Biologics and other complex biomolecule modalities present challenges to fill/finish steps. Being able to ensure a sterile environment during aseptic processing is one of them.

The aseptic/fill finish process for biologics can be challenging because of the sensitivity of biologic products. In addition, where the product is located in the manufacturing process at a given time makes aseptic fill/finish difficult, says Michael Francis, senior product manager, CPC Biopharma.

According to Francis, two primary challenges are maintaining sterility and minimizing contaminants, and, because the fill/finish steps for complex modalities such as cell therapies, for example, are the last processing steps before a product is delivered to a patient, biomanufacturers must carefully consider patient safety along with the high costs—in time and money—if a batch is lost and has to be reproduced.

“Biologics are often more sensitive to contamination with bacteria, viruses, or particulates, so maintaining sterility is paramount. Even with advanced automation, human intervention can still be the source of contamination risks, so ensuring operators can easily and stringently adhere to aseptic techniques is critical,” Francis states.

In addition, one of the most critical responsibilities in biopharma aseptic fill/finish is ensuring the integrity and viability of the molecule, explains Jackie Klecker, executive vice-president and general manager at Lifecore Biomedical, a US-based contract development and manufacturing organization. Ensuring molecular integrity and viability requires careful and accurate characterization of the key properties of these highly complex, sensitive, and expensive products. “Each molecule differs from the next and any number of forces can negatively impact the product, including light, temperature, shear, oxygen, and product contact, among others,” Klecker says.

Pirkko Kortteinen, PhD, chief operating officer, 3PBIOVIAN, agrees that product stability is one of the most significant challenges for the aseptic fill/finish of biologics and complex biotherapeutics. “The stability of large complex molecules such as proteins, living virus particles, or viable cells can be compromised during aseptic fill/finish by environmental factors such as temperature, high pressure, metal ions, adsorption agitation, or shear stress,” she adds.

“The aseptic fill/finish process must be designed to preserve molecule structures, biological activity, and cell viability and avoid degradation, aggregation, or other damage. Many products cannot withstand holding at room temperature,” Kortteinen further emphasizes.

“Understanding the limitations of each molecule is essential to establishing and maintaining expert control of the optimal environment, across all aspects and timepoints of the fill/finish process,” says Klecker. “This can include strict temperature control requirements/timing during production steps, such as controlled thawing timing, as well as use of low-shear peristatic pumps for filling.”

Meanwhile, Kortteinen explains that, due to the nature of these biopharma products, total processing time must be kept short—in hours rather than days, in some cases—to complete the operations. Therefore, all processing steps, including melting, sterile filtration (if applicable), filling, closing, visual inspection, sample withdrawal, and secondary packaging must be carried out within a tight time frame.

The sensitive nature of biotherapeutics limits choices of sterilization methods, so, although heat sterilization in the final container is recommended, it is most often impossible, Kortteinen points out. Sterile filtration of the final bulk solution for many biological products must instead be performed before aseptic fill/finish. In contrast, a final cell therapy product, which consists of viable cells or cell-derived matrices that are not amenable to final sterilization or filtration, may instead require aseptic techniques throughout the manufacturing process, Kortteinen remarks.

Establishing an aseptic fill/finish strategy

Francis also notes that, because many aseptic fill/finish operations are performed in an isolator, aseptic fill/finish for biopharmaceuticals can be extremely expensive, and the equipment challenging to use. “Open manipulations within the isolator require good aseptic handling procedures to be successful. Incorporating single-use systems (SUS) into these applications has helped reduce contamination and particulate risks; however, these SUS designs are often very complex, sometimes resulting in ‘tubing spaghetti’,” Francis states. “These overly complex systems can be very difficult for an operator to handle—and any difficulty in assembly can introduce unintended risks of operator error.”

Furthermore, minimizing product loss at the aseptic fill/finish stage is critical because the starting materials, and therefore the drug substance, for biotherapeutic products are extremely valuable, Kortteinen points out. “Minimizing the loss of volume during processing is an important target for fill process designers,” she states.

“Facilities with the flexibility to implement creative solutions, whether it be utilizing state-of-the-art equipment with advanced control features or optimizing aspects of the filling process, are best equipped to minimize product waste,” Klecker adds.

Meanwhile, product freezing and shipment, which are more common with biotherapeutic products, also present challenges, Francis explains. Kortteinen points out that many biotherapeutics, especially in their early product life cycle, are stored at low temperatures, such as -80 °C or cryopreserved in liquid nitrogen. These low storage temperatures challenge container integrity during cryopreservation, she specifies.

“System designers need to consider component materials that can handle the wide temperature ranges associated with cryopreservation and subsequent thaw cycles that many biologic products undergo,” Francis adds. “Component suppliers should be able to provide leak, burst, microbial ingress, and other testing that demonstrates how their products perform throughout the entire process and associated activities [such as] sterilization, shipping, and freeze-thaw.”

Overall, notes Klecker, the complexities and specific requirements of biologics manufacturing necessitate a high level of expertise and meticulous process management to address these challenges effectively.

Solving the problems encountered during aseptic fill/finish of biopharmaceuticals was greatly helped by the advent of single-use technology (SUT).

SUTs have seen vast development in the past two decades, emphasizes Kortteinen, who explains that single-use supplies, typically sterilized plastic components or assemblies, have changed aseptic fill/finishing processes by adding operational efficiencies.

“Using single-use filling lines for fluid transfer can shorten overall manufacturing time,” Kortteinen says. “By using ready-made and sterilized assemblies, one can avoid time-consuming and laborious campaign changeover procedures of equipment. The need for sterilization in place for the fill line disappears when the suppliers sterilize the disposable fill line. Also, using high-quality, high-capacity disposable sterilizing grade filters shortens the manufacturing time.”

A significant benefit to using single-use materials in aseptic fill/finish is the minimization of cross-contamination risks, which is a crucial concern, especially for multi-product facilities and contract manufacturing organizations, Kortteinen remarks.

However, Francis explains that, although SUTs such as disposable filling lines and single-use bags help reduce cross-contamination risks and simplify cleaning and validation processes, manufacturers still need to ensure that the SUS components perform as intended within their processing parameters. “For example,” Francis says, “newer polymer SUS must be shown to withstand the applicable processing temperature and pressure levels that traditionally posed no issues for stainless-steel equipment.”

“Previously,” explains Kortteinen, “fill/finish manufacturers washed and sterilized primary packaging materials in-house. The processes needed heavy equipment and facility investments. Validation of such quality critical processes and qualification and maintenance of equipment and systems was labor-intensive.” In comparison, today, high-quality ready-to-process vials, stoppers, and other packages are available from suppliers.

“Outsourcing the preparation and sterilization of primary packages has simplified the fill and finishing operations. Validation activities when using ready-to-process components focus on material transfer and loading sterile components into the filling line to demonstrate that all components are kept sterile throughout the processing,” Kortteinen states.

Francis further notes that, to create optimal systems, manufacturers should ask component suppliers for key information on chemical compatibility, flow performance, life cycle testing, extractable data, and product integrity in freeze-thaw cycles, among other information. “Many new therapies are being cryopreserved at temperatures beyond -150 °C, for example, so the components in the fill/finish stage need to deal with these ultralow temperatures,” he says.

Relying on the latest disposable systems, utilizing low shear peristatic pumps within fillers, and streamlining the isolator filling line setup to maximize yield and minimize opportunities for contamination are also important solutions, says Klecker. “Equally important as these in-process solutions are the extensive testing protocols that we develop with our customers to incorporate into the fill/finish process. These play a key role in not only characterizing the molecule and identifying its vulnerability to external factors, but also in monitoring for any unwanted impact during the aseptic fill/finish work,” she adds.

Klecker also emphasizes the point of “keeping the end in mind” for each product’s commercial fill/finish process. “By working to learn about and address any unique, product-specific behaviors early in our work with a molecule,” she stresses, “we can ensure that our final process is optimized for the valuable commercial lots we will produce.”

Manufacturers these days are also looking for ways to simplify SUS that make their way into the isolator, according to Francis. For instance, sterile connectors allow SUS to be used outside of the isolator, where the connectors function as a passthrough on the beta port. “Removing the surge bag and even a portion of the tubing manifold, for example, can reduce the ‘tubing spaghetti’ that otherwise complicates handling by an operator. And as part of a closed system, aseptic connectors help stop particulates and contamination from entering the flow path when connecting filling equipment,” he explains. “These connectors also make modular systems possible by connecting components within the systems such as tubing, bags, filters, and manifolds. The integration of closed processing and modular systems enables efficient, flexible workflows while providing the aseptic processing biologics manufacturers need to minimize contamination risks.”

Filling line manufacturers have already developed innovative new designs and technologies for aseptic fill/finish that are suitable for biotherapeutics, points out Kortteinen. For instance, small batch sizes used in gene therapy and cell therapy have created a need for small automatic filling lines suitable for multi-product fill/finish operations in cell and gene therapy manufacturing facilities. Meanwhile, automatic filling lines improve quality by avoiding human interventions, and automation adds operational efficiencies and enables effective scaling up of fill/finish operations, she notes.

“[T]he industry will continue to optimize facilities and equipment to improve the ability to monitor for and address external factors that may jeopardize the viability of complex biotherapeutic products,” remarks Klecker. These innovations may include: the addition of continuous temperature controls throughout the entire fill/finish process and more low-temperature storage capacity; greater adoption of disposable components to reduce burden of cleaning and cleaning validation; and facilities that are designed with specific light spectrum ranges.

Meanwhile, Francis expects that there will continue to be greater use of closed SUS, which he points out are adaptable to any scale or system depending on a unique biologic or therapy needed. “SUS allow smaller, modular segments to process specific batches of product, so modularity will be more broadly deployed. Modularity helps simplify operator SOPs [standard operating procedures] and workflow, too, because all personnel use the same or similar systems.,” he says.

Francis also notes that the ability to continuously filter in upstream processing via perfusion is starting to create a continuous flow of product to the filling stage. This continuous processing, along with modular SUTs, is creating a future of faster manufacturing. However, while there is a need for more automation, Francis points out that increased automation as a solution may be difficult to implement because there is no single solution. “With more process data collection and quick analytics through AI [artificial intelligence], there’s an expectation that future filling will be tailored and precise. Automation can provide greater reliability, faster processes, and less risk of operator error, but current automation designs are often very complex so you can lose some of the benefits automation is intended to deliver. Also, there’s a need to standardize on those designs. The industry recognizes the benefits of standardization, but it’s tough to implement for a variety of reasons,” he explains.

Furthermore, Francis anticipates that biologics manufacturers will seek more efficient processes earlier in drug development to allow for more streamlined scaling because thinking ahead to the commercial manufacturing process while still in the drug discovery and efficacy testing stages saves time later on. “For example, the more manual and operator-dependent aseptic techniques such as tube welding and the use of biosafety cabinets might work fine in small-scale processes, but that doesn’t translate well when it comes to commercialization,” he says.

“Finally,” Francis adds, “many hurdles and challenges occur when researchers and developers, especially universities and start-ups in the [cell and gene therapy] space, look to transfer their technology or product from lab scale to commercial scale. As start-ups gain a broader understanding of how their products might eventually be produced—and if they begin incorporating those approaches into their own early-stage processes—the more seamless tech transfer can be.”

Kortteinen also highlights newer regulatory considerations that may affect the future of aseptic fill/finish. She brings up that the new Annex 1 guideline (1) introduced in Europe, for example, has a broader scope to include new technologies (e.g., isolators and restricted access barrier systems [RABS]), especially for new facilities or installations. Kortteinen explains that isolators can be completely closed and decontaminated with hydrogen peroxide, which minimizes contamination or cross-contamination risks. “Automatic filling in an isolator is a choice for viral products that require containment at biosafety level 2, as it protects operators from exposure to the products. In the future, aseptic [fill/finish] in either isolator or RABS will be an expectation,” she states.

“Annex 1 requires a unidirectional flow for the transfer of materials, equipment, and components. Separate change rooms for entering and leaving the filling are desirable,” Kortteinen summarizes. “These requirements will influence the cleanroom design of new facilities and may induce facility renewals in existing cleanroom setups.”

1. EC. Annex 1: Manufacture of Sterile Medicinal Products. 

Feliza Mirasol is the science editor for 

®
Vol. 37, No. 9
October 2024
Pages: 8–11

When referring to this article, please cite it as Mirasol, F. Understanding Molecule Sensitivity in Aseptic Fill/Finish. 

Articles

Cover Story

Aseptic fill/finish of biopharmaceuticals requires an understanding of the structure and limitations of each molecule.

Understanding Molecule Sensitivity in Aseptic Fill/Finish

A standard pharmaceutical or biopharmaceutical process equipment cleaning cycle consists of an initial rinse, caustic wash, intermediate rinse, acid wash, and then a series of post-acid rinses ending with a final purified water rinse and drying step. The current good manufacturing practice (CGMP) regulations define critical process parameters (CPPs) and predetermined critical quality attributes (CQAs) applicable to a cleaning cycle. The desire for a more environmentally sustainable cleaning cycle had previously led to recovery of final rinse water to be used for the initial rinse step; change to formulated chemistries to reduce chemical consumption, impact on the environment and waste treatment; and change in cleaning temperature to decrease energy and cycle time. In this article, the authors explore removing the intermediate rinse and blow down step before the acid wash for a biopharmaceutical upstream and downstream process step resulting in both rinse volume and time savings. A short blow down will still be recommended to reduce residual liquid in the system between washes.

An acid wash may not be required for all cleaning cycles, but this step helps remove inorganic residues (e.g., iron oxide) on the surface, provides continuous maintenance of the chromium oxide passive surface, neutralizes wastewater, and reduces bioburden.

The elimination of a water rinse and blow down between the caustic and acid wash steps seems practical, but before being considered, an evaluation should be performed with an assessment of the risks, controls in place to mitigate the risk, and monitoring of the cleaning process to ensure continuous control of the validated state. A list of questions and answers (see Table I) based on the International Conference for Harmonisation (ICH) Q9 

 guideline helps in the risk assessment process (1). Common sources of hazards in the pharmaceutical industry include handling and storage, human error, emissions, use of volatile organic compounds, reactions, and leaks of effluents (2). The identified concerns from the risk assessment include: a change in the cleaning solution temperature due to an exothermic reaction when mixing caustic and acid solutions, potential off gassing of chemical compounds, and redeposition of residues removed during the caustic wash step (3–5). To investigate these concerns, it is important to know the exact chemical formulation of both caustic and acid cleaning agents. The physical properties of the acid rinse solution were assessed with temperature and pH checks, using different ratios of caustic and acid solutions. The volatile chemicals were assessed using gas chromatography with mass spectrometry (GC–MS). The cleaning and rinsing of the caustic cleaner, followed by the acid cleaner was also investigated using 304 stainless-steel coated surfaces.

Testing strategy to investigate process risk

All changes to CGMP processes require a change review, and based on the significance of the change, a new validation or revalidation may be required. For an automated cleaning process, this may include repeating the spray device coverage testing, ensuring the cleaning equipment has been commissioned and validated, and confirming that the rinse water recovery is consistent with surface cleanliness.

Submitted: Aug. 5, 2024
Accepted: Aug. 30, 2024.

, Step 4 version (2005).
2. Bhusnure, O. G.; Dongare, R. B.; Gholve, P. S.; et.al., Chemical Hazards and Safety Management in Pharmaceutical Industry. 

 (3).
3. Dermaut, W. Chapter 3: Process Safety and Reaction Hazard Assessment. In 

Chemical Engineering in the Pharmaceutical Industry: Active Pharmaceutical Ingredients

,2nd ed.; am Ende, D. J.; am Ende M. T., Eds.; John Wiley & Sons, 2019. DOI:10.1002/9781119600800
4. Allian, A. D.; Shah, N. P.; Ferretti, A. C.; et.al., Process Safety in the Pharmaceutical Industry—Part 1: Thermal and Reaction Hazard Evaluation Processes and Techniques. 

 (11), 2529–2548. DOI: 10.1021/acs.oprd.0c00226
5. Agarwal, P.; Goyal, A.; Rajat, V. Chemical Hazards in Pharmaceutical Industry: An Overview. 

 (2). DOI: 10.22159/ajpcr.2018.v11i2.23160

Dayna Turner is group leader, Science & Technology; Dijana Hadziselimovic is laboratory manager, Technical Services; Paul Lopolito is director, Technical Services; Mary Schanne is senior account manager; and Amy Thanavaro is manager, Science & Technology; all at STERIS, Saint Louis, Mo. Jeff Felker is deputy director, Cleaning Validation SME, Sanofi MSAT Swiftwater, Pa.

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Vol. 37, No. 9
October 2024
Pages: 23–28

When referring to this article, please cite it as Turner, D.; Hadziselimovic, D.; Lopolito, P.; et al. Strategic Changes to a Legacy Cleaning Approach Result in a More Sustainable Process. 

Peer-Reviewed Research

In this article, the authors explored the elimination of a water rinse and blow down following the caustic wash step, examining potential safety considerations, the effect on the quality of the cleaning process, and the potential benefit of implementing this change.

Strategic Changes to a Legacy Cleaning Approach Result in a More Sustainable Process

Biopharmaceutical manufacturing largely involves biomolecules whose stability depends on temperature. Antibodies, insulin, and, more recently, messenger RNA (mRNA)-based vaccines are examples of biotherapeutics that require cold storage. This article explores the difficulties with developing stability-enhancing formulations for temperature-sensitive biomolecules and technology innovations that are enabling their formulation.

Factors that have been most challenging in developing formulations that enhance stability in temperature-sensitive biomolecules include buffer, pH, and sugar. These are usually the typical factors that need to be evaluated to thermodynamically stabilize monoclonal antibodies (mAbs), notes Joseph Cao, PhD, senior scientist, Analytical and Formulations Development, Bionova Scientific. He explains that there are different types of buffers, sugars, and a range of pH to choose from when developing a proper formulation for mAbs that will prevent aggregation, degradation (such as deamidation, oxidation), and particle formation. Besides those factors, amino acids, salts for ionic strength, and excipients are also important in developing a formulation recipe, he adds.

In addition, the limited amount of therapeutic protein to work with poses another challenge to formulation development. “With design of experiment (DoE), it has allowed us to cut the amount of protein and help us efficiently screen for factors,” Cao says. “Freeze-thaw cycles, container combability, and manufacturing impurities should also be considered during formulation development.”

Heonchang Lim, director, Formulation Development, Samsung Biologics, agrees that finding the ideal range of pH and buffer conditions while selecting the optimal formulation condition to get a good thermal stability property are primary factors that challenge formulation development in these molecules. However, he notes, the thermal stability problem can mostly be solved by using optimal pH buffer and excipient combination.

“Nowadays, we bump into another challenge to develop an optimal formulation condition. That is regarding solubility and hydrophobicity of the molecule. Though clients would prefer higher concentrations, when taking unique characteristics of molecules into consideration, formulation scientists cannot always get high enough concentrations. In addition, pH shift may occur due to the Donnan effect,” Lim says. “Consequently, when a client requests a highly concentrated formulation, particularly above 100 mg/mL, [the] formulation team at Samsung Biologics implements rigorous gate checks to prevent such challenges from arising during formulation stages.”

Caroline Ailhas, Pharmaceutical Development director, CARBOGEN AMCIS says that, for her, the main factors challenging formulation development for temperature-sensitive molecules revolve around maintaining the structure and functionality of the molecule and defining the required duration of stabilization. The latter can vary from a few days—to allow for manufacturing and visual inspection before storage at 2–8 °C—to several months, or even years. “The definition of this duration significantly impacts the formulation strategy,” Ailhas says.

“One of the key performance indicators for the development of biotherapeutic formulations is colloidal stability to prevent protein aggregation and potentially precipitation,” Greg Chrimes, site head and vice-president, Analytical and Formulation Science, KBI Biopharma, adds. He points out that proteins may denature and aggregate at interfaces such as air/liquid, liquid/liquid, and liquid/solid. Chemical modifications and degradation may also impact effector function, efficacy, conformational stability, and other important parameters, he emphasizes.

“Excipients are evaluated during formulation development to limit product denaturation that may lead to particle formulation or chemical modification. Those may include buffering components, polyols, surfactants, amino acids, and antioxidants, to name a few. Finding the optimal combination components requires a methodical approach with matched analytics such as differential scanning calorimetry (DSC), dynamic light scattering (DLS), differential scanning fluorometry (DSF), and other product-specific techniques to down-select to a final formulation,” Chrimes states.

Lipid nanoparticles (LNPs) are emerging as a formidable technology that can facilitate molecule stability in biologic-based medicines. “LNPs facilitate the stabilization of the molecule due to their amphiphilic nature. This property allows large molecules to maintain their structure by interacting with either the polar head of the lipid or with the hydrophobic part of the lipid,” says Ailhas. Ailhas also points out that the variety of available lipids offers numerous options for LNP composition and stabilization strategies. Because of this variety, LNPs composed of different lipids are highly versatile, enabling them to stabilize various molecules, such as peptides or nucleic acids, with different charges.

Because LNPs can be used to encapsulate biotherapeutics, they protect the fragility of these therapies from accelerated degradation 

, Chrimes says. He explains that LNPs are biocompatible and naturally break down; however, the biodegradation needs to be timed to allow mRNA (as one example) to enter the target cells. “This type of delivery platform has accelerated the use of mRNA therapies. The control of lipid impurities generated during production of LNPs has also been reported to improve shelf life,” he adds.

LNP encapsulation shields molecules, such as mRNA, from temperature change, oxidation, and enzymatic degradation, Cao states. However, formulation development for mRNA-based therapies will still face the same challenges as mAb formulation development, Cao notes. “LNPs require different ratios of lipid components, such as ionizable lipids, PEG [polyethylene glycol]-lipids, cholesterol, and phospholipids, for their stability,” he emphasizes.

In addition to LNP technology, protein engineering and lyophilization are other techniques employed to facilitate the development of formulations that can offer better stability for temperature-sensitive molecules. “Development of stable products at ambient temperature is typically the preferred endpoint for biopharmaceutical formulations. However, it is not often obtained due to the physical forces experienced during transport, storage, and delivery,” says Chrimes. He explains that product liabilities can be removed in the primary sequence of a biotherapeutic, in some cases to eliminate the instability. He points to lyophilization as an often-successful technique to avoid colloidal instabilities that occur during shipment or long-term liquid storage.

Protein engineering and the use of machine learning, meanwhile, has been increasingly used to develop mAbs that are more thermostable, says Cao. Furthermore, the use of AI to analyze the local solvent-accessible surface area of the variable region of previously approved mAbs have been used to make predictions on aggregation, he notes.

“If proteins can get re-engineered, then the YTE mutations [M252Y/S254T/T256E] could be employed to achieve thermal stability,” adds Lim, who explains that once a molecule passes the discovery phase, a formulation scientist would then need to analyze basic characteristics of the molecule to identify its distinguished traits. “These analyses help us determine the onset temperature (Tonset) and melting point (Tm) of the molecules and provide us insight into how much the molecule can resist thermal stressors,” he says.

Furthermore, identifying pH/buffer levels is required to earn both thermal and chemical stability, Lim adds. “We can also add various saccharide excipients to formulations, such as sucrose and trehalose, to further enhance thermal stability by about 2–3 degrees Celsius. For sensitive/complex molecules [such as] antibody-drug conjugates, lyophilization may be the preferred technique to achieve maximum stability,” he states.

Meanwhile, other types of nanoparticles, such as polymeric ones, are being explored for thermal stability, says Ailhas. “Additionally, lyophilization combined with the appropriate selection of excipients should be investigated to enhance the stability of temperature-sensitive products,” she states. Unique excipients such as polyols, surfactants, amino acids, and antioxidants have been demonstrated to improve protein chemical stabilization and colloidal stability, Chrimes notes.

“Beyond LNPs, other type nanoparticle carriers such as polymeric nanoparticles, silica nanoparticles, and gold nanoparticles are being investigated for the capability to stabilize the molecules through encapsulation,” says Cao.

At a certain point, once a formulation strategy is in place, focus shifts to the drug delivery method. Drug delivery systems are usually considered in later clinical stages of drug development, notes Lim, who emphasizes that in early stages of drug development, getting a fast investigational new drug (IND) application approval is a high priority for drug developers. Speed in securing an IND approval grants a competitive edge to drug developers, especially in a drug discovery market that is dynamic. “The emphasis during the early stages is less on selecting a delivery system and more on obtaining reliable thermal and physical stability results for the targeted molecule,” he says.

Formulation development is usually initiated at the early stages of drug development as well, says Cao, who explains that early formulation development ensures the stability of the product and reduces the need for cold storage with, for example, techniques such as lyophilization. Formulations that result in stability can then inform the design of the delivery mechanism, he notes.

“A study for delivery can also be conducted first to test which delivery method (intravenous [IV] bag, subcutaneous injection, etc.) is effective for the therapeutical drug, followed by formulation development,” Cao also says. “Different modes of delivering the drug will require different drug concentrations. IV-bags do not require high concentrations of drug, but sub-cutaneous does. Challenges and limitations observed in the delivery mechanism can drive further optimization of the formulation,” he adds.

“In my opinion,” says Ailhas, “it is more beneficial to prioritize an optimized formulation that can function in a non-cold environment. This approach simplifies production and storage, eliminating the need to find specific drug product manufacturers capable of handling cold manufacturing processes, which can be challenging to locate.” Ailhas also points out that, although a formulation-first strategy may incur slightly higher costs at the beginning of a project, the long-term cost savings during the transition to good manufacturing practice manufacturing, either for clinical or commercial supply, will be significant.

Chrimes agrees that is it important to prioritize a formulation-first strategy: “Optimizing the formulation to limit the impact of temperature excursions would be the preferred development path for biotherapeutics,” he says, adding that every effort should be explored to limit potential liabilities as well as screen applicable excipients and explore presentations to “lock” the product in a stable state through techniques such as lyophilization, for example. Lyophilization removes water from sensitive products without damaging them. “Developing liquid formulations that are compatible with lyophilization can be an effective strategy for cost savings during clinical development where lyophilization cycles are deferred to commercial development,” he states.

Finally, what technical considerations remain to be solved that can conceivably facilitate a breakthrough to realistically realize temperature-stable biomolecules that no longer require stringent cold-chain handling?

Cao answers the question by pointing out that developing advanced stabilizers and excipients, as well as improving lyophilization and spray drying techniques, can aid in maintaining biological molecule stability without compromising efficacy or safety. Such advancements would allow biological molecules to be less dependent on stringent storage and transportation conditions.

“Don’t be afraid of lyophilization,” stresses Ailhas. “It can significantly help solve this problem, and it is not so difficult to manage, at least for mAbs. For mRNA vaccines formed with LNPs, the breakthrough will involve finding a way to remove water from the inner part of LNPs during lyophilization without damaging the LNP structure and ensuring they can return to their original form during reconstitution.”

Meanwhile, Chrimes says that the solutions are going to look different based on the modality, mechanism of action, mode of delivery, and more. Across the board, however, progress always starts with understanding what is causing the instabilities in a given biotherapeutic. “From there, we can work … to optimize not just for temperature stability, but shelf-life and other critical parameters that can impact commercial success. For the most part, it’s an ongoing process of optimization and refinement.” Chrimes adds that innovations in predictive modeling and machine learning could accelerate the development of unique excipients and formulation development.

“The key focus during the process development or clinical trial stages is to minimize the risk of failure,” adds Lim, who notes that, to minimize risk, a pre-molecular developability assessment is crucial. “Through this evaluation process, scientists can find any potential issues, such as lack of thermal stability, which can bring out exclusion or implementation of risk mitigation strategies for further development,” he says.

“This assessment can help researchers optimize strategies for thermal stability, including lyophilization as part of the formulation development process. Not only can this reduce the risk of failure but also save time during the development timeline,” Lim concludes.

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Vol. 37, No. 9
October 2024
Pages: 12–14

When referring to this article, please cite it as Mirasol, F. Prioritizing Formulation Strategies for Temperature-Sensitive Biotherapeutics. 

Development

Solving the challenge of better-stabilized temperature-sensitive biomolecules hinges on innovative formulation strategies.

Prioritizing Formulation Strategies for Temperature-Sensitive Biotherapeutics

Space-time yield is a metric to analyze upstream process yields throughout a production campaign. This metric enables distinct methods for protein production, such as batch, fed-batch, or continuous fermentation, to be directly compared to one another. This approach for direct comparison provides researchers and process developers with the capability to consider process yields, input costs, production time, and facility constraints within their evaluation of potential unit operations for the design of a goal-oriented manufacturing strategy. This article demonstrates how to calculate space-time yield using 

) and Chinese hamster ovary (CHO) cells as model organisms and highlights the unique differences between fed-batch and continuous fermentation processes that result in divergent space-time yields. As higher space-time yields ultimately result in more protein for less space and time, considering space-time yield when choosing a manufacturing plan can be a useful tool for lowering future commercial production costs.

Product concentration, or titer, is often used to describe the productivity of fed-batch fermentations, where the goal is to achieve a large quantity of a heterologous protein for further downstream processing. Protein titer is the amount of protein present in the bioreactor at any given time reported as a concentration (e.g., g/L). The protein titer reached at the end of a fed-batch fermentation is essentially the total quantity of protein made throughout the process, which can be used to compare the productivity of processes performed in a similar format (time, volume, media, host organism, cultivation type, etc.).

In continuous processes, however, nutrients are constantly fed to the bioreactor while secreted protein and waste products are continuously removed from the bioreactor. This constant removal of waste and replenishment of nutrients results in an extremely dense biomass that can maintain protein expression at high levels throughout an extended fermentation campaign. For example, in perfusion fermentation secreted protein is continuously harvested from the healthy biomass throughout the fermentation campaign, which typically runs for time periods twice as long as similar fed-batch fermentations. In this situation, the protein titer inside the bioreactor at a given point in time is not an appropriate representation of the overall protein yield from continuous processes, because protein is continuously being removed from the bioreactor.

Space-time yield is a normalized metric for productivity that can be used for any cultivation mode or protein-expressing host organism. Space-time yield is defined as the total mass of protein produced per bioreactor working volume per cultivation day irrespective of the method of cultivation, whether batch-based or continuous. This versatile metric normalizes the quantity of protein per cultivation scale and cultivation length, allowing for convenient comparison across scales or process lengths, which often differ between cultivation methods. For example, continuous fermentation campaigns are typically lengthy and can often be extended with minimal additional effort.

Fed-batch campaigns, however, are usually shorter than continuous ones and cannot be significantly lengthened due to fundamental limitations in nutrient availability and accrual of waste products as the campaign extends in time. This accrual of waste and lack of nutrients leads to increasingly unhealthy biomass over time, which ultimately causes a culture to stop producing heterologous protein in fed-batch processes. Given these differences in cultivation operations, space-time yield provides researchers and process developers with a tool to select the optimal process for their production needs based on a normalized comparison.

Space-time yield data enables the evaluation of process design improvements, including process intensification and facility layout optimization. Herein, we describe how to calculate the space-time yield for different processes and demonstrate the utility in using this metric for comparison across fermentation modes, cultivation lengths, and scales.

Fed-batch and continuous fermentation of 

The method used is based on the mathematical framework presented in Bausch 

, to determine the space-time yield of several cultivations using different manufacturing strategies and hosts (1). The key characteristics for the model cultivations are shown in 

The comparison of a traditional fed-batch fermentation (Process 1) to a perfusion fermentation process (Process 2) was performed using assumptions for key process parameters relevant for the fermentation of 

 fermentation modes, a two-stage process was assumed, including a biomass accumulation phase at the maximum growth rate, followed by a production phase after the maximum viable cell density is met. Fermentation lengths of six days for fed-batch and 12 days for perfusion were assumed based on literature reports and operational experience. The specific productivity, defined as micrograms of product produced per gram of cells per hour during the production phase of fermentation, is assumed to be the same in both types of operations. The maximum viable wet cell weight was assumed to be higher for the perfusion process based on the healthier cell environment provided by continuous fermentation and routine maintenance of >600 g/L wet cell weights during perfusion campaigns executed with a single-use perfusion fermentation reactor. The perfusion rate and cell bleed rate were reported in vessel volumes per day (vvd). For the continuous process, protein removed through the cell bleed line is not considered in the product yield, because it is directed to waste and not typically recovered.

Parameters for the CHO fed-batch cultivation were taken from Bausch 

 (1). Production and growth were assumed to happen simultaneously. For the CHO fed-batch process, the maximum viable cell density (20 x 106 cells/mL) and specific productivity (25 pg/cell/day) were converted assuming an average mass of 2 ng per cell (1,2).

In this study, the productivity of cultivation processes with different host organisms and manufacturing approaches are compared. The wet cell weight, instantaneous protein titer, cumulative protein titer, and space-time yield were calculated for each process.

Comparison of fed-batch and continuous fermentation of 

A fed-batch and a continuous fermentation process were compared using the same host—

). Two key differences in these fermentation processes are the biomass achieved during production and the overall fermentation length. Continuous fermentation provides a healthier cell environment in the bioreactor because nutrients are continuously replenished, and waste products are continuously removed. This healthier cell environment results in higher achievable biomass that can be sustained for significantly longer as compared to fed-batch processes (

 shows the comparison of protein titers between the two fermentation modes. In the fed-batch process, the titer increases over time until the fermentation is stopped due to declining cell health after day 6. The final titer reached in the bioreactor is 3.7 g/L. In the continuous process, a steady state titer of 0.73 g/L is reached after about five days. This titer is maintained for the next seven days until the end of the campaign (12 days total fermentation length) as the biological process is held in a steady state through continuous feeding and continuous removal of cell waste.

In Process 1 (fed-batch), the protein titer in the bioreactor at harvest is representative of the cumulative amount of protein made during the cultivation (Figure 2). In contrast, the titer observed upon sampling Process 2 (continuous) is not representative of the cumulative protein expressed because protein is continuously harvested during the production process.

, the cumulative protein in the continuous process is immediately higher than that of the fed-batch process due to the higher achievable cell mass at the time of induction. After six days, the continuous process has produced 5.6 grams of product. This is over 40% more protein expressed than during the entire fed-batch process (3.7 grams). Furthermore, the continuous process extends for twice as long as the fed-batch process, ultimately resulting in over 13 grams of harvested protein, more than three-fold more protein than the fed-batch process (

As the cumulative protein harvested will vary across cultivation scales and lengths, a normalized metric is needed for a direct comparison between fermentation operations. Space-time yield, which is the total protein harvested per bioreactor volume per cultivation day, is a normalized metric for productivity that can be used for any cultivation mode.

, the space-time yield for a continuous process is typically also higher than that for a fed-batch process of the same length. Notably, the space-time yield of a continuous fermentation improves over longer cultivation times, because the initial cell growth period is amortized across the total cultivation length.

 shows the comparison of a fed-batch cultivation using CHO cells to produce heterologous proteins to both fed-batch and continuous fermentation processes using 

In this comparison, we assumed that the CHO cells had a five-fold higher specific productivity (using parameters from Bausch 

[1]). The growth rate and maximum cell viability, however, are significantly lower for CHO cells. This results in slower biomass accumulation and significantly less biomass overall during cultivation (Figure 3A). Accumulated biomass is frequently ten times higher in 

 fermentation processes compared to CHO, suggesting that researchers should consider protein composition, time constraints, and equipment usage when selecting an expression organism (3).

, the titer achieved in a fed-batch campaign executed with CHO cells is higher compared to either of the 

fermentation processes, but it takes substantially longer campaigns to achieve those titers, which has significant implications for facility utilization and process scheduling within a commercial operation. Using the normalized metric of space-time yield (

), it is clear that the space-time yield achievable for 

-derived processes in fed-batch or continuous operations are significantly higher than that achievable for a comparable CHO-based process, even using the assumption that CHO cells are typically five-fold more productive on a per cell mass basis. Overall, the continuous fermentation process results in a nearly three-fold higher space-time yield, as compared to the campaign executed with CHO in fed-batch. It should be noted here that the calculations made in this work model space-time yields, which are ultimately derived from cell-specific productivities. This fundamental metric should be calculated for each protein and strain based on growth rate and volumetric productivity (2–4).

Space-time yield is a normalized metric that can be used to directly compare productivity across cultivation modes and different host organisms. Of the three processes modeled here, the continuous fermentation process using 

 showed the highest achievable space-time yield, even with the assumption of a five-fold lower specific productivity than CHO. High space-time yields ultimately result in more protein for less space and time, and therefore lower process and facility investments and production operating costs. Space-time yield should be considered as a critical metric when assessing process designs to achieve translational, clinical, and commercial manufacturing goals for a given protein product.

Bausch, M.; Schultheiss, C.; Sieck, J.B. Recommendations for Comparison of Productivity Between Fed-Batch and Perfusion Processes. 

Kunert, R.; Reinhart, D. Advances in Recombinant Antibody Manufacturing. 

Kunert, R.; Gach, J.; Katinger, H. Expression of a Fab Fragment in CHO and Pichia pastoris. A Comparative Case Study. 

Maccani, A. et al. Pichia pastoris Secretes Recombinant Proteins Less Efficiently than Chinese Hamster Ovary Cells but Allows Higher Space-Time Yields for Less Complex Proteins. 

Laura Crowell*, laura@sunflowertx.com, is director, R&D; Stacy Martin is strategic consultant; and Kerry Love is co-founder and CEO; all at Sunflower Therapeutics PBC.

*To whom all correspondence should be addressed.

®
Vol. 37, No.9
October 2024
Pages: 15–19

When referring to this article, please cite it as Crowell, L.; Martin, S; and Love, K. The Optimal Metric of Space-Time Yield. 

Upstream Processing

Space-time yield is a critical metric for comparison of upstream biomanufacturing processes and can be useful in reducing commercial production costs.

 The Optimal Metric of Space-Time Yield

Glycan modifications of recombinant proteins and antibodies can impact their function and stability and thus the safety and efficacy of drug products based on these molecules. Understanding these important critical quality attributes (CQAs) is essential, and therefore, regulatory bodies expect a comprehensive understanding of glycans for submission.

Comprehension necessitates overcoming inherent challenges such as positional isomers and heterogeneity, as well as method-induced artifacts that influence sensitivity and specificity, according to Paula Orens, senior global market development manager, Biopharma, at SCIEX.

Multispecifics, including bi-, tri-, and tetraspecific antibodies, present additional challenges to glycan analysis beyond those of traditional monoclonal antibodies (mAbs) because the complexity of these molecules is much greater.

“Site-specific and intact mass analysis may become more challenging for increasingly complex molecules, particularly when the number of N-glycosylation sites, post translational modifications, and potential degradation products increases,” observes Oscar Potter, biological chemistries R&D manager in the Chemistries and Supplies Division at Agilent.

Structurally, multispecific antibodies are a combination of different antibody domains that allow the multispecific to bind at multiple sites. “The various domains will have their own glycosylation patterns (integral to efficacy, safety, and stability) and their own impurities, all of which need to be characterized comprehensively, effectively multiplying the glycosylation analysis complexity by the number of binding sites,” Orens explains. She adds that as the number of binding sites increases, so too does the risk of intra-protein cross talk.

Multispecifics can also include candidates in which an antibody-portion is combined with some other protein-based component. Chimeric proteins, where the domains are not only antibody in origin, are complicated to analyze due to the individual properties of each component, according to Orens. “For example,” she says, “fusion proteins are typically heavily glycosylated with N- and O-linked glycans to improve biological activity, properly stabilize the structure, or improve solubility.”

“Overall,” Orens concludes, “while the complexity of analysis is dependent on the types of domains used in a multispecific, it is certain that the analysis of these molecules will be more complicated than that of a mAb.”

Consequences of incorrect glycosylation analysis

The greater complexity of multispecifics raises the stakes for achieving correct glycan analysis. “Not only can the glycosylation patterns in multispecifics impact the stability, pharmacokinetics, off-target effects, and effector functions such as complement activation and antibody-dependent cellular cytotoxicity, conceivably the additional functions that multispecific antibodies are capable of might result in unique biological consequences from incorrect glycosylation,” Potter comments.

In addition, because glycosylation is a critical and highly regulated quality attribute of all antibodies, misunderstanding or incorrectly characterizing glycosylation patterns could lead to a variety of consequences, depending on the development stage of the candidate, notes Orens. She highlights a couple of examples. “At the hit-identification stage, a mis-characterized but suitable candidate could be eliminated due to poor efficacy or stability. At later development stages, meanwhile, a drug metabolism and pharmacokinetics study could exhibit faster-than-expected clearance or undesired concentration in the target tissue. An incorrect analysis could also result in promotion of a misunderstood candidate through to late-stage toxicology studies, causing unnecessary investment in time and resources for the project only to be shut down later than expected.”

There are several different techniques used for the glycan analysis of antibody-based candidates. “Fundamentally, the same glycan analysis approaches are used for multispecific antibodies as mAbs, most commonly liquid chromatography (LC), capillary electrophoresis (CE), and mass spectrometry (MS). Each analytical approach offers a plethora of techniques which provide complementary or alternative details about the glycosylation profiles,” Orens observes. She does note, though, that the inherent complexity of the molecule will impart different challenges on each approach.

Typical analytical methods for glycosylation analysis of multispecifics are similar to those used for more traditional therapeutic mAbs, agrees Potter. “Released glycan analysis methods generate a glycan profile, usually based on separation by CE or LC. Intact LC/MS analysis can provide limited information about the major glycoforms, while LC/MS of protease-digested samples can give site-specific information for molecules with more than one glycosylation site,” he outlines.

Released glycan analysis relies on high-resolution separation of fluorescently labeled glycans by hydrophilic interaction liquid chromatography (HILIC) or CE. HILIC is used in conjunction with fluorescence or mass detection to separate and quantify individual glycan species over long gradients, according to Orens. Similarly, CE systems can offer comparable quantitation details with an alternative separation mode, often with faster separation. “These approaches are often used as monitoring techniques to ensure batch consistency during manufacturing,” she says.

Released glycan analysis once suffered from tedious sample prep, according to Potter, but protocols have been greatly simplified in recent years through rapid-release and instant fluorescent labeling sample prep kits. He observes that HILIC methods enable the most exact assignment of glycan structures, either using retention time reference standards or retention libraries, or by hyphenating with MS detection. “HILIC separations can often distinguish between isomeric structures, including potentially harmful alpha-galactose (α-Gal) structures masquerading as beneficial galactosylated complex glycans,” he says.

Measuring the intact mass of multispecific antibodies via LC/MS does not require any sample prep, which can be advantageous. A well-optimized method run on a high-resolution instrument such as a time-of-flight (TOF)-based system is needed, however, Potter observes.

Orens adds that TOF systems can be used as the detection method for several techniques to help identify and localize glycans, as well as quantify, resolve isomers, and structurally elucidate the different species.

Potter cautions, though, that while very convenient, measuring the intact mass may only reveal the sum of masses of the two or more glycans on each molecule, which may confound assignment of exact glycan structures. Distinguishing between isomers is also not possible.

The most information can be obtained by first digesting the multispecific with a protease such as IdeS (immunoglobulin G-degrading enzyme of 

) or trypsin into smaller peptides, according to Potter. “Digestion allows for site-specific glycosylation analysis by LC/MS, which may be particularly useful when distinguishing between glycosylation in the fragment antigen-binding (Fab) and fragment crystallizable (Fc) regions, the latter of which greatly impacts the Fc effector functions of the antibody,” Potter contends.

Orens further notes that when peptide mapping is performed using a MS system with specialized fragmentation capabilities such as electron activated dissociation (EAD), it is possible to identify unknown modifications or impurities, then localize the species to a specific domain or amino acid of the protein. “EAD,” she says, “is integral to this process, as it differentiates between isomers and maps specific amino acids, and thus provides a comprehensive understanding of the protein with its modifications.”

Ultimately, Orens emphasizes, the appropriate analytical approach is entirely dependent on the purpose of the analysis.

Given the importance of accurate glycan analysis for multispecifics, the best strategy for ensuring success according to both Orens and Potter is to use a combination of available methods.

“While using top down, sub-unit, or peptide mapping methods and state-of-the-art MS systems enables comprehensive glycan analysis of multispecifics since it provides the most information in a single step, including molecular weight, domain/site localization, species identity, and species quantity, most organizations employ multiple analytical approaches to support their characterization efforts and obtain secondary, confirmatory evidence,” says Orens.

“The best way to ensure accurate and comprehensive characterization,” agrees Potter, “is to use more than one orthogonal method. Released glycan analysis, intact mass LC/MS, and LC/MS after protease digestion needn’t be mutually exclusive—they can be complementary,” he concludes.

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

®
October 2024
Vol. 37, No. 9
Pages: 29-31

When referring to this article, please cite it as Challener, C.A. Glycosylation Analysis for Multispecifics. 

Analytics

The best strategy is to use a combination of complementary methods.

Glycosylation Analysis for Multispecifics

Materials used in the formulation and manufacture of drug products must meet certain qualifications, as do the companies that manufacture these materials. Contract development and manufacturing organizations (CDMOs), contract testing laboratories (CTLs), and contract manufacturing organizations (CMOs) can assist sponsor companies with the testing of these crucial drug components. Testing may include analytical testing, impurities testing, and qualification services.

According to Iain McGhee, vice-president of Quality at Ascend Advanced Therapies, contract organizations can provide proprietary and sourced analytics and assays as standalone services or included in a complete program. “Regardless of who you work with, CMO/CDMOs should be able to provide suggestions on a range of testing depending on the customer program,” says McGhee. “If they do not offer this in house, they should have validated partners to do this with.”

Contractors can either do the testing or work with other, outside testing facilities to perform testing on raw materials to ensure compliance with specifications and standards. At Andelyn, according to Rajiv Vaidya, head of MS&T, the company uses a two-phased approach to raw material testing. The process is performed in-house as much as possible to keep everything streamlined. “We have a program in place to continuously evaluate and in-source as much material testing as possible,” says Vaidya. “There is a sweet spot to understanding the balance between what should and should not be done in house—it depends not only on speed and cost but what is the best or most excellent provider for any given test, whether outsourced or in-house. We will only in-source a testing method after we’ve confirmed definitively that the methodology and result will be at least equivalent to the CTLs.”

Determining how to test bio/pharmaceutical materials depends on the API, the dosage form, and the stage of the material, according to Mayank Nagar, vice-president and head–Tech Services and New Product Launches, North Americas at Dr. Reddy’s Laboratories, and Himanshu Joshi, director, New Product Launches, North Americas at Dr. Reddy’s Laboratories. Testing may be performed from pre-formulation through packaging and life-cycle management, say Nagar and Joshi.

Contract organizations can provide custom material testing services for a sponsor company’s needs, including identity tests, purity tests, assays, polymorph testing, and compatibility testing, say Nagar and Joshi. “Various physicochemical testing [such as] dissolution, particle size, description, density, LOD are routinely being serviced by CMOs. Additionally, safety, sterility testing, microbiology, and confirmatory testing are other services provided to sponsor companies,” they say.

CDMOs can also provide final product release testing, according to Kim Arsenault, Quality Compliance manager, BIOVECTRA, such as the following:

using high-performance liquid chromatography (HPLC) to provide assay and impurity content utilizing ultraviolet (UV), charged aerosol (CAD), or mass spectrometry (MS) detectors

testing for residual solvents by using gas chromatography (GC)

performing Karl Fischer (KF) titration to test water content

detecting elemental impurities by using inductively coupled plasma with mass spectrometry (ICP–MS) or optical emission spectroscopy (ICP–OES)

microbial limits and bacterial endotoxins testing

performing identity testing using chemical techniques or infrared (IR) spectroscopy

performing enzyme-linked immunosorbent assay and sodium dodecyl sulfate-polyacrylamide gel electrophoresis biochemical methods

testing for compendial compliance of pH, optical rotation, and loss on drying

performing gravimetry, titrimetry, and colorimetry bench techniques.

Production stage and the grade of materials used matters, according to McGhee. “Ironically, a lower grade of material with impurities can sometimes makes results look better. However, these results will not scale as the grade tightens—we need to know this early on,” he cautions.

Utilizing CMOs and CDMOs to perform the necessary analytical and quality testing of raw materials used in the production of bio/pharmaceutical products can ensure that these medicines are safe and effective for patients. Contract organizations typically have the knowledge, expertise, and equipment to perform the necessary testing.

“Generally, CMOs/CDMOs should be able to perform the tests outlined for characterizing APIs as listed in ICH [International Council for Harmonisation] Q6A, including characterization of physicochemical properties (e.g., pH, melting point/range, IR), particle size determination, polymorphic form, assay and impurity testing (including tests for chirality, identification tests, residual water content, residual solvents, inorganic impurities), and microbial limits (if applicable),” says Joshua Hoerner, general manager and executive vice president, Purisys (part of the Noramco Group). “It is also important to have hyphenated or specialized techniques [such as] LC–MS, GC–MS, LC–CAD/LC–ELSD, and NMR [nuclear magnetic resonance] for investigative or characterization purposes, should a sponsor’s product experience unexpected results during release or stability testing,” he concludes


Vol. 37, No. 9
October 2024
Pages: 32–33

When referring to this article, please cite it as Haigney, S. Contractors Support Material Testing. 

Outsourcing

Contract organizations offer assistance for testing raw materials obtained from outside suppliers.

Contractors Support Material Testing

It’s an election year in the United States, and it’s not just the cost of groceries that Americans are concerned with. The cost of medications has been a long-standing debate in the US government. How the Republican and Democrat presidential candidates might appeal to voters on this topic is starting to be seen. But will pharmaceutical companies take a hit?

In the past, according to Allison Gatlin of 

, the previous administration under Donald Trump proposed an approach whereby the Medicare prices for drugs given in doctor’s offices are linked to an international pricing index. There was also a plan to pass rebates to Medicare enrollees that would go to insurers and pharmacy benefit managers (1). If Trump is elected for a second term, it is possible that he could seek to implement the use of international price referencing for prescription drug costs, which had failed to get approval during his first term in office (2).

The current Administration, which includes Democrat presidential nominee, Vice President Kamala Harris, is jumping into the ring by announcing lower prices for the first 10 drugs selected for Medicare price negotiation (3). Medicare can negotiate prescription drug prices as part of the power given to it by the Inflation Reduction Act, which was signed into law by President Biden in August 2022.

Harris has also backed a draft guidance to allow federal agencies to exercise “march-in rights” (4). This guidance, if approved, would mean that federal contractors could retain the rights to patents for innovations developed with federal financial backing. Essentially, this is aimed at enabling greater competition within a specified market, such as healthcare.

However, this is not the first time that market competition has been assessed in the US. In fact, this year sees the 40th anniversary of the Drug Price Competition and Patent Term Restoration Act of 1984, which was created to increase market competition between generic-drug companies and pharmaceutical companies. This Act, according to Darby Kozak, PhD, deputy director for the Center for Drug Evaluation and Research, Office of Generic Drugs, in FDA, resulted in a growth in the generic-drug market, with generic drugs increasing from 19% of the market in 1984 to 90% in 2024 (5).

Whichever way the pendulum swings in November 2024, the bio/pharma industry should probably brace itself for an impact.

How the Republican and Democrat presidential candidates might appeal to voters on this topic is starting to be seen. 

BioPharm International, October 2024

Understanding Molecule Sensitivity in Aseptic Fill/Finish

Strategic Changes to a Legacy Cleaning Approach Result in a More Sustainable Process

Prioritizing Formulation Strategies for Temperature-Sensitive Biotherapeutics

The Optimal Metric of Space-Time Yield

Glycosylation Analysis for Multispecifics

Contractors Support Material Testing

Drug Prices on Debate

Key Takeaways from the Peer Exchange Discussion “Aligning mRNA Progress with Regulatory Streamlining”

Using Compendial-Grade Materials for 503B Compounding Facilities