EXECUTIVE INTERVIEW - Capsugel DFS: Integrating Technology for Innovative Finished Dosage Forms

With the push to bring new drugs to market faster, the healthcare industry has made significant advances in utilizing liquid and semi-solid fill technology, and incorporating lipid-based drug delivery systems to expedite development. While lipid-based formulations have proven to be capable of addressing bioavailability, high active pharmaceutical ingredient (API) potency, low dosing levels, and stability challenges, many formulation challenges still remain. With a very high proportion of the industry’s development pipeline consisting of molecules with poor bioavailability, advances in lipid-based formulation technologies are essential to the future of drug development. Amit Patel, President of Capsugel’s Dosage Form Solutions (DFS) business unit, speaks to Drug Development & Delivery about the formulation challenges facing the industry and the increasing pressure on companies to innovate and accelerate speed from lab-to-clinic and clinic-to-commercial to remain competitive in today’s dynamic marketplace.

Q: Can you provide our readers with some background on industry challenges related to formulations and what action Capsugel has taken to address them? 

A: Two primary, high-level challenges come to mind. First, nutritional and pharmaceutical product companies are constantly seeking ways to bring improved products to the market. “Improvement” can mean a number of things – enhanced bioavailability and absorption, optimized active ingredient dosing for highly potent compounds, improved stability, and even taste- and odor-masking, amongst others. Second, companies are interested in accelerating the speed from lab-to-clinic and from clinic-to-commercial. 

Capsugel’s new Dosage Form Solutions (DFS) business unit was created to fully leverage our encapsulation leadership, especially in liquid fill, to help address some of our customers’ most pressing challenges for existing and new nutritional and pharmaceutical products. DFS integrates various areas of Capsugel expertise – proprietary technology platforms, formulation R&D centers, and finished dosage commercial manufacturing sites – to work with customers to develop more innovative products. For example, the LIPIDEX platform integrates recently acquired Encap Drug Delivery and consolidates our leadership in liquid fill, giving us an additional FDA accredited manufacturing site and specific technologies in capsule banding, sealing, and coating. Some aspects of our proprietary platforms, taking a liquid fill approach to solid oral formulations, or having targeted release functionality as being intrinsic to the capsule shell (rather than applied through a coating), are naturally suited to help improve time-to- market because the approaches eliminate numerous time-consuming or technically challenging development steps.

Our premier capability in encapsulation in a vertically integrated B2B model allows us to partner with customers throughout the formulation process, clinical evaluation, and manufacturing of encapsulated dosage forms. We also leverage our specialized capabilities in polymer science, equipment design, and process engineering to help our customers develop better products faster, in an integrated and focused manner. 

Q: Given the increasingly dynamic marketplace, companies are trying to carve out specialist positioning. Where are the emerging opportunities for drug development companies?

A: It is a very “dynamic” marketplace, due not only to multiple recent acquisition transactions, but also to other factors, including evolving customer preferences, changing regulatory landscapes, technology advances, and new emerging business models. The pharmaceutical customer is facing tremendous pressure in bringing small and large molecules to market and increasingly needs specialist partners. Such partners need to determine what their best value proposition is for the industry – how can they best meet marketplace and customer demands. DFS is currently focused on liquid fill, inclusive of lipid and semi-solid, as well as targeted release technologies.

What differentiates Capsugel from other companies that align themselves with traditional roles such as CRO, CMO, or CDMO is robust intellectual property (IP). Capsugel DFS has an extensive IP estate surrounding our encapsulation technology platforms, as well as select internally funded finished dosage products that we are developing for subsequent marketing by licensed partners. We focus on leveraging our specific depth in liquid fill and lipid formulation expertise, as well as tailoring the hard capsule shell for modifying release. Our expertise in these technology platforms is premier in the industry.

Q: Do you see bioenhancement remaining as a primary formulation challenge for the drug delivery industry?

A: There are numerous industry challenges. Bioenhancement is one of many. Other formulation challenges include API potency, low dosing levels, and stability problems. Determining how best to meet these formulation challenges is paramount to the success of the industry. Without continued innovation, new or improved products will not be developed. I believe significant opportunity exists in two key areas:

(1) Bioavailability from a formulation and commercial viability standpoint and;

(2) Speed of formulation development and evaluation.

Today, up to 90% of new chemical entities in development are said to fall under either Biopharmaceutics Classification System (BCS) Class II or Class IV. Specifically, the bioavailability of the vast majority of drug candidates is expected to be low. There are a variety of different approaches utilized to improve solubility, often dependent upon the companies’ experience, to bring the bioavailability to an efficacious level and take these products to market.

Similar to solid dispersion approaches, lipid-based formulations can address a wide range of bioavailability challenges and are therefore utilized in the decision trees of many companies. However, formulators often seek deep technical assistance in identifying and developing an optimal bio-enhanced formulation, e.g. a lipid-based solution, suspension, or SEDDS/SMEDDS. To meet this demand, DFS has pulled together Capsugel’s collective historical capabilities and experience in lipid-based applications and approaches.

Capsugel has invested heavily throughout the past decade in lipid technology development with more than 400 reference formulations developed and a multitude of products brought to market. This experience has facilitated the development of a proprietary lipid expert system that is core to our fast-to-clinic program.

Our established fast-to-clinic program can complete preformulation work in five weeks and then move through formulation evaluation and dosage form selection, leveraging the liquid fill expert system where applicable, in an additional 15 weeks. Our encapsulation and liquid fill expertise is being leveraged for unparalleled speed and precision in formulation development and manufacturing.

Specialized equipment has been developed for capsule filling and sealing at clinical scale (CFS 1500), as well as commercial scale (LEMS 70), further facilitating clinical evaluation, ease, and predictability of scale-up while optimizing commercial manufacturing.

Q: Let’s talk about 505(b)2 filings – what role will they play in driving industry growth?

A: New Drug Applications (NDAs) based on 505(b)2 filings are likely to continue to be an industry growth driver. Developing a New Chemical Entity (NCE) requires significant time and resources (as long as a decade, and, at times, upward of a billion dollars per successful NCE). Additionally, the rate of commercialization success for small molecules is low, partially due to the bioavailability challenge previously referenced. Therefore, it is prudent for the industry to be pursuing new indications and improved target product profiles based on existing APIs.

The 505(b)2 NDA proposes a limited change to a previously approved product while demonstrating the required efficacy and safety of the change. Cost-value for the FDA 505(b)2 application is the avoidance of time-consuming, costly, and sometimes repetitive preclinical and clinical trials.

Further, revenue-value for the 505(b)2 can be extensive, offering the sponsor with three to five years of market exclusivity dependent upon the extent of change against the innovator product, as well as potential for exclusivity driven by intellectual property. Contrast this with only 180 days of exclusivity for an ANDA (and that for only successful first-to-file Paragraph IV filings), and it’s easy to see why there is increased pursuit of 505(b)2 approvals.

Q: What are the technology platforms Capsugel offers to address industry challenges of NCE and 505(b)2 development?

A: Unveiled in June, our new LIPIDEX® technology platform provides customers a comprehensive lipid, liquid, and semi-solid fill offering unique in the industry. LIPIDEX consolidates the breadth of lipid technologies developed by Capsugel, its extensive R&D formulation background, and liquid/semi-solid fill commercial manufacturing capability.

We have been formulating with lipids for many years with extensive project experience in meeting a myriad of formulation challenges – solubility, permeability, dose uniformity, low dose/high potency issues, food effect – as well as reformulating from non-oral dosage forms to liquid fill encapsulation. Improving solubility can facilitate smaller, more efficient dosage forms, as well as format changes. More efficient targeted release, our other area of focused investment, can also facilitate improved bioavailability as well as large molecule reformulation to solid oral dose.

We bring options and flexibility to pharmaceutical formulators and commercial teams. Our dosage form options include SGcaps® soft gelatin capsules and Licaps® liquid filled capsules. Capsugel continues to innovate and expand its lipid-based technology. A new solid lipid pellet dosage form is currently being used in both internal and client product development and is anticipated to launch in the coming months.

Our research and development capabilities are built around three state-of-the-art R&D centers located strategically in the United States and Europe. Collectively, these teams in Cambridge, MA, Strasbourg, France, and Livingston, Scotland, have over 20 years of focused formulation development experience for pharmaceutical and nutraceutical applications. These teams utilize a fast track evaluation protocol incorporating expert systems. Our formulation scientists have extensive background in simple to complex lipid systems in solution, suspension, or SEDDS/SMEDDS formulations. Small-scale liquid fill manufacturing technology is also available at our R&D locations.

Commercial manufacturing rounds out the LIPIDEX technology platform. We have liquid/semi-solid fill manufacturing in the United States, United Kingdom, France, and Japan. We have FDA- and MHRA-accredited finished dosage form manufacturing sites as well as high containment capability, hormone and controlled substance manufacturing, and modified release applications.

Q: With the industry’s focus on speed to market, does it make strategic sense for companies to seek formulation or development partners earlier in the development process no matter what challenges the compound may have?

A: Absolutely. In today’s competitive development environment, companies should seek collaborations with specialist companies possessing deep science and engineering capabilities in key technologies early in the development process. We believe that such early involvement maximizes the value-add we can bring our partners, eliminating or minimizing a costly trial-and-error formulation approach.

Q: As you look ahead, what industry trends beyond lipid-based drug delivery are on the horizon for the industry?

A: There are several emerging areas in the industry that we are addressing, but the following two in particular come to mind: (1) Targeted drug delivery systems and (2) Abuse-resistance technology. With the recent acquisition of Encap Drug Delivery, our formulation teams are looking ahead toward further development of our targeted drug delivery systems. Effective targeted delivery, inclusive of more consistent release at a targeted pH dissolution point, is important in improving the bioavailability and efficacy of the drug.

Encap’s dual release technology (DUOCAP) and Colonic Delivery Technology (ENCODE) are being integrated with our dual release approaches and DRcaps® acid-resistant technology. Our capsule coating capability, utilized for both controlled and targeted release applications, gives us additional flexibility in tailoring dissolution profiles and/or facilitating dual drug release where needed to meet a target product profile. We will soon launch an intrinsically enteric capsule for the pharmaceutical segment, positioned for rapid clinical evaluation without time-consuming tablet and enteric coating preparation and application steps. We believe that the enteric capsule will have further applications in large molecule delivery, and additional applications in conjunction with liquid fill formulations.

Another area of growth for Capsugel DFS is abuse resistance – especially noteworthy given the recent US FDA ruling preventing generic oxycodone products coming to market without abuse resistance. We have multiple projects underway, some customer-sponsored and some internally funded, that are leveraging our experience with abuse deterrence formulations and ABUSOLVE technology platform.

In summary, Capsugel will continue to apply and expand our offering in bioenhancement and specialized drug formulation to remain at the forefront of this rapidly evolving industry.