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.”

Meanwhile, 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.

Pharmaceutical Technology’s Trends in Formulation

Feliza Mirasol is the science editor for 

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

Articles

Formulation

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

Prioritizing Formulation Strategies for Temperature-Sensitive Biotherapeutics

The lungs are one of the most complicated organs in the body. Therefore, there are several considerations that come into play when formulating a new inhaled drug. “I don’t think I would be exaggerating if I [said] that [the] lungs are probably one of the most complex organs in the body,” said Vivek Gupta, PhD, associate professor, Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John’s University, in 

1). “We are talking about multiple branching going from trachea to brochi, and … millions of air sacs, where most of the blood gas exchange happens, [and] where the lungs will give oxygen into the blood for circulation all over the body.”

Because the trachea branches off, the delivery pathway decreases. Therefore, according to Evonne Brennan, consultant at Evonne Brennan Consulting, “To reach its region of impact, a precise micronized dose of drug substance will need to be delivered in an aerosolized state, through the aid of a device and a formulation designed for delivery from that device, through simple actuation or a synchronized undertaking by the patient, the aerosolized particles travel with the patient’s airflow through a series of pathways where it is deposited.”

Obstacles caused by disease could restrict delivery further and cause increased mucus, remarks Brennan. “Deposition of the drug substance is required to deliver its pharmacological response,” Brennan stresses. Other complications for delivery of drug substance via inhalation can be caused by age, post-reflux cough, and patient compliance.

“For a given indication and drug substance, there are many physiological factors that need to be considered during product development for inhalation, such as patient pulmonary function, clearance mechanisms, etc., and these are addressed in an integrated way at the formulation and device development levels,” says Eunice Costa, R&D director–Inhalation and Advanced Drug Delivery, Hovione.

Attributes such as formulation particle size and density and inhaler dispersion performance need to be controlled to ensure successful deposit of the product into the lungs, according to Costa. “Once deposited, bioavailability of the drug becomes a function of additional factors such as intrinsic chemical properties as well as solid state and formulation composition, being that dissolution and/or permeation needs to occur at a faster rate than the clearance mechanisms in place in the local diseased microenvironment,” Costa says.

When referring to this article, please cite it as Haigney, S. Formulating Inhaled Medicines. 

Pharmaceutical Technology Trends in Formulation 

Excipient and delivery device selection play crucial roles in the formulation of inhaled drugs.

Formulating Inhaled Medicines

There are a variety of factors pushing innovation in formulation of drug products forward. The desire to create new delivery methods for biologics, the need to increase patient adherence, and technologies such as artificial intelligence (AI) are some of the trends drug developers in the industry are cultivating.

According to Sibaji Biswas, executive director and chief financial officer at Syngene International, patient-centric approaches have led to formulation strategies being reshaped, especially for biologics, with compounds for low solubility and oral bioavailability in small-molecule drugs continuing to see growth. “This has increased demand for solubility and bioavailability enhancement technologies, with CDMOs [contract development and manufacturing organizations] now needing more comprehensive capabilities so they can take a ‘fit-for-purpose’ approach to any challenge,” says Biswas. “Solid dispersion technology and other solubility enhancement methods are gaining prominence, while AI and machine learning [ML] are helping transform pharmaceutical formulation by predicting properties and behaviors.”

The use of ML and AI has been increasing in the bio/pharmaceutical industry. For formulation, they are being used to enhance modeling and predictive approaches, according to Shahrzad Missaghi, senior manager of Product Development, at Colorcon.

ML and AI allow for rapid innovation, according to Asma Patel, VP, Integrated Development Services, Quotient Sciences, as long as members of the industry are open to using these technologies. “From a discovery perspective, this can continue to fuel complexity in small new chemical and new molecular entities (NCEs/NMEs). Regardless of AI/ML, NCEs/NMEs continue to see an increase in average molecular weights and generation of new classes such as PROTACs [Proteolysis targeting chimeras], both creating solubility challenges for pharmaceutical formulation,” says Patel.

Vincent Levet, PhD, director, Formulation Development and Production, Ardena, agrees. “[AI] is showing great potential to revolutionize formulation development, from supporting excipient selection to predicting outcomes and optimizing processes.”

Additional formulation trends include delivery through lipid nanoparticles, ultra-high protein concentration formulations, continuous manufacturing, automation, and the creation of orphan drugs.

Automation has had a significant impact on the development of medicines delivered in capsule and tablet forms, according to Vinay Patil, Product Development Manager at Sharp Services. “Modern machines offer high-speed, precision filling and can handle various fill materials such as powders, granules, pellets, and even liquids,” says Patil. “Even more currently, micro-dosing technology allows us to accurately dose small quantities of API, which is critical when working with potent drugs. These advancements have increased the speed and precision of drug production and expanded the range of materials that can be used.” Patil also points to advances in granulation, compression, and coating that have impacted formulation.

“The introduction of high-shear granulators, fluid-bed processors, and roller compaction has enhanced the production of tablets with better mechanical properties and dissolution profiles. Coating technologies have also advanced, with enteric coatings and controlled-release formulations becoming more common,” says Patil. “Recently, continuous manufacturing processes have improved tablet production efficiency, allowing for real-time monitoring and increased production speed. One very recent advancement is the use of 3D printing technology, which has allowed for the production of tablets with controlled release profiles personalized to individual patients.”

®
eBook: Trends in Formulation 2024
September 2024
Pages: 34–37

When referring to this article, please cite it as Haigney, S. Forging Ahead in Formulation. 

Pharmaceutical Technology®/Pharmaceutical Technology EuropeTM

New and existing technologies, as well as a patient-centric focus, are pushing drug formulation into exciting directions.

Forging Ahead in Formulation

Oral drug delivery has been and remains to be a fundamental approach in pharmaceutical as well as nutraceutical administration. It continues to evolve to ensure the successful integration of cutting-edge innovations and to meet the challenges posed by emerging technologies.

Renowned for its user-friendliness, manufacturing convenience, and therapeutic advantages, oral delivery represents the gold standard for administering therapeutic agents. It enables the efficient delivery of a diverse array of therapeutics, spanning from small molecular drugs to proteins, peptides, nucleic acids, and even bio-actives.

A pivotal advancement in this field, multi-particulate systems are emerging as a well-established methodology across various industries. This system has not only amplified scope to modify the physicochemical properties but also redefined the paradigm of release modulation for active compounds. Serving as a versatile platform for formulating both pharmaceuticals and nutraceutical supplements, the multi-particulate system boasts a plethora of advantages over traditional dosage forms. This includes particle fractionation to divide active constituents into minute particles, yielding benefits such as precise dosing, heightened bioavailability, and enhanced stability. The approach offers exceptional flexibility in modulating release kinetics, enabling tailored delivery profiles to improve therapeutic efficacy and patient adherence.

Among multi-particulate formulations, pellets stand as the foremost dosage form in the market due to their versatility across various therapeutic ranges. Their adaptability across capsules, tablets, and sachet forms offers distinct advantages that cater to diverse patient preferences and therapeutic requirements in both the pharmaceutical and nutraceutical sectors.

The technique used for pellet formation is known as pelletization. It involves the conversion of active ingredients into small, spherical units typically ranging from 0.4 to 2 millimetres in size (or larger). (

) This method confers multi-fold advantages in terms of therapeutic efficacy and manufacturability. With respect to efficacy, pelletization offers advantages such as: increased palatability, diminished risk of dose dumping, improved distribution within the gastrointestinal (GI) tract, reduced irritation to the GI mucosa, expedited onset of action, and modulated release kinetics (controlled, slow, sustained release). Whereas, and from a manufacturability perspective, pelletization offers the advantages of increased flow properties, encapsulation capability, and reduced dusting.

Pelletization utilizes several manufacturing techniques such as extrusion-spheronization, fluid bed coating-powder layering/solution layering, and hot-melt extrusion, offering precise control over particle size, shape, and composition. These methodologies are instrumental in the creation of uniform pellets with tailored release profiles, allowing for optimized drug delivery kinetics and enhanced therapeutic outcomes. But first, it is important to understand the basics of how pellets are formed.

When it comes to the primary aspects of pelletization mechanisms, these include: nucleation—the initial formation of particles within a solid or liquid state; coalescence—where small nuclei collide to form larger particles; layering—where solid particles or liquid layers form over existing nuclei; abrasion—resulting in material transfer between particles and size reduction—where well-formed particles may undergo attrition-induced size reduction (

These mechanisms involve different approaches for pellet development, including compaction and, layering.

 Compaction in pellet formation, involves the application of pressure to compress materials into denser particles. This process can be executed through various types of equipment including extruders, tablet presses, roller compactors, or pellet mills. Compaction entails subjecting a mass comprising active ingredients and excipients to mechanical force, leading to the creation of denser particles/flakes.
However, to produce spherical pellets with consistent size and shape, the widely utilized technology is the combination of an extruder and a spheronizer. This method entails extruding the wet-mass or hot-melt noodles, which are then processed through the spheronizer to form spherical pellets, followed by drying. This process is crucial for achieving precise control over pellet characteristics, including size, shape, and density. By adjusting parameters such as pressure, dwell time, and speed of the compaction equipment, manufacturers can customize the properties of the resulting pellets to meet specific and desired formulation requirements.

 Layering, a fundamental technique in pellet formation, involves depositing successive layers of material onto seed particles or nuclei to construct the pellet structure. It can be executed by diverse methods, including spray coating, powder layering, or solution layering. During layering, a coating solution containing soluble active constituents or suspension (particularly for low-loading actives) is carefully applied onto the surface of the seed particles, enabling the gradual build-up of material and resulting in the formation of multi-layered pellets.
Powder layering involves the sequential or simultaneous deposition of powdered materials onto the seed particles through various mechanisms, such as fluidized bed technology or pan coater. This is particularly recommended for actives with low solubility and high loading. After this step, a polymeric solution coating can be applied to modify release characteristics. This method allows for precise control of over-active content and release kinetics, ultimately improving the quality and efficacy of the final pellets.

Two types of pellets are commonly encountered: functional and non-functional.

 are designed to serve a specific purpose or function within a formulation, such as providing modified release properties, enhancing stability, or improving the overall performance of the product. These pellets are carefully formulated to meet certain criteria and requirements to achieve the desired effect in the final dosage form. For example—multivitamin pellets, diclofenac pellets, proton pump inhibitors(PPI) pellets, cQ10 pellets—with or without modified release.

The manufacturing process for functional pellets varies depending on the formulation needs, whether high- or low-drug loading is required, accompanied with the release control. High-loading formulations often utilize the extrusion-spheronization technique. Here, the inner core matrix comprises the active ingredient itself, followed by coating with a functional polymer to modify the release pattern. This approach allows for efficient encapsulation of a large amount of drug substance within the pellet. Alternatively low-loading doses are typically prepared by coating a solution onto non-functional pellets, which can be achieved through layering mechanisms.

 are necessary components in both pharmaceutical and nutraceutical formulations, serving as inert carriers or a core material essential for the manufacturing process and structural integrity of pellet dosage forms. These non-functional pellets are also known as the base pellets or non-peril seed (NPS). They provide a starting point for pelletization, ensuring consistent pellet size, shape, and weight, which is crucial for achieving accurate dosing and content uniformity. Acting as carriers for active components, they create a stable matrix for the equal distribution of ingredients throughout the pellet.These pellets also serve as substrates for functional coatings applied to the pellet surface, enhancing stability, modifying release profiles, or improving appearance and taste. This ensures uniform coverage and adhesion of the coating, which further enhances the quality of the final product.

Various types of non-functional pellets are available, for example, sugar spheres, starch spheres, tartaric acid spheres, mannitol spheres, and microcrystalline cellulose (MCC) spheres. Each type offers unique properties suitable for specific formulation requirements, including flowability, compressibility, and compatibility with active ingredients.

Key considerations in the development of pellet formulations, requires the special attention to critical parameters that directly or indirectly impact formulation quality. These considerations include: coating uniformity, adhesion and performance of coating material, moisture content optimization, particle size of excipient used, and core material selection, etc. Some of these considerations are discussed below.

Uniform coating is crucial in pellet development, especially for maintaining the integrity of the coating process and achieving the desired drug release pattern, which—in turn—guarantees pellet quality. To ensure these critical factors are met there must be consistent application of the coating material to each pellet. This includes drug coating, seal coating, functional coating, or color coating. Inadequate coating integrity may result in the failure to protect the sensitive core material, as the coating also serves as a protective barrier, shielding the active ingredient from degradation. It also causes premature dose dumping; and variability in release rates, which can compromise therapeutic outcomes.

There are numerous factors that can affect coating integrity, including solution variables, excipient-coating agent used, equipment selection, process parameters, machine variables, and environmental conditions. Solution variables such as viscosity, percent solid content, and glass transition temperature of polymer should be considered during the formulation process as they play important roles in the coating process. Furthermore, variations in machine parameters such as spray rate, atomization pressure, dew point, and drying conditions may affect pellet quality. Additionally, environmental factors such as relative humidity and temperature can also impact coating integrity. Therefore, precise control over these variables is essential to maintain consistent coating thickness and to enhance the overall quality of pellet formulation.

The adhesion of coating materials pertains to their ability to firmly adhere to the surface of pellets without experiencing peeling or flaking. This characteristic is pivotal for ensuring the efficacy, quality, and overall appearance of the product.During formulation specifically in coating and drying processes, the behavior of the polymer structure is crucial, influencing adhesion, uniformity, and durability of coating. Polymer sticking at the surface is very much dependent upon the surface property of the core material. Irregularities on the surface may cause issues, such as sticking.

The adhesion of coating material may be influenced by mechanical stress or handling during the coating process, such as tumbling in the coating pan or transfer between equipment. The same appropriate selection of the polymer is crucial. For instance, hydroxypropyl methylcellulose provides a flexible coating that withstands stress and deformation, maintaining pellet integrity during handling and storage, while rigid coatings like ethyl cellulose may result in brittleness and cracking, compromising overall formulation quality. So, the formulator should choose the polymer wisely while formulating.

Sometimes the single polymer does not provide sufficient adhesion, necessitating the use of dual-polymer chemistry. At this point the use of the mixture of two polymers yields better results. Additionally, to increase the flexibility to the polymer coating, it is advisable to add plasticizer to strengthen the film property. The optimization of the material concentration and preparation method is therefore vital.

The physiochemical properties of the material chosen for the pellet preparation plays a key role—impacting the overall performance of the product. It can affect the surface properties as well as the quality. The surface properties of pellets are a critical factor in pelletization, as coating integrity, the physical appearance, and patient acceptability rely on these. This is attributed to various factors including particle size, particle size distributions, particle shapes, density, and surface area of the same.

The properties of starting materials, including actives, polymers, and binders, have a significant influence on the surface roughness of pellets. It is evident that smaller particles result in smoother pellet surfaces due to better packing. For instance, MCC may yield smoother pellets compared to other excipients such as cross-povidone or lactose because of its ability to disaggregate into smaller particles during wetting.

The hydrophilicity and hydrophobicity of the active ingredients play significant roles in pellet formulation. A powder containing hydrophobic drugs can pose challenges during extrusion and spheronization due to limited wettability. Whereas the pellet containing the hydrophobic drug can pose a challenge due to its higher wettability. Hence, the selection of the solvents and the technique also depends upon the solubility and quantity of active material.

There exist few moisture-sensitive actives that can pose challenges during pelletization. To address these challenges, materials like glyceryl monostearate (GMS) can be utilized. GMS effectively reduces water content in the formulation, resulting in smoother surfaces and reduced porosity in the pellets. By minimizing moisture content, GMS facilitates better pellet formation—enhancing overall product appearance.

The moisture content of the wet mass significantly influences the size, shape, and strength of pellets produced during extrusion. Pellet size increases with higher moisture content. Excessive moisture in the wet mass tends to increase cohesiveness among the powder particles, leading to the formation of agglomerates. Conversely, low moisture content can result in the generation of fines (powder particles) during pelletization due to reduced plasticity of the liquid phase, which prevents proper adhesion of powder particles to the core bead. It is important to optimize the drying process to stabilize the prepared pellets.

Quality attributes of core particle or base pellet

The quality attributes of the core material or base pellets are considered, especially in coating by layering, designed for high-potency and modified-release pellets. Critical properties to consider when selecting base pellets include shape (sphericity), size, and density. The shape of base pellets influences how they attach to the coating material, affecting the efficiency of coating and the final product's physical properties. Spherical particles tend to pack more efficiently, resulting in better flow properties and uniform film distribution. However, irregularly shaped particles may lead to uneven coating due to their poor flow characteristics, which will have an impact on the overall quality.

Variations in particle size can lead to differences in the surface area available for coating and may affect the quantity of coating material applied. The surface area of core particles influences the rate of coating adhesion and the dissolution characteristics of the final product. A higher surface area enables greater coating adhesion, leading to better coating uniformity and release. Therefore, meticulous attention to these attributes is critical to ensure the quality and efficacy of the delivery system.

Overall, pelletization represents a revolutionary technique, offering a multitude of advantages in formulation with unmatched flexibility and adaptability. This technique facilitates the pellets formation, each filled with a tailored combination of active ingredients, excipients, and coatings, thereby allowing for customizable dosages and release profiles with improved efficacy and stability. Such flexibility not only caters to diverse patient needs but also enables the development of complex drug formulations that were previously unattainable.However, the seamless integration of this technique into practice relies heavily on a comprehensive knowledge of material properties, adapted technology, and process parameters. These factors are paramount in guaranteeing the efficacy of final products and maintaining adherence to stringent quality standards. By prioritizing these critical considerations during formulation, one can formulate superior quality pellets, which enhance the therapeutic impact and reliability of the end product.

Surya Singh, PhD, is senior manager of product development at Vantage Nutrition LLP (India). 

Jnanadeva Bhat, PhD, is head of formulation R&D, pharma and nutra, at Vantage Nutrition LLP and ACG Capsules (India). 

Manali Dalvi, M Pharm, is the lead whitepaper and publications, pharma and nutra, at Vantage Nutrition LLP and ACG Capsules.

Pelletization, a popular oral drug delivery method in pharmaceuticals and nutraceuticals, offers numerous benefits. This article delves into the critical parameters for formulation development and technological consideration in pelletization, elucidating its significance in advancing pharmaceutical solutions.

Trends in Formulation, September 2024 eBook

Prioritizing Formulation Strategies for Temperature-Sensitive Biotherapeutics

Formulating Inhaled Medicines

Forging Ahead in Formulation

Pelletization: Revolutionizing Drug Formulation and Delivery