Complex biotherapeutics present unique analytical challenges for developers.

Complex Biomolecules Require Analytical Evolution

EMA starts review of Sanofi vaccine; Regeneron's EUA expanded

Emergent BioSolutions Gets FDA OK to Resume Operations

Public-private consortium is tasked with advancing domestic pharmaceutical production.

HHS Strategizes for Domestic Drug Supply

New biotherapeutics both drive and benefit from innovative development technologies.

Innovation Demands and Spurs Invention

The average cost of bringing a new drug to market is estimated at $1.3 billion (1), and the average timescale from initial discovery to market often spans 10 years or more. It is well documented that the investment and time involved in developing new drugs has resulted in big pharma organizations choosing to outsource some or all of their R&D operations to academia, contract research organizations (CROs), or contract development and manufacturing organizations (CDMOs). CROs and CDMOs are facing increasing competition, cost pressure, technological innovation, and consolidation activities (2), meaning that they, in turn, might outsource specific activities, such as stability studies and the associated requirements, to smaller specialists.

Many big pharma organizations instead choose to acquire or buy formulations from small-cap developers once they have been proven. A report in 2020 found that large and mega-cap companies were the most likely group to source new molecular entities (NMEs) through company acquisitions (3). For example, in October 2020, Gilead purchased US biotech Immunomedics and its potential cancer blockbuster Trodelvy (sacituzumab govitecan-hziy), and Sanofi added a potential multiple sclerosis drug to its pipeline when it bought Principia Biopharma in August 2020. These smaller players are likely to be dependent on outsourcing, with key partners already firmly in place when they are acquired.

As of February 1, 2021, there were 365,829 clinical studies registered globally, which is a monumental increase since 2000, when there were just 2119 (4). In that time, the focus has also shifted to rare disease and personalized medicine, with orphan drugs, biotechnology, and gene therapies attracting significant investment. Because of this, packaging requirements are becoming more complex, to accommodate sensitive formulations and APIs, as well as the small-scale nature of personalized medicines. The more sensitive or potent a drug is, the higher the barrier properties are, therefore, the more emphasis placed on the packaging.

With discovery work of these kinds of drugs being done more often by smaller players, the scale, size, and resources of these smaller players dictate their dependence on outsourcing of key activities, such as stability testing, to specialists. These activities often require small batches of packaging to be produced. Developers might invest in small-scale equipment to produce the packaging in-house, or they might outsource production; there are benefits and possible risks to both approaches that need to be weighed.

The shift towards personalized medicine sees therapies targeted to particular groups of patients (stratified) or individuals (personalized), such as the case of patient-specific autologous cell and gene therapies (5). These therapies will require a shift in manufacturing to agile, small-scale individualized production, in which the patient quickly receives individualized drugs, suited to their specific needs. This new reality is to be facilitated by Industry 4.0—which includes connectivity, advanced analytics, automation, and advanced-manufacturing technologies (6)—and is expected to better enable quality by design. In this new paradigm, outsourcing becomes even more important, with fast, efficient, small-batch packaging a key requirement.

Enabling fast, effective stability studies

Each new drug application requires a stability study, as regulation requires expiration dates to be indicated on all pharmaceutical products, and stability is a critical quality attribute.

In a stability study, the effects of variations in temperature, time, humidity, light intensity, and partial vapor pressure on the pharmaceutical product are investigated (7). Accelerated stability studies are common for process validation and material selection pre-commercialization. In accelerated studies, developers imitate a two-year shelf life in the space of around three months, usually at 45 ºC and 75% humidity.

Multiple accelerated stability studies might be required to test different packaging materials pre-production. Some stability studies may require one to 200 packs, while others may require up to 2000, depending on the amount of pull points in the stability study. Developers need flexibility and speed from their packaging department or supplier to accommodate increasingly complex and varied stability studies.

Stability studies are not only critical for regulatory approval, they prove key for the newer types of drugs when material selection can be challenging. When it comes to material selection, it is common that developers will over-specify their blister-pack material. They might know from past experience that aluminum gives close to the best barrier possible, so without always knowing exactly how sensitive their material is, might request it regardless of need.

Contract packaging suppliers can provide advice on material selection and, for example, recommend testing the originally requested high-spec packaging alongside alternatives, such as high barrier thermoform materials, which might be half the price and also faster to form, easier to fill, and smaller. Stability studies will then establish what barrier is actually required, for example, whether thermoform is suitable, or whether cold form is necessary. The small investment in running stability trials with different blister packaging materials could save a significant amount of time and money when the product is scaled up.

Stability studies are required for material selection or shelf-life validation, process validation, and through the lifecycle of the drug. While post-commercialization studies will use the final product and packaging, for the accelerated studies, it is important to have ready access to quick turnaround, small-batch packaging to achieve compliant, effective stability studies.

Whether drugs are developed by CDMOs or by small cap players, careful consideration would need to be made as to whether to outsource the packaging for stability studies. In both cases, a hesitation not to do this might be to protect intellectual property (especially with experimental, high-value drugs); the benefits of outsourcing, however, might outweigh that risk.

In the case of CDMOs, some key benefits of outsourcing packaging for stability studies might include:

Reducing the risk of cross-contamination if developing a potent or experimental drug

No need to change lines over for small batch runs

No delays due to availability of stability chambers.

For smaller developers, the benefits might include:

No need to invest in equipment/facilities

No requirement for auditors, licensing, etc.

Achieve milestones in a shorter timeframe

Provide technical expertise, because many employees in smaller developers have biological, chemical, or medical backgrounds, but may not always have detailed knowledge of packaging operations.

If the decision is made to outsource packaging for stability studies, there are some key questions to ask of a potential supplier. These questions might include:

Cost? Note that there may be additional cost to the packaging, such as design services and tooling manufacture.

Minimum quantity? This question should be asked early in supplier qualification as they may not have the capacity or motivation for small-batch packaging.

Material availability? Some materials have relatively long lead times, so it is worth looking for a supplier with a large selection of material grades in stock.

Material selection expertise? Working with a supplier who can help give guidance through the available material grades can be beneficial.

Design expertise/experience? A good supplier will be able to understand your requirements immediately and may be able to meet them with an existing toolset, reducing the overall cost of your project. Experience in larger production environments can be beneficial to help you design a package that is scalable with common packaging processes.

Cleanroom capabilities? Understanding the options for environmental conditions will help to determine which type of drug the supplier can handle.

Leak testing? Non-destructive leak detection can be beneficial for stability trials, as it ensures all packs are leak-tight prior to stability so package integrity can be immediately ruled out as a risk/concern if outliers are found in the stability data.

In the case of stability studies, experts in packaging can deliver small batches quickly and cost-effectively for accelerated stability studies that are crucial to the future success of a new drug.

PWC, “Current Trends and Strategic Options in the Pharma CDMO Market,” 

GlobalData, Contract Manufacturing of Novel In-Licenced Drugs, 

Statista, “Total number of registered clinical studies worldwide since 2000,” 

M. Agrawal, “Industry 4.0: Reimagining Manufacturing Operations After COVID-19,” 

Res. J. Pharma., Biological and Chem. Sci.

Scott Kenny is Business Development Manager, Sepha Ltd.

 
Vol. 45, No. 8 
August 2021 
Pages: 28–29

When referring to this article, please cite it as S. Kenny, “Packaging for Stability Studies: to Outsource or Not?," 

Pharmaceutical Technology Outsourcing Resources

Articles

Developers might invest in small-scale equipment to produce packaging for stability studies in-house, or they might outsource production. Manufacturers should consider the benefits and risks to both approaches.

Packaging for Stability Studies: to Outsource or Not?

On Aug. 2, 2021, AstraZeneca announced that FDA approved Saphnelo (anifrolumab-fnia), a type I interferon (type I IFN) receptor antagonist, for treating moderate to severe systemic lupus erythematosus (SLE) in adult patients who are receiving standard therapy. The approval was based on efficacy and safety data from Phase III and Phase II trials.

The clinical trials showed that patients treated with Saphnelo experienced a reduction in disease activity across organ systems, including skin and joints. The patients further achieved sustained reduction in oral corticosteroid use compared to placebo.

According to AstraZeneca, the approval of Saphnelo marks the first regulatory approval for a type I IFN receptor antagonist. The approval also marks the first new treatment for SLE in more than 10 years, the company stated in a press release. Saphnelo is also under regulatory review for SLE in the European Union and Japan. AstraZeneca has initiated testing the drug using subcutaneous delivery in a Phase III trial in SLE and plans to start additional Phase III trials in lupus nephritis, cutaneous lupus erythematosus, and myositis.

AstraZeneca acquired the global rights to Saphnelo via an exclusive license and collaboration agreement with Medarex in 2004, but an option for Medarex to co-promote the product expired when it was acquired by Bristol-Myers Squibb (BMS) in 2009. Instead, by agreement, AstraZeneca will pay BMS a royalty for sales dependent on geography.

“Our treatment goals in systemic lupus erythematosus are to reduce disease activity, prevent organ damage from either the illness itself or the medications, especially steroids, and improve one’s quality of life. Today’s approval of anifrolumab represents a big step forward for the entire lupus community. Physicians will now be able to offer an effective new treatment that has produced significant improvements in overall disease activity, while reducing corticosteroid use,” said Richard Furie, chief of the Division of Rheumatology at Northwell Health, New York, US, and a principal investigator in the Saphnelo clinical development program, in the press release.

“Today’s landmark approval of Saphnelo is the culmination of years of AstraZeneca’s pioneering research in the type I interferon pathway, a central driver in systemic lupus erythematosus pathophysiology. This ground-breaking medicine has the potential to meaningfully improve the lives of patients living with this often debilitating disease,” said Mene Pangalos, executive vice-president, BioPharmaceuticals R&D, AstraZeneca, in the press release.

FDA has approved AstraZeneca’s Saphnelo, a type I interferon receptor antibody for treating systemic lupus erythematosus.

FDA Approves AstraZeneca’s Lupus mAb, Saphnelo

Genentech, a member of the Roche Group, announced that FDA has accepted its biologics license application (BLA) with priority review for faricimab, a bispecific antibody for treating wet age-related macular degeneration (AMD) and diabetic macular edema (DME). The company also said that FDA has accepted its submission of the drug for treating diabetic retinopathy, according to a July 28, 2021 press release.

Faricimab targets two pathways—angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). These two pathways drive a number of retinal conditions that can cause vision loss. Ang-2 and VEGF-A contribute to vision loss because they destabilize blood vessels, which causes the vessels to leak and causes inflammation. Faricimab simultaneously blocks both the Ang-2 and VEGF-A pathways, thus stabilizing blood vessels and potentially improving vision.

Genentech’s BLA submission is based on positive results from four Phase III studies in wet AMD and DME, which consistently showed that faricimab offered vision gains comparable to that of aflibercept; faricimab was given at intervals of up to four months and aflibercept was given every two months. The studies also showed that approximately three-quarters of people who were eligible to receive extended doses of faricimab were able to be treated every three months or longer within the first year. Genentech is additionally conducting long-term extension studies for faricimab in wet AMD and DME. Faricimab has been granted marketing authorization in Europe by the European Medicines Agency for treating wet AMD and DME.

“If approved [by FDA], faricimab would be the first in a new class of eye medicines targeting two key pathways that drive retinal disorders, with the potential to offer durable vision outcomes with fewer eye injections than the current standard of care,” said Levi Garraway, chief medical officer and head of Global Product Development, Genentech, in a company press release. “Therefore, we hope faricimab will become a new treatment option for millions of people living with wet AMD and DME.”

FDA has accepted Genetech’s BLA for faricimab, a bispecific antibody in development for treating wet age-related macular degeneration and diabetic macular edema.

FDA Accepts Genentech’s Application for Bispecific Antibody to Treat Eye Diseases 

GlaxoSmithKline and Vir Biotechnology announced on July 28, 2021 that they signed an agreement with the European Commission (EC) to jointly supply up to 220,000 doses of sotrovimab, an investigational single-dose monoclonal antibody (mAb) in development for treating SARS-CoV-2 infection. The joint agreement will allow participating European Union (EU) member states quick purchase access to the mAb, following emergency authorization at the local level or at the EU level. Early access will allow for the treatment of high-risk patients with COVID-19.

The EC’s move follows a positive opinion granted by the European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP). Sotrovimab is included in the EC’s portfolio of promising COVID-19 candidate therapies. Documentation to support a marketing authorization application for the mAb is currently in an ongoing regulatory review with the EMA. GSK and Vir announced results in June 2021 from a Phase III clinical study, which met its primary endpoint and demonstrated a 79% reduction in hospitalizations.

Sotrovimab was granted Emergency Use Authorization in the United States in May 2021 for treating mild-to moderate COVID-19 in high-risk patients. GSK and Vir plan to submit a biologics license application to FDA in the second half of 2021. Other countries in which sotrovimab has been authorized for emergency use include Bahrain, Kuwait, Qatar, Singapore, and United Arab Emirates.

“This agreement with the [EC] represents a crucial step forward for treating cases of COVID-19 in participating EU Member States, as it enables access to sotrovimab for high-risk patients who have contracted the virus. As the COVID-19 landscape continues to evolve and we meet new challenges—such as the Delta variant spreading across the globe—there remains an urgent need for treatment options to help those who do get sick to potentially avoid hospitalization or death,” said George Katzourakis, senior vice-president, Europe, GSK, in a company press release.

“It remains abundantly clear that additional treatment options are needed to fully address the toll of this pandemic. This agreement recognizes that monoclonal antibody treatments for those who become infected are essential, and we are pleased that European healthcare providers and their patients now have access to sotrovimab. Notably, the fact that sotrovimab was designed from the beginning to maintain activity against the evolution of this virus and has demonstrated, 

, its ability to maintain activity against the tested circulating variants of concern and interest, including Delta and Lambda, underscore its critical role in the fight against COVID-19,” said George Scangos, CEO of Vir, in the press release.

The European Commission has entered into a supply agreement with GlaxoSmithKline and Vir Biotechnology for up to 220,000 doses of sotrovimab, an investigational mAb for treating COVID-19.

EC Makes Supply Agreement with GSK and Vir Biotechnology for mAb COVID-19 Treatment

On August 2, 2021, DisperSol Technologies and Catalent announced a strategic manufacturing collaboration aimed at accelerating the production of various DisperSol pharmaceutical products.

DisperSol’s KinetiSol technology manufacturing line will be installed at Catalent's oral solids development and manufacturing facility in Somerset, NJ. This technology is designed to turn molecules with great clinical promise but poor bioavailability into viable medicine.

Per the agreement, DisperSol will provide the KinetiSol technology while Catalent will provide staff for the development, scale-up, and commercial stages of KinetiSol product creation.

“This strategic collaboration with Catalent is integral to our company as we now move into late clinical-stage development and commercial-scale manufacturing of our products,” said DisperSol CEO Edward M. Rudnic in a press release. “The commercial amorphous solid dispersion manufacturing expertise of Catalent’s team and their globally accredited quality systems make them a perfect partner for DisperSol.”

DisperSol and Catalent announce manufacturing collaboration to accelerate DisperSol’s pharmaceutical production. 

DisperSol and Catalent Announce Manufacturing Collaboration

On August 2, 2021, the FDA’s Division of Pediatrics and Maternal Health (DPMH) launched the “Send Your Pediatric Research Questions to the FDA” campaign. The goal of this challenge is to crowdsource new ideas for internal pediatric research.

FDA’s pooled analyses have investigated relationships between biomarkers and different clinical endpoints in regulatory submissions, explored the use of novel trial designs in small populations, and deepened understanding of how adult efficacy data can be extrapolated. The DPMH hopes to accelerate findings of this nature through the crowdsource campaign.

Following the end of the challenge, all submissions will be reviewed and the DPMH may select one or more questions for future use in internal research projects. However, those who submit these questions will not be granted access or be allowed to collaborate in these research studies.

Submissions must be received by August 20, 2021. For more information about submission guidelines, visit DPMH’s site at https://shareyourvoice.ideascalegov.com.

FDA is launching a new crowdsourcing challenge to solicit ideas for pediatric research.

FDA Launches New Crowdsourcing Challenge for Pediatric Research Questions 

Editor of Pharmaceutical Technology Europe

Research investment in the global biopharmaceutical market helps to drive innovation and development of novel therapeutic products to treat many diseases and illnesses. According to recent figures highlighted by the International Federation of Pharmaceutical Manufacturers and Associations, there are currently more than 8000 compounds in development around the world (1).

“A recent market report has shown that there was an influx of new products in the pipeline at all stages of clinical development during the 2020/2021 period (2), especially of early-stage clinical products,” notes William Chin, manager, global scientific affairs, Catalent, citing recent research studies. “Moreover, cancer, infectious diseases, and diseases of the central nervous system came up as the top areas of clinical trial activity last year. The number of people suffering from these chronic conditions is expected to rise as population growth is anticipated in many developing countries (3). The development of complex dosage forms is also expected to grow in parallel to increased diversity in the drug pipeline.”

Over the past five to 10 years, the low water solubility of new molecular entities (NMEs) has been a major drug product development challenge, emphasizes Julien Lamps, product manager, Lonza Capsules and Health Ingredients. “Knowing the solubility performance attributes for the compound is important as it will aid selecting the right dosage technology,” he says.

“There have been numerous developments and innovations in drug delivery over the last few years to overcome challenges with products and formulations, such as biologics and complex entities like larger molecules,” adds Jnanadeva Bhat, head—formulation R&D (Pharma and Nutra), ACG Group. “Other trends that have evolved are prefilled syringes, wearable injectors, and needleless syringes, each of which have a niche market.”

Considering the route of delivery, Chin states that injectable dosage forms are dominant in the development pipeline. “The intravenous route [is] seen to offer more advantages in early-stage studies as a means to quickly deliver the desired concentration of drug to the target via systemic circulation, and to achieve the required pharmacological response,” he confirms. “However, simply having injectables may no longer be sufficient anymore because of the growing demand for more patient-friendly formats, such as oral solid dosage (OSD) forms.”

Bhat concurs that even though the sector for specialty products has witnessed growth, OSD forms have remained steady throughout the past decade. “There is demand for continuous innovation to improve efficacy, efficiency, and competence in [oral solid] dosage forms,” he says. “Developing novel and more efficient oral delivery routes also helps brands reach a larger audience. Thus, development scientists prioritize OSD forms because not only are they key to patient compliance, but they also have broad application.”

The growing demand for OSD forms has driven innovators to focus on patient-centricity early on in development, Chin continues. “This [trend] is especially true in the past year, where there has been an expectation to increase both the convenience of use and the therapeutic efficacy of the drug product, as well as ease of deployment without the need for cold-chain considerations, especially given the current focus on oral COVID-19 vaccine development,” he states.

“In biologics and small molecules, the trend shifted towards patient centricity,” adds Tatiana Nanda, director and program leader, The Center for Breakthrough Medicines. “Historically, the sole focus for drug product development was effective treatment of the disease while now additional emphasis is put on patients experience and quality of life during treatment.”

“As innovators are focusing more on solutions that allow them to develop patient-centric drug products, the priorities of drug development are expected to not only demonstrate clinical efficacy and safety in patients, but also to address key challenges such as improving usability, bioavailability, stability, and palatability, while eliminating any variability due to food effects,” confirms Chin. As a result of this shift in priorities, advanced dosage forms, such as modified-release products, multiparticulates, ODTs, or new fixed-dose combinations, are increasingly in demand, he adds.

Dosage form priorities have certainly been adjusted, Lamps specifies, with the deployment of common strategies and platforms that help to enhance drug oral bioavailability, such as cosolvents, salts, surfactants, particle size reductions, polymorphs, lipid-based systems, amorphous solid dispersions, and so on. “Additionally, it is becoming a best practice to evaluate the end dosage form earlier in the development cycle,” he adds.

“Drug product design is more focused on meeting patient-centric target profiles and has become the goal for drug companies,” agrees Nanda. “Previously drug product profiles were a derivative of what upstream/downstream capabilities allowed. Now the selected profile and dosage form drive the required API process, needed concentration, and purity.”

The priorities of pharmaceutical companies have shifted as a result of the drive toward patient centricity, Bhat concurs, with manufacturers seeking the most patient-friendly form that supports maximum therapeutic efficacy and safety of the formulation. “Regulatory bodies also encourage patient-centric dosage forms, which fuels this new focus,” he says.

Additionally, the change of priorities for development have led to the integration of patient-centric design early on in the development cycle, Bhat continues. “The physicochemical properties of an API usually point the formulator to the most suitable route of administration, as well as dosage form. The solubility of APIs specifies approaches for dose selection, excipient selection, and stability of the final product,” he says. “Bigger challenges are observed for larger molecule oral absorption, which need to be addressed adequately by formulation scientist.”

Discussions between innovators and contract development and manufacturing organizations (CDMOs) on dosage form design are taking place relatively early on now, Chin states. Furthermore, manufacturability of the dosage form is being addressed earlier on by innovators, which is an aspect that has received less attention historically speaking, he notes. “Innovators have recognized that a druggable molecule alone does not automatically imply successful commercialization of a pharmaceutical drug product, but that there is also a need at an early stage to establish all other key considerations that will meet the target product profile covering patient and manufacturing requirements,” Chin says.

Taking patient opinions and assessments of dosage forms into consideration during design and development can also help to create user-friendly products, Bhat highlights. As patient-centricity is becoming more prominent, so too are tailored dosage forms, which directs the industry away from a one-size-fits-all approach in terms of dosage forms, he explains. “With this trend, dosage forms will perform more effectively for individuals, and this is shifting pharma R&D towards new pathways,” Bhat says.

For Bhat, some of the most important innovations in drug dosage forms have been seen in the area of inhalation. “Local inhalation administration delivers sufficient levels of drug to the target organ, the lungs, while minimizing systemic exposure and side effects (primarily due to the reduced drug dose needed as compared to oral administration),” he says.

“Additionally, there is mounting interest in inhalation segment, where conventional molecules are converted into inhalation formulations,” Bhat continues. “In this area, dry powder inhalation formulations via hard capsules is a trend formulators and manufacturers are showing great interest in. Capsules are not only robust and easy to use, but also help with effective delivery through the inhalation devices.”

Capsule-based dry powder inhalation (cDPI) formulations offer an affordable option that incorporate characteristics—such as reduced dosing frequency and side effects—and easy administration, which are preferable for patients, Bhat asserts. “The most impressive developments taking place in this field go beyond conventional respiratory therapeutic segments,” he says. “Many leaders are exploring cDPI for other therapeutic segments like Parkinson’s disease, migraine, tuberculosis, cystic fibrosis, and lung infection.”

Techniques, such as particle size reduction, spray-dried dispersions, and lipid-based formulation platforms, have helped overcome solubility-related issues, Lamps states. Additionally, as the techniques are complementary, they are applicable to a broad compound space, he says.

For large molecules, being able to reach high protein concentration and co-formulating with dispersion enhancers, such as hyaluronidase, has been a significant advancement, reveals Nanda. “[This innovation] allowed delivery of a high volume—up to 20 mL—of drug product as a single injection into subcutaneous space,” she stresses.

However, it is also important to consider innovation from the perspective of manufacturing, rather than just on new technologies that are centered on the discovery and development path, Chin emphasizes. “For example, one of our core expertises is in manufacturing softgel dosage forms for both immediate- and modified-release applications. The typical development option for a modified-release softgel is through the formulation of the fill content followed by the coating of the capsules,” he says. By using a proprietary modified-release softgel capsule, which combines pectin and gelatin, a separate capsule coating step can be avoided, Chin adds.

“The capsule technology allows innovators to design the delayed-release profile to be incorporated directly into the softgel capsule shell, thereby making a separate capsule coating step unnecessary,” Chin continues. “This [innovation] reduces manufacturing time and yield loss and eliminates potential quality issues associated with coated softgels.”

“An important driver that could steer the dosage form market is the increasing demand for solutions that could overcome cold supply chain bottleneck constraints, especially given the current focus on vaccine development for COVID-19, as most vaccines are available as solution for injection that require ultra-cold chain storage,” Chin asserts. “A lot of effort and investment will be made to develop an alternative dosage form that could effectively deliver such biomolecules via the oral route. If this alternate dosage form could not only overcome enzymatic and permeability barriers, but also ensure stability and biological activity without the need for ultra-cold storage solutions, this could be expected to positively impact the global pipeline in the coming years.”

A rising demand for tailored or customized formulations and precision medicine will greatly impact drug dosage form development in the near future, according to Bhat. “The increased focus on patient centricity will certainly lead the development pipelines away from a generalized approach to more individualized treatments,” he stresses. “[This shift] will also allow for the creation of more innovations in combination delivery to achieve better dose compliance by minimizing the number of medicines that need to be taken separately.”

For example, combining dosage forms in one hard capsule is a possible option, Bhat adds. “Pellet technology, or minitablets, are a great example of converting conventional technology into personalized solid oral dosage form,” he says. “Minitablets can be filled in capsules as it is relatively easy to blend them together to attain combinations of multiple drugs in accurate doses and with different release profiles, if required. This solution is customized and user-friendly as it will reduce the dose regime.”

In Lamps’ opinion, lipid-based formulations will continue to impact dosage form developments in the future by addressing the solubilization challenge. “As [the technology] maintains solubilization during the dispersion/digestion step in the gastrointestinal lumen, it’s favoring efficient diffusion through the mucus layer to reach the intestinal epithelium,” he explains.

Additionally, amorphous solid dispersions (ASDs), which dissolve rapidly to higher concentration than crystalline forms and maintain supersaturation in the intestine, promoting drug absorption, will impact dosage forms in the future, Lamps continues. “[ASDs] broad applicability, flexibility, and quenching rates makes them amenable for high-dose compounds,” he says.

A high priority effort for many drug developers is the creation of an appropriate dosage form for cell and gene therapies (CGT), Nanda specifies. “Formulation and manufacture of CGT drug products represents specific challenges not encountered by small molecules and biologics,” she says. “Early-phase clinical trials for advanced therapies are rather complex and include wide dose ranges. It becomes extremely important to introduce a proper, robust formulation for CGT therapies early on, to be able to accommodate an intended route of administration, indication, and dose level.”

Although CGTs are still only administered in a clinical setting, the requirement for an optimal dosage form is just as critical as it is for therapies (large and small molecule) that are administered at home, Nanda emphasizes. “Both healthcare professionals and patients greatly appreciate using a therapy that allows a streamlined and simple administration, reduces the number of doses, or does not require specialized surgical instrumentation for delivery,” she says. “CGTs will require significant development in the container closures most suitable for efficient storage and shipment and convenient withdrawal for administration. Continued innovation of novel devices and adaption of existing platforms will also help enable advanced (tissue specific) therapy delivery.”

1. IFPMA, “The Pharmaceutical Industry and Global Health: Facts and Figures 2021,” 

 (April 2021).
2. K. Sedo, “2020 Global Drug Delivery & Formulation Report: Part 4, The Drug Delivery and Formulation Pipe-line,” 

 (June 2021).
3. PricewaterhouseCoopers, “Chronic Diseases and Conditions Are On the Rise,” 

Felicity Thomas is the European editor for Pharmaceutical Technology Group.


Vol. 45, No. 8
August 2021
Pages: 16–20

When referring to this article, please cite it as F. Thomas, “Putting the Patient at the Heart of Dosage Design,” 

Dosage form priorities are shifting to focus on user-friendliness, leading to greater engagement with outsourcing partners earlier in development timelines.

Putting the Patient at the Heart of Dosage Form Design

Deanna Mudie, PhD, is principal scientist, Lonza, Bend, OR, USA.

Oral delivery is the preferred route of drug product administration for maximizing patient compliance and lowering costs. However, successful oral delivery can be challenging for poorly water soluble drugs that resist dissolving in gastrointestinal (GI) fluids. Formulating drugs as amorphous solid dispersions (ASDs) can increase drug solubility, thereby enhancing drug product dissolution in GI fluids and maximizing the amount of drug that reaches the bloodstream (1). By increasing the drug in the bloodstream (i.e., enhancing oral bioavailability), ASD dosage forms can enable effective oral delivery and increase patient safety, efficacy, and compliance.

ASDs can improve crystalline drug products in many ways, including by removing food–drug and drug–drug interactions (DDIs), decreasing dose, and reducing variability in plasma exposure (2). While these benefits can be realized across therapeutic areas, oncology is particularly relevant as it accounts for 25% of drugs approved by FDA in the last decade, and many oncology drugs are poorly water soluble across at least part of the GI pH range (3,4). Poor oral bioavailability in oncology is common, often manifesting as food–drug interactions, variation in exposure, and DDIs (5). Numerous marketed weak base, oral oncology drugs show decreased absorption as a result of high gastric pH when taken with acid reducing agents (ARAs) (6,7).

Insights into underlying mechanisms of ASDs

Researchers from the University of Basel in Switzerland and The Peoples’ Friendship University of Russia (RUDN University), investigated the underlying drug absorption mechanisms of amorphous solid dispersions (ASDs), proving the effectiveness of a novel, particle-forming ASD drug-delivery system for poorly soluble compounds (1).

 employed a model ASD formulation of efavirenz, which is an antiretroviral medication that is classified on the biopharmaceutics classification system as a class II drug—one with poor solubility but high permeability. The model formulation comprised hydroxypropyl methylcellulose phthalate (HPMCP) as a polymer with sucrose palmitate and polysorbate 80 as surfactants in a hot-melt extrusion process.

Sixteen healthy male patients were included in the study and were randomized to receive efavirenz in three different ways: intervention 1 was ASD of efavirenz (50 mg) as a capsule with 500 mL buffer solution; intervention 2 was dissolved ASD of efavirenz (50 mg) in 500 mL of buffer solution, forming drug-rich particles; and intervention 3 was efavirenz (3 mg) solution in a 500 mL buffer solution. The study participants were randomly selected to receive the interventions in different orders (either 1-2-3, 2-3-1, or 3-2-1) and a washout period of 14 to 21 days was performed between interventions.

Blood samples were obtained pre-dose and at multiple time points post-dose so that the plasma concentration of efavirenz could be determined through bioanalysis techniques. The pharmacokinetic profiles of efavirenz plasma concentrations compared to time were used as the primary study endpoints, with further pharmacokinetic analysis and modeling used as secondary endpoints. Furthermore, study results were compared with existing pharmacokinetic data available for a marketed formulation of efavirenz (Stocrin).

Based on the study results, it was found that the dissolved ASD of 50 mg of efavirenz (intervention 2) pharmacokinetically behaved nearly identically to the solution of efavirenz 3 mg (intervention 3). Therefore, intervention 2, which comprised a supersaturated aqueous solution containing drug-rich particles, behaved as a solution, and assuming passive absorption, the researchers deduced that the dissolved drug concentration in the intestine of intervention 3 was higher by a factor of 16.7 than intervention 2.

As a result of the drug concentration exceeding that of the aqueous solubility of efavirenz, it was concluded that drug-rich particles from ASDs are efficient oral drug delivery systems and drug absorption was fast and complete in humans. Additionally, the findings of the study confirmed the conceptual models of how drug molecules are released from ASDs and how they are subsequently absorbed into the intestinal tract.

Non-classical nucleation theory and application on ASD design

A group of international researchers (from Northern Ireland, China, Switzerland, and the United States) have recently reviewed the potential theory behind the formation of drug-rich phases of ASDs with a focus on non-classical nucleation (2). In the study, Kaijie Qian 

 specifically assessed the associated thermodynamics and kinetics of the formation of drug-rich phases from the dissolution of an ASD, as well as the in-vitro permeability enhancement and 

 bioavailability enhancement of the ASD formulation, among other aspects associated with drug-rich phases.

Elaborating on the mechanistic understanding of ASDs solubility, dissolution, and potential phase separation process during dissolution and storage, the researchers found that if amorphous drug particles are suspended in solution, the drug concentration can temporarily reach beyond the drug crystalline solubility threshold, as a result of their higher Gibbs free energy, and achieve a higher solubility than their crystalline counterparts. The resultant high supersaturation of drug solution leads to phase separation, which the researchers noted will typically happen via a classical nucleation and growth process.

However, as a result of the imperfect miscibility of drug and excipients, there is the possibility for an amorphous-amorphous phase separation (AAPS) phenomenon to occur during manufacture or storage of ASDs. The researchers revealed that several models have been described on the drug-polymer-water interactions, in relation to moisture/solvent presence. Using the same concept, the researchers found that when dissolving the ASD in water the presence of excipients played an important role in the drug’s phase separation. Furthermore, it was found that certain excipients can kinetically stabilize the drug-rich metastable phases of ASDs for a considerable period of time, which may promote oral absorption of the drug due to high concentration levels in solution. Additionally, it was highlighted that the properties of polymeric excipients were important to drug permeability enhancement of ASDs.

Based on their work, the researchers suggested that the enhanced oral bioavailability achieved with supersaturated ASD solutions is aided by the excipient-assisted formation and stabilization of drug-rich metastable phases, which follow a non-classical nucleation pathway. ASD formulations that are designed to enable synergistic effects of a variety of different mechanisms could provide benefits for drug oral absorption and, as such, future medicine development, the researchers concluded.

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Calquence (crystalline acalabrutinib) is an example of a commercially marketed oncology drug that could benefit from bioavailability enhancement using ASDs (8). Acalabrutinib is a weak base with poor solubility at high gastric pH, resulting in clinically significant DDIs with ARAs. When administered with the proton pump inhibitor (PPI), omeprazole, the area under the plasma drug concentration–time curve (AUC) decreased by 43% in healthy volunteers (9). To prevent this issue, patients must avoid coadministration with PPIs and stagger dosing with histamine type 2 (H2) receptor antagonists (H2RAs) and antacids (9). Because ARAs are commonly taken by oncology patients, this DDI can reduce efficacy and patient compliance because of the complex dosing schedules required (10).

ASDs can improve outcomes for patients taking Calquence (acalabrutinib) by increasing acalabrutinib bioavailability at high gastric pH, thereby removing the DDI with ARAs. This article describes development of an ASD tablet that removed the acalabrutinib pH effect and outperformed Calquence 2.4-fold in the presence of the ARA, famotidine, at the human-prescribed (100 mg) dose in beagle dogs (11). ASD tablets were 60% smaller than Calquence and achieved good stability and manufacturability. These results have positive implications for using ASDs to solve bioavailability challenges, particularly for weak base drugs, which make up 78% of new molecular entities approved between 2003 and 2013 that showed clinical DDIs with ARAs (12).

Designing tablets to overcome the Calquence ARA effect required an understanding of acalabrutinib’s physicochemical properties and the mechanism of reduced performance of crystalline acalabrutinib when taken with ARAs. Acalabrutinib is a Biopharmaceutics Classification System (BCS) Class II drug with low intrinsic solubility and moderate log P (8). The drug is a weak base (pKa values = 3.5 and 5.8) causing it to become ionized at low pH, resulting in moderately high solubility in the stomach of fasted humans (pH ~1–3) (13). However, as gastric pH increases with ARA administration (pH ~3–7) acalabrutinib is largely non-ionized and solubility is reduced, resulting in decreased dissolution, which decreases absorption across the intestinal membrane and increases the extent of dose metabolized in humans (8,14–17). Therefore, an immediate-release ASD tablet was designed that maintained high dissolved acalabrutinib concentrations at both high and low gastric pH during in-vitro dissolution testing. In this case, high concentrations were defined as being at or above the value achieved with Calquence at low gastric pH (i.e., as prescribed). In addition, ASD tablets were designed to achieve good physical and chemical stability, good manufacturability, and to minimize size.

ASD tablet manufacturing and characterization

ASDs contain amorphous drug molecularly dispersed in a polymer matrix, which is used to stabilize the amorphous form during storage and in GI fluids (18). The acalabrutinib ASD consisted of 50/50 (% w/w) acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS-H) (Aqoat, Shin-Etsu Chemical Co., Ltd., Tokyo, Japan). HPMCAS is an ideal polymer for ASDs as a result of its high glass transition temperature and low hygroscopicity, facilitating high ASD physical stability during storage, and its amphiphilicity, promoting favorable interactions with hydrophobic drugs and intestinal fluids to inhibit crystallization in the GI tract (11,19).

The ASD was manufactured in a customized, laboratory-scale spray dryer and secondary dried in a vacuum dryer with high yield (97%) and low residual spray solvent (100 ppm methanol). In the spray drying process, drug and polymer are dissolved in an organic solvent and sprayed through an atomizer nozzle to create small droplets. At the same time, a drying gas is pumped into the spray dryer to rapidly evaporate solvent and lock the drug and polymer into a homogeneous amorphous solid dispersion. The resulting ASD particles are separated from the gas stream and collected for processing into a final dosage form (20). Spray drying is a scalable process precedented in commercial manufacturing of ASDs (21).

ASD was confirmed to be amorphous and homogenous using powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC), with a lack of surface crystals using scanning electron microscopy (SEM) (11). In addition, the ASD was confirmed to remain amorphous and homogenous after open storage for six months at accelerated temperature and relative humidity (40 °C/75% RH) as measured by PXRD, mDSC, and SEM, indicating good ASD physical stability and a good outlook for storage at ambient or refrigerated conditions over a typical product shelf life (i.e., two years) (11).

ASD was dry granulated with excipients and compressed into tablets using a small-scale manufacturing process. ASD tablets had a 100-mg unit dosage strength, a 25 wt% drug loading, and a 60% smaller volume than Calquence capsules (11). ASD tablets were found to be chemically stable when stored at room temperature with desiccant or in the refrigerator, which are acceptable storage conditions for pharmaceutical drug products (11).

Effective development of ASD dosage forms requires use of biopredictive 

 dissolution methods to evaluate drug formulation performance under varying GI conditions (22). In this study a custom, controlled-transfer dissolution (CTD) apparatus containing simulated gastric and intestinal compartments was selected to study dissolution performance of the ASD tablet and commercial Calquence capsule (11,23). Testing was conducted prior to the 

 study in conditions representative of fasted beagle dogs treated with either pentagastrin or famotidine to lower or raise gastric pH, respectively. Simulated gastric fluid comprised hydrochloric acid adjusted to pH 2 or 6, and simulated intestinal fluid consisted of pH 6.5 phosphate buffer containing bile salts and phospholipids (i.e., FaSSIF powder, Biorelevant.com Ltd. [London, UK]) at levels characteristic of fasted beagle dogs (average of 6.7 mM) (11). Dosage forms were added to the gastric compartment of the CTD, and fiber-optic ultraviolet probes were used to monitor acalabrutinib concentrations in the gastric and intestinal compartments with time as gastric contents transited to the intestinal compartment at a physiological gastric emptying rate (15-min mono-exponential half-life).

, the ASD tablet and Calquence capsule achieved similar concentration–time profiles at low gastric pH (pH = 2) due to the high solubility of both crystalline and amorphous acalabrutinib. Both dosage forms reached high drug concentrations in the gastric compartment and supersaturated in the intestinal compartment for the duration of the experiment. However, at elevated gastric pH simulating fasted beagle dogs taking an ARA (pH = 6), the ASD tablet outperformed Calquence due to the higher solubility of amorphous acalabrutinib. At elevated gastric pH the ASD tablet reached higher maximum concentrations and a 3.4-fold higher average AUC in the intestinal compartment than Calquence. Whereas the ASD tablet achieved supersaturated drug concentrations in both compartments, the Calquence capsule was solubility-limited and did not achieve supersaturated drug concentrations. The ASD tablet mitigated the ARA effect 

, where average AUC in the intestinal compartment at elevated gastric pH is 83% of that at low gastric pH.

 Acalabrutinib concentration time profiles in the in-vitro controlled transfer dissolution (CTD) test for amorphous solid dispersion (ASD) tablet and commercial Calquence capsule at gastric pH 2, ‘without acid reducing agent (ARA)’ (top) and gastric pH 6, ‘with ARA’ (bottom) (11). [

Beagle dogs are a commonly used species for testing dosage form performance prior to clinical testing in humans. To demonstrate mitigation of the Calquence ARA effect i

, ASD tablets and commercial Calquence capsules were administered to beagle dogs in a crossover study at the human prescribed 100-mg dose in compliance with the Animal Welfare Act Regulations (9 

 3). To study performance in the absence of an ARA, six dogs were given a subcutaneous injection of pentagastrin to lower gastric pH; whereas to determine performance in the presence of an ARA, the same dogs were treated with oral famotidine to increase gastric pH (24,25). Blood was collected for up to 24 hours after dosing, and acalabrutinib plasma concentrations were determined by liquid chromatography–tandem mass spectrometry (11).

Acalabrutinib plasma concentration time profiles in fasted beagle dogs for amorphous solid dispersion (ASD) tablets and commercial Calquence capsules at low gastric pH (without acid reducing agent [ARA], treated with 6 mg/kg subcutaneous pentagastrin) and high gastric pH (with ARA, treated with 40 mg oral famotidine) (7 day washout between phases, n=6) (11).

, ASD tablets achieved similar concentration–time profiles and AUC at low and high gastric pH conditions and matched performance of Calquence at low gastric pH conditions. Whereas, Calquence capsules demonstrated an ARA effect, achieving only 37% of the average AUC achieved at low gastric pH conditions. At high gastric pH conditions, ASD tablets outperformed Calquence capsules, with a 2.4-fold higher average AUC. These results show that ASD tablets overcame the ARA effect and achieved performance (e.g., average AUC) of Calquence as prescribed (11). Furthermore,

 dissolution testing in the CTD apparatus, which predicted similar performance of the ASD tablet and Calquence at low gastric pH, ability of the ASD tablet to mitigate the ARA effect, and superior performance of the ASD tablet to the Calquence capsule at high gastric pH.

 Acalabrutinib under the plasma drug concentration–time curve (AUC) from time zero extrapolated to infinity for amorphous solid dispersion (ASD) tablets and commercial Calquence capsules at low gastric pH (without acid reducing agent [ARA], treated with 6 mg/kg subcutaneous pentagastrin) and high gastric pH (with ARA, treated with 40 mg oral famotidine) (7 day washout between phases, n=6) (11).

ASD tablets were shown to overcome the ARA (i.e., pH) effect observed with the oral oncology medication, Calquence, at a 60% smaller dosage unit size in fasted beagle dogs. Whereas ASD tablets achieved similar average AUC in dogs under low and high gastric pH conditions, Calquence capsules achieved a 63% lower,

statistically different, average AUC in dogs under high gastric pH conditions (i.e., in the presence of an ARA). This outcome suggests that ASD tablets are a promising alternative to Calquence for improving patient convenience, compliance, and efficacy. Not only could ASD tablets allow patients to take acalabrutinib with or without highly prescribed ARAs, but ASD tablets promote swallowability due to their smaller size. Further, ASD and ASD tablets showed promise in attaining a long product shelf life and achieved good manufacturability using scalable spray drying and tableting processes, indicating potential to become a robust commercial drug product.

ASD dosage forms can improve efficacy, convenience, and compliance for patients taking a variety of poorly water-soluble medicines by increasing solubility and improving oral bioavailability. Like Calquence, many oral oncology and weakly basic drugs show clinical DDIs with ARAs, a challenge that can be overcome by using ASDs to improve drug solubility at high pH (3,12). Additional difficulties prevalent in oral oncology include variation in plasma exposure and food–drug interactions (5). As with the ARA problem statement, these challenges can be solved with ASDs when poor solubility is to blame. Knowledge of drug product and physiological properties combined with 

 tools can be used to determine which drugs can benefit from ASDs, and to design robust ASD drug products. Trends in oral oncology and favorable results of ASD development indicate that ASDs are ripe with potential for creating new, effective oral medicines and improving medicines already on the market.

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Vol. 45, No. 8
August 2021
Pages: 24–28

When referring to this article, please cite it as F. Thomas, “

 Demonstration of Enhanced Bioavailability of Acalabrutinib ASD Tablets,” 

Amorphous solid dispersions can overcome the pH effect encountered with oral oncology medications.

In-Vivo Demonstration of Enhanced Bioavailability of Acalabrutinib ASD Tablets

Richard J. Forsyth is principal consultant with Forsyth Pharmaceutical Consulting, 907 Shamrock Ct, Royersford, PA 19468, tel. 484.535.1688, forsythpharmaconsulting@gmail.com.

Submitted: December 1, 2020
Accepted: February 5, 2021

Cleaning validation requires a significant effort to design a strategic and effective program that is defendable with regulatory agencies. Of primary concern is what to validate. A robust selection of which product(s) and equipment to validate for cleaning is the cornerstone of a successful cleaning validation program. A strategy for selection of products and equipment for cleaning validation is presented.

Richard Forsyth is a Principal Consultant with Forsyth Pharmaceutical Consulting.

 
Vol. 45, No. 8 
August 2021 
Pages: 44–51

When referring to this article, please cite it as R. Forsyth, "Grouping Products and Equipment for a Worst-Case Cleaning Validation Study," 

A robust selection of which product(s) and equipment to validate for cleaning is the cornerstone of a successful cleaning validation program. A strategy for selection of products and equipment for cleaning validation is presented.

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