Biologics are becoming more established in the development pipeline as a result of their ability to treat a variety of conditions and diseases in a targeted and effective way. The increasing prevalence of diseases, such as cancer, autoimmune diseases, and genetic diseases, globally is driving continued growth for biologic therapies (1).

However, the inherent complexities associated with biologics makes formulation and development uniquely challenging when compared with small-molecule drug products. To learn more about the formulation challenges associated with biologics, potential solutions and approaches that are helping to overcome these challenges, the regulatory landscape, and how outsourcing partners can be beneficial, 

® spoke with Aaron Frimel, manager, Process Development at Thermo Fisher Scientific.

 Could you highlight the main challenges associated with biologics formulation development?

 With early phase development, the hardest challenge can be getting enough representative material early enough in the development lifecycle to support a thorough formulation study (time and size) to achieve the target product profile. Another challenge is having methods ready for the formulation studies so that method performance is understood well enough to know whether a change in product quality is due to assay performance or formulation performance.

With late-phase development, routes of administration, dosing, and degradation products on long-term stability are better understood and may necessitate changes that can sometimes be difficult to accommodate and may even require altering the target product profile.

: What strategies can companies employ to overcome these challenges?

: High-throughput, characterization-type assays [can be employed] to uncouple the start of formulation work from method development, as well as reduce material per sample in order to screen larger design spaces, which sets the project up for earlier success with less potential for re-development. [Additionally, with] in-house cell line development, the material requirements and representativeness are dealt with by using high-titer cell lines and targeted integration. Process development groups can then perform material generation runs using the center-point of their platform processes to generate material early in the project lifecycle so that the final formulation is selected at or before the conclusion of process development activities.

With late-phase projects, material representativeness and availability are much less of a problem, but clients may choose to go to a higher concentration for dosing purposes or to change the route of administration. With an existing formulation, and known degradation patterns, [it is possible to] stage a small-scale robustness study with the critical stability indicating assays to achieve the target concentration while mitigating the most significant liabilities.

If the client is trying to blunt the formation of a degradant, [then it is beneficial] to have an analytical suite that is larger than just release analytics. [Thermo] had a program recently that saw some charge heterogeneity issues and [by using a] multi-attribute-method (MAM) [it was possible] to understand that the shift in the acidic shift in a cIEF [capilliary isoelectric focusing] profile was a trade-off between deamidation and oxidative modifications, and [it was possible] to reduce both degradation patterns by raising the pH 0.5 units while adding methionine—something [that] would have never been [possible without] such a powerful analytic to tease apart these modifications on the amino acid level.

 Have there been any technological innovations or novel approaches implemented that have helped with biologics formulation?

 With biologics formulation, the range of available excipients is limited, and a lot of the advancements come from the development of more sensitive, stability-indicating analytics that are precise and trend with a high degree of linearity. [Because] the range of excipients that are available (and not patent protected, if possible) is small, being able to achieve the maximum potential of what is available is the best option.

Increases in throughput or decreases in material requirement and touch time are the things that allow a formulator to screen wider ranges and are what gives a project a good chance of finding a global optimum, rather than a local optimum, when screening formulations.

 Has the regulatory landscape changed for biologics formulation? If so, how can companies navigate these regulations with ease?

 The most common thing [being seen] since the pandemic is an increase in the amount of early phase projects targeting a subcutaneous format, many times using a pre-filled syringe. The benefits are obviously easier self-administration, and opinions on self-administration have rapidly changed both as a result of the pandemic and as a result of the Type 2 diabetes drugs that are being used to treat obesity.

Pre-filled syringes are regulated as combination products. While this isn’t a new regulatory landscape, FDA has clarified its guidance on combination products and streamlined the process for triaging whether the primary mode of action of the product classifies it as either a drug or a device while eliminating the need to get approvals for both.

 How can partnerships benefit in biologics formulation development? Are there any best practices you can share?

 A great thing about outsourcing biologics formulation work is that the teams at these outsource facilities see a wide range of molecules and molecule behavior and can act on this breadth of experience. What separates a good partnership from a great one is how well the outsource partner works to understand the client’s goals and mentality when it comes to risk in order to customize the approach to meet the customers goals while incorporating the technical knowledge gleaned from previous projects into the design. Some of the most productive conversations we have with clients are the informal sidebar discussions where a project member casually mentions the long-term goal for the project. It is surprising how many times pieces of information from informal conversations can be incorporated into the existing work and eliminate the need for future studies.

Both the technical experience and establishing rapport come down to the same thing, listening. Both listening to the data during study execution and actively listening and questioning the client to understand their long-term goals so that they can be addressed in the project design.

Being on the outsource side, [Thermo encounters] a range of client mentalities, both in terms of clients shopping projects as well as clients that commit to a workscope with [a particular] team. The clients who put in the work to understanding a CDMO’s [contract development and manufacturing organization’s] technical capabilities, resourcing, and any client-specific considerations prior to committing to a CDMO tend to be the more satisfied clients. Specifically, the customer that takes the time to evaluate, understand, and articulate their internal needs as best as possible tend to be more skilled at evaluating whether a particular CDMO will match these needs as closely as possible.

Biologics Market Size, Share, and Trends Analysis Report by Source (Microbial, Mammalian), by Product (MABs, Recombinant Proteins, Antisense & RNAi

), by Disease Category, by Manufacturing, by Region, and Segment Forecasts, 2023–2030. Market Report, May 2023.

Felicity Thomas is the European/senior editor for 

Articles

Features

Innovative strategies and good partnerships are means by which developers can overcome the unique challenges in biologics formulation. 

Learning How to Navigate Biologics Development

TriLink BioTechnologies, a Maravai LifeSciences Company, announced on Nov. 2, 2023 that it has launched the Analytical Sciences Center of Excellence (ASCE). The new ASCE hub expands the company’s suite of analytical testing capabilities and, according to the company, will minimize cost and delays associated with outsourcing testing to multiple laboratories. The ASCE, which is located in Maravai LifeSciences’s Pacific Center Boulevard facility in San Diego, Calif., features a 4000-square-foot lab to support plasmid DNA and messenger RNA (mRNA) manufacturing and will be responsible for developing analytical methodologies such as mRNA fingerprinting and sequencing.

“TriLink's new Analytical Sciences Center of Excellence will be a transformative force in the development of nucleic acid therapies,” said Khaled Yamout, senior director of Analytical Services at TriLink, in a press release. “This new lab will allow us to expand our analytical capabilities to meet the growing demands of the market, including specific method development.”

TriLink has developed and qualified 10 unique methods for mRNA characterization with 40 various constructs. The ASCE’s new instrumentation to improve nuclear magnetic resonance, next-generation sequencing, and lipid nanoparticles characterization builds on the company’s method development for construct-specific assays.

“We continue to witness exciting growth in nucleic acid therapeutics—and rapid expansion calls for rapid innovation,” added Kevin Lynch, TriLink’s vice-presdient and general manager of GMP Operations, in the press release. “The ASCE’s centralized analytical capabilities and development of analytical methodologies for the characterization of nucleic acids will advance the industry as we continue to find ways to meet the needs of developers working on life-saving therapeutics.”

TriLink, in addition to the new hub, has an extensive mRNA capping portfolio, advanced scale-up capabilities, and expertise in mRNA, oligonucleotide, and plasmid production. It has been a leader in nucleic acid and mRNA solutions for more than 25 years and provides chemical and biological experiences, contract and development manufacturing services, and readymade and custom materials.

News

The new centralized hub will provide advanced testing of nucleic acids, which is expected to simplify mRNA substance testing.

TriLink BioTechnologies Launches Analytical Sciences Center of Excellence

On Oct. 25, 2023, the winners of the 2023 CPHI Pharma Awards were announced at the 

 event. The awards are given out for outstanding achievements and contributions to the pharma industry in 12 categories. This year’s winners include:

CEO of Procos, Enrico Zodio, won CEO of the Year as recognition for the company’s development and growth, which exceeds €200 million and includes capacity to further increase production.

Snapdragon Chemistry (a Cambrex company) topped the API Development & Innovation category for its ultra-high temperature (>300 °C) continuous flow manufacturing process for racemization of sotorsib (LUMAKRASTM) P-dione, which harnessed greener technology that resulted in a 58% reduction of process mass intensity.

Lubrizol Life Science Health took home the prize in the Finished Formulation category for its solubility-enhancing excipient designed for parenteral use. Apisolex is a poly(amino acid)-based excipient that provides formulators with methods to enhance the solubility of hydrophobic BCS Class II and IV APIs, by up to 50,000-fold.

The Manufacturing Excellence category went to Luminary Therapeutics for its manufacturing platform, Gamma Delta 2.0+, that brings allogeneic cell therapies to market for less than 10,000 without sacrificing function.

Gasporox took the honors in the Packaging & Machinery section for its AutoMAP Pharma gas measurement system for high or low concentrations of O2 in modified atmosphere packaging.

Catalent won the Supply Chain Excellence category for its Case Management Services, which provides end-to-end supply chain management for autologous and allogeneic cell and gene therapies.

The Regulatory Compliance category went to Lambda Therapeutic Research for their EDC solution that enhances research and data management. The software suite, including IMPTrack, KnowledgeNET, and Biolyte, enables real-time, accurate data capture through advanced functionalities like barcode scanning and retina-based verification. It also manages and retrieves study-related data to improve compliance with regulatory guidelines.

Medicsen took the Drug Delivery & Device Innovation category for its SMARTPATCH. The wearable patch uses ultrasounds to deliver drugs subcutaneously and combines the main benefits of current patch pumps with the upside of eliminating invasive and painful components.

The Accelerating Innovation category went to React4Life’s MIVO (Multi In Vitro Organ), a patented organ-on-a-chip that can host and culture 3D human biological cells or tissues under fluid dynamic conditions as 

Schneider Electric won the Sustainability category for its Energize program. The program leverages the scale of the global supply chain in a pre-competitive fashion to drive system-level change. 

The new Start-Up Initiative category went to InSyBio for its ability to revolutionize the medical ﬁeld, clinical trials, and food/nutrition industries through its targeted biomarker discovery. The company’s highly accurate predictive analytics enables personalization of tests for drugs, nutraceuticals, and nutrition products.

The ‘Heart of Pharma’ award, also new this year, went to Merck KGaA for its Embracing Carers initiative that recognizes the role of family carers.

“CPHI aims to position itself at the ‘heart of pharma’ by creating an environment where everyone in our industry can come together to exchange ideas and build productive new alliances for the ultimate benefit of patients. I whole-heartedly congratulate all winners of this 20th edition of the CPHI Pharma Awards. Those committed to driving innovation across the key disciplines that shape the success of our industry. I’d also like to thank all those who submitted an entry this year, and the members of our jury who so diligently reviewed them,” commented Tara Dougal, Content Director–Pharma at Informa Markets, in a press release.

The winners of the 2023 CPHI Pharma Awards were announced on October 25 at the CPHI Barcelona event.

Winners of the 2023 CPHI Pharma Awards Announced

On Oct. 19, 2023, Waters Corporation announced that it has launched OligoWorks solid phase extraction (SPE) Kits and components, which are meant to improve sample preparation for liquid chromatography (LC)–mass spectrometry (MS)-based bioanalytical quantitation of therapeutic oligonucleotides.

The kits are designed to deliver up to 2x higher oligonucleotide recovery from biofluids, according to a company press release. The kits’ design also delivers improved LC­MS sensitivity and reproducibility for supporting robust quantitation. Because these capabilities enable lower limits of quantitation, the kits can reduce the need for repeat experiments.

The kits also use an innovative, enzyme-enhanced, and detergent-free sample pre-treatment that, according to Waters in the press release, reduces washing steps and improves mass spectrometer compatibility. This design enables for direct injection LC–MS analysis and is also what allows for the lower limits of quantitation. The kits can also be fully automated, which can improve productivity or simply help scientists gain back time via the reduction of manual steps and oversight.

The OligoWorks SPE Kits are available immediately and complement other Waters tools, including MaxPeak Premier Columns, ACQUITY Premier LC System and Arc Premier LC System, Andrew+ Pipetting Robot. The new kits also support the sensitivity of the Waters Xevo TQ Absolute Mass Spectrometer.

" … Waters is committed to solving customer pain points and enabling greater analytical performance and productivity. Our new OligoWorks SPE Kits directly address oligonucleotide bioanalysis sample prep challenges across diverse oligo therapeutics," said Erin Chambers, vice-president, Consumables and Lab Automation, Waters Corporation. "The science and societal effects of these therapies are exploding given their ability to address human health issues. Our workflow and kits will drive an acceleration of oligo bioanalysis projects and drug development timelines; ultimately improving the experience for drug candidates."

New Technology

Waters has launched OligoWorks SPE Workflow and Kits, which is aimed at accelerating the bioanalysis of oligonucleotides.

Waters Launches New Oligonucleotide Bioanalysis Kits

On Oct. 18, 2023, SCHOTT announced that it has launched a new component for biopharmaceutical process analysis, the ViewCell flow cell. The purpose of this new component is to optimize downstream processes in the biopharmaceutical industry by enabling safe, continuous process control directly in the production line.

The introduction of the ViewCell flow cell follows the company’s launch of its ViewPort sensor port for bioreactors. Through a sterile-safe optical window, the flow cell allows for 

 measurements of biological and physical parameters in downstream processing. The flow cell can be used during purification and filtration as well as during subsequent formulation. This capability thus reduces the need for both physical sampling and storage tanks, according to a company press release.

According to the press release, optical sensors or spectrometers are connected to the flow cell for monitoring, which means that the measuring instruments do not come into contact with the medium, and thus do not penetrate the sterile barrier. This allows for the sensors or spectrometers to be easily replaced during ongoing production, which the company states in its press release is a major advancement compared to fixed probes. In addition, a glass-to-metal connection allows for a sterile-safe design, which also increases the safety and efficiency of process analysis, contributing to an overall optimized yield.

The company stated in the press release that ViewCell allows biomanufacturers to quickly build and test small-scale flow systems for Raman analysis, which are used to mimic real-world industrial processes. The compact design of the device reduces the overall volume of sample material required, which cuts down on waste and costs—key considerations in the handling of expensive or difficult-to-obtain test materials.

SCHOTT now offers ViewCell, a new component meant to add flexibility to biopharmaceutical process control.

SCHOTT Launches ViewCell Flow Cell for Biopharma Process Control

On Oct. 11, 2023, Cellares, an integrated development and manufacturing organization (IDMO) specializing in cell therapy manufacturing, announced it has expanded its agreement with Bristol Myers Squibb (BMS) to include a second chimeric antigen receptor T-cell (CAR-T) program as part of the Cellares Technology Adoption Partnership (TAP) program.

Under the expanded agreement, Bristol Myers Squibb will begin a second proof-of-concept tech transfer process for the manufacture of its CAR-T cell therapy, and Cellares will optimize, automate, and tech-transfer the additional CAR-T cell therapy process onto its automated manufacturing platform (Cell Shuttle).

Cellares’ manufacturing technology supports both autologous and allogeneic cell therapy processes and approximately 90% of cell therapy modalities, according to a company press release. Meanwhile, the company’s TAP program is a fast and low-risk means by which cell therapy developers can adopt Cellares’ automated manufacturing technology for products in their pipeline.

With the TAP program, manual processes can be automated and tech-transferred onto Cellares’ Cell Shuttle platform in six months, and the transfer can happen at any stage of the therapy’s development—whether it is in pre-clinical development, clinical development, or after regulatory approval.

initial partnership between Bristol Myers Squibb and Cellares

 began in August 2023, which is also when Cellares 

launched its commercial-scale IDMO smart factory in Bridgewater, NJ

 factory was built to integrate advanced robotics, purpose-built technology, and interconnected software and will be capable of producing 40,000 cell therapy batches per year.

“We’re excited to expand our relationship with Bristol Myers Squibb even further beyond the Series C investment and the first TAP program for cell therapies,” said Cellares CEO Fabian Gerlinghaus, in the press release. “The optimization and automation of this additional CAR-T cell therapy process through our TAP program expands on our first partnership with BMS and helps our mission to accelerate access to life-saving cell therapies for patients.”

Under an expanded agreement, Cellares will provide proof-of-concept manufacturing for a second CAR-T cell therapy from Bristol Myers Squibb.

Cellares Expands Agreement with Bristol Myers Squibb for Second CAR-T Program 

Sweden-based Salipro Biotech and Estonia-based Icosagen, a contract research, development, and manufacturing organization, announced on Oct. 10, 2023 that they have entered into a multi-target antibody research agreement to advance drug discovery programs. The companies intend to discover and characterize monoclonal antibodies (mAbs) against several challenging membrane proteins, including G protein-coupled receptors (GPCRs) and solute carrier (SLC) transporters.

Under the agreement, Icosagen will leverage its expertise in protein production and analytics. The company’s knowledge in antibody discovery encompasses high-throughput antibody screening and a variety of lead optimization techniques that the company expects will support the collaboration and form a solid basis for future biologic drug development, according to a company press release.

The partnership between the companies aims to build on Salipro's strength in establishing multiple collaboration and licensing agreements with leading pharma and biotech companies that enable drug discovery against complex membrane protein targets. The company’s experience includes small-molecule drug discovery programs as well as structural biology and antibody discovery.

“Our Salipro technology provides an enabling platform for the discovery of therapeutics against challenging drug targets. We are excited to unlock the potential of these targets with Icosagen and develop novel drugs that can improve patient outcomes," said Jens Frauenfeld, CEO of Salipro Biotech, in the press release.

"We are delighted to apply our QMCF technology and protein analytics capabilities in this project. Both teams in Icosagen and Salipro Biotech are always finding ways to push the boundaries in novel technologies of biologics development. It will be interesting to see what we’ll be able to achieve as we put our heads together for this project,” said Mart Ustav Jr., chief scientific officer, Icosagen, in the release.

Salipro Biotech and Icosagen have entered into a multi-target collaboration to discover and characterize monoclonal antibodies.

Salipro Biotech and Icosagen to Collaborate on Antibody Discovery

BIOVECTRA and Acuitas Therapeutics have entered into a technology transfer service agreement, through which Acuitas’ lipid nanoparticle (LNP) technology platform for manufacturing messenger RNA (mRNA)-based therapeutics will be transferred to BIOVECTRA’s new biomanufacturing center currently being built at its Charlottetown, Prince Edward Island site in Canada.

Under the agreement, BIOVECTRA will formulate Acuitas’ LNP for licensed therapeutic partners for clinical and commercial products using a variety of payloads. Acuitas’ LNP technology is currently used in multiple vaccines and therapeutics in clinical development. The technology is also used in the Pfizer-BioNTech COVID-19 vaccine, COMIRNATY, according to an Oct. 5, 2023 company press release.

The tech transfer will occur in BIOVECTRA’s biomanufacturing center in Charlottetown, which is expected to be completed in late 2023. Upon completion, the facility will support the good manufacturing practice manufacturing of plasmid DNA, mRNA, and LNP formulations. The 36,000 additional ft2 will be able to produce the equivalent of 160 million doses of mRNA vaccines and will have the capability to fill/finish 70 million final vaccine doses per year for commercial distribution, according to the press release.

“We are thrilled about this partnership with Acuitas Therapeutics … ,” said Marc Sauer, chief science officer, BIOVECTRA, in the press release. “Our work together will provide their licensed partners with faster market access to CGMP [current good manufacturing practice]-quality LNPs for early and late-stage products. BIOVECTRA looks forward to continuing to make a difference in patients’ lives by supporting GMP and commercial-ready LNP formulation at our new mRNA biomanufacturing facility in Atlantic Canada.”

“LNP-based mRNA medicines provide the opportunity to address an incredibly wide range of health conditions, from infectious diseases such as COVID-19, flu, and malaria to therapeutic areas related to heart disease, or cancer, as well as many rare diseases,” said Chris Barbosa, vice-president, Technology Development, Acuitas Therapeutics, in the release. “As we move forward in the development process in all of these areas with our partners, the demand for Acuitas’ clinical-grade LNP for our partners increases exponentially. We look forward to working with the BIOVECTRA team to expand the CGMP manufacturing capacity for Acuitas’ LNP so that we can continue to meet the growing needs of our global partners.”

Under this agreement, Acuitas Therapeutics’ LNP technology platform will be transferred to BIOVECTRA for use in manufacturing mRNA-based therapies.

BIOVECTRA in Tech Transfer Agreement with Acuitas Therapeutics for LNP Delivery System

As CPHI Barcelona approaches, the pharmaceutical world is gearing up to explore promising innovations that could shape the future of healthcare. This year is historic for CPHI, as it introduces a dedicated exhibition zone exclusively for start-ups, which are the innovation hubs of the industry. As part of its overarching mission to accelerate the journey of innovative medicines to patients worldwide, CPHI is shining a spotlight on some of the most promising early-stage technological innovations poised to impact the global pharmaceutical landscape. In this context, we had the privilege to engage with two emerging start-ups, one in the realm of devices and the other specializing in enhancing solubility, both offering unique solutions set to reshape the pharmaceutical landscape.

This article was written by the CPHI Content Team.

The Start-Up Market at CPHI Barcelona brings together 27 start-ups, innovators, and small enterprises from across the pharma landscape.

BioPharm International's BP Elements, November 2023