Biologics raise unique formulation and development challenges, and industry is still on a learning curve to get the best out of these diverse and complex therapies.

The global biologics market has experienced significant growth over recent years and, according to market research, is expected to continue to grow in the near future, potentially being worth $625.6 million by 2026 (1). Advancement of the sector is projected to be driven by an increase in prevalence of chronic conditions, technological advancements, mergers and acquisitions, more market approvals, and the development of more efficient biologics (1).

However, biologics raise unique challenges in formulation and development, not least as a result of the large size of the molecules but also due to other characteristics of the complex API. According to Fran DeGrazio, vice-president, Global Scientific Affairs and Technical Services, West Pharmaceutical Services, the size of biologic drug products is particularly challenging when approaching drug delivery. “To be most effective, biologics must typically be injected directly into the bloodstream,” she says. “Additionally, biologics are sensitive to their environment and can easily aggregate or denature, leading to problems such as the formation of particles, which may then be injected into the patient.”

“Biological molecules are not only larger in size but also more complex in structure when compared with small molecules,” concurs Constança Cacela, director—RD Analytical Development, Hovione. “This structural complexity can lead to challenges in ensuring stability during processing and long-term, which may result in potential losses of activity and increased immunogenicity.”

Circumventing phenomena, such as denaturation, aggregation, and other forms of structural change, are of key importance when processing and developing formulations with biological molecules, Cacela further explains. “These aspects of biologics are responsible for an increased difficulty, requiring advanced technical expertise,” she says.

Administration: Moving from IV to SC?
When developing large molecule formulations, and depending on the delivery route, there will be different challenges to address with implication on the respective excipient selection, explains Eunice Costa, director—RD Drug Product Development, Hovione. “For injectables, concentration and viscosity of subcutaneous formulations are the main points to address and optimize, whereas for oral enzymatic and acidic degradations low absorption needs to be addressed as well,” she says. “Finally, for nasal, the challenge is mainly related with the low absorption while inhalation is targeting the lung.”

There has been an upswing in the proportion of drugs in the pipeline to be administered via a subcutaneous (SC) delivery route, with biomolecules that are currently administered intravenously (IV) being formulated for SC instead. “Major issues associated with SC administration for biologics are the small volumes that require high concentrations of the API,” Costa adds. “The need for high concentrations results in increases of viscosity and challenges in maintaining isotonicity of the liquid formulation as well as in preventing aggregation. Moreover, viscous formulations are difficult and painful to administer. Addressing these issues includes careful optimization of the excipients in the formulation.”

For DeGrazio, there are multiple approaches available for developers of formulations to be administered subcutaneously. “One approach is through optimization of the drug formulation design,” she asserts. “This can be accomplished using technologies that help the drug meet deliverability criteria for SC injections.”

Another approach includes using a suitable delivery device. “An example of this approach may be drugs that are delivered to the patient through wearable injector devices,” DeGrazio continues. “Typically, a combination of both formulation optimization, and an appropriate delivery device, facilitates the transition from IV administration to SC.”

Alternative routes
The size of biologic drug products—ranging from 3000 atoms to more than 25,000 atoms—has meant that the primary route of administration is via injection, states DeGrazio. “Size is a challenge for crossing the barriers into the body using other routes,” she says. “The oral route is preferred for any drug product. However, due to the sensitive nature of active ingredients, they will not survive the acidic pH and digestive enzymes of the stomach. This would be just the initial challenge, the next would be absorption into the bloodstream.”

However, there are several benefits in developing biologic formulations for alternative routes of administration, argues Cacela, with probably the most obvious one being improved patient adherence. “In the development pipeline, there are increasing programs in the areas of oral, inhalation, and nasal, with the first one generally being considered as the optimal route,” she says.

To overcome the enzymatic and pH-dependent degradation of drugs in the stomach, in addition to permeability issues and the potential for degradation via first pass metabolism, formulation strategies, such as enzymatic activity inhibitors, permeation enhancers, enteric coatings, and carrier molecules, can be employed, Costa reveals.

“The increased focus on inhalation delivery reflects the benefits offered by this route of administration,” Costa continues. “Delivery by inhalation bypasses the harsh conditions in the gastrointestinal tract, allowing the administration of lower doses with reduced side effects, particularly for respiratory drugs delivered directly to the site of action.”

For systemic delivery, administering drugs to the lungs can also allow direct absorption into the bloodstream, leading to a more rapid onset of action, Costa explains. “The main challenges for inhalation include ensuring that the drug reaches the lung (e.g., delivery efficiency), a limited array of excipients available to interact and stabilize large molecules that are safe in the lung, as well as the lack of permeability to very large biomolecules,” she says. “Overall strategies include optimal design of the inhaler device, study of the interactions between excipients and biomolecules, biomolecule engineering (e.g., fragmented antibodies, anticalins) with the purpose of maximizing efficiency.”

Nasal delivery, historically, has tended to be used for local delivery of drug substances. However, Costa adds that more recently it is becoming recognized as an interesting route for direct access to the brain. “It has been actively pursued for biologics, in particular peptides, due to the ease of administration,” she states. “As opposed to inhalation, one of the major limitations of this route is the relatively limited low surface area available for absorption. To increase absorption, mucoadhesive polymers are commonly added to the formulation.”

Cacela emphasizes that an overarching technological solution, useful for overcoming the limitations for the various delivery routes discussed, is the use of particle engineering. “Through the preparation of optimally sized and shaped particles, the bioavailability of the drug can be improved,” she says. “As an example, nanoparticle-based delivery systems, such as lipid nanoparticles, are used for improving penetration of large molecules. In addition, these systems provide protection to the drugs, which is particularly relevant for large molecules administered orally.”

A common technique used to engineer particles is spray drying, which Cacela states is the most commercially advanced solution capable of preparing stable and effective formulations. “Despite being generally used for oral small molecules, its benefits can be easily expanded to other systems and routes of administration,” she adds. “The anticipated forecast growth for spray drying services being applied to biologics (2) is a strong indicator of that.”

Reformulation and self-administration trends
SC administration of biologics, in particular antibodies, is a strategy being employed by industry to improve patient comfort and provide pharmacoeconomic benefits (3), highlights Cacela. Highlighting another example (4), she adds that in some cases using SC administration can result in improved safety due to reduced adverse effects. “Besides the aforementioned benefits, reformulation of existing biologics may also be of potential value for the originators as a means of life-cycle managements,” she says.

In agreement, DeGrazio notes, “We are definitely seeing the trend towards reformulation as part of lifecycle management to enable self-administration. New biologic drug products in competitive therapeutic categories are being introduced in self-administration systems. This is one of the main reasons for the growth of drug-device combination products in the marketplace.”

The move toward self-administration is being driven by a number of factors, DeGrazio continues. “One of the most significant is the potential cost savings if the delivery of a drug product can be done at home, versus in a hospital or clinic,” she says. “Additional reasons include improved quality of life for patients and product differentiation in a therapeutic category.”

Mitigate risks, save costs
The costs associated with any medical therapy are being scrutinized by regulatory bodies, governments, and patients. Biological therapies, due to the molecular complexity and associated challenges during development means that they come with a high price tag.

“One of the best ways to impact costs is by mitigating risks early in the development process,” asserts DeGrazio. “Many drug product formulators think that all problems can be solved through their ability to adjust and optimize a formulation. However, not all formulators have a broad understanding of the impact of aspects beyond the drug formulation, aspects of which they need to be cognizant.”

Highlighting some examples, DeGrazio notes that formulators must be aware of the potential impact primary packaging may have on the biological drug product. Additionally, whether or not it is possible to use the drug product with a delivery device is an important consideration. “Both packaging and device options are essential when looking at improving the patient experience,” she adds.

“The route chosen regarding drug pricing must not inhibit innovation and must ensure economic sustainability,” warns Cacela. “However, R&D effectiveness may be improved and, therefore, have an impact on the final cost of biologics.”

To improve R&D effectiveness, Costa explains that industry is using many different approaches. “Approaches such as preclinical models that more closely resemble the human conditions to be treated, reducing late-stage (Phase II and III) attrition rates and cycle times during development by using a better model,” she says. “New tools and technologies arising from the digital transformation era, such as the application of artificial intelligence algorithms to experimental and clinical data, further improve R&D effectiveness.”

Specifically looking at formulation, Costa reveals, “As more biomolecules are screened models can be improved allowing for in-silico screening and reducing the chances of failure later on in clinical development.”

Still on a learning curve
For Cacela there is still much to learn and more development required in both the delivery and formulation of biologics. “Besides this, the diversity of these drugs and therapies is very large and it is difficult to find a common solution even within a same class of biomolecules,” she states. “Therefore, the coming years will be marked by advances in the delivery of novel biologics, as well as biosimilars, with new solutions, new excipients, and new delivery support molecules.”

“We have learned that the drug formulation itself can have a detrimental impact on the function of a delivery device, such as a prefilled syringe system,” adds DeGrazio. “By understanding issues early in the development process, however, downstream problems can be avoided. Partnership with suppliers who are familiar with such challenges can be of great benefit. An openness to engage, and learn from each other, can benefit effective drug development and the patient.”

References
1. Reports and Data, “Biologics Market By Product (Monoclonal Antibodies, Vaccines, Recombinant Hormones/Proteins), By Application (Cancer, Infectious Diseases, Autoimmune diseases), By End use (Hospitals, Clinics, Diagnostic Centres), and Region, Forecasts to 2026,” Market Report, reportsanddata.com (October 2019).
2. Research and Markets, “Pharmaceutical Spray Drying Market (2nd Edition), 2018–2028,” Roots Analysis, researchandmarkets.com (April 2018).
3. K. Papadmitriou, et al., Facts Views Vis. Obgyn., 7 (3) 176–180 (2015).
4. P. Moreau, et al., Lancet Oncol., 12 (5) 431–440 (2011).

Article Details
Pharmaceutical Technology
Vol. 44, No. 1
January 2020
Pages: 33–35

Citation
When referring to this article, please cite it as F. Thomas, “Fresh Thinking in Biologic Drug Formulation,” Pharmaceutical Technology 44 (1) 2020.

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