Despite the rise in biologics, oral solid dosage forms continue to be the preferred route of administration due to their cost-effectiveness, relative ease of manufacturing, and patient-friendly dose form options.
In fact, the small molecule outsourcing market is expected to reach $69.4 billion by 2024, with the demand being driven by complex molecules, according to Visiongain’s report, “Pharmaceutical Contract Manufacturing Market 2019-2029.”
“The oral solid dose development and manufacturing market is a mature market that continues to be a growing space,” said Ania VanDyke, associate director of business development, contract manufacturing, AbbVie. “Oral solid dose products are a preferred option due to convenience and improved patient compliance. However, as there is an increase in challenging and difficult to manufacture molecules in the developmental space, formulation and manufacturing of oral solid dosage forms is becoming more complex.”
The market is robust as the pipeline of oral solid dose products in development is strong and continues to grow, according to Terence Novak, chief operating officer, Tedor Pharma, especially with the small to mid-size companies that have products in development and are looking for clinical trial supply or development expertise.
“These companies have little to no production infrastructure and need quality contract development and manufacturing organization (CDMO) services,” he said. “In 2018, NDA approvals for tablets and capsules outstripped approvals for injectables, a notable shift in the market, and companies continue to look to develop products that are more convenient for patients. There has also been a fair number of generic companies looking for additional manufacturing capacity.”
Smaller Batches, Higher Potency
A number of trends are having an impact on today’s OSD market, which is and will continue to be dominated by small- and medium-sized sponsor companies. One is a growing emphasis on smaller batch sizes, according to John Ross, president, Mayne Pharma USA. “With drug sponsors, distributors and patients demanding more flexibility regarding cost, access and cycle times—and blockbuster drugs losing patent protections—the entire industry is moving toward smaller batch processing,” he said. “Another trend is the extensive demand for high-potency API (HPAPI) handling. The HPAPI market is expected to increase to $27 billion by 2023, representing a 63% jump from 2016.”
Yet a third driver involves supply expectations from global consumers. “While sales in North America and Western Europe account for about 55% of the world’s pharmaceutical market, the Asia Pacific market is growing substantially, fueled by improved access to medicines,” said Ross. “This challenges pharma companies when it comes to building global supply chains that are cost-effective and flexible.”
According to Angela Hoffnagle, product manager Rx oral dose, Catalent, advancements in drug delivery technologies for modified-release dosage forms, molecules requiring bioavailability enhancement, and the growth in highly potent compounds are significant influences on this market’s continued growth.
“Due to the number of poorly soluble and complex compounds in the pharmaceutical industry’s pipeline, there has been an increase in demand for bioavailability-enhancing technologies such as spray drying and hot melt extrusion (HME),” she said. “We are also seeing an increase in demand for specialized dosage forms such as controlled release, pediatric and geriatric delivery forms. This is in part driven by an increase in oncology treatments that are commonly of greater potency.”
Also addressing the solubility issue, AbbVie’s VanDyke said as many as 70% of New Chemical Entities (NCEs) have poor solubility and/or bioavailability. “As a result, we are seeing an increased demand for technologies such as HME to aid in improving solubility and enhancing bioavailability,” she said. “Products are also targeting more specific indications with smaller patient populations requiring smaller manufacturing scales. In addition, there is an increase in potent molecules particularly in the growing oncology space.”
Lean Mean Machine
In addition to HPAPI handling and enhanced capacity to offer solubility and bioavailability solutions already discussed, another key opportunity for growth exists in lean manufacturing pursuits for both, according to Ross. The capital investments required to successfully offer HPAPI handling and solubility and bioavailability solutions are significant.
“While the ideal of lean manufacturing is a challenge for any industry, this has been especially true for pharma, which traditionally has experienced high profit margins and carried large inventories as insurance against unreliable supply chains,” he said. “Latent inefficiency has been ‘affordable’ when compared to the profit margins of a drug product. Those days are gone, however. Now, optimizing manufacturing operations enables the ROI of more capital-intensive operations to be attainable and the cost-of-goods to be reasonable.”
Novak agreed that lean processes are the way forward. “Lean and more efficient manufacturing processes are other opportunities for growth as, given the smaller batch sizes, changeover will be important in order to serve more customers and diversify CDMO portfolios,” he said.
In addition, Novak said vertical integration to add select capabilities that can best serve the companies from development through commercialization is important in today’s market.
Catalent’s Hoffnagle concurred. According to her, the need for end-to-end solutions, from drug discovery to screening, scale-up from early development to clinical trials, and on to commercial manufacturing, and packaging, continues to be a major driver across the pharma outsourcing landscape.
“As an outsourcing partner that is involved in a project from the early-development phase through to scale-up and commercial manufacturing, we can increase the likelihood for a program’s success through an intimate understanding of the project’s milestones and interplay between each phase along the product’s development and manufacturing journey,” she said. “This allows for a strategic, long-term partnership, where both parties understand the important project requirements, while keeping the patient in mind at every stage.”
Solving Solubility Issues
Today’s leading contract service providers are continuously developing new technology solutions to overcome formulation and manufacturing challenges.
“As newly identified APIs increasingly prove to be less soluble or poorly bioavailable, reliance upon solutions such as fluid bed and spray drying will increase,” said Ross. “Likewise, dry granulation processing continues to trend upward.”
He said mini-tablets are emerging as an advantageous approach to treating pediatric and geriatric patients because of their inherently flexible dosing capability.
There is also growth potential in the development and manufacturing of amorphous solid dispersions (ASD) utilizing HME, according to VanDyke, who said this an effective way to improve solubility and/or bioavailability for BCS class II and IV APIs. While not a new technology for many other industries, extrusion is newer to the pharmaceutical industry and can be used to manufacture ASDs as well as to replace batch granulation processes.
“ASD offers a solution to the 70% of NCEs today that are poorly soluble and/or bioavailable,” she said. “Rationally designed ASDs can achieve higher apparent solubility and improved bioavailability while HME is an effective enabling technology to manufacture ASDs. During the HME process, a powder blend consisting of crystalline API and polymer(s) is transformed into an extrudate, which contains molecularly dispersed amorphous API in a polymer matrix. The extrudate is subsequently converted into granules or pellets for downstream processing using standard oral solid dose equipment. The extrusion process can also replace batch granulation processes as a continuous melt or wet granulation process. Compared to a traditional batch process, this exciting yet complex technology offers many advantages including but not limited to excellent product uniformity and higher manufacturing efficiency.”
When developing poorly soluble drugs as oral solid dosage forms, Hoffnagle said companies are sometimes not sufficiently rigorous in identifying future potential problems with their molecules. “There are various technologies to solubilize poorly soluble drugs, but the real challenge is to pick the most suitable technology for the molecule throughout its development journey,” she said. “Each technology is best suited to molecules with certain characteristics, so consideration should be given to the product’s physicochemical properties, drug targets and absorption sites, dose, and pharmacokinetic (PK) characteristics, among others. When patient-centric drug product design is considered, this adds another level of complexity. For example, manufacturing a pediatric oral solid dosage form with taste-masking properties and the flexibility for dose titration and administration across the pediatric age groups is probably one of the biggest challenges in drug development.”
Another area that is seeing greater demand is for instrumented technologies to enable deeper process understanding and facilitate continuous process validation. Data analytics coupled with machine learning or deep learning is an upcoming field of interest in the pharmaceutical drug development community.
“Deep learning methods have recently demonstrated to be able to predict the in vivo and in vitro characteristics based on the formulation and process data,” said Hoffnagle. “As we continue to develop a better understanding of deep learning methods within the pharmaceutical domain, it is foreseen that it will be a key technology driving pharmaceutical experimental design that will support and control product quality in the entire product development cycle.”
Moving forward OSD drug developers and manufacturers face some clear challenges ahead. One is delivering competitive cost of goods related to small-batch production, according to Ross. “Batch fixed costs make up a significant proportion of overall drug product cost—typically greater than 50%,” he said. “This is commercially prohibitive for small batches and will require manufacturers to reconsider long-established practices in order to reduce fixed costs.”
He also said accommodating to the varied expectations of sponsors and diverse global markets in a cost-effective manner is another challenge facing OSD manufacturers.
Customers who have utilized CDMOs to develop formulations and processes for their poorly soluble APIs are not always optimal, according to VanDyke. This makes technical transfers into facilities challenging and often requires reformulation work.
“When a formulation and process design is flawed, it can cause many challenges downstream, such as the need to repeat clinical studies, stability failures, and manufacturing challenges that can impact drug product supply,” she said. “It is therefore critical to establish a robust formulation upfront to minimize loss of time and increased costs.”