Considering Alternative Dosage Forms in Biologics

The global biopharmaceutical market is projected to experience significant growth in coming years (1). An aging population, increasing prevalence of chronic conditions, rising proportion of obesity amongst the global population, and more sedentary lifestyles have all been noted as contributing factors to the increasing demand in biopharmaceuticals.

Biopharmaceuticals are also known to offer great efficacy and safety for a number of illnesses that were previously thought to have been untreatable (2). However, it is also widely understood that biopharmaceuticals present specific challenges during drug development and finished dosage form production, as a result of the complexity, sensitivity, reactivity, viscosity, and expense of these macromolecules.

In general, to overcome the formulation and bioavailability challenges associated with biopharmaceuticals, administration is, more often than not, performed via a parenteral (e.g., intravenous infusion or injection) usually given by a healthcare professional. As biopharmaceuticals are often used in the treatment of chronic conditions, however, administration of treatment is required at regular intervals over a long period of time (3). Therefore, the potential treatment burden of biopharmaceuticals can have a negative impact on patient experience and adherence rates. An industry viewpoint, which is becoming increasingly popular, is that patient-centric approaches to drug development are conducive to a more commercially successful outcome for a therapy (4).  

“Of note, a survey conducted by eyeforpharma in 2014 (5) revealed that 86% of pharma executives feel that patient-centric drug development is key to profitability, with benefits increasingly recognized by patients and payors,” states Jessica Rousset, chief operating officer, CURE Pharmaceutical. “Alternative dosage form strategies, such as replacing an injection with a transdermal patch or metered dosing, align fully with the trend toward personalized medicine.”

Optimizing the patient experience

“Biopharma and pharma companies often develop alternative dosage forms to optimize the patient experience, such as parenteral dosage form for subcutaneous administration,” explains Matthew Huddleston, executive vice‑president and chief technology officer, Enable Injections. He highlights the example of the Enable enFuse injector, which comprises a bolus injector and infuser. “This infusor was designed to optimize the patient experience by enabling patient self-administration of high-volume therapeutics outside of a healthcare facility,” he notes.

“Patient acceptability of a medicinal product is a key aspect in the development of medicines,” adds Rousset. “Developers typically consider alternative dosage forms with patient experience and population in mind. Considerations such as patient population age, disease state mobility, and body function are drivers.”

Huddleston concurs that additional care during the development of alternative dosage forms should be taken depending on the target patient population. “Ease-of-use and the physical limitations of the patient can be a major factor in the development of drug-device or biologic-device combination products,” he says. “For example, pediatric patient populations may have device size or dose limitations based on age, whereas geriatric patients may have hand dexterity limitations during drug administration.”

Hanns-Christian Mahler, head of Drug Product Services, Lonza Pharma & Biotech, further emphasizes the point that development of any given drug product must carefully and closely consider both the target indications and patient populations. “This consideration should relate to possible variability in a given patient population, but should also reflect patient preferences, duration of drug use (acute vs. chronic), required co-medications, and other factors,” he says. 

Benefits of alternative dosage forms

Assessing the role of delivery systems to improve biologics therapy, alternative routes of administration could greatly benefit many biologics, reported Nataša Škalko-Basnet (professor and head of the Drug Transport and Delivery Research Group, Department of Pharmacy, University of Tromsø, Norway) in a 2014 paper (6). Yet, the unique features of biologics have led to challenges during formulation development, with most strategies employed for small-molecule compounds being non-transferrable to the large‑molecule arena.

As biologics are more often delivered via the parenteral route, which features specific limitations in terms of product development (6), alternative dosage forms could offer developers opportunities in terms of logistics and user experience, Mahler stresses. “Alternative dosage forms for biopharmaceuticals may provide opportunities to allow biologics to be stored, shipped and used outside 2–8 °C, facilitating supply chain,” he says. “And, it may be possible to also improve the user experience-for example, by using better needles or devices for parenteral administration and/or exploring non-parenteral administration routes such as oral, pulmonary, rectal, or vaginal administration.” 

Choosing an alternative dosage form can positively affect medication adherence as well, particularly when improvements in the patient experience are gained, concurs Rousset. “Improvements can be made by replacing an injectable drug with a sublingual drug, simplifying the dosing schedule with a sustained release dosage form, and reducing toxicities by avoiding the GI tract (e.g., through transdermal or transmucosal delivery),” she notes. “For all these solutions, developers must put consumers directly at the center of the business.”

A supplementary advantage of alternative dosage forms may be present in accelerated and less costly regulatory pathways, Rousset adds. “Companies that change the dosage form of an approved drug may pursue the regulatory 505(b)(2) approval pathway, which relies on existing data, thereby saving time and expense, while maintaining market exclusivity for three to as many as seven years,” she notes. 

Furthermore, Rousset explains that intellectual property benefits may be achieved when developing an alternative dosage form. “The patent landscape around alternative dosage forms may be less crowded, resulting in a lower barrier to entry to develop and commercialize drug product,” she says. “In the event that less prior art is directed toward an alternative dosage form, the time and cost of obtaining new patents of decent claim scope on a drug product in such dosage form can be reduced, with an opportunity to create a patent ‘thicket’ and further market exclusivity.” 

Challenges facing developers

The economic burden of research and development of a new molecular entity (NME) is well known. In a paper published by the Office of Health Economics (OHE) (7), it was noted that mean estimations of R&D cost should be treated with caution but that the most important factors impacting cost are therapeutic area, firm size, type of molecule (traditional vs. biologic). 

Based on the estimates in the OHE paper, however, it was deemed that R&D costs are increasing partly driven by more complex disease targets and the trend toward personalized medicine (7). Biologics and biopharmaceuticals were subject to longer development times and higher costs per approved new molecule. Yet, the authors of the study also found that the estimated overall clinical success rate for biological products was higher than that for other traditional pharma products.

In terms of developing alternative dosage forms, associated cost implications ranked highly by Rousset, Huddleston, and Mahler. “With innovation comes risk, and so alternative dosage forms must overcome challenges such as an uncertain regulatory pathway and unproven technologies that can, at times, fall short or be costlier,” notes Rousset. “There may be a higher bar to pass with the regulatory agencies if they are not familiar with a certain dosage form, and they may require multiple additional studies for approval.” 

Costs may also be incurred during the initial formulation or product development stage, adds Huddleston. “Further cost challenges may arise as a result of delays or extensions to timeframes due to stability testing programs, unforeseen impacts on drug safety and/or efficacy, and the potential introduction of new use errors identified due to a novel user interface and human factor challenges,” he says.

For Mahler, two main challenges face developers in terms of non-parenteral administration of biologics-risk of degradation of the biologic and lower bioavailability-giving rise to costlier products. “First, the size, charge, and poor stability of biologics products render them very susceptible to degradation when administered non-parenterally,” he explains. “For example, upon oral administration, biologics will be exposed to harsh pH conditions that will destroy the biological active ingredient in-vivo.

“Secondly, the size and charge of biologics mean poor biological membrane permeation. However, transfer via biological membranes is required for any non-parenteral administration where systemic exposure of the drug is desired. Thus, biologics have very poor bioavailability, if being absorbed at all. Low bioavailability means a higher amount of drug must be dosed, which leads to significantly higher cost of goods,” he stresses.

Finally, Rousset states that when an innovative dosage form makes it to commercial launch, there may be challenges surrounding adoption by patients, payers, and clinicians. “Humans have a natural tendency to go with what they know and trust,” she says. “New dosage forms must demonstrate clear patient benefits and be introduced at an optimal price point to ensure market adoption.”

Best practices

“The decision to pursue alternate drug delivery can occur at any stage of the drug discovery, development, or commercialization lifecycle,” states Rousset. “However, early awareness of potential benefits of alternative dosage forms and the pharmacokinetic parameters associated with the various routes of administration are key to shape robust development strategies.”

Additionally, there is a responsibility with the developer to engage and educate the relevant health agency about the latest cutting-edge technology. “It is best practice to gain clarity early by way of a pre-investigational new drug meeting, on the regulatory pathway, preclinical, clinical and any chemistry, manufacturing, and controls requirements that may be unique to the dosage form,” Rousset adds.

Some technological advances that Rousset specifies as being noteworthy include:

• Coextrusion formulations and various printing approaches for flexible oral drug delivery systems suitable for personalized dosing and formulations-on-demand (8) 

• Modern analytical tools for assessing critical quality and safety attributes of novel excipients that are critical enablers of desired drug product performance (e.g., permeation enhancers)

• Advanced top-down fabrication methods such as microfluidic synthesis and photolithography can enable more effective scale-up of nano-formulations

• Digital dispensing devices can pair uniquely with novel dosage forms, such as a roll dispenser with a continuous film that can be cut into desired sizes for personalized dosing and tracking of drug administration (9)

• Crystal engineering, as well as advances in polymer science, offer great promise in alternate dosage forms.

Finally, Rousset believes that the formation of a consortium of developers of alternate dosage forms that meets regularly, publishes white papers and builds consensus around alternate dosage forms, would catalyse establishing best practices. “While this might represent a long-term approach, it is one that could prove very fruitful,” she says.

Promising future

In Huddleston’s opinion, the most promising dosage form for the future is that of parenteral forms for subcutaneous administration. “Parenteral dosage forms for subcutaneous administration are the most promising as they can provide an opportunity for therapies to be administered in the home setting,” he says. “Thus, subcutaneous delivery platforms with simple, patient-friendly designs will be the preferential dosage form in the future.”

Apart from subcutaneous administration, the local (topical) use of biologics, where systemic administrations and hence absorption are not relevant, offers potential as a ‘future sweet spot’ for Mahler. “Potential applications range broadly, such as using biologics in creams for wound healing, by inhalation to treat pulmonary diseases such as cystic fibrosis, or the potential use of biologics for local therapy of diseases such as Crohn’s disease,” he notes. “However, the in-vivo destabilization of biologics remains a key challenge for these topical administration routes.”

Additionally, he reiterates that the industry will continue to face challenges when attempting systemic administration via non-parenteral delivery for biologics as a result of molecular degradation in-vivo and the high cost of production. “These challenges may not be easily overcome without increasing patient safety risks,” he says. “Another approach that may be more worthwhile to focus efforts into is making parenteral products more attractive for patients and users, by decreasing potential pain sensations or related concerns, for example.”

According to Rousset, there are clear reasons as to why the majority of dosage forms on the market are oral, this dosage form is cost-effective, offers good stability, and is preferred by the patient due to the ease of administration. “Dosage forms such as oral thin films and orally disintegrating tablets are widely accepted and palatable, with the further potential benefits of circumventing first-pass metabolism and increasing drug onset,” she notes. “However, delivering proteins via the buccal or sublingual route remains a lofty goal in the field, but with advances in nanosized drug delivery systems and advanced manufacturing technologies, such applications may be realized in the not-so-distant future.”

References

1. Mordor Intelligence, “Biopharmaceuticals Market,” mordorintelligence.com, Market Report 2019–2024.
2. W.R. Strohl and D.M. Knight, Curr. Opin. Biotechnol. 20 (6) 668–672 (2009).
3. A. Siew, BioPharm. Int. 31 (4) 10–13 (2018).
4. A. Siew, Pharm. Tech. 41 (11) 16–23 (2017).
5. Eyeforpharma, “Industry Healthcheck 2014,” [accessed Feb. 9, 2019].
6. N. Škalko-Basnet, Biologics 8 107–114 (2014).
7. J. Mestre-Ferrandiz, J. Sussex, and A. Towse, “The R&D Cost of a New Medicine,” Office of Health Economics (London, UK Dec. 2012).
8. G. Tucker, et al., J. Pharm. Sci. 105 (9) 2489–2497 (2016).
9. E.M. Hoffmann, A. Breitenbach, J. Breitkreutz, Expert. Opin. Drug Deliv. 8 (3) 299–316 (2011).

Article Details 

BioPharm International
Vol. 32, No. 3
March 2019
Pages: 16­–18, 50

Citation 

When referring to this article, please cite it as F. Thomas, “Considering Alternative Dosage Forms in Biologics," BioPharm International 32 (3) 2019.