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The Importance of Appropriate Supplier Oversight

Ask the Expert

Siegfried Schmitt, PhD, is Vice President Technical at Parexel International, Siegfried.Schmitt@parexel.com.

Question mark background | Image Credit: © Leigh-Prather - © Leigh Prather - stock.adobe.com

Q. According to our quality management system, we assess the suitability of all our suppliers in one way or another. Is this sufficient with regards to supplier oversight?

A. The supply chain for pharmaceutical products is complex and involves many actors, often in different countries and jurisdictions. Importantly, the ultimate responsibility for the product and its quality always remain with the Marketing Authorization Holder (MAH) (i.e., the license holder). Therefore, the MAH must have a supplier oversight system in place that assures that any materials (e.g., excipients), equipment (e.g., laboratory instruments), or services (e.g., transport and storage) meet the appropriate quality requirements and specifications. Such a supplier oversight system, which obviously is part of the pharmaceutical quality system (PQS) (1), must comply with the applicable rules and regulations for the good practices (e.g., good manufacturing practices). That this is by far not always a given is demonstrated by the regulatory agency inspection observations, such as those made public in warning letters by FDA (2).

The question is not whether we can trust a supplier, but what controls one must put in place to be able to trust said supplier. A risk-based approach (3) is required. This is where companies can do too little (non-conforming with the regulations) or too much (waste of valuable resources). This is best demonstrated with two examples.

Company A relies on the Certificates of Analysis (CoAs) from their suppliers for raw materials, including excipients and APIs without performing any incoming tests. The company argued that they only buy from reputable suppliers. However, FDA insists on at least identity testing and additional testing depending on the criticality of the material: “Without adequate testing, you do not have scientific evidence that your raw materials conform to appropriate specifications prior to use in the manufacture of drug products. As a manufacturer, you have a responsibility to sample, test, and examine drug components before use in production to assure adequate product quality” (4).

Whereas, Company B performs a large amount of testing. For example, the microbiology laboratory purchases media and performs several incoming tests, including identity and mycoplasma testing. The media is in use with a large number of pharmaceutical companies globally and comes with a CoA that covers mycoplasma testing. The company needs to assess if the risk from the media warrants mycoplasma testing. A review of testing data showed that there never had been an issue with the media. Equally, an Internet search found no evidence of any issues with that media. Furthermore, the supplier is qualified by the contract giver, and an identity test is always performed when the media is received. Thus, this testing is not necessary.

It requires experience and expertise to devise a supplier oversight system that is compliant and optimized. Such a system assures that all activities, including supplier audits, material testing, etc., are risk-based, meet the minimum legal requirements, and are of a manageable complexity. This means, for example, that suppliers are assigned to risk categories. Therefore, risk assessments don’t have to be performed for each supplier, only for each supplier category. Such systems need to be reviewed, revised, and updated based on the company’s evolving needs and any changes in the regulations and their interpretation.

Becker, G. The FDA Warning Letter Report 2023. 

Siegfried Schmitt, PhD, is vice president, Technical at Parexel.

®
Vol. 48, No. 11
November 2024
Page: 34

When referring to this article, please cite it as Schmitt, S. The Importance of Appropriate Supplier Oversight.

Articles

The product license holder must have a supplier oversight system in place, says Siegfried Schmitt, PhD, vice president, Technical, Parexel.

The Importance of Appropriate Supplier Oversight 

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - © Artur - stock.adobe.com

FDA’s Patrizia Cavazzoni, director, Center for Drug Evaluation and Research (CDER), and Peter Marks, director, Center for Biologics Evaluation and Research (CBER), provided an update on the agency’s 

 (the Hub) in a Nov. 1, 2024 FDA Voices blog post (1). The Hub was created in July 2024 (2) as a cross-center program that operates as a single point of engagement with stakeholders in the development of treatments for rare diseases. The Hub is the agency’s way of creating a community that can share new approaches for drug development for rare diseases.

In establishing the Hub, FDA gathered feedback from stakeholders through a public meeting, held on Oct. 16, 2024 in collaboration with the Reagan-Udall Foundation. The meeting included advocates from rare disease patient groups, academics, regulators, and other stakeholders who discussed how the Hub can work with the community to prioritize work.

A Hub director was also appointed. Amy Comstock Rick will be the Director of Strategic Coalitions for the Hub and be accountable to both Cavazzoni and Marks. Previously, Ms. Rick worked as a consultant at Leavitt Partners and was president and CEO of the Food & Drug Law Institute.

“Ms. Rick brings to this new role more than 20 years of experience as a leader and trusted ally in advocating for policies throughout healthcare, biomedical research, and nonprofit communities, which includes extensive engagement with patient communities and government agencies on issues related to rare diseases. We are excited to have her join and begin creating the important partnerships needed to strengthen the Hub’s engagement throughout the rare disease community,” stated Cavazzoni and Marks in the blog post.

As part of their work with the Hub, Marks and Cavazzoni plan on collaborating with other FDA centers that work with rare diseases, such as the Center for Devices and Radiological Health, the Oncology Center of Excellence, and the Office of Orphan Products Development. In addition, a Rare Disease Innovation Hub Steering Committee has been established to bring the groups together, and a new CBER-CDER Rare Disease Policy and Portfolio Council has been created. The council will bring experts from the different FDA centers together to discuss scientific, regulatory, and policy issues.

“The collaborative model of the Hub will build upon the knowledge and skills of staff within their respective centers, promote adoption of best practices, and avoid confusion over decision-making authorities within those organizations. Meetings between the FDA and sponsors relating to specific drug or biological products will remain the same, as will the way decisions are made about specific programs and how advisory committee meetings are structured and run,” Cavazzoni and Marks stated. “By working together, we believe that we can further facilitate the development, evaluation, and availability of safe and effective therapies. We are committed to ongoing and open communication and look forward to continuing this dialogue with the rare disease community.”

Cavazzoni, P. and Marks, P.FDA Takes Exciting Steps Toward Establishing the Rare Disease Innovation Hub. 

https://www.fda.gov/news-events/fda-voices/fda-takes-exciting-steps-toward-establishing-rare-disease-innovation-hub

FDA. FDA Rare Disease Innovation Hub to Enhance and Advance Outcomes for Patients.

CDER Director Patrizia Cavazzoni and CBER Director Peter Marks provided an update on the rare disease innovation hub in a new FDA Voices blog post.

FDA Rare Disease Innovation Moves Forward

Patrick Lavery is an Editor for the MJH Life Sciences brands 

. Previously at MJH, he filled the same role for 

Text sign showing Industry News. Business photo text delivering news to the general public or a target public | Image Credit: © Artur - stock.adobe.com

Hapman, a Kalamazoo, Mich., company focused on the design and manufacture of custom bulk material handling equipment, announced in a press release on Oct. 30, 2024 that it would be introducing a new conveyor at Pack Expo 2024, to be held in Chicago from Nov. 3–6, 2024 (1).

After a yearlong, intensive R&D initiative, Hapman said, the conveyor system—emblematic of the company’s nearly eight decades of expertise in tubular drag conveyors—represents Hapman’s first major product launch since 2008 (1). Hapman said the unveiling of the conveyor will serve to fill a gap in the market for material handling operations in the packaging and processing sectors and offers enhanced performance and versatility (1).

The uniqueness of the demands of Hapman’s customers, the company said, requires that the solutions provided to those customers be efficient and customizable, and designed to ease packaging and processing operations. Additional considerations include safety, productivity, user-friendly design, and the minimization of product loss. Further details about the conveyor are being kept “under wraps” by Hapman until the exhibition gets underway, according to the press release (1).

Hapman additionally plans to show its Bulk Bag Unloader, which features heavy-duty, 3” tubing construction offering adjustable heights that accommodate numerous bag sizes, as well as high durability (1). Dust control systems, vibration devices, and optional, 1- or 2-ton hoists and trolleys with certified, load-tested bag adapters are listed as some of the other features.

Other companies are also previewing their exhibits and offerings ahead of the 2024 edition of Pack Expo. Brewerton, NY-based Pacteon Group announced in a press release on Sept. 9, 2024 that it had added Descon Conveyor Systems to its portfolio, and would be displaying a Descon product at one of its booths at the event (2).

And on Sept. 26, 2024, TekniPlex Healthcare, a full-service contract development manufacturing organization for medical materials science, particularly in the minimally invasive and interventional therapy devices space, announced in a press release that it would unveil its strongest-ever reinforced paper for medical device packaging applications as part of its display (3).

 at INTERPHEX 2024, held in New York City in April 2024; that interview can be viewed 

Hapman can be located at Booth #LU-7561 at Pack Expo 2024, where the company plans to roll out the new conveyor system alongside the Bulk Bag Unloader.

1. Hapman. Hapman to Showcase Material Handling Solutions at PACK EXPO 2024. Press Release. Oct. 30, 2024.
2. Pacteon Group. Pacteon Exhibits New Packaging Automation Solutions at Pack Expo International 2024. Press Release. Sept. 9, 2024.
3. TekniPlex Healthcare. At Pack Expo, TekniPlex Healthcare to Debut Its Strongest-ever Reinforced Paper for Medical Device Packaging Applications. Press Release. Sept. 26, 2024.
4. Bigica, A. 

How TekniPlex is Expanding to Support Innovative Solutions in Materials Science.

The system is Hapman’s first major product launch since 2008, following a year of intensive R&D that builds upon the company’s eight decades of tubular drag conveyor expertise.

Hapman to Showcase New Conveyor at Pack Expo 2024

ROSS FDA-50 Fixed Tank Dual Shaft Mixer |© Charles Ross & Son Company

The ROSS FDA-50 Fixed Tank Dual Shaft Mixer is a custom-design agitated pressure reactor built to handle a wide range of formulations and viscosities. It is ideal for processes that require meticulous control over mixing, temperature, and pressure and comes in a compact, portable module. The design comprises a stainless-steel type 316 dished bottom vessel and removable dished cover that can accommodate internal pressures of up to 100 psi. The mixer/reactor is equipped with two agitators and has a high-speed disperser with two 6” sawtooth blades (one fixed at the bottom and one adjustable along the shaft), driven by a 5 HP explosion-proof motor that moves up to 1760 rpm. This speed creates a vortex into which dry ingredients can be delivered for fast wetting. The disperser is belt-driven and has a removeable drive motor, belt, and guard. In addition, the two-wing anchor agitator is direct-driven by a 5 HP explosion-proof removable gearmotor that moves up to 45 rpm. The agitator is designed with a heavy-duty triangular cross-section and has removeable Teflon sidewall scrapers. The anchor feeds product toward the high-speed disperser blades, ensuring that batch contents do not stagnant in any one area. The mixer shafts use dry-running single mechanical seals that are compatible with various solvents. In addition, all product wetted surfaces are polished to a 320-grit finish. This mixer/reactor also houses a 2” flush tank discharge ball valve that leads to a sanitary outlet connection. It also contains an assortment of sanitary inlet ports on the cover. The mobile mixer remains stable on four splayed stainless-steel legs with foot pads and non-marking urethane casters, two of which lock and two of which are rigid. The casters make it easy to move the unit around.

The ROSS FDA-50 Fixed Tank Dual Shaft Mixer is built to handle a wide range of formulations and viscosities and is ideal for processes that require meticulous control over mixing, temperature, and pressure.

Fixed Tank Dual Shaft Mixer/Pressure Reactor

MilliporeSigma Mobius ADC Reactor| © MilliporeSigma

MilliporeSigma, the US and Canada Life Science business of Merck KGaA, Darmstadt, Germany, introduced the Mobius ADC Reactor, a single-use reactor designed specifically for the manufacture of antibody drug conjugates (ADCs). The reactor is the first of its kind for ADC production, according to the company. The Mobius ADC Reactor is designed to meet the unique requirements for linking the necessary components for ADCs and aims to enable these critical therapies to be produced faster and more safely with faster turnaround times and fewer cross-contamination risks. Performance improvements using the single-use reactor include elimination of potent liquid waste and a 70% increase in efficiency. The reactor’s single-use assemblies are made of Ultimus Film technology, which provides enhanced bag strength, improved durability, and leak resistance.

The Mobius ADC Reactor is the first single-use reactor designed specifically for the manufacture of antibody drug conjugates.

Single-use ADC Reactor

CPC MicroCNX ULT Series aseptic microconnector | © CPC

The MicroCNX ULT Series from Colder Products Company (CPC) is the first aseptic micro-connector that can be fitted directly into freeze cassettes used in cell and gene therapy (CGT) processing. It can be frozen to -190 °C. It is compatible with the most common types of tubing, including polyvinyl chloride (PVC), used in developing advanced therapies. The connectors are compact enough to fit into a freeze cassette and can be frozen with vaporized liquid nitrogen. They are designed to provide a simple, efficient method of sterile connection of tubing used for small CGT assemblies. They also eliminate the need for adding extra tubing into the process, thus helping to reduce the amount of product hold-up or product loss. The MicroCNX ULT series termination and flow path are constructed from polyphenylsulfone, a high-performance polymer that is chemically compatible with the harsh chemicals, such as dimethyl sulfoxide, used in cryopreservation processes. This new series adds to CPC’s 1/8” MicroCNX Series Connectors, an alternative to tube welding in creating closed sterile connections at small volumes. Similar to earlier MicroCNX products, the MicroCNX ULT series features a 1/8” flow path and offers options for 1/8”, 3/32”, and 1/16” hose barb terminations to support a variety of tubing sizes and materials, such as PVC, silicone, and thermoplastic elastomer.

CPC’s MicroCNX ULT Series represents the first aseptic microconnector that can be fitted directly into freeze cassettes for GCT production.

Aseptic Micro-Connector

In this episode of Drug Digest, industry experts discuss the ongoing development of automating biomanufacturing processes, including its challenges and practical applications. 

The biopharmaceutical industry has seen the use of automated technologies in biomanufacturing processes grow over the years from theory to reality. In this episode of 

, industry experts discuss the ongoing advancement of automation in the biopharmaceutical industry. They give insight into how automated technologies are put to use today and how they are streamlining process development, with an eye toward saving cost, time, and manufacturing footprint.

John Hatzis, Global Life Sciences Industry Consultant, Rockwell Automation

John Hatzis has been with Rockwell Automation for ten years where he has leveraged his expertise using Rockwell technology in a variety of applications in the Life Sciences industry. He works with BiofabUSA consulting on control systems for new tissue therapies. John has a BSc in Chemical Engineering from Worcester Polytechnic Institute.


Smriti Khera, Global Head of Life Sciences Strategy and Marketing, Rockwell Automation

Smriti Khera is the global head of Life Sciences Strategy and Marketing at Rockwell Automation. She holds a PhD in Pharmaceutical Sciences from the University of Arizona, where her focus was drug discovery from natural products. After working as a pharma research scientist, she pivoted to strategic marketing to increase her impact. Over the past 12 years she has held strategy and marketing leadership roles with increasing levels of responsibilities at both Fortune 500 and early stage startups. She is passionate about leveraging her unique expertise to generate sustained impact across healthcare and life sciences using automation and digital technologies.

This episode of Drug Digest is sponsored by:

Drug Digest is a tech talk video series with the 

® editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

Solid Dosage Drug Development and Manufacturing

Videos

Drug Digest: From Theory to Reality: Automating Process Development

Feliza Mirasol is the science editor for 

Gefion, a new artificial intelligence (AI) supercomputer built on an AI data center infrastructure known as NVIDIA DGX SuperPOD (1), is now operational in Copenhagen, Denmark, the Novo Nordisk Foundation announced on Oct. 23, 2024. The supercomputer was launched at an event in Copenhagen, where it was symbolically “turned on” by His Majesty King Frederik X of Denmark; Jensen Huang, founder and CEO of NVIDIA, a US-based supercomputing company; and Nadia Carlsten, CEO of the Danish Centre for AI Innovation (DCAI).

Following its launch, Gefion is being readied for customers, beginning with a pilot phase in which select customers interested in using AI will use it to accelerate innovation in many areas, from quantum computing to drug discovery to societal challenges, such as the transition to green energy.

“Gefion provides our Danish enterprises with entirely new opportunities,” said Morten Bødskov, the Minister for Industry, Business, and Financial Affairs, Denmark, in a press release. “Gefion will drive the advancement of the green transition, enable tailor-made solutions, and strengthen the competitive standing of our companies in the global market. In a time of heightened international competition, this supercomputer acts as a vital enabler for advancing Danish businesses into the future. This ground-breaking technology represents an important opportunity for Danish companies and researchers to develop innovative solutions to future challenges.”

A public–private partnership between the Novo Nordisk Foundation and the Export and Investment Fund of Denmark (EIFO) resulted in the establishment of the new supercomputer. This partnership funded and established DCAI, a new company that owns and will operate Gefion.

“It’s a remarkable achievement that it has taken only six months from announcement to completion of this complex state-of-the-art supercomputer,” said Carlsten. “I am extremely proud of the team that came together and collaborated to turn this vision into a reality, delivering a leading capability that is now ready for customers to start testing new use cases. Gefion is the game-changer that many innovators had been waiting for.”

Huang added in the release, “Denmark recognizes that to innovate in AI, the most impactful technology of our time, it must foster a domestic AI infrastructure and ecosystem. The Gefion supercomputer will supercharge the scientists of Denmark with local AI computing infrastructure to drive advancements in life sciences, climate research, and quantum computing.”

Gefion is powered by 1,528 graphic processing units (GPUs) (NVIDIA H100 Tensor Core GPUs) and is interconnected using networking (NVIDIA Quantum-2 InfiniBand). According to the press release, “Denmark up to now had no GPU-accelerated supercomputers, and a thorough consulting process with relevant stakeholders across the country had identified access to computing power as a key roadblock to progress in Denmark’s otherwise thriving AI-based research ecosystem.”

Digital Realty, a global data center provider, hosts the supercomputer in an AI-ready data center facility in Denmark, which is designed and built sustainably, running on 100% renewable energy, according to the press release. Gefion was assembled and installed by Eviden, a European-based high-performance computing company.

In addition to the Novo Nordisk Foundation’s funding, EIFO contributed DKK 100 million (US$15 million) and owns a 15% minority stake in DCAI.

“Establishing Gefion is a milestone, and it fits very well with the Novo Nordisk Foundation’s vision of improving people’s health and the sustainability of society and the planet, as it creates new opportunities and can accelerate finding new solutions to pressing challenges,” said Mads Krogsgaard Thomsen, CEO of the Novo Nordisk Foundation, in the release. “In the future, we must cooperate even more with exceptional partners from all over the world if we are to solve the enormous challenges facing not only our own countries but the planet.”

Researchers will have the opportunity to engage with expert teams from NVIDIA in selected flagship project areas to co-develop solutions to complex problems. These areas include pharmaceuticals and biotechnology research, accelerating the green transition; and developing fault-tolerant (i.e., error-free) quantum computing using an open-source hybrid quantum computing platform (NVIDIA CUDA-Q).

With DKK 600 million (US$87.4 million) in funding from the Novo Nordisk Foundation, the new supercomputer offers the potential to accelerate innovation in drug discovery.

Denmark’s First AI Supercomputer for Drug Discovery Now Operational Under Novo Nordisk Foundation Commitment

Sartorius’ Vivaflow SU tangential flow filtration (TFF) is designed to be more user-friendly and to allow for more flexibility in laboratory workflows. The new cassette offers more efficient and sustainable ultrafiltration and diafiltration processes for feed volumes in the range of 100 mL–1000 mL. Vivaflow SU is an all-in-one cassette, which reduces cost and complexity and streamlines workflows for molecule isolation. Each cassette is ready to use and has a standard laboratory pump for simple set-up, which avoids the need for expensive systems and expensive process optimization. It also allows for faster and more reliable concentration and rebuffering of any molecule. The cassette eliminates the need for cleaning and reduces contamination risk while minimizing waste. Sustainability features include a new housing that uses 30.5% less plastic. It also incorporates several eco-friendly design improvements, such as locally sourced raw materials, customized tubing kits for each cassette configuration, a digital user manual, and reduced non-recyclable packaging; all of which are meant to contribute to a lower research footprint. Vivaflow SU is the-next-generation TFF cassette that replaces the previous Vivaflow 50 model. It is applicable for research scientists who require a fast and reliable means for concentrating and rebuffering large feed volumes in molecule isolation workflows.

The new cassette offers more efficient and sustainable ultrafiltration and diafiltration processes for feed volumes of 100 mL–1000 mL.

Tangential Flow Filtration Cassette

The National Institute for Health and Care Excellence (NICE) has published a final draft guidance recommending Wainzua (eplontersen) for treatment of hereditary transthyretin-related amyloidosis (ATTR) in adults with stage 1 or 2 polyneuropathy (PN) in England and Wales, AstraZeneca announced in a press release on Oct. 29, 2024 (1).

“We are delighted that eligible patients now have access to this treatment for this significant disease which can be delivered in-clinic or in their own home to support more personalized care,” Tom Keith-Roach, president of AstraZeneca in the United Kingdom, said in the press release (1).

This recommendation of Wainzua closely followed that of the Committee for Medicinal Products for Human Use (CHMP) of the European Union for approval by the European Commission, 

announced by AstraZeneca on Oct. 21, 2024

 and 10 months after FDA approved eplontersen under the brand name Wainua for treatment of adults in the United States in December 2023 (2,3).

"ATTR amyloidosis is a serious, rare disease where people experience neuropathy symptoms, such as pain, discomfort, progressive weakness, and loss of sensation in the legs and arms, and mobility difficulties,” Paul Pozzo, chairman of Amyloidosis UK, said in the Oct. 29 press release. “There is no cure for ATTR amyloidosis, but today’s announcement offers an alternative treatment option to support those living with this condition in the UK ATTR community."

As with CHMP’s recommendation, NICE made its decision based on a 66-week Phase III trial (NEURO-TTRansform) (1).

“Eplontersen provides a new, disease-modifying treatment option, and this is positive news for eligible patients with ATTR-PN and the wider amyloidosis community in the UK,” Marianna Fontana, a professor of cardiology and honorary consultant cardiologist of the National Amyloidosis Centre, Division of Medicine, University College London, said in the press release. “Without treatment, ATTR-PN can lead to extreme polyneuropathy, severe disability, and premature death. In the NEURO-TTRansform Phase III clinical trial, eplontersen significantly lowered serum transthyretin concentration, resulting in less neuropathic impairment and an improved quality of life for patients.”

ATTR-PN, according to AstraZeneca, is caused by a mutation in the transthyretin (TTR) gene responsible for TTR production in the liver (1). The mutation causes the TTR protein to misfold, leading to amyloid fibril accumulation, in turn damaging peripheral nerves in the body. AstraZeneca said ATTR-PN is “frequently under-recognized” because its clinical manifestations are frequently heterogeneous and non-specific (1).

Left untreated, the severe polyneuropathy and motor disability that develops within five years of the onset of ATTR-PN can result in death within a decade (1).

1. AstraZeneca. AstraZeneca Secures Accelerated NICE Recommendation for Wainzua (eplontersen) in England and Wales Following MHRA License to Treat Hereditary Transthyretin Amyloidosis in Adult Patients with Stage 1 or 2 Polyneuropathy. Press Release. Oct. 29, 2024.
2. AstraZeneca. Wainzua (eplontersen) Recommended for Approval in the EU by CHMP for the Treatment of Adult Patients with Polyneuropathy Associated with Hereditary Transthyretin-Mediated Amyloidosis. Press Release. Oct. 21, 2024.
3. AstraZeneca. Wainua (eplontersen) Granted First-Ever Regulatory Approval in the US for the Treatment of Adults with Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis. Press Release. Dec. 21, 2023.

The treatment for ATTR in certain adults with polyneuropathy had just been recommended for approval across the European Union and had gained regulatory approval in the United States at the end of 2023.

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