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As biologics continue to push boundaries, the industry needs to take a holistic approach to formulation to ensure success.
Over the coming years, the growth in the biologics market is projected to be rapid, reaching US$580.5 billion (approximately €513.5 billion) by 2026 (1). This growth is partly being attributed to an expansion in product portfolios, which is reflected in the higher number of biologics that are being approved by regulatory bodies globally (2).
“Medicine has experienced a revolution since recombinant DNA technologies moved from novel therapies in the mid-1980s to mainstream in recent times. The number of biologics gaining approval for an orphan indication has climbed to more than 50% in the current decade,” confirms Victoria Morgan, biologics marketing director, West Pharmaceutical Services. “Last year, 2018, was a record-setting year for new-molecular entity (NME) approvals by the United States Food and Drug Administration (FDA), 59 versus 46 in 2017. More than half (58%) of NME approvals were for orphan drugs (patient population less than 200,000 in the US) 17 of which were biologic NMEs.”
According to Peter Ferguson, global market manager for biopharma at Roquette, the past decade has witnessed a marked shift in the pharmaceutical industry. “Companies traditionally seen as ‘small molecule’ have pivoted their emphasis and pipelines towards biologics,” he says.
Currently, there is a wide range of modalities within the biopharmaceutical industry, Ferguson explains, with the repertoire of biologics now spanning monoclonal antibodies (mAbs), fusion proteins, and emerging areas such as cell and gene therapies. “Of all therapies classified as biologics, mAbs stand out far above the rest in terms of prominence,” he continues. “Representing approximately 50% of the market (well above the next category, vaccines) mAbs are not only the most commonly marketed biologic today, but if we look at pipelines, where there are nearly 4000 mAbs in development, the future of biopharma looks set to be dominated by this class of medicines.”
Poorly formulated drugs can have a significant impact on a development programme, and if poorly formulated candidate drugs progress to the clinical trial stage, developers may be looking at wasted resources and erroneous data sets, stresses Ferguson. “This [concern] further exemplifies why formulation optimization and pre-formulation activities are so important to delivering a successful programme,” he says.
Regarding biologics in particular, the challenges associated with formulation, such as aggregation and degradation, must be extensively considered as these could have a severe impact on patient safety. “If an aggregated biologic is injected into a patient, there is a high chance of induced immunogenicity occurring,” continues Ferguson. “The impact of this [reaction] will be uncomfortable for the patient, but more importantly, will lead to the reduction in the therapeutic effects of the medicine. For a patient suffering with a life-threatening disease, such as cancer, a lack of efficacy in their treatment could be fatal.”
Morgan concurs that an extensive series of pre-formulation checks are imperative to ensure that developers avoid formulating an unstable, non-viable product (3). “Developers must determine whether the injectable biologic will break down within the intended formulation or the manufacturing process,” she says. “The drug must be thermally stable, possibly resistant to oxidation, and tolerate variations in light and other environmental stresses placed on it during manufacturing and packaging. Assessment of any residual solvents or other chemicals remaining after bulk preparation of the biologic will need to be accounted for in the formulation and manufacturing process. Finally, the solubility of the biologic must be assessed, to ensure that the formulation will result in high bioavailability without degrading or otherwise damaging the biologic itself. Ideal formulation conditions are then set, which may include the introduction of excipients, specific parameters that must be maintained during manufacturing, and/or the presence of vacuum during certain steps.”
“From speaking to formulators across the industry, preventing and reducing the level of aggregation is what we see as the critical issue facing biologic formulators in the market,” notes Ferguson. “This issue affects most biologic drugs, in particular monoclonal antibodies. It is not easily solved, with further challenges created due to the varied nature and three-dimensional structure of different biologics, as well as a limited number of approved excipients available on the market.” Specifically approaching this issue, Roquette has introduced a hydroxypropyl modified betacyclodextrin excipient (KLEPTOSE BioPharma), which was originally used in the smallâmolecule arena, Ferguson reveals.
The mechanics of administration is also an important consideration for formulators. The increasing trend for subcutaneous formulations to be developed for high-dose drugs raises specific challenges, explains Morgan.
“The greatest challenge associated with the delivery of biologics lies in the limited delivery mechanisms available,” confirms Ferguson. “As most biologics are proteins, their chemistry makes them unsuitable for oral administration, due to the hydrolysis and degradation that would occur. If it were possible to formulate biologics into oral dosage forms, you would see a significant reduction in their total delivery cost.”
In agreement, Morgan explains that the complexity of biologics, compared with small-molecule drugs, has meant that the oral administration route has not been mastered. “There is enzymatic and pH-dependent degradation of drugs in the stomach and intestines,” she says. “Low permeability of epithelial cells that line the gastrointestinal tract means that proteins and peptides typically have extremely low bioavailability, in the range of around 0–2%, when taken by mouth.”
The size of biologics presents further delivery challenges. Molecular weights that can reach 150,000 Da, compared to a few thousand usually encountered with small-molecules, give rise to viscosity issues, emphasizes Ferguson. “The administration preference for high-viscosity formulations tends to be intravenous, which is a costly option, requiring clinicians and trained medical professionals to deliver the treatment,” he says.
However, Morgan notes that if it is possible to formulate the biologic to within the traditional <1 mL space, maintaining stability in liquid form, and with a reasonable viscosity, an auto-injector may be a suitable option for a combination product. However, if there is any deviation from the standard formulation parameters, then different technology for delivery is required. Morgan points out the example of Repatha (Amgen) in combination with the SmartDose wearable device (West Pharma Services).
“Bringing biologic combination products to market has numerous potential pitfalls, however,” she says. “One must ensure the right analytical methods are in place; have a repeatable, controlled manufacturing process; manage poor yields; test compatibility of drug with device; design an ideal device through human factors; and navigate successful clinical trials, all whilst regulating and testing to the appropriate regulatory agency expectations. Navigate these challenges well and you have a robust process and product.”
Fundamental challenges affecting biologics may be addressed during the formulation stage. During formulation, many of the critical quality attributes and parameters of the drug product are defined, Ferguson explains. He notes that for aggregation, selecting the correct and optimum excipients is of paramount importance. However, the ability to be able to perform this task is dependent upon the tools the formulator has available to them.
“The area of pre-formulation stands out as an under utilized area of formulation optimization,” Ferguson continues. “I often ask those working in drug discovery how many lead candidates never make it through to trials simply due to a lack of screening robustness. The answer seems clear-potentially a lot. Often separated both organizationally and physically, groups working within formulation refer to an issue termed a ‘silo’ mentality within research and development. Uniting and harmonizing these different disciplines could bring numerous benefits to big pharma during the development of drug products.”
In Morgan’s opinion, both formulation and delivery device technologies can be employed to improve the overall patient experience. She says that formulating drugs to higher concentrations and using higher volume delivery systems can reduce dosing frequency, and using delivery systems that enable administration in the home setting can benefit the end user and potentially reduce healthcare expenses.
“Formulating drugs that can be self-administered by the patient has progressed the treatment and compliance of disease states such as rheumatoid arthritis and diabetes,” she adds. “The fundamental shift in this field has been the move to subcutaneous delivery rather than intravenous or infusion.”
Subcutaneous delivery is challenging, however, and requires formulators to balance the pharmacological needs of the drug with the tolerability of the patient. Potential solutions available include increasing the dose concentration or increasing the dose volume, Morgan further explains.
“Upstream we see challenges as these increased viscosities and volumes may not be amenable to existing fill/finish processes,” she adds. “Concentration to the necessary level in the final product may not be possible for all products because, in many cases, upstream purification and manufacturing processes may limit the maximum concentration for the final drug product more than delivery and fill/finish process concerns.”
Furthermore, limitations to the concentration can result from the drug-product properties, such as pH and osmolality, and the use of certain excipients. “Certain emerging formulation technologies, including the use of non-aqueous solutions, have shown promise towards mitigating such concerns, but are awaiting regulatory approval,” Morgan says.
Subcutaneous delivery is still causing concern in the industry, with difficulties encountered in the patient’s ability to tolerate rapid injection with the larger dose volumes. “However, the launch of ENHANZE (Halozyme) drug delivery technology has potentially turned that argument on its head,” Morgan notes. “Based on a patented recombinant human hyaluronidase enzyme, the technology enables some biologics that are administered intravenously to potentially be delivered subcutaneously, providing a better experience for patients and increasing health system efficiency by reducing administration time, injection pain, and infusion site reactions.”
Furthermore, she emphasizes the importance of wearable drug delivery devices in solving the issues surrounding larger volume doses. “A wearable allows longer dosing times, patient comfort and convenience, even allowing home administration, which opens up historically limiting parameters for formulators,” Morgan says.
“When I look to the future of the biopharmaceutical industry, I see two main agents of change within the next 10 years: advancements and adoption of innovative manufacturing techniques and the rise of advanced therapy medicinal products (ATMPs),” says Ferguson.
In his view, traditional manufacturing techniques for biologics, which use stainless steel technology, will need to adapt to the changing targets for drug developers-narrower patient populations and more focus on specific disease categories. “The implication here is that manufacturing techniques will need to mirror the required flexibility and productivity increase required,” he says. “Single-use manufacturing techniques currently represent a small proportion of the installed biopharmaceutical capacity. Looking forward, I see a fundamental shift in the approach taken to the manufacture of biologics-one only has to look at plants currently under construction, of which 25–50% use single-use technology, to see the fundamental shift that is taking place.”
Morgan also touches upon manufacturing as an element she believes will witness change in the near future. “As biosimilar competition increases and pressure for biologics manufacturing costs to reduce, the number of approved biologics will continue to increase,” she explains. “We will see more outcome-based pricing as funders are under ever increasing pressure to stretch their funds.”
In terms of modality, Ferguson states that even though he believes mAbs will continue to dominate the biologics market into the future, there will be emerging areas, such as cell and gene therapy, that are set to play an increasingly important role. “The result that can be obtained with these therapies is outstanding, something of which the wider industry is starting to take note,” he says. “Formulations for these treatments will pose new challenges and significant benefits to patients. The stability and efficacy challenges confronting a formulation scientist in traditional biologics will not be the same for these advanced therapies.”
One trend that is being witnessed across the industry is that of a patient-centric approach to formulation. “Developers need to look beyond the formulation of a stable drug all the way to patient compliance. How will the patient receive the dose, in what setting, and with what level of pain are all factors which should be considered from early development stages,” Morgan summarizes. “As biologics continue to push the boundaries of what was historically possible, use of delivery devices to allow patients to successfully comply with stated dosing regimens is becoming widespread.”
1. Research and Markets, “Global Biologics Market Size, Market Share, Application Analysis, Regional Outlook, Growth Trends, Key Players, Competitive Strategies, and Forecasts, 2018 to 2026,” researchandmarkets.com, April 2018.
2. C. Challener, Pharm. Tech. 43 (1) 30–33 (2019).
3. R. Peck, “Injectable Biologic Formulation Development,” Feb. 6, 2018, accessed Feb. 9, 2019.
Vol. 32, No.
When referring to this article, please cite it as F. Thomas, “Rising to the Challenge of Biologic Drug Formulation," BioPharm International 32 (4) 2019.