essential Tremor Clinical Trial in Platform Presentation at the American Academy of Neurology. News Release. 24 Apr. 2019.
16. Neurolixis. Successful NLX-112 Clinical Results were Discussed in an Interview with the Parkinson’s UK Foundation. 15 Jan. 2024.
17. AC Immune. ACI-7104: Updates on Clinical Progress. 2024.
18. AskBio. AskBio Phase Ib Trial of AB-1005 Gene Therapy in Patients with Parkinson’s Disease Meets Primary Endpoint. News Release. 4 Jan. 2024.
19. MeiraGTx. MeiraGTx Announces Positive Data from Randomized, Sham-controlled Clinical Bridging Study of AAV-GAD for the Treatment of Parkinson’s Disease. News Release 15 Oct. 2024.
20. Cai M.; Wei, J.; Ren, X.; et al. NouvNeu001, A Phase 1 Stage Chemically Induced Human Dopaminergic Progenitor Cell Therapy for the Treatment of Mid- to Late-stage Parkinson’s Disease. 2024 International Conference. Abstract Number 700.
21. BlueRock Therapeutics. BlueRock’s Phase I Study with Bemdaneprocel in Patients with Parkinson’s Disease Meets the Primary Endpoint. News Release. 28 Aug. 2023.
22. LCT. NTCELL. Accessed 30 Oct. 2024.
23. Cure Parkinson’s. Parkinson’s Drug Therapies in the Clinical Trial Pipeline: 2024 Update. News Release. August 2024.
24. Kingwell, K. Gene Therapy Zeroes in on Parkinson’s Disease Brain Circuits. 

Cheryl Barton is director of Pharmavision, info@pharmavision.co.uk.


Vol. 36, No. 10
November/December 2024
Pages: 16–18

When referring to this article, please cite it as Barton, C. European Biotechs Unlocking Parkinson’s Disease. 

Centogene NV and ROPAD consortium publish data from a landmark study identifying genetic variants that may respond to innovative cell and gene therapies.

European Biotechs Unlocking Parkinson’s Disease

Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Use of process analytical technology (PAT) and advanced digital solutions such as artificial intelligence (AI) and machine learning (ML) is a crucial component of the move to Pharma 4.0. Online/inline/at-line PAT enables real-time monitoring of processes during development and manufacturing. That information can then be applied to support process control, leading to more consistent performance. When PAT is integrated with AI/ML algorithms, it is possible to develop predictive models that enable improved control, support more effective decision-making, and reduce risks, leading to optimized operations, enhanced customer experiences, and better financial outcomes, according to Edita Botonjic-Sehic, head of process analytics, data engineering and data science at ReciBioPharm.

Several PAT tools are particularly well-suited for integration with AI and ML algorithms. At the top of the list are soft sensors, which integrate a software layer based on a mathematical model that is employed to monitor process states, observes Stacy Shollenberger, senior manager, process analytical technology with MilliporeSigma.

Analysis of the results is complex, however, and requires a high level of expertise to identify, correlate, and quantify the signal and use it for predictive analysis, according to Kaschif Ahmed, principal data scientist with ReciBioPharm. “The best integration solution is one that has an extreme amount of flexibility for measurement and analysis and can easily be validated without the constant need for calibration,” he adds.

AI/ML models can be directly integrated inside the PAT tool, providing a data-driven means to estimate or predict parameters that are otherwise difficult to measure or cannot be measured directly, says Moritz von Stosch, chief innovation officer of DataHow.

Shollenberger points to spectroscopic sensors including Raman, nuclear magnetic resonance (NMR), and near-infrared (NIR) technologies, which offer near-instantaneous measurement of key metabolites and nutrients (e.g., lactate, glucose). However, the spectra generated by these techniques require interpretation using chemometric models leveraging AI/ML algorithms tailored for chemical analysis. Mass spectrometry, she notes, can also greatly benefit from AI/ML interpretation of the produced spectra.

High-performance liquid chromatography (HPLC) and ultra-high performance liquid chromatography (UHPLC), meanwhile, can also be coupled to online analyzers that rely on models and used to monitor product purity in near real-time, according to Shollenberger.

Importantly, in comparison to standard linear regression approaches, ML can increase prediction accuracy when nonlinearities arise (e.g., due to superimpositions in the spectra), says von Stosch. Fusion of data from different sensors is also possible, enabling capture of the overall state of the process better and reducing the impact of measurement noise. “By fusing sensor information with predictions coming from process models, the performance of such approaches can be extended, (e.g., in the case of low signal-to-noise ratios),” he remarks.

Depending on the monitoring scope, Shollenberger notes that hybrid models combining AI/ML with mechanistic understanding can be better suited for real-time monitoring than AI/ML models alone because the former generally better capture the complexity of bioprocesses, leading to more reliable, interpretable, and generalizable simulation results. Upstream processes in particular stand to gain the most from hybrid models, she says, as they are characterized by the high degree of unpredictability inherent in living cells.

There are applications for AI/ML outside of soft sensors as well. For example, van Stosch notes that the advent of deep learning, a specific ML method, has also made real-time-based image processing possible. “Today, ML methods are used to count cells or particles, classify different types of cells or particles, inspect vials for release, and other applications,” von Stosch comments.

PAT tools integrated with AI/ML-driven models can be used in many different applications across modalities, the drug development and manufacturing cycle, and unit operations. “Such integrated tools are suitable for all types of processes, including those that produce small molecules and biotherapeutics and for both upstream and downstream unit operations at process development and manufacturing scale,” states Botonjic-Sehic.

“Real-time operation and immediate decision-making using PAT tools and digital twins will increase throughput and reduce failures during process development and manufacturing,” adds Ahmed. For these and other reasons, Botonjic-Sehic notes that the use of PAT and digital infrastructure is supported by regulators, with some guidelines available to help the industry move in this direction.

Real-time process optimization relying on process models is one specific activity that can particularly benefit from AI/ML at the upstream level, according to Shollenberger. “Integration of AI/ML/hybrid models with PAT in process development helps to accelerate process understanding, including the impact of different critical process parameters (CPPs) on product critical quality attributes (CQAs), and facilitates the extrapolation of process knowledge across different scales,” she says.

Process development activities can greatly benefit from more continuous tracking of the process state and the ability to make decisions during or after the run, rather than having to wait for the analytics for several hours or days, agrees von Stosch. “In addition to accelerating process development, PAT tools with integrated AI/ML models can render on-the-fly process optimization possible,” he states.

Such knowledge management is also crucial for a smooth process scale-up and transfer from development to pilot and manufacturing scales, all while ensuring stable and effective performance, Shollenberger contends.

As examples, Shollenberger highlights the use of multivariate statistical process control methods within a quality-by-design approach to process development to maintain CPPs and CQAs within the identified design space and new AI/ML design-of-experiment (DoE) tools such as the Bayesian DoE to reduce experimental effort and development costs by providing experiments that are the most informative for characterizing processes. Finally, she points to the use of digital twins for predicting process performance at production scale by mirroring and extrapolating insights gained from smaller-scale experiments. “This approach allows for a more accurate representation of how processes will behave in full-scale production, ultimately streamlining process development and enhancing overall efficiency,” Shollenberger comments.

In addition to supporting the scale-up from process development to production by learning to adapt scale-dependent process parameters and optimizing their configurations, AI/ML/hybrid models supporting real-time or near real-time monitoring and control can greatly improve process efficiency, reliability, yield, and product quality, says Shollenberger. PAT and digitally driven infrastructure can, agrees Botonjic-Sehic, reduce uncertainty by providing insights into process conditions through simulators enhanced with integrated AI/ML and PAT real-time data. “Real-time release testing will also be enabled by AI/ML with PAT due to the ability to achieve rapid quality verification,” she notes.

Improved responsiveness and better decision-making

The integration of AI, ML, and hybrid models with PAT tools offers numerous benefits that extend beyond simple process monitoring. Having an infrastructure that includes novel PAT tools, ML models, and automation allows researchers to identify their targets of interest faster and more accurately during process development and manufacturing, according to Ahmed. “Having predictive models available for each step in the process enhances process understanding and ultimately allows businesses to deliver drugs to market more quickly with greater quality while also reducing waste and cost,” he states.

Increased (near) real-time insight into the evolution of processes makes several actions possible, adds von Stosch. He highlights the ability to take corrective actions either manually or via closed-loop control, make more informed decisions about when to harvest or release material for further processing, introduce changes that afford greater insights into the process, and ultimately increase process capability.

Specifically, according to Shollenberger, chemometric models can interpret spectroscopic data and predict in near real-time process variables of interest. Advanced control techniques based on these predictive models can anticipate future deviations, enabling timely interventions and process adjustment. “It is the combination of real-time deviation monitoring and process optimization that enhances process understanding and control, leading to better quality, increased speed, and greater flexibility in the manufacturing process,” she concludes.

The potential presented by integrating AI/ML with PAT technologies is limited to some degree by several challenges to successful implementation of these solutions. Complexity, connectivity, and data availability and quality are the top issues.

“The complexity of model building and maintenance, particularly in the highly regulated biopharmaceutical environment, necessitates extensive qualification and validation efforts,” says Shollenberger. Identifying the right PAT tools that are suitable for the right level of analysis, developing soft sensors specifically targeting each CQA in the process, and building in the analytics and logic to enable process control must be achieved first, according to Botonjic-Sehic. Appropriate automation solutions that support collection and use of real-time information to predict process performance and identify failures as they occur must also be developed. Then once deployed, validation, compliance and data integrity components must be well understood before a drug is processed for release, she comments.

In addition, Shollenberger notes that executing models in a real-time process control environment involves managing time latencies and ensuring seamless connectivity and full compatibility between sensors, other equipment, software, and all interfaces.

Effective training of AI/ML models, meanwhile, requires substantial volumes of experimental data to ensure reliable predictions, placing a considerable burden on operators to generate these datasets. “ML data quantity and quality requirements are rarely met today as current datasets often consist of infrequent data points, such as daily measurements as PATs are mostly offline, limiting the availability of high-frequency historical data for model training,” Shollenberger observes. Hybrid models, she says, are therefore a good alternative for reducing the data quantity required for model training.

On a positive note, Botonjic-Sehic emphasizes that once digital models are developed using historical run data, the robustness and validation is integrated into the process, resulting in faster manufacturing with better quality while decreasing the cost of operation.

The implementation of PAT solutions and AI/ML-enabled PAT solutions in the pharmaceutical industry at production scale is more prevalent in the small-molecule segment. “The chemical nature and synthesis of small molecules are relatively straightforward, and well-established manufacturing technologies dominate the production environment. In the face of intense generic competition and cost pressures, however, drug makers are increasingly seeking innovative, speedy, and cost-efficient production approaches, and AI/ML-enabled PAT solutions have attracted significant interest,” Shollenberger explains.

Biotherapeutics producers are moving toward the use of integrated AI/ML/PAT, but at a slower pace due to the greater complexity of biomolecules, according to Ahmed. While there is significant potential for AI to enhance process understanding and control, enabling informed decisions in the future, today human involvement remains essential to address the current limitations of AI, Shollenberger adds. “Human expertise is still necessary to interpret analytical results accurately and to develop robust models that will leverage AI support in the future,” she says. In fact, she believes collaboration between human insight and AI capabilities will be crucial for advancing biomolecule production.

One example already under development is ReciBioPharm’s novel process for RNA-based vaccines and therapeutics, which it is developing in collaboration with the Massachusetts Institute of Technology using grant money from FDA. The continuous GMP process is extensively enabled by real-time analytical technologies leveraging AI/ML models, including new fit-for-purpose solutions. It is expected to be operational in mid-2025, according to Aaron Cowley, CSO, ReciBioPharm.

DataHow, meanwhile, released a spectral data analytics module within DataHowLab, its advanced process data analytics solution that deploys AI/ML with hybrid models (1).

Integration of AI/ML within PAT tools will, according to Ahmed, eventually make real-time data analysis more autonomous and ultimately support real-time release and thus a paradigm shift in pharma manufacturing.

Indeed, Shollenberger believes significant advances in PAT capabilities will be achieved in the coming years, with integration of AI and ML representing a crucial next step toward the envisioned “facility of the future”.

In the short term, she expects the push for cost reduction and environmental sustainability to drive the miniaturization and cross-unit factorization of automated PAT devices, making these advanced PAT solutions more accessible and cost-effective. In addition, use of calibration-free or limited-calibration PATs could help to streamline the integration of these technologies into existing processes with lower cost.

Other advances will occur in knowledge management, as it is vital for collecting and structuring knowledge coming from different devices and PATs. “Scale agnostic, cross-process, cross cell line, and cross-proteins knowledge management is essential for enabling the application of AI and ML across various processes and steps,” Shollenberger states.

Once these advances are achieved, it will be possible to deploy integrated AI and ML solutions that facilitate near real-time quality assurance, process optimization, and continuous improvement. “These advances will help ensure that final products consistently meet regulatory and quality standards, enhancing the efficiency and reliability of pharmaceutical manufacturing,” observes Shollenberger. She cautions, however, that integration of AI and ML models into GMP processes introduces regulatory challenges related to data security, algorithm transparency, and the validation of AI-driven processes against existing industry standards, all of which must be addressed to ensure their effective use while maintaining compliance with regulatory requirements.

Cynthia A. Challener, PhD, is a contributing editor to 

®
Vol. 48, No. 12
December 2024
Pages: 16–18

When referring to this article, please cite it as Challener, C.A. Integrating Advanced Technologies for Pharma Analysis. 

Automation technologies provide real potential to improve responsiveness and decision-making in drug development.

Integrating Advanced Technologies for Pharma Analysis

Lipid nanoparticles (LNPs) have been gaining traction as a primary formulation and drug delivery tool in the manufacture of messenger RNA (mRNA)-based therapeutics, having proven their utility in the development of mRNA COVID-19 vaccines. As the development of LNP-enveloped mRNA therapeutics advances, what other nanoparticle technologies offer the opportunity for optimizing the formulation of mRNA—and potentially other nucleotide-based—therapeutics? This article explores the advancement of LNP formulations as well as additional nanoparticle technologies in this space.

Developing an mRNA therapeutic involves both the manufacture of the mRNA molecule itself and combining that molecule into some sort of delivery technology, whether that delivery technology is a LNP or other platform, says Colin McKinlay, PhD, senior director, Chemistry and Delivery Technologies, at Nutcracker Therapeutics. One of the challenges McKinlay points out is the type of approach a developer must take in manufacturing these types of drugs, which are unique in that they are personalized therapies, where every patient, each therapy, and the drug components are basically different.

“I think one of the lessons learned from the whole COVID-19 pandemic and putting together the mRNA-based vaccines for COVID-19 was that we could actually scale these [vaccines] up to worldwide scales, and that we were able to do that fairly effectively,” said McKinlay. “But starting to think about distributing and manufacturing mRNA drugs, where every patient has a different type of formulation, I think that starts to be a different type of challenge.”

Somewhat related to the logistics of distribution, McKinlay goes on to explain that many of the challenges associated with mRNA drug manufacturing are tied into having the ability to bridge smaller-scale companies—that is, their research work—into Phase I, Phase II, clinical-trial scale, and get these companies the materials they need for conducting those trials. “There are [many] commercial suppliers that are available for research-grade mRNA and for making mRNA at that small scale when [companies] are doing [their] discovery work. And obviously, if [a company] wants to invest a large amount of money into manufacturing, there are [many] opportunities available for large-scale commercialization, but getting strategies that are suited for … small clinical-trial stage where it is not too cost prohibitive upfront is something [where] there is a definite need in the market for,” McKinlay says.

With personal background experience in academia and moving up to a small startup and eventually to a mid-size startup, McKinlay relates the lessons learned in dealing with LNP manufacturing. “One of the things I’ve found throughout my career is that when you’re doing those initial discovery experiments and early stage experiments, you really want to be able to run high-throughput type experiments—screening different formulation chemistries, different combinations of components, or even different mRNA cargo types. However, at that small [of a] scale, [many] commercial options for making LNPs are not really tailored towards that small scale,” he explains.

In the course of his work, McKinlay noted that, although there are production systems available from various different suppliers, these systems generally have a rather large minimum volume or minimum scale at which they can operate. “What [many] people end up doing is to just pipette-mix or hand-mix their components, which means that the LNPs you’re making are very different than the LNPs you’re going to be making farther down in your development process during scale up,” he says.

One of the ways that a company can address this problem is by having its own engineering team in-house, McKinlay emphasizes. With this in-house capability, the company can have the team think about the challenges and ways to design LNPs on both a manufacturing level and at a system level. The results of the engineering team’s work can be used in research that is applied to much of the same core technologies. This gives the company the advantage of having information that can be translatable at every stage of development. “I think there are other companies that are starting to pick up on that importance,” McKinlay says, “but if you don’t think about that early on, you might end up optimizing for something that doesn’t end up being quite as good later on [and further] into your manufacturing process.”

Looking beyond the manufacturing challenges, innovations are in development to address these hurdles. McKinlay notes that some of those innovations are just starting to kick off. “The first wave [of innovation] has [involved the use of] a lot of the existing manufacturing technologies in the biologic space for these mRNA molecules. Now, [the industry is] actually starting to get different companies that are thinking about: how do we actually pursue this workflow for an mRNA specific platform? Not just pushing ourselves across the finish line, but really trying to adapt things to the advantages of mRNA and the unique challenges associated with mRNA?” he states.

McKinlay has also observed that some of the larger mRNA companies are starting to consider the problems in the mRNA space much more deeply with an aim to innovate in this space in a more mRNA-centric way. “For instance, one of the things I brought up earlier is the personalized medicines aspect. One of the exciting things about mRNA is some of the personalized therapies and personalized vaccines [that have come out of this space],” he remarks.

With a growing number of personalized medicines coming onto the scene, the industry is now looking at unique manufacturing challenges associated with them. “I think those are areas where we’re going to continue to see different types of innovation in the field,” McKinlay adds.

Broadly speaking, McKinlay considers the fact that not everybody is going in the same direction with mRNA therapeutic development an exciting trend. “There are a lot of different places that mRNA can be applied. In some cases, moving past the early stages of this field, one of the things that people are going to have to do is start specializing in different areas and saying, ‘Okay, this company is going to take mRNA in this direction.’ ‘This company is going to take it in a different direction.’ I think [this attitude] is one of the great things about a broad field like mRNA,” McKinlay says.

Vaccine development is an area where mRNA has truly demonstrated its effectiveness. But McKinlay points out the importance of not pigeonholing that platform technology such that mRNA is only thought of as a vaccine technology. Moving beyond infectious disease vaccines, or even COVID-19 vaccines, is going to be crucial to the growth of the mRNA field, McKinlay believes.

In terms of the LNP side of this field, McKinlay emphasizes that a number of LNP technologies exist that will focus on expression in the liver and that are directed towards the liver. “One of the [notions] that a lot of folks in the field are really focusing on is, ‘how do we actually direct these lipid nanoparticles to other organs in the body so that we can address other types of disease areas?’,” he says. Many companies are on this train of thought as well as researchers in academia, McKinlay explains. However, there has not been large-scale clinical successes in this area yet, he notes. “I think that’s definitely a place where more development is going to be taking place, and there’s going to be a lot of kind of handoffs between academia and industry in finding some strategies to address that,” he states.

Exploring other delivery vehicles and opportunities

In terms of non-viral RNA delivery, LNPS have largely dominated this field in terms of clinical approvals and later-stage development, according to McKinlay. However, he cautions against the industry getting stuck in these local maxima, “where the field does a lot of optimization, and [players] are able to climb in efficacy, but then [they] reach a point where there’s not too much [left] that [they] can really optimize anymore.”

Nutcracker’s exploration of alternative delivery vehicles has resulted in the company’s peptoid-based platform. According to McKinlay, these peptoids can be used in a traditional LNP-type formulation. “We’re able to branch away from traditional LNP type particles and have particles that are a little bit more unique to the chemistry of these peptoid molecules. We think that [this technology] is pushing us over, a little bit away from where the rest of the field is working; there may be a little bit more room to grow and a little bit more room to improve,” he states. McKinlay also believes that, with more and more people in the field exploring different respective local maxima, the industry as a whole can net benefit together by improving the overall safety and efficacy of the mRNA delivery vehicles that it has available to it.

Meanwhile, in academia there is also focus on using LNPs for other types of genetic cargo, such as other types of RNA or even DNA. “Beyond nucleic acids, there is also significant opportunities for using LNPs in, maybe, combination therapies, where you may have an mRNA molecule, but you also have a lipophilic, small molecule that you can incorporate into the LNP. By combining those two together, you can [potentially] see increased efficacy,” McKinlay says. “Regardless of what the future holds for mRNA therapeutics, a tight handshake between therapeutics discovery and manufacturing will be necessary for its success.”

®
Vol. 48, No. 12
December 2024
Pages: 20–21

LNPs have gained solid ground as a drug delivery system for mRNA due to their success in the vaccines arena.

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