Issue:June 2014

EXECUTIVE INTERVIEW – The Integration of Bend Research With Capsugel Dosage Form Solutions (DFS)

Small molecules have properties that pose increasing challenges for drug formulators. These include physical properties that lead to low bioavailability, high-potency/low-dosing requirements, and the need for modifying dissolution profiles. Market drivers, such as pediatric dosing and FDA 505(b)2 filings, also require innovative solutions. These dynamics are combined with an ongoing emphasis on speed to market, minimized development costs and risk, and enhanced patent protection. Bend Research, now integrated with Capsugel’s Dosage Form Solutions (DFS) business unit, has a broad spectrum of technologies for bioavailability enhancement and other key formulation challenges facing its clients, and provides integrated design, formulation, and commercial manufacture of products. Rod Ray, former Bend Research CEO and now a member of Capsugel’s Scientific and Business Advisory Board, speaks to Drug Development & Delivery about the enhanced capabilities of Capsugel DFS and the advantages offered to companies developing new and/or enhanced medicines.

Q: How did the acquisition of Bend Research enhance the capabilities of Capsugel DFS, and how do these capabilities differ from other CROs/CMOs?

A: Bend Research is well known in the industry for its technologies, including spray-dried dispersions (SDDs) for solubility enhancement. Additionally, Bend Research has a reputation for its depth of scientific and engineering expertise, including a long history of developing new drug delivery technologies. Capsugel is the world leader in hard capsule technology and supply, with a reputation for quality and innovation in capsule product range, materials, and manufacturing technologies. In addition, formulation and commercial manufacture of liquid-fill hard capsule and soft-gel capsule products have historically been among Capsugel’s core capabilities and formed the basis of the Capsugel DFS business  unit, which was further augmented by the acquisition of Encap Drug Delivery in March 2013.

The subsequent acquisition of Bend Research in October 2013 has created a powerful combination with substantial synergies to the Capsugel DFS technology offering, especially in the areas of bioavailability enhancement, modified formulation services. The technology range, intellectual property estate, collaborative product development approach, and internal product development pipeline differentiates Capsugel DFS from typical CRO/CDMO players. Customers can now come to one partner to develop, optimize, and manufacture robust drug or nutritional products.

Another differentiator, and shared value between Bend Research and Capsugel, is working collaboratively with the customer for the best solution to a drug delivery problem. The customer knows its drug best and often has market-driven preferences on the type of technology and final dosage form most appropriate for the target patient population. Capsugel DFS respects these preferences, and our multidisciplinary teams work with clients to identify the best platform, based on meeting the target product profiles within the commercial parameters.

Q: Bioavailability continues as a key formulation challenge – and has always been core with Bend Research. How has this capability been enhanced with the integration?

A: The breadth of technologies, technology selection processes, and overall formulation know-how has been enhanced. Bend Research has extensive experience, expertise, and capitalization in amorphous bioavailability-enhancement technologies. Most broadly applicable is the SDD technology, which has been used to advance numerous compounds through feasibility screening, with many advancing to Phase III and moving toward commercialization. Bend Research also has deep capabilities and understanding of hot-melt extrusion (HME) technology, as well as of attrition milled and assembled nanocrystals.

Lipid/liquid-based formulations (LBF) have long been a core technology platform and capability of Capsugel and Encap Drug Delivery, and hundreds of compounds have been advanced and commercialized. This formulation expertise is further evidenced with the development of lipid multiparticulate (LMP) technology and an expert system for accelerating LBF development.
The end result is that regardless of the compound’s properties Capsugel DFS has the technology platform and experience to advance compounds rapidly to market, while also incorporating a range of modified-release profiles and finished dosage formats.

Q: Spray-Dried Dispersion Technology has always been core to Bend Research. What are the plans and capabilities now and in the future in this area?

A: For more than 20 years, Bend Research has been focused on designing and developing SDD formulations through the clinical supply stage, which can typically be accomplished in 6 months or less. Our process experience, mathematical engineering models for process development and scale-up, capitalized scale-up train, and above all else, skillful Bend Research engineering staff, have led to a rapid, robust process-development effort. Years of engineering work devoted to understanding the SDD process have resulted in efficient scale-up efforts today, as well as efficient transfer to the GMP Phase III and commercial processes. Our deep process understanding has also resulted in a natural Quality-by-Design (QbD)-ready process. This gives our clients the option of filing a QbD regulatory document and also results in such thorough process understanding that post-approval improvements and/or troubleshooting are facile.

With the newly combined resources and expertise of Bend Research and Capsugel, we are now ready to take SDD and our other technologies to the next level. Extensive capital is being invested in the late-stage development and commercial capabilities at Bend Research. Central to this investment is the addition of a commercial “wing” in the Bend Research GMP facility, equipped with a large spray dryer capable of commercial production of multiple compounds. This addition is being designed and constructed with a high-containment capability that will be unique in the industry. We have been awarded multiple commercial contracts to date.

Q: How will Bend Research’s technologies in modified release be utilized in Capsugel DFS?

A: Modified release is another exciting growth area for us – one in which our collective technology and know-how is very complementary in both established and IP-protected technologies. The integrated Capsugel DFS has a full array of technologies with which to modulate dissolution profiles – delayed release/enteric protection, first- and zero-order controlled-release profiles, combination drugs and/or pulsatile release, and specific GI tract targeting, such as colonic delivery.

Optimal technology selection has been developed for determining the right type of coating and the right process for applying the coating for modified-release applications. This protocol gives the customer a coating formulation with the best performance and a coating process that is scalable and transferrable – key issues in the industry.

Additionally, our capsule technologies – intrinsically enteric capsules, capsule-in-capsule formats, and specialized capsule coating approaches – provide additional and proprietary formulation options to our clients. It is also worth noting the complementary nature of our technology platforms. Our modified-release approaches are often used in conjunction with bioavailability-enhancing technologies to meet pharmacokinetic profiles and optimize finished dosage forms, which can be supplied as osmotic or matrix tablets, multiparticulates in capsules or sachets, liquid fill hard capsules, or soft gels.

Q: Multiparticulate formulations continue to grow in application – can you speak to the Capsugel DFS offering?

A: Multiparticulate formulations are quite versatile and increasingly utilized in meeting our client formulation challenges. Once it has been determined that multiparticulates are appropriate, the choice of type of multiparticulate follows our rational technology-selection process. Layered multiparticulates are routinely developed using fluid-bed coating technology, a core capability of Bend Research, when there is a need for modified release or “triggered” release of either solubilized or non-solubilized drug. A range of mechanisms are utilized, eg, pH trigger, time trigger, or diffusion controlled to modulate release and/or provide taste-masking.

Bend Research also has fundamental capabilities in matrix multiparticulates, including mini-tablet formulations and melt-spray-congeal (MSC) processing for lipid multiparticulates (LMP) manufacture. Our LMP technology can provide a combination of bioavailability enhancement, controlled-release, and taste-masking functionality, and are manufactured by hot-melt extrudate being introduced to a spinning disc that generates particles with a very narrow size range. The resultant particles can be formulated into capsules, tablets, or sachets, and have market precedence – the Pfizer Zmax® commercial product utilizes this technology. Commercial-scale LMP production is being installed currently at one of Capsugel’s commercial manufacturing sites to fully integrate this offering.

Q: How does Capsugel DFS approach technology selection and project de-risking?

A: Technology selection is a core capability of the integrated Capsugel DFS that differentiates our product development process and results in optimized dosage forms, rapid first-in-human trials, and reduced costs in terms of client time, API usage, and scale-up activities. Our breadth of technologies especially in bioavailability enhancement, fundamental science and engineering, and extensive formulation experience are the foundation of our technology selection processes. With the integrated Capsugel DFS, a customer can now bring its molecule(s) to a single partner for integrated development with rapid technology selection, instead of evaluating various specialized technologies with multiple contract vendors. Avoiding the management of multiple programs decreases risk, cost, and overall complexity of product development. We can develop enabling formulations for evaluation in as little as 2 to 3 weeks with minimal API, and reach clinical in 6 months or less independent of technology utilized. We typically begin with consideration of the drug’s physicochemical properties and biological factors that can drive technology selection: solubility, dose, potency, and other properties that are relevant, based on our extensive investigation and experience.

Biomodels have been developed that accurately predict the performance of the API based on its properties and the characteristics of the formulation technology. This type of modeling has proven highly useful in choosing the best bioavailability-enhancement technology and/or controlled-release technology, as well as key process parameters.

Additionally, after formulating literally thousands of drug compounds, we have formulation guidance “maps” centered on key drug properties. These maps can help immensely in combining knowledge of drug properties, dose, and solubility over many compounds to choose the right technology for a given situation without parallel empirical testing that would otherwise unnecessarily consume valuable time and API.

Q: How do the Capsugel DFS offerings benefit 505(b)2 and product-enhancement trends in the industry?

A: Our offering is especially suited to the growing 505(b)2 category and continued trends in re-positioning established drug compounds (ie, technologies to improve bioavailability, modify or target drug release for improved therapeutic effect or reduced pill burden, and develop pediatric or geriatric applications leveraging multiparticulate or other finished dosage forms). Our integrated product development and technology selection processes provide optimal speed to market, critical for the 505(b)2 product concepts.

Proprietary technology plays a key role, and a few specific examples are worth mentioning in addition to the aforementioned LMP technology. Our new intrinsically enteric capsule technology provides unique enteric protection and delivery profiles without coating. Specialized approaches for abuse deterrence and colonic delivery are also increasingly utilized in developing products.

Capsugel DFS is also utilizing its technologies to develop enhanced “in-house” nutritional and pharmaceutical products for eventual licensing to commercial partners.

Q: What does the future hold for Capsugel DFS?

A: We are very excited about our future and will continue to invest to drive growth and innovation. Three key areas of investment for Capsugel DFS will be infrastructure, new technologies, and the optimal use of data.

We will continue to scale our premier bioavailability-enhancement, as well as modified- and targeted-release technology platforms. As previously mentioned, our infrastructure is being expanded with commercial production investments ongoing for both SDD and LMP technologies. We are also adding additional non-GMP SDD capability to enhance and speed our development work. High-potency suites, already in place at our co-located product development and manufacturing sites, also continue to be enhanced.

Additionally, we are leveraging core capabilities and synergies in two key growth areas: inhalation and abuse-deterrent formulation technologies.

Our inhalation formulation offering for pulmonary and nasal delivery benefits from Bend Research’s particle engineering expertise, based on spray drying, and Capsugel’s specialized dry powder inhaler (DPI) capsules. We have a number of client projects underway with both pharmaceutical and delivery device clients. Our abuse-deterrent formulation technologies, offering formulation options tailored to the likely route of abuse for a particular API, are increasingly utilized and driven by regulatory requirements. We have a number of client projects underway, several of which also utilize our modified-release technologies.

Finally, we are investing in the broad area of “getting the most from our data” or “big data.” It is well known in many industries, with Pharma being no exception, that more valuable information can be created from existing data sets. Bend Research is a “center of excellence” in this area, given its extensive work in developing science of scale, process understanding, and QbD approaches for Pharma companies for various small molecule and large molecule applications. This capability, combined with breadth and depth of technology offerings, is a key differentiator for Capsugel DFS, and should reduce the number of direct experiments and studies that must be performed and paid for, while extracting more information.

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