Felicity Thomas is Associate Editorial Director of Pharmaceutical Technology, Pharmaceutical Technology Europe, BioPharm International.

Felicity Thomas

Quality Considerations in Changing Excipient Providers

Ask the Expert June 2024

Changing excipient providers is not as simple as it may seem. The surge of complex therapeutics makes it even more complicated, according to Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates. “I would go visit them and look at their culture and what they're doing in the way of change control and how their QMS is handled, because that is going to be critical to securing your supply chain with this new excipient provider,” Schniepp says.

According to Siegfried Schmitt, vice president, Technical at Parexel, excipient providers are inspected by regulators and require audits to be performed by the company purchasing the ingredients. “And there are various ways of performing an audit. Of course, it doesn't always have to be on site, in person. It can also be, for example, [a] questionnaire [sent to the supplier], and you hope you get something filled in truthfully. You can perform online searches. Many excipient providers have very good reputations and standings in industry, and some also provide audit reports or certifications from independent companies like EXCiPACT,” Schmitt adds.

Click the video above to watch Sue and Siegfried answer the question: “My company is looking at changing our excipient provider for our therapeutic pipeline, what quality issues should we consider when choosing the grade of our excipients and what should we ask of our new provider?”

 video series. This series is an extension of the PharmTech Group’s long-running print column in which industry experts answer common quality and regulatory questions. This new video series will expand on topic areas to include development and manufacturing concerns to help those working in the industry better understand bio/pharmaceutical requirements. We hope you enjoy the discussion!

Susan J. Schniepp is distinguished fellow at Regulatory Compliance Associates and a member of 

Siegfried Schmitt is vice president, Technical at Parexel and a member of 

Videos

In the premiere episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, vice president, Technical at Parexel, discuss the challenges involved in changing an excipient supplier. 

Pipette adding fluid to one of several test tubes | Image Credit: © motorolka - stock.adobe.com

Comprehensive tests are required to analyze drug substances to ensure optimum quality and safety. To learn more about the categories and types of drug substance tests, 

 spoke with Pavan Kumar Kunala, biopharma manager, Almac Sciences.

 Could you run through the different types of tests used in drug substance testing of bio/pharmaceuticals?

 Analytical methods for drug substance testing are diverse and can be broadly categorized based on the quality attributes and the intended use of the method. These categories include identity methods, purity methods, impurity methods, potency methods, safety methods, excipient methods, and general methods.

[Identity methods] are used to confirm that a biologic is what it is claimed to be. The most commonly used identity tests for biologics include peptide mapping, capillary isoelectric focusing (cIEF), imaged capillary isoelectric focusing (icIEF), ion-exchange chromatography (IEX), and enzyme linked immunosorbent assay (ELISA).

[Purity assessment methods] are employed to evaluate the level of purity of the intended biologic product. Commonly utilized techniques encompass Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) or capillary gel electrophoresis (CGE), and size exclusion chromatography (SE-HPLC).

[I]mpurities can be classified into two main types—process-related impurities and product-related impurities. Process-related impurities [are] impurities in the drug substance [that] are derived from the biologic manufacturing process itself. For example, they could be originating from cell substrates such as host cell proteins (HCPs), host cell DNA (HCD), or downstream manufacturing processing such as Protein-A column leachate.

ELISA is a commonly employed technique for analysing HCPs and Protein-A leachate in biologic drug substances. Similarly, Real-Time Polymerase Chain Reaction (RT-PCR) is utilized to determine the amount of residual HCD in the drug substance.

[Product-related impuritiesare] directly associated with the drug substance itself. They may be variants that differ from the intended product, or they could be byproducts or degradation products formed during production, storage, and handling. The typical methods to monitor these impurities include CGE, SE-HPLC, RP-HPLC [reverse-phase HPLC], and cIEF or icIEF.

[Potency methods] are used to determine the efficacy of the product. However, the choice of method depends on the type of biologic and its intended use. The typical methods include cell-based assays, ligand binding assays, and effector function tests.

[Safety methods] are used to ensure that the product of interest does not pose any harm to patients after administration. The commonly used methods at the drug substance stage include bioburden and endotoxin.

[Excipient analysis methods] are employed to determine the amount of excipients in a drug substance, provided it has already been formulated. The commonly used methods include surfactant methods, polyol methods, chelating agent methods, and preservative agent methods.

[General methods] include pH, appearance, osmolality, visible particles, sub-visible particles, [and so on].

Articles

Here, Pavan Kumar Kunala from Almac Sciences runs through the different types of tests used to analyze drug substances to ensure quality and safety.

Reviewing the Categories of Substance Tests

In this episode of the Drug Solutions podcast, Felicity Thomas, Associate Editorial Director, chats with Hanns-Christian Mahler, CEO and board member of ten23 health, about the growing demand for fill/finish services, technological advances and novel approaches helping to advance fill/finish, sustainable and green practices, the impact of smaller batch sizes, and regulatory guidance updates in the space.

 holds a PhD in Toxicology from the Institute of Pharmacy at the University of Mainz and is an adjunct faculty member and lecturer at the universities of Frankfurt and Basel. He previously worked for Lonza, Roche, and Merck, and currently serves on the boards of Bionter and KriyaBio. Hanns-Christian is also an editor for several pharmaceutical journals.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

Podcasts

In this episode, Hanns-Christian Mahler from ten23 Health chats about the advances in fill/finish.

Drug Solutions Podcast: Growth and Advancements in Fill/Finish 

Abstract Futuristic Technology Background with Clock concept and Time Machine, vector transparent | Image Credit: ©chakisatelier - stock.adobe.com

Chronic illnesses or non-communicable diseases that affect the health of the global population are on the rise and, in turn, attributing to a large proportion of deaths and a higher economic burden year-on-year (1). To help combat these long-term illnesses, the bio/pharmaceutical industry has been investing in the development of novel therapies that are increasingly complex in nature.

“The complexity of drugs and their delivery has been increasing over the past few decades,” explains Peter Droc, vice president, head of Drug Product Services, Lonza. “Combined with a growing prevalence of chronic illnesses, this market evolution is putting more pressure on pharmaceutical manufacturers to develop novel therapies that might also have unique formulation needs.”

Many of these novel, complex therapies are biologic-based drugs that are delivered parenterally. “The injectable drug market is experiencing significant growth,” adds Gareth Jenkins, vice president, Science and Technology, Candidate Development, Quotient Sciences. “As a result, robust and efficient sterile manufacturing lines are essential across the manufacturing scales from the early phase to the commercial launch.”

“In its very nature, the aseptic processing market is bound to be less efficient than other market sectors,” remarks Nate Smart, process engineer, CRB Group. “[The] focus is delivering critical therapies to vulnerable patient populations in methods that bypass many of the body’s natural defense systems. Therefore, in contrast to other drug product markets (i.e., OSD [oral solid dosage]), the greatest care must be taken to ensure product quality is maintained.”

However, attaining high quality in aseptic processing is a time-consuming endeavor, as manufacturers need to pay close and accurate attention to adherence to strict guidelines, confirms Maximilian Kappler, process engineer, CRB Group. “The highest quality is imperative in aseptic processing to ensure product safety and effectiveness, making it non-negotiable to invest time for quality whether in design, processing, and product testing,” he states.

Regulatory authorities are scrupulous of all aseptic processing facilities and hold manufacturers to stringent standards, agrees Smart. “As a result, aseptic fill lines and their associated barrier systems are custom and costly,” he says. “In many facilities the aseptic filling equipment is the most expensive and longest lead equipment in the facility.”

As a result of these overheads, many manufacturers try to make their lines flexible so that the utility of their equipment can be maximized and new products, formulations, or formats can be added, Smart specifies. “The more products and formats you can run on a single line, the greater utilization and return on investment you can get out of your line,” he says.

“Despite these efforts, fill lines have notoriously low OEE [overall equipment efficiencies],” asserts Smart. “Many lines, even recent installations, have turnaround times of up to 24 hours or beyond. Any reusable critical contact parts (direct and indirect) must be washed and sterilized out of place and then installed in an aseptic manner.”

“The regulatory bodies are currently pushing for a continued reduced risk of contamination,” adds David King, senior director of Aseptic Processing at Samsung Biologics. “This push is focused on the removal of humans from the aseptic filling process, as humans are the primary source (directly and indirectly) of aseptic area microbial intrusions. The primary change is an industry-wide transition from open RABS [restricted access barrier system] filling systems to isolator contained filling systems.”

“The distinct advantage is that the environment around the open packaging container is sterilized (typically with vaporized hydrogen peroxide [VHP]) with the use of isolator systems,” King specifies. “Isolators cause a bottleneck in regards to small batches as the [process changeover times] can be complex with the requirement to reduce the risk of product contamination from hydrogen peroxide.”

“Ensuring sterility through the manufacturing process is critical and can lead to bottlenecks both for product release and during product changeovers or when there is a temporary issue on the line that is holding up production,” confirms Jenkins. A microbiology team can play a crucial role in helping to minimize such disruptions, he explains, as microbiology considerations can be incorporated at the process design stage and when optimizing operations.

“Sterility assurance is critical for quality control (QC) release of sterile drug products, and the industry-wide approach involves a two-week incubation period—both for testing the drug product and environmental monitoring of the facility,” Jenkins continues. “Numerous rapid sterility testing methods are now commercially available to help address this and can be applied in later stages of development.”

Additionally, supply chain disruptions, which have impacted many global industries over the past few years, can be challenging for aseptic processing, asserts Aimee Hodge, vice-president Business Operations, PCI Pharma Services. “Lengthy lead times for components and drug substance can be very challenging, especially for time critical projects,” she says.

“Delays or disruptions in the procurement of essential packaging materials can significantly impact production timelines and quality assurance efforts in aseptic processing,” states Kappler. “Addressing these supply chain challenges early in a project is crucial to maintaining the integrity and efficiency of the aseptic processing workflow.”

Improving the efficiency of the aseptic workflow is key to ensure critical therapies reach patients in a timely fashion while also being safe and effective. “Automating processes and bringing robotics into aseptic processing, together with single-use systems, [are] helping to streamline processes, minimizing human intervention and reducing the risk of errors or contamination,” emphasizes Hodge.

“Innovations in analytical testing such as rapid microbial and particle detection and rapid sterility testing can save valuable time for releasing drug product to clinical trials or commercial supply,” Hodge adds. “For example, with rapid sterility testing sample results are available in less than seven days, providing time efficiencies when compared to the 14-day incubation required for compendial sterility.”

However, regulatory requirements for viable particulate monitoring are based upon colony forming units, which “cannot easily be directly correlated with fluorescent particle counting results,” Smart asserts. “Manufacturers must be able to validate new methods against the existing standards to demonstrate the new method’s equivalence or superiority.”

Smart points out that rapid micro methods use biofluorescent particle counters in place of settle plates for viable particulate monitoring. “This technology has enormous potential to benefit manufacturers by providing real-time microbial data during aseptic processing,” he says. “Rather than waiting weeks to find out about EM [environmental monitoring] failures, operations can respond to issues as they occur and limit or avert resulting investigations and batch losses.”

“[Another] advancement that is now being more accepted by the regulatory bodies is the use of rapid microbial monitoring systems, [which not only] monitor particles within the filling environment, but also have the capability to determine if the particle is viable or non-viable,” King adds. “If the particle is viable, it is captured real time on a growth medium. This is reducing environmental monitoring excursion identification time frames.”

The presence of particles, subvisible or visible, in parenteral products causes delays and contributes to medicines shortages worldwide, specifies Belinda Holdsworth, strategic growth project lead, Drug Product Services, Lonza. “Having a robust, fast, and reliable method for visual inspection is therefore of utmost importance to drug developers, as well as to their patients,” she says. “An important trend in this space is the utilization of robotics and automated visual inspection (AVI) for defect and visual particle identification in drug products.”

“[Additionally,] the utilization of AI [artificial intelligence] for data analysis [of] image and pattern recognition significantly enhances the detection of difficult-to-inspect parenteral drug products and decreases false reject rates,” Holdsworth specifies. “Combined with an automated robotics approach, this robust process can eliminate the formation of air bubbles, thus greatly enhancing process timelines.”

Focusing on an engineering perspective, Kappler believes that industry will move toward more standardized processes. “In terms of smaller batches, the industry apparently tends to move toward established and validated components such as ready-to-use/ready-to-fill containers,” he says. “This [approach] allows [the manufacturer to] focus on the product core without investing too much time and effort on side processes.”

It has been a decade since ready-to-use pre-sterilized nests of vials were launched by glass pharmaceutical packaging specialist, Schott, explains Jenkins. “These [nests of vials] were designed in collaboration with filling-line manufacturers to eliminate certain processing steps, such as vial washing, drying, and sterilization at the drug product manufacturing line,” he says.

“The nested packaging also reduced incidents of glass vial damage due to vial-to-vial and vial-to-machine contact,” Jenkins states. “This [innovation] paved the way for advancements in robotics and automation, leading to a range of filling solutions, from small-scale support for early clinical supply to more robust systems capable of filling hundreds of vials per hour.”

Further innovation is being seen in the machine manufacturing space that reduces operator interactions, Kappler continues. “Advancements have been made surrounding environmental monitoring that is causing streamlining of operations of critical monitoring steps that ensure that the product remains aseptic throughout the process,” he confirms.

“Advancements in automation and robotics are revolutionizing aseptic fill/finish processing,” confirms Hodge. “From vial loading to stoppering, advanced robotics are streamlining and enhancing the efficiency of sterile fill/finish operations with reduced human interventions, minimizing contamination risks, while optimizing production speed and time to provide life-changing therapies to patients.”

Although, robotics still have some limitations, particularly in responding to faults, jams, and other unplanned events that are not programmable, Smart stresses. “In these cases, there is future potential for use of vision systems and machine learning/AI to provide robotics the capacity for responding to unplanned interventions without the risks inherent in human operations,” he says. “Manufacturers looking to maximize the benefit of robotics and other automation should seek to understand how to maximize flexibility in how they implement these solutions. A set of robotic tooling that is fit to a single format does not provide significant operational advantages over a set of single size format parts in a traditional line.”

“Time-to-market can mean the difference between having a viable product or the competing product taking the market,” emphasizes King. “The best way to reduce the time[-to-market] is to have all production activities at one site. If a company can produce the drug substance and drug product at the same site, product testing, storage, and release times can be greatly reduced.”

Managing to get a product to commercialization quicker also helps to provide patients with life-changing therapies in a better timeframe and ultimately improves their health outcomes, Hodge adds. “Biopharma companies can endeavor to accelerate the delivery of their drug product to patients by developing well defined processes and testing methods together with a product road map early in the drug development lifecycle to identify the steps to plan for to advance along the journey to commercial readiness and launch,” she says.

“Contract development and manufacturing organizations (CDMOs) also play a crucial role in supporting the accelerated supply of life changing therapies to patients by providing expert solutions for drug development, manufacturing, and clinical trial services,” Hodge specifies. “When partnering with a CDMO, to ensure a robust supply chain and support speed to market, it is vital that a preferred CDMO has global reach together with flexible, scalable solutions to support clinical trial from early phase through to commercialization.”

For Droc, the use of sterile, ready-to-use, and single-use packaging solutions is valuable when trying to increase product quality and patient safety, and also reduces time-to-market. “From the perspective of drug developers, these solutions can also accelerate time to market by streamlining operations and expediting product development,” he says. “For drug product manufacturing, pre-sterilized containers, such as vials, syringes, and cartridges, that are ready for filling are especially relevant.”

“Flexibility will be another key aspect of future time-to-market aspects,” reveals Kappler. “[Because] the variety of single products during clinic is high, systems that allow switching between different packaging materials, and quick change between different product set ups will increase usage and allow pharmaceutical manufacturers to quickly react on formulation in early phases.”

Although the benefits of reducing the time it takes to commercialize products are obvious, there is also a need to balance leveraging the use of innovative technologies with standard “tried-and-true” practices, Smart adds. “No one in pharma wants to jump in at the ‘peak of inflated expectations’ in the Gartner Hype Cycle, whereas waiting too long jeopardizes potential competitive advantages,” he says.

“While in many ways the [aforementioned] technologies are not new to the industry, their adoption still has far to go,” concludes Smart. “Courage is required to innovate, but the potential gains are significant. Given that regulatory agencies are themselves recognizing the benefits of these technologies, it seems that the way is paved for industry to reap the rewards of implementation.”

Hacker, K. The Burden of Chronic Disease. 

®
Vol. 48, No. 6
June 2024
Pages: 10–13

When referring to this article, please cite it as Thomas, F. Streamlining Aseptic Processes through Automation. 

Leveraging automation advancements can help improve efficiency in aseptic processing and speed up commercialization of critical drug products. 

Streamlining Aseptic Processes through Automation 

Pharm Tech Group looks at the challenges surrounding the development and manufacture of ATMPs in more detail with Agne Vaitkeviciene, CEO of Memel Biotech.

Finding a More Optimal Way for ATMPs (BIO 2024)

Advanced therapy medicinal products (ATMPs) are a promising class of therapeutics that can provide useful treatment options for a wide variety of diseases. However, the development and manufacture of these advanced therapeutics is complex and challenging.

“The ATMP field is developing relatively slow,” explains Agne Vaitkeviciene, CEO of Memel Biotech, a Lithuanian-based specialized contract development and manufacturing organization. Development of ATMPs is hindered by factors such as the cost of the final product or the cost of manufacture, she specifies. One way to overcome such challenges, is “to find a more optimal way for manufacturing using innovative technologies using innovative solutions,” Vaitkeviciene adds.

However, manufacturing capacity and general expertise around ATMPs are also being discussed as potential hurdles to the advancement of these promising therapies. “I think the general capacity for biomanufacturing, not just ATMPs, is already an issue, especially in Europe; a lot of manufacturing was relocated somewhere else,” Vaitkeviciene says. Yet, a lot of the ATMP manufacturing is now returning to Europe and the United States, she continues, explaining that there has also been a push from policymakers to increase capacity.

“There has been a lot of [action to improve ATMP capacity] to catch up with the capacity manufacturing needs,” Vaitkeviciene notes. “And I think it will, [capacity] will catch up [with demand], I don't think it will go into a critical or crisis stage, I'm positive in that.”

Watch the video for the full interview. Memel Biotech will be exhibiting at the 2024 BIO International Convention in San Diego, Calif., from June 3–6.

 holds a BS in Molecular Biology (Vilnius University, Lithuania) and an MS in organ, tissue, and cell donation for Cell Therapy (University of Barcelona, Spain). Since 2006, she has been working in the field of cell therapy and ATMP manufacturing under GMP conditions. In 2013 Agne Vaitkeviciene co-founded a life science startup company and managed its activities in the field of advanced therapy medicinal product (ATMP) research and manufacturing as CEO until 2019. Since 2019, she has been actively involved as an expert in EU programs, such as IMI2, EIT Health Innostarts, and consults biotechnology companies in life science product development management. For the past five years, Agne has been actively involved in life science expert groups within Lithuanian governmental organizations such as the Innovation Agency of Lithuania and Invest Lithuania. Association LithuaniaBIO elected Ms. Vaitkeviciene as a Vice-President in 2019 and delegated her responsibilities of coordinating foreign affairs and startup support activities within the Association. In 2020–2023, she was the Executive Director of LithuaniaBIO. In 2020, Agne joined Cureline Group as a COO of Cureline Baltic and later, together with Dr. Olga Potapova, founded Memel Biotech in 2021 in Klaipeda, Lithuania. Currently, Agne is responsible for overall Cureline Group activities in Lithuania, provides leadership for the ATMP CDMO program, and coordinates BD efforts in the EU region for member companies of the Cureline Group.

Pharm Tech Group sits down with Bernard Sagaert, CEO of etherna, to examine the role of mRNA in the treatment of autoimmune diseases.

Exploring the Potential of mRNA (BIO 2024)

Messenger RNA (mRNA) technology was propelled into the limelight during the COVID-19 pandemic. In fact, the pandemic, which saw mass vaccinations using mRNA-based vaccines and financial support for their production, had a significantly positive effect on the mRNA market that is predicted to grow to approximately $40 billion by 2033 (1).

Since the pandemic, much work has been done to explore other potential therapeutic applications of mRNA. One such area is autoimmune diseases, where etherna, a Belgian mRNA technologies company, has been working on a tolerizing mRNA-lipid nanoparticle (LNP) platform that restores immune homeostasis (2). “So together with [Hasselt University], we want to further develop our platform and make sure that we have all the data to show that this platform can be used in an autoimmune setting, and specifically that RNA and LNPs can be used in that setting,” notes Bernard Sagaert, CEO of etherna.

“Everybody knows that the RNA-LNP platforms have proven their use in vaccines,” Sagaert says. “The approach in autoimmune diseases is similar yet very different. You could call it an inverse vaccination, where the depletion of the disease-causing autoreactive T effector cells and the amplification of the regulatory T cells is what we’re looking for, and RNA-LNP technologies have the potential of doing that in different ways.”

Watch the video for the full interview. etherna will be exhibiting at the 2024 BIO International Convention in San Diego, Calif., from June 3–6.

. mRNA Therapeutics Market (by Application: Oncology, Respiratory Diseases, Infectious Diseases, Others; by Type: Prophylactic Vaccines, Therapeutic Vaccines; by End User: Hospitals and Clinics, Research Organizations, Other)—Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2024–2033

. Market Report, May 2024.
2. etherna. etherna and Hasselt University Announce Autoimmune mRNA Therapeutics Research Collaboration. Press Release. May 21, 2024.

Bernard comes with extensive operational and strategic experience in the pharmaceutical and life sciences industry. He has expertise in manufacturing and distribution, and has an extensive operational background, both in companies and as consultant. He is a pharmacist from the University of Leuven, (Belgium) and has obtained the qualification of Qualified Person. He was a former QA and Supply Chain Director at Mylan in Belgium, and VP QA EMEAA at Sterigenics, a Sotera company.