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

Felicity Thomas

Delving into Biopharmaceutical Development and Manufacturing

In this exclusive Drug Digest video interview, Felicity Thomas, Associate Editorial Director, 

Group, interviews experts from Biosynth and the University of Maryland about biopharmaceutical drug development and manufacturing. During the discussion, Hans de Backer and Peter Timmerman from Biosynth and Anupreet Kaur from the University of Maryland go into detail about the evolution of biopharmaceutical development, highlighting challenges and potential future trends. Additionally, the intricacies of monoclonal antibodies and the complexity of the supply chain are explored.

Post Doctoral Associate, Dr. Robert Brinson Research Group, Institute for Bioscience & Biotechnology Research (IBBR), National Institute for Standards and Technology (NIST), University of Maryland.

Anupreet is a dedicated structural biochemist with more than seven years of experience in structural biology, specializing in protein structural, dynamic and interaction studies. Her strength includes investigating proteins dynamics or conformational exchange using High Resolution Nuclear Magnetic Resonance (NMR) spectroscopy. Anupreet completed her PhD in India and later joined George Washington University as a Post doctoral Research fellow where she did protein engineering to enhance its ligase activity. Currently in IBBR, Anupreet is elucidating the biophysical mechanisms of pharmaceutically relevant excipient-Fab Interactions. Her ultimate aim is to explore the dynamics of monoclonal antibodies at atomic level and characterize the conformational changes in various pharmaceutically relevant formulations using NISTmAb, reference antibody and NIST-Fab with the help of advanced NMR.


Hans received a BSc and MSc in Industrial Engineering and Management Science from the Eindhoven University of Technology in the Netherlands. He spent over seven years at Roland Berger Strategy Consultants, specializing in life sciences. In the four years after that, he spent time in API operations at Aspen Pharmacare, where he built his operational management expertise, first as a Program Manager of a company-wide IT transformation, and later as a Manager of Technical Affairs. In 2019, he joined Pepscan as CEO, which became part of the Biosynth Group after three years, and now Hans is the Head of the Peptide Division at Biosynth.

Peter, Head of Peptide Science at Biosynth, joined the group following the acquisition of Pepscan in 2022, where he had served as CSO since 2012. He drives advancements in protein mimicry for peptide drug discovery programs. Timmerman is the inventor of CLIPS technology and held a chair as a Professor in Protein Mimetic Chemistry at the University of Amsterdam from 2007-2022. He obtained his MSc Chemistry degree from Vrije Universiteit (Amsterdam) and earned his PhD cum laude from the University of Twente. Timmerman has co-authored over 100 scientific papers in peer-reviewed journals.

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.

 Small Molecule APIs, Excipients, and Formulation

Videos

In this exclusive Drug Digest video interview, Felicity Thomas, Associate Editorial Director, Pharmaceutical Technology Group, interviews experts from Biosynth and the University of Maryland about biopharmaceutical drug development and manufacturing.

Drug Digest: Delving into Biopharmaceutical Development and Manufacturing

Quality Considerations for Using AI in Bio/Pharma

Ask the Expert Episode Two

The use of artificial intelligence (AI) is seeing a surge in a variety of industries. But does the regulated nature of bio/pharmaceutical development, manufacturing, and commercialization serve up unique challenges for incorporating AI into processes? According to Siegfried Schmitt, vice-president, Technical, at Parexel, using new technology will most likely require the assistance of experts in that technology. And if you’re contracting a third party for that help, you need to do an assessment of that vendor.

“[T]he thing with AI, it being a computer-based technology, there is sometimes the issue of, do you have sufficient or good documentation practices applied? It's all too easy to play around with computer code and settings and so on, but you do need to have appropriate documentation, and because you're applying it to process development … It is something that can get inspected, so be ready for an inspection,” Schmitt cautions.

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, stresses that a robust quality management system and document control are necessary when adding AI to a process. “I also worry about if there's the expertise to interpret what the data [are] telling you. You're going to be collecting a lot more data than you've collected before, and data that's new, and how it impacts your organization. And the data you're collecting may prompt you to want to make a change in the coding, [but] you need to follow that stream through your quality management system,” Schniepp says.

Click the video above to watch Sue and Siegfried answer the question: “My company is researching the possibility of using AI in the formulation of a new product. Are there any quality considerations we should be aware of?”

 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. 

Have a question you want answered, sent it to 

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 

In the second 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 quality requirements needed when incorporating AI in bio/pharmaceutical development and manufacturing.

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

Agilent Technologies has signed a definitive agreement to acquire BIOVECTRA, a contract development and manufacturing organization (CDMO) based in Canada, for a sum of $925 million. The acquisition agreement was announced in a July 22, 2024 press release (1).

While the transaction is still subject to the customary closing conditions, once closed, Agilent will benefit from BIOVECTRA’s specialized services and will be able to build upon its offerings in three key areas. These areas are expansion of the portfolio of services through adding sterile fill/finish services, plasmid DNA and messenger RNA capabilities, and lipid nanoparticle formulation services; growth in modalities including antibody-drug conjugates, highly potent APIs, and glucagon-like peptide-1 segments; and capabilities to support customer’s gene-editing needs as a single-source provider.

"We look forward to welcoming BIOVECTRA to Agilent," said Agilent President and CEO Padraig McDonnell, in the company’s press release (1). "The company has an outstanding record of innovation, and its employees share our commitment to providing integrated biopharma solutions that continuously deliver more value to customers. Plus, BIOVECTRA's manufacturing capabilities further expand Agilent's end-to-end biopharma offerings into new growth vectors, including workflows that seamlessly integrate analytical instrumentation, consumables, and a wide range of lab services."

"BIOVECTRA is excited to join Agilent, a company whose dedication to people and customers is very much aligned with ours," added Oliver Technow, CEO of BIOVECTRA, in the press release (1). "BIOVECTRA has dedicated nearly 55 years to the relentless pursuit of helping our customers solve complex problems that improve patients' lives. This synergistic pairing of our capabilities with Agilent's will further enhance the value we can offer to our customers."

This latest acquisition follows on from the 2019 deal, where an affiliate of H.I.G. Capital, a private equity firm, completed its acquisition of BIOVECTRA from Mallinckrodt Pharmaceuticals (2). Since 2019, BIOVECTRA has pursued strategic growth opportunities, with the latest expansion of capabilities being realized early in 2024.

“BIOVECTRA and H.I.G. Capital developed a fantastic and satisfying partnership. We supported Oliver and his exceptional team to exponentially grow the company’s value through the expansion of its capabilities and workforce, as well as create a diversified customer pipeline,” said Mike Gallagher, managing director of H.I.G. Capital, in a press release (3). “We believe that Agilent is a first-class organization that will help BIOVECTRA grow to even greater heights.”

Agilent will acquire all BIOVECTRA employees and sites, which are located in Prince Edward Island and Nova Scotia, Canada. The transaction is expected to close before 2025.

1. Agilent Technologies. Agilent to Acquire North American CDMO BIOVECTRA. Press Release, July 22, 2024.
2. BIOVECTRA. BIOVECTRA Inc. Excited for Continued Growth Under Experienced CDMO Investor, H.I.G. Capital. Press Release, Nov. 4, 2019.
3. BIOVECTRA. Agilent Technologies to Acquire BIOVECTRA Inc., Creating New Synergistic Opportunities to Improve Patient Care. Press Release, July 22, 2024.

Articles

The addition of BIOVECTRA’s biologics capabilities to accelerate drug development and manufacturing will allow Agilent to expand its end-to-end offerings for biopharma services. 

Agilent Expands Biopharma Offerings with BIOVECTRA Acquisition

medical vials on ice. | Image Credit: © sudok1 - stock.adobe.com

Parenteral drug development and manufacturing within the bio/pharma industry is growing, due, in part, to the rising number of therapeutic biologics being developed and approved. As a result of this market trend, lyophilization services for bio/pharmaceuticals are also experiencing greater demand (1,2).

Lyophilization, or freeze-drying, has been used for healthcare products for over eight decades and enables the preservation of aqueously unstable products (3). “Freeze-drying or lyophilization in pharma requires the removal of water from a frozen drug as dry powder,” confirms Shaukat Ali, PhD, FAAPS, senior director, Scientific Affairs and Technical Marketing at Ascendia Pharma. “[The technique] is required for maintaining the stability, structure integrity, and a longer shelf life and efficacy of [numerous drug] products.”

“Lyophilization holds several promising applications in the biopharmaceutical sector, significantly enhancing the stability and usability of products,” adds Greg Sacha, associate director, Research & Development at Simtra. “One of the most promising applications is the ability to significantly extend the shelf-life of biopharmaceuticals. When correctly formulated, biopharmaceuticals can be frozen and dried without compromising their efficacy. This process stabilizes the product, preventing degradation over time, which is a common issue with liquid formulations.”

Prolonging the shelf life and ensuring the stability of biologics and biopharmaceutics is key, continues Ali. “Lyophilized formulations help enhance the product stability of biologics both for therapeutics and vaccines including proteins, antibodies, enzymes, polypeptides, DNA, siRNA [small interfering RNA], mRNA [messenger RNA], oligonucleotides, antibody-drug conjugates, liposomes, polymeric and lipid nanoparticles, among others,” he says.

Additionally, Sacha points out that lyophilization can help to reduce the need to store products at low temperatures. “This [application] is particularly advantageous for global logistics, as maintaining a cold chain can be both costly and complex. Freeze-dried biopharmaceuticals can be stored and transported at room temperature, simplifying the supply chain and reducing costs,” he notes.

“Overall, lyophilization offers significant benefits in terms of stability, storage, and logistics, making it a vital process in the development and distribution of biopharmaceuticals,” Sacha specifies.

Not all molecules can be lyophilized, however, and there are specific limitations associated with the technique, Sacha warns. “[For example], some molecules, like certain cephalosporins, degrade during freezing and drying,” he says.

Another limitation can be the requirement of long drying times and precise temperature control as a result of very low molecular critical temperatures, Sacha adds. This limitation is particularly difficult at full scale, he highlights.

“Longer primary and secondary drying time could be an impediment in mass production of lyophilized products,” agrees Ali. Additionally, scale-up of lyophilization can be challenging as a result of the stringent requirements for freeze-dried processes and products, he states.

Volatility is a further limitation to lyophilization, notes Sacha. “Some molecules are volatile under the shelf temperature and vacuum conditions used during freeze-drying, meaning they can be removed as a vapor from a solid during the process,” he specifies.

Furthermore, achieving uniformity and quality of a lyophilized product can be limiting, Ali remarks. “The product’s uniformity depends upon multiple factors and is often controlled by fine tuning the process parameters,” he says.

A lack of control over the uniformity of lyophilized products can impact the potency of certain drug products, Ali asserts. For example, in a study by Bennett 

 (4), the potency and stability of live varicella-zoster virus (Oka strain) vaccines were found to be negatively impacted by a longer controlled vacuum preparation method, Ali states.

Interfaces should be kept in mind for lyophilization, Sacha continues. “Biopharmaceuticals can interact at the container/solution, solution/air, and ice/solution interfaces, leading to unfolding and aggregation,” he says. “Aggregation results in the loss of the active molecule and, consequently, a loss of potency.”

The use of cryo- and lyoprotectants is also crucial, Sacha stresses. “These protectants, such as amorphous sugars, provide necessary water and hydrogen bonding, preventing the unfolding and aggregation of the biopharmaceuticals during freezing and drying,” he says.

Excipients play an important role in stabilization of drugs and are commonly used as cryoprotectants, adds Ali. “Sugars, amino acids, surfactants, and polymeric excipients are commonly used as stabilizers and lyoprotectants,” he specifies.

“Without proper protectants, biopharmaceuticals can be over-dried, leading to destabilization and reduced potency. Amorphous sugars help maintain the structural integrity by preventing over-drying,” states Sacha. “Proper formulation and the use of appropriate protectants are essential to maintain the potency of drug products during lyophilization.”

However, advancements in the field of lyophilization have emerged that are helping to enhance efficiency and product quality, Sacha asserts. “One significant advancement is the implementation of quality by design (QbD) in the development of primary drying cycles,” he says. “This approach involves applying fundamental principles of heat and mass transfer to comprehensively understand the freeze-dryer and the thermal characteristics of the product. By doing so, it removes the guesswork from the development process, ensuring that primary drying conditions keep the product temperature well below its critical threshold.”

Controlled ice nucleation techniques represent another notable advancement for Sacha. “By controlling the nucleation of ice during the freezing step, variability between vials on a shelf and across different shelves is significantly reduced. This innovation is particularly impactful for amorphous products, as it can dramatically shorten primary drying times and improve product uniformity,” he explains.

“Recent advancements in freeze drying technology and process optimization parameter using controlled devices and equipment designs have been made for more efficient and to achieve reliable pharmaceutical dosages,” agrees Ali. “For instance, in improving the refrigeration system, state-of-the-art condensers are designed to handle high vapor loads to facilitate the efficient vapor flow during lyophilization. In addition, sterilization methods, automation, and isolators are all considered for improving the lyophilization process.”

Companies have also innovated with lyo beads, which are spherical freeze-dried solids, that have proven useful with products that are difficult to freeze in conventional vials, Sacha continues. “The spherical shape of lyo beads provides excellent flow properties and efficient freeze-drying due to their relatively small size,” he says.

“Moreover, there have been advancements in microwave-assisted freeze-drying,” Sacha asserts. “This technique can substantially reduce primary drying times without adversely affecting the product. By integrating microwave energy, the drying process becomes faster and more efficient, preserving the product’s integrity.”

Sacha expects that a few key advancements will form the future focus for lyophilization. One such advancement will be reducing the footprint of lyophilization systems, he says. “Developing more compact lyophilization systems to handle smaller volumes of biopharmaceuticals efficiently is increasingly important for personalized medicine and small-batch production,” Sacha confirms.

The implementation of continuous lyophilization processes will also be important in the future, Sacha specifies. “This approach aims to streamline production and improve efficiency,” he says.

There has been a recent emphasis on continuous freeze-drying technology that allows real-time monitoring, confirms Ali. “Process analytical tools (PAT) such as near-infrared spectroscopy (NIR) and Raman spectroscopy are very promising methods for monitoring inline quality attributes. Both techniques are highly sensitive and complementary to each other,” he states.

Through automation, it will be possible to reduce contamination risks and remove the potential of human error, Ali continues. “For example, advanced freeze-drying sensors and PAT allow better control of the process in primary and secondary drying processes under controlled nucleation regime by QbD for robust continuous manufacturing of lyophilized drug products,” he remarks.

“Ongoing improvements to make lyophilization more efficient, such as optimizing energy use, reducing cycle times, and enhancing automation and control systems [will be explored],” summarizes Sacha. “[All] these advancements will help meet the evolving needs of the biopharmaceutical industry, enhancing both scalability and efficiency.”

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

. Market Report, April 2024.
2. The Insight Partners. 

Lyophilization Services for Biopharmaceuticals Market Report 2023–2028

. Market Report, September 2023.
3. Trappler, E.H. Application and Insights for Lyophilization of Parenteral Products. In 

Practical Aseptic Processing Fill and Finish, Volume 1

, Lysfjord, J. Ed.; Parenteral Drug Association, 2009; pp. 31.
4. Bennett, P.S.; Maigetter, R.Z.; Olsen, M.G.; et al. The Effects of Freeze Drying on the Potency and Stability of Live Varicella Virus Vaccines. 

®
Vol. 48, No. 7
July 2024
Pages: 16–17

When referring to this article, please cite it as Thomas, F. The Rising Iceberg of Lyophilized Innovations. 

The increased demand for biopharmaceutical products is increasing the demand for lyophilization innovations and services.

The Rising Iceberg of Lyophilized Innovations

The analytical testing of drug substances is a critical aspect of development and manufacturing within the bio/pharma industry. These comprehensive tests are used throughout the drug development lifecycle to ensure each product used within a therapy is safe and effective for use, and of the highest quality. To learn more about drug substance testing, 

® spoke with Pavan Kumar Kunala, global biologics lead, Almac Sciences, and Sander Kok, PhD, director Analytical Sciences at Ardena.

 Could you run through the role of drug substance testing for bio/pharmaceuticals and the types of tests generally used?

Read more about the various categories and types of tests used to analyze drug substances:

Reviewing the Categories of Drug Substance Tests

https://www.pharmtech.com/view/reviewing-the-categories-of-substance-tests

 The analytical methods for drug substances play a pivotal role in the journey of biologics development, from the early clinical phase to commercialization, ensuring that the product meets the highest standards of quality, safety, and efficacy for therapeutic use. Moreover, some of the drug substance [DS] methods are instrumental in testing in-process samples, providing insights into process development and ensuring that manufacturing remains consistent and robust during the early phases of product development. The characterization of the [DS], which involves understanding the critical quality attributes (CQAs) and selecting appropriate orthogonal analytical methods to assess them, is another vital application of these methods. Additionally, these methods are employed in the release and stability testing of the bulk [DS], thereby ensuring consistent quality across different batches. (See 

 for a link to a detailed review of drug substance test categories.)

 Typical tests in a drug substance analytical laboratory consist of in process control, release, and stability testing of DS batches. In the pre-clinical phase, analytical methods are developed, including forced degradation and robustness tests. In terms of methodologies, DS tests include at least the methods to verify identity, assay and impurities following [the] ICH [International Council for Harmonisation] Q6A guideline.

Technological advances and novel approaches

 Have there been any technological advances or novel analytical approaches that are helping to improve efficiencies in drug substance testing?

 For many years, ultra-high pressure liquid chromatography (UHPLC) has brought the pharmaceutical analytical community additional separation power and reduced analysis time. Particularly the strong improvement in resolution compared to conventional HPLC enabled a further and detailed characterization of drug substances with a complex impurity profile.

 Certainly, the advent of advanced analytical techniques is boosting the testing efficiency of biologic drug substances. For example, the use of next-generation sequencing (NGS) in identity testing of mRNA [messenger RNA] therapeutics brings significant improvements in efficiency. Traditional methods for identity testing often involved time-consuming and laborious processes such as Sanger sequencing or mass spectrometry. In contrast, NGS can process millions of sequences concurrently, drastically reducing the time required for comprehensive analysis. This high-throughput capability allows for rapid identity confirmation, accelerating the pace of mRNA product development and production.

Similarly, the use of nucleic acid testing (NAT) methods for mycoplasma testing have shown significant benefits over traditional culture methods in terms of efficiency for cell and gene therapy products. NAT-based methods are highly sensitive, specific, and can provide results within few hours, whereas culture methods often require weeks to grow and identify mycoplasma colonies. This rapid turnaround time is particularly advantageous for cell and gene therapies, where time is of the essence. It enables prompt detection of contamination and immediate intervention. Furthermore, the timely identification of mycoplasma contamination can prevent substantial financial losses.

 What are the main challenges in terms of drug substance testing nowadays given the evolving therapeutic landscape?

 More and more highly potent drug substances are of interest to our clients. This brings a challenge to create a safe work environment: not only to prevent cross-contamination towards subsequent manufacturing campaigns, but of even importance is the containment of these highly potent materials from the operators and analysts. Patient and employ

Another important and challenging subject is the quantification of potential genotoxic impurities (PGI). As PGIs are frequently highly reactive, a careful approach is needed in the development of a reliable, quantitative analytical methodology. Detection of low levels [of PGIs] are required, and this [necessitates] analytical creativity in sample preparation, separation, and advanced detection techniques to meet the strict [regulatory] r

 The evolution of newer biologic modalities is transforming the landscape of treatment options available to patients, offering more effective and targeted therapies for a wide range of diseases. This is a significant step forward in the pursuit of personalized medicine and improved patient care. However, this changing therapeutic landscape presents its own challenges.

For example, analytical ultracentrifugation (AUC) is a widely used analytical technique for determination of empty and full capsid ratios in adeno-associated virus (AAV)-based gene therapies. AUC is favored for its high-resolution capabilities and minimal sample preparation requirements. However, the deployment of AUC in a good manufacturing practice (GMP) environment for the release of AAV therapy drug substances present considerable challenges. These [challenges] include limited availability of instrumentation models that could be used in a quality control laboratory, instrumentation software which may not be fully compliant with current data integrity standards, and the complexity involved in training analysts in the comprehensive workflow of data analysis.

[Additionally], the diversity of biologics, ranging from long-peptides and proteins to complex monoclonal antibodies and gene therapies, complicates the establishment of universal standards for characterization of impurities. The lack of specific limits for the reporting and identification of impurities in biologics presents a significant regulatory challenge, given the potential impact of these impurities on the safety and efficacy of the biologic.

As we continue to innovate and develop new dosage forms and therapeutic modalities, the analytical techniques and tools we use to test these substances must also evolve to comply with current regulations.

®
Vol. 48, No. 7
July 2024
Pages: 18–19

When referring to this article, please cite it as Thomas, F. Advancing Analytical Testing Techniques. 

Although advancements in analytical drug substance testing are being made, the increasing diversity of the therapeutic landscape is necessitating further innovation.

Advancing Analytical Testing Techniques

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!

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. 