Features

Oral Solid Dosage Outsourcing: Trends & Challenges

By Tim Wright, Editor, Contract Pharma | March 7, 2017

Despite the increasing number of biologics, oral solids remain the dominant dosage form in the pharmaceutical market.

Oral solid dosage forms are used across the entire spectrum of pharmaceutical candidates and products. They are the dominant mode of delivery in the pharmaceutical market and are the preferred option for many pharmaceutical products because of their cost-effectiveness and patient compliance. In addition, the use of tablets or capsules for a drug product can provide many other advantages, such as increased chemical and physical stability, unique brand recognition by shape and color, convenience of handling, and controlled-release options.

Due to their popularity and widespread use, the demand for contract manufacturing of solid forms is strong. The market continues to perform well and the industry experts we spoke to for this article anticipate further, long-term growth based on aging populations, increased affluence in emerging markets, continuing scientific breakthroughs and industry consolidation.

“The overriding trend is, of course, continued outsourcing, whether by Big Pharma due to divesting its manufacturing capacity or small-to-mid-sized companies that do not have the clinical and/or commercial scale manufacturing capacity,” said Stephen Brown, managing director, Capsugel Edinburgh. “Contract development and manufacturing organization (CDMO) partners fill this gap and we see more preference for those that offer ‘enhanced’ services, including effective product design, while being able to address complex formulation challenges and have the ability to effectively scale specialized processing techniques.”

This interest is coming from a range of clients, according to Mr. Brown. Not just innovators, but virtual companies, specialty companies, and increasingly, generic players as they reposition from the tail end of the patent cliff. Flexible, small-scale, more modular manufacturing is important to support many specialty products such as orphan, pediatric and 505(b)2 programs.

As molecules become increasingly complex, Elliott Berger, vice president, global marketing and strategy, Catalent, said customers are needing to apply best formulation technology earlier in the development process. “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,” he said.

Increasingly, he said, compounds in the pipeline require more complex delivery profiles, including precise release requirements, combinations of different active pharmaceutical ingredients (APIs), and delivery needs in specific parts of the body for increased efficacy. There are also increased demands from payers and patients for convenience in administration, reduced pill burden and improved adherence.

Consolidation in the contract manufacturing organization (CMO) and CDMO space continues as predicted with technology providers being acquired either by larger CDMO/CRO players or specialty pharmaceutical companies. “Consolidation appears to be centered around the acquisition of key enabling technologies, such as spray drying, that play a key role in providing enhanced or innovative dosage forms,” said Mr. Brown. “The emergence of CDMO’s with integrated capabilities across the API, advanced formulations and concept-to-commercial manufacturing is a more recent trend and applicable to both small and macromolecules. It provides clients with accelerated product development timelines, as well as reduced cost, program complexity and overall risk.”

Moving forward, as larger companies continue to consolidate their partner bases and smaller companies take more compounds further into the clinical process, there is an increasingly imperative need for strong partnerships across all development phases.

Market Growth
There are many opportunities for growth in today’s solid dose market, both from a technology standpoint as well as an integrated model for supporting client projects. It is important for CDMOs to have a flexible business model to adapt to the changing demands of the industry.

“Funding from the VC community continues to flow well supporting new investment into emerging companies,” said Anil Kane, executive director, global head of formulation sciences, Patheon. “Big Pharma are looking at various opportunities to balance their portfolios and focus investment in their core capabilities and outsource the rest to experienced CDMOs with a good regulatory and quality track record. Patheon has offered several options to our clients to meet their specific needs including flexible manufacturing solutions from a traditional business model, condominium model, dedicated facility and other options as well.”

There are many specialized products looking for suitable CMOs, including both innovative drugs and niche generics, and they constitute a great opportunity, according to Manuel Leal, business development director, Idifarma. “Also, the complexity of generics coming off patent in the coming years is increasingly high, including controlled release applications, high potency, low bioavailability, etc. Those CMOs that have the capabilities to handle them will grow quickly,” he said.

Increased regulatory requirements are also both a challenge and an opportunity to grow for compliant CMOs. “The serialization deadline will be a challenge, mostly for bigger-scale CMOs, which will have to make significant investments,” said Mr. Leal. “The current regulatory and financing situation for the so-called supergenerics in Europe is an obstacle when compared to the U.S., where the 505(b)(2) regulatory pathway represents an important number of applications. Such an approach in Europe would bring a lot of needed innovation to old generics and would have a positive impact on patient compliance and eventually in the sustainability of healthcare systems.”

Erik Haeffler, vice president manufacturing services, Recipharm, said there are three types of projects that are driving the contract solid/semi-solid dosage business. “Firstly, customers with high volume products are looking for a better set-up from a total cost of supply point of view,” he said. “While previously customers would typically consider just the cost of contract manufacturing, they are now recognizing that there are other factors at play. For example, the location of manufacturing can cause issues, slowing down the supply chain and in some cases even jeopardizing supply.

“Secondly, with products that require complex manufacturing processes, customers struggle to find the required technical set-up that is also manageable from a cost standpoint. Consequently, CDMOs with a breadth of capabilities are best positioned to simplify the supply chain.

“Thirdly, we are seeing a trend where relatively small/virtual companies are developing new drugs but do not intend to manufacture the products themselves.In this case, they are partnering with CDMOs with development capabilities from the start.”

For some years, mounting pressure on development budgets has, for many, placed a demand on R&D teams to quickly identify the best few candidates, according to Catalent’s Mr. Berger. “R&D productivity can be optimized by improving these early stages of the drug development process and outsourcing can make prioritizing development portfolios faster and more efficient. From a market perspective, increasing demands from doctors, patients and especially payers, for ‘demonstrable efficacy’, require that early stage drug design focuses more on patient outcomes in order to deliver better treatments. Drug delivery technologies are vital to help deliver these outcomes, with tools to reduce patients’ pill burdens, improve palatability, eliminate dose variation, for example, due to food effect, and offer dose forms that patients prefer and that less frequently require a medically trained person to administer.”

Capsugel’s Mr. Brown, said, “Enabled formulations for improved bioavailability are a key ongoing opportunity regardless of the regulatory pathway being pursued. Pediatric formulations are another area for growth, and we are seeing increasing application of our multiparticulate technologies and requirements for effective taste-masking.”

Microbiome and live biotherapeutics, i.e. using a living microorganism that is applicable in the prevention, treatment and cure of a disease, represent a vast and exciting new field, according to Mr. Brown. In addition, the oral delivery of biologic APIs is an area representing many key challenges, and will remain a huge area of R&D investment. “Effective solutions for addressing the physical and chemical properties of large biomolecules and the biochemistry of the gut have yet to be identified,” he said. “Many approaches have been explored, e.g. permeation enhancers, nanocarrier and pro-drug approaches, with success in animal models but none have advanced into a commercial product.”

Much discussed in recent years is the rise of patient-centric drug development, according to Mr. Berger, which he says will continue to accelerate. “The economic sense of developing medicines that will be taken properly will be made increasingly apparent to developers, and be recognized by those who pay for medicines, whether they be insurers, or state-owned healthcare systems,” he said. “CDMOs such as Catalent have much to contribute in this area,  with proprietary technologies such as Zydis orally disintegrating tablets, and a wealth of experience in controlled and modified release oral dose forms, to help deliver drugs optimally over time, or to targeted parts of the body.”

Mr. Brown agreed that moving forward we will see a continued focus on patient-centric drug delivery, in addition to an increase in patient access to the most effective therapies, and an overall increase in patient demand for innovative drug products. “Further, there will be an emphasis on smaller scale products such as orphan drugs and pediatric applications,” he said. “We remain optimistic about the market due to the continually increasing number of Phase 3 projects coming to market, the promise of biotherapeutics and the amount of investment capital raised by biotech companies over recent years. Finally, we see increased throughput of new drug applications by the regulatory authorities, and do not foresee any pending changes in government policy to curtail R&D.”

Innovation Through Investing
One of the ways successful innovation can be achieved in today’s market is by making the right investments either through acquisition of a company or key technology, or capital expenditure in facility and/or equipment upgrades.

For its part, Catalent recently completed two key acquisitions to supplement its range of drug delivery technologies. In 2016, it acquired Pharmatek Laboratories, Inc., a West Coast, U.S.-based specialist in drug development and clinical manufacturing. The acquisition has added extensive early-phase drug development capabilities from discovery to clinic, bringing spray drying into its portfolio of bioavailability enhancing solutions and expanding its capability for handling highly potent compounds.

Then, towards the end of last year, Catalent announced the acquisition of Accucaps Industries Limited, the Canada-based developer and manufacturer of over-the-counter (OTC), high potency and conventional pharmaceutical softgels. This move complements Catalent’s global OTC and prescription pharmaceutical softgel capabilities and capacity with the addition of a portfolio of products supplied to pharmaceutical companies in North America, and two state-of-the-art facilities offering integrated softgel development, manufacturing and packaging.

“As a business, we are continually looking to provide solutions to the increasing number of development molecules suffering bioavailability issues,” said Mr. Berger. “Speed of development remains a challenge to all drug research, and Catalent has responded by giving clients a fast, fixed price methodology to profile candidate molecules and provide an assessment of the most suitable formulations, and a selection of drug delivery methods. Our multiple award winning OptiForm Solution Suite combines rapid screening technologies to match the best drug delivery technologies to each developmental molecule, with the goal of providing optimal animal PK materials in just twelve weeks.”

Catalent recently extended this platform with OptiForm Solution Suite Bio, which allows the rapid screening of macromolecules, and the identification of suitable oral methods of drug delivery for biological drug products.

Idifarma has continued to grow its contract manufacturing client base steadily since it started offering services just a few years ago. The company recently invested in hard capsule filling equipment, which will allow it to provide contract manufacturing services in this dosage form in the coming 2-3 months, in addition to its current capability to manufacture IR/MR tablets. The company’s specialization in high potency drugs for manufacturing, as well as development, is and will remain one of its most relevant assets.

“Our approach to CMO services is very particular, since we are focusing on niche products, highly potent or not, requiring a small-mid batch size and customized packaging,” said Mr. Leal. “Being able to manufacture commercial batches has also attracted relevant contract development business as well, which explains our yearly growth of over 20% in the last few years. Our recent investment in capsule filling equipment reinforces our mission of becoming a strategic partner for our clients in the manufacture of niche products in solid dosage forms.”

Recipharm recently signed a master supply agreement (MSA) with Tillotts Pharma to manufacture commercial quantities of established products Entocort and Asacol, anti-inflammatory oral drugs to treat bowel conditions such as Crohn’s disease and ulcerative colitis. In addition, a new product, TP05, has been developed for commercial launch in the U.S. as well as the rest of the world.

“Recipharm has been able to offer a solution that covers the whole supply chain, removing the need to work with multiple suppliers,” said Mr. Haeffler. “In this case, we are utilizing capabilities at multiple Recipharm facilities, something which we believe differentiates our offering in the market.”

The company’s team in Pessac, France is using advanced pellet coating technology to enable controlled release, while tablet and capsule manufacturing as well as packaging takes place in Fontaine, France. Recipharm’s facility in Lisbon, Portugal is also assisting with bottle filling and packaging. In areas where it is experiencing customer demand, the company continues to make capital investments into new capabilities to support contract manufacturing projects. For example, an upgrade, co-funded by the customer, is currently taking place at Recipharm in Fontaine to allow it to handle new solvents as part of the tablet coating process.

On Feb. 1, 2017, Patheon announced that it had completed the acquisition of a state-of-the-art manufacturing facility in Florence, SC, from Roche Holdings, Inc. and has begun integrating the site into its network. The site adds a 300,000 square-foot facility with manufacturing capacity for APIs ranging from development to manufacturing services. With the addition of this site, the company also expands its capacity for manufacturing highly potent compounds, adds capabilities to support solid state chemistry, small and large micronization and future commercial spray drying.

In its production space the facility features reactors ranging from 50-11,000 liters producing multiple products simultaneously. According to the company, the facility is fully compliant to all applicable regulations, fully validated to meet the most stringent production, quality, cGMP, safety and environmental standards, while providing highly flexible operations that allow it to quickly adopt to new production needs with capabilities in small and large-scale manufacturing.

“The site will serve as Patheon’s flagship U.S. API operation for commercial scale and mid-scale API production of small molecules, and will also enhance Patheon’s emerging pharma presence in the U.S. market,” said Mr. Kane. “This acquisition is the sixth in the last five years and supports the company’s plans to create the only integrated, end-to-end provider of pharma development and manufacturing services. The small molecule APIs manufactured at this plant along with other plants in North America and Europe can feed into the oral solid dose network for our clients.”

Patheon has also invested in a continuous manufacturing suite in its Greenville, NC, site. According to company, the construction of the suite is complete, the equipment is in the final stages of qualification and it will be ready to run feasibility trials in Q2/Q3 2017. The suite is designed to run direct blending, roller compaction or high shear wet granulation processes leading to downstream encapsulation or tabletting.

After successfully completing four transformational acquisitions, as well as several other strategic investments, Capsugel unveiled a new corporate campaign in September 2016 that unites all the companies under one umbrella, highlighting its expanded capabilities for the design, development and manufacture of a wide range of dosage forms.

“We continue to transfer best practices between our U.S. and European sites in key technologies such as lipid-based formulations, spray drying, melt-spray-congeal processing and more,” said Mr. Brown. “The investments we have made in the last year are myriad and are very much in line with key industry trends and needs.”

The company installed lab-scale spray-drying capability at its integrated product development and commercial manufacturing sites in Europe, complementing its concept-through-commercial capabilities at Capsugel Bend. The spray dryers are based on proprietary designs and complement the lipid-based formulation expertise, liquid-filled hard capsule and soft gel capabilities based at these sites.

It also expanded micro-dosing/powder-in-capsule services using Capsugel Xcelodose equipment, which provides rapid screening of API candidates while reducing early stage product development time. It now has multiple Xcelodose units to support both development and clinical trial manufacture in the U.S. and Europe, inclusive of high containment capabilities. 

Capsugel also expanded its micronization capacity, including state-of-the art high containment technologies, for both non-GMP development work and suites dedicated to commercial manufacturing. Its jet mills are based on proprietary designs and the company has integrated its particle engineering and formulation development services.

Lastly, Capsugel highlighted a new containment laboratory and formulation capability dedicated to live biotherapeutics inclusive of microbiome, a growing area of industry research and development. Specialized equipment has been designed for liquid-filled capsules tailored to these applications.