The oral solid dosage form is a cornerstone of the contract manufacturing industry. The market remains ripe with opportunities for contract manufacturers that are able to differentiate through niche technologies, capabilities and other value-add propositions. The service providers Contract Pharma spoke to about the state of the market all cited an upswing in outsourcing activity.

A new report published by Transparency Market Research titled “Oral Solid Dosage Forms and Pharma Excipients Market,” said the global oral solid dosage forms market was worth $571 million in 2011 and is projected to climb to $870 million by the end of 2018, growing on average of 6.3% per year.

“There is a lot of capacity in solid dose manufacturing across the globe, so just having capacity is not necessarily a differentiator,” said Kaspar van den Dries, senior director and principal scientist of solid dose development, Patheon. “Pharmaceutical companies are looking for expanded services such as integrated API, drug product services and flexible manufacturing capacity to be able to handle the intrinsic variable demands, especially at the time of product launch.”

At the same time there is a dwindling number of independent companies now left in the U.S. as a result of the need for scale in technology. “More European companies with less advanced facilities are in need of U.S. real estate, but cannot afford it,” said Derek Hennecke, president and CEO, Xcelience, part of Capsugel Dosage Form Solutions. “Asia is becoming less important for U.S.- and European-based companies, which have been hit hard by quality problems in India.”

The strong market demand for oral technologies is also witnessing an increased focus on robust formulation development due to fewer blockbusters, patent cliffs and constrained R&D budgets.

“The market for contract manufacturing and development services is strong as companies look to optimize their networks,” said Aileen Ruff, vice president, strategy and marketing, advanced delivery technologies, Catalent Pharma Solutions. “In the years ahead, this network optimization trend will likely drive increased consolidation across both pharma companies and suppliers. We will also see significant focus on oral delivery of large molecules as science and technology rapidly evolve to achieve this ‘holy grail’ of oral drug delivery.”

Ms. Ruff also pointed out an increased demand for generics as marketed products come off patent, particularly in Europe where price pressures are significant. “In the U.S., the specialty pharmaceutical segment remains strong, but from companies of all sizes there is continued demand for modified release and other complex formulations across both branded prescription and consumer health products, for example, to address compliance issues and minimize side effects,” she said.

Mr. Hennecke sees an emphasis on smaller scale products such as orphan drugs and pediatric applications. “We remain optimistic about the market as a whole based on the number of Phase 3 projects coming to market, and the amount of spending money raised by biotechs last year,” he said. “We do not see any pending changes in government policy to curtail R&D. The orphan drugs laws and incentives remain in place and are not likely to be revoked over the next two years.”

While the CDMO market is growing at a healthy rate, and this growth is expected to continue, one complexity involved is the fact that transferring, changing or improving existing manufacturing processes is still an under-evolved aspect of pharmaceutical manufacturing, according to Mr. van den Dries. “Global supply chains of pharmaceutical products are complex and regulations sometimes restrict the ability for continuous improvement or increasing flexibility in the supply chain,” he said. “Of course, there is also increased pressure on healthcare budgets, meaning that efficiency has to increase and costs have to go down to remain competitive in the business.

“Another aspect of today’s solid dose manufacturing is increased attention to the science and knowledge of these processes,” he continued. “Where in the past some processes were developed by art rather than science, significant efforts are currently being made through the Quality by Design (QbD) paradigm to improve the robustness of processes, and thereby the reliability.”

Living in Niche Times
The age of the blockbuster is widely acknowledged to be over. Innovative company strategies now include operating in more niche fields and developing more complex formulations that are difficult to replicate by generic players.

As a result, more specialized niche plants are being built, which fulfill the need for specialized enabling technology as well as enhanced speed and agility, according to Mr. Hennecke. “They are perfect for growing patient-centric dosage forms such as pediatric formulations, orphan drugs and 505(b)(2) applications,” he said. “Specialized partnerships can be formed for product development and manufacturing of such small scale/high value products.

“We continue to focus on such specialty applications, with an array of bioavailability enhancing technologies,” he added. “Indeed, the majority of products in the pharmaceutical pipeline are in the specialty and orphan drug designations, oftentimes requiring enabling technologies and specialized processing. These applications also typically need small and flexible scale manufacturing and high containment to efficiently and safely produce these products. We are operating in a pretty open field right now, as most CMOs were built for the large volumes of yesterday’s blockbuster.”

Ms. Ruff concurred, saying that with fewer blockbusters in the pipeline, companies are taking a more targeted approach to treat narrower disease states or patient populations, or looking to improve upon existing marketed products with next generation treatments that offer more optimal results. “More and more compounds in the pipeline have more complex delivery profiles, including precise release requirements, combinations of different APIs, and delivery needs in specific parts of the body for increased efficacy,” she said.

Mr. van den Dries said, “As the blockbuster drug model continues to evolve into a more personalized medicine and orphan indication, which means an increase in low-volume products and more specialized dosage forms, the pharmaceutical industry is just starting to react to these trends and understanding what it means for existing business models and manufacturing technologies.”

Opportunities Abound
There are a number of opportunities for growth, both from a technology standpoint as well as an integrated model for supporting client projects. New technologies are in high demand for overcoming bioavailability challenges.

“Bioavailability issues are common in today’s market, with an estimated 70% of drugs in the pipeline classified as poorly soluble,” said Ms. Ruff. “One challenge in optimizing the solubility of a molecule is that it often requires a multi-faceted approach to optimize the API, optimize the formulation, select and optimize the processing technology, and develop the desired marketed product form, such as a tablet or capsule.”

She said another challenge is in delivering drugs that are broken down by low pH in the stomach. “Tailored enteric coating or resistant capsules containing mini-tablets or pellets are a potential solution for local gut delivery and improved systemic availability. Then there are also the challenges of controlling release, tailoring delivery, preventing abuse and ensuring patient adherence. 

“There is also opportunity for innovative oral solid products that offer flexibility in timing of medication release, reduce side effects, optimize dosing schedules, drive patient adherence, or address the unique needs of certain patient segments such as pediatrics or the elderly, or individuals that may have trouble swallowing. These types of advanced drug delivery forms offer distinct marketing and brand advantages for customers while adding clear value for patients.”

In addition to technology for improved bioavailability, pediatric formulations are another area for growth, according to Mr. Henneke. “We are seeing increased application of our multi-particulate technologies and requirements for effective taste-masking,” he said. “Also, enabling viable alternatives to IV delivery remains an open opportunity. We see growing demand for new oral delivery approaches targeting the lungs.”

The CDMO market is still growing as more and more pharma and biotech companies are divesting chemistry and manufacturing controls (CMC) development and commercial manufacturing to focus on their core strengths of researching new molecules for treatment of diseases, according to Mr. van den Dries. “In addition, so-called virtual companies are also increasing in number, but have no internal manufacturing capacity and rely on contractors to assist them in bringing their inventions to reality,” he said. “One key challenge is that the CDMO market is highly fragmented with a lot of niche players in the field. This makes it complicated for pharma companies to identify the best solution providers for them, as the number of CDMOs and offerings they must screen as part of their due diligence in finding the best partner is significant.”

Customer Expectations
Pharmaceutical pipelines today require more flexibility in manufacturing than ever before. According to Ms. Ruff, there is an increasing demand for customized technical and business solutions, as blockbusters are replaced by more targeted treatments that have unique requirements. “We believe that the need for flexible solutions to bring specific products to market faster as part of a flexible manufacturing network strategy is key,” she said. “This entails providing customers with deep capabilities in key areas including customized solutions for complex products, potent drugs, fast and reliable product launches and meeting the need for fast and efficient technology transfers, unique solutions such as customized manufacturing suites and the capacity to support the demand for tailored manufacturing solutions.”

Mr. Hennecke said he is seeing more demand for drug design work versus “rescue missions,” as clients realize the need to involve their development partners at the earliest stages in order to better ensure success. “Historically, many clients engaged us to develop products based on their or other partners’ design, and oftentimes we would redefine the problem statement and redesign the formulation,” he said. “Speed to clinic remains a key concern and does not differ from the virtual client to big pharma—clients expect a tailored approach regardless of size, a high degree of collaboration, and the ability to take the product to clinic and commercial scale.”

For Mr. van den Dries, Patheon’s clients are evolving from treating the company as a tactical vendor to viewing it as a strategic partner. “Where in the past requests were largely about the capacity to manufacture clinical and/or commercial supply, the dialogue is now more about providing solutions in development and supply chain, and the desire to reduce total cost of ownership of these outsourced projects,” he said.

Solid (Dosage) Investing
Service providers continue to respond to client-specific needs and the general market trends with continued expansion of service offerings, capabilities and capacity.

In April 2015, Catalent opened a $52 million dollar expansion to its Winchester, KY, facility, doubling its footprint to 180,000 square feet. The investment included a new fluid bed, large analytical lab, and ability to provide integrated specialty packaging services. The expanded space provides the flexibility to handle large volumes, and the open footprint and large interstitial space also offers flexibility in designing custom or dedicated suites based on program requirements. In December 2015, Pfizer selected Catalent’s Winchester facility to formulate and manufacture its leading over-the-counter heartburn treatment, Nexium 24HR.

Across the oral solids business as a whole, Catalent has established end-to-end hot melt extrusion (HME) delivery platforms in both the U.S. and Europe. This HME offering, along with softgel and micronization capabilities, provides a suite of solutions to address bioavailability challenges. The Zydis orally dissolvable tablet (ODT) technology offers adherence and swallowability advantages, with a formulation that dissolves in less than three seconds. Catalent continues to invest in its Zydis platform to achieve higher drug loading and optimal taste masking.

Investment in 2015 at Catalent’s headquarters in Somerset, NJ, created a manufacturing Center of Excellence for potent handling across the company’s portfolio of oral solid manufacturing solutions, which included expansion in its high-shear and wet granulation processing, solvent-based capability, extrusion/spheronization, fluid-bed processing, Wurster coating, and compression and encapsulation platforms.

Catalent also recently announced it had created a dedicated Science and Technology organization within the company that will bring together internal experts across multiple technologies and disciplines to enhance collaborative scientific development between Catalent, its customers and partners, and accelerate the development of drug products through the use of advanced formulation and drug delivery technologies.

Catalent is also developing a novel dry coating process using acoustic mixing to taste-mask API molecules. These APIs, when formulated into tablets, provide effective taste masking while maintaining the desired dissolution release characteristics.

For Capsugel, the big news is that it acquired both Xcelience and Powdersize on Jan. 4 with both being integrated into the Capsugel Dosage Form Solutions business unit. Capsugel can now fully integrate the design, development and manufacture of innovative dosage forms across its range of solid dosage forms while addressing key formulation challenges, including low solubility and controlling or targeting release more effectively.

The acquisition of Powdersize gave Capsugel micronization capabilities, allowing it to engage clients at the earliest stages of development. Capsugel also wanted to offer solid dispersion technology, specifically spray drying, to its clients facing solubility challenges. The company said it would have been relatively easy to add a small-scale spray dryer, but quite a challenge to develop the operating expertise or provide phase-appropriate scale throughout the product development process. 

As the integration gains momentum, Capsugel is adding capacity and capabilities across technologies and product development sites. Capacity and product development teams have been expanded at sites to support liquid fill hard capsule and softgel technologies. A spray drying commercial manufacturing facility was added at Bend Research, also part of Capsugel Dosage Form Solutions. Powdersize just added a new Netzsche nano-mill to complement Capsugel’s particle engineering offering. In addition, Capsugel has expanded its product development teams and capabilities in Tampa, FL, where Xcelience is based.

Capsugel has a number of oral dosage enhancing technologies. Last November, it launched enTRinsic drug delivery technology, the industry’s first fully enteric dosage form without the need for functional coating, according to the company, and is seeing a lot of interest for enabling oral delivery of sensitive molecules such as proteins, nucleotides and live biotherapeutic products.

Patheon is making significant investments to expand its solid dose development and manufacturing capabilities. An example of this investment is visible in its solid dose site location at Bourgoin-Jaillieu in France, where the pharmaceutical development services (PDS) business has invested in a small scale GEA high shear/fluid bed granulation line with an operating range between 4-20 kg and a Gerteis roller compactor. Since the industry is seeing an increasing trend in the demand for handling high potent APIs (HPAPI), this additional equipment has containment at source and the ability to develop processes for HPAPIs. The commercial unit is investing in expanded high potency capabilities, with a large-scale pan coater (~350 kg) and dedicated dispensing isolator. Also, pharmaceutical packaging investments are being made in new lines able to handle high-potent products, including serialization.

In addition to the capacity expansion in its high-potency offerings, one other unique investment is happening at the Greenville, NC, site where Patheon is currently installing a continuous manufacturing line that is able to produce solid dose products by dry mixing, wet granulation or dry granulation in a continuous process.

Another key acquisition was that of Agere, based in Bend, OR, which specializes in spray drying and solubilization technologies. With its existing footprint in solubilization technologies in Milton Park, U.K. and through softgel sites in High Point, NC, and Tilburg, The Netherlands, Patheon now has a comprehensive offering of solibilization enhancement solutions. This not only focuses on screening and production of clinical supplies, but also includes the option to screen technologies in silico through molecular modeling capabilities and technology selection tools. According to the company, since more than 70% of molecules exhibit poor solubility that could limit bioavailability, these services are an important aspect in support of current pharmaceutical development programs.