Sven Stegemann is Director for Pharmaceutical Business Development at Capsugel. Within this role he is leading common research projects with all major pharmaceutical as well as SME companies on a global base. He holds a PhD in pharmacology and is an endowed professor for patient-centric drug development and manufacturing at Graz University of Technology in Austria. Mr Stegemann worked in different roles of the pharmaceutical product. We asked him several questions about the future of the capsule market.
Mr Stegemann, many compare the capsule and the tablet market - and often the capsule market takes the second lead. What is the role of capsules as a choice dosage form today and in the future?
First, it is important to recognize that dosage form selection is an essential part of a medicinal product. Each product is unique in its technical requirements, the patient it targets and its commercial implications. In order to understand the current and future role of specific dosage forms like capsules, we need to look to scientific evolution, the dynamic changes in research and development, evolving patient needs and the market environment.
Since effective drugs are available for major chronic diseases and new research tools allow drug research on a molecular level (genome sequencing), drug research has shifted to finding new treatments for life-threatening diseases. When these drugs prove to be effective early in the development, fast patient access through Adaptive Licensing (EMA) or Priority Reviews, Breakthrough Designation, Fast Track and Accelerated Approval (FDA) becomes a critical factor, which has to be addressed by efficient product development programs. It is not surprising that capsules are often the dosage form of choice for such development programs, reducing significant product or process related risks in formulation and manufacturing.
Advancements in polymer science, design, manufacturing and finishing of capsules have enabled new functionalities and broadened the range of applications for this dosage form with powders, multi-particulates and liquid fills.
Continuing enhancements in the quality systems of capsule manufacturing applying the principles of Six Sigma is leading to higher standards, allowing pharmaceutical companies to significantly reduce their incoming controls, increase the yield and continuously meet stringent regulatory requirements. Additionally, this high quality level enables product development based on Quality by Design (QbD) principles, and advanced manufacturing technologies like continuous processing. Examples where capsules have been used specifically as the dosage form of choice include oral oncology drugs, inhalation drugs for respiratory diseases and fixed dose combination products.
When we think on a global scale, what are the major diffrences between mature and emerging market in regard to capsules?
Capsules are a popular dosage form worldwide. Moreover, capsule filling capabilities are available in most regions and in multiple pharmaceutical and consumer healthcare companies around the globe. There are many reasons why capsules are specifically used in certain regions.
In mature markets, where innovative drug products are developed, capsules are favored due to dose flexibility, product differentiation and speed-to-market. Moreover, innovative drug delivery technologies, for bioenhancement through spray drying and modified or dual release using pellet technology, are further driving preference. This combination of the capsule dosage form with drug delivery technology is one of the most exciting opportunities to deliver personalized and patient-centric drug products through tailored dosing and reduced therapeutic complexity. Recent examples include the introduction of new capsule delivery options, such as Coni-Snap® Sprinkle capsules, to address swallowability concerns and specialty polymers, like Capsugel's enTrinsic™, an extrinsically enteric capsule, and Vcaps® Plus capsules, with unique properties that broaden the formulation space for capsules while at the same time provide patients with a vegetarian option to gelatin.
In emerging markets, capsules are used because they allow formulation of regional products (traditional Chinese medicines), can be efficiently manufactured and may carry a lower cost compared to other dosage forms. For example, capsule-based dry powder inhalation systems help meet the World Health Organization's demand due to their relative simplicity in product design, efficient and unlimited manufacturing capacities and cost efficiency. There is an increasing trend towards regional and domestic manufacturing of pharmaceutical products, which require highly flexible manufacturing platforms. Capsule filling technology allows for filling of several types of formulations. This unique feature of capsule technology has recently been used successfully for the polypill, which also performed successfully in clinical trials.
In the pharma industry, capsules are the second most important dosage form after tablets. Yet, what about the nutrition sector. How will the ratio between pharmaceutical and nutritional markets change for capsules?
The pharmaceutical and nutritional markets are two very distinct segments and have their own dynamics. That said, the two segments are coming closer together as large companies increasingly serve patients and consumers with healthcare solutions ranging from pharmaceuticals to over-the-counter (OTC) to nutritionals. Also, recent EFSA action requires sufficient clinical evidence for the health claims made by nutritional products.
There were 21 new oral pharmaceutical drug products launched in Europe in 2015, of which nine, or nearly half, were capsules. There are many reasons that capsules are the dosage form of choice, including shorter development time, low development risk, dose flexibility and the availability of new polymer choices like HPMC capsules manufactured by a thermogellation process (Vcaps Plus®).
The OTC and nutritional market is driven by consumer demand and attributed product value. Constant innovation in nutritional ingredients and composition as well as dosage form are critical elements for the market's continued growth and commercial success. Capsules and capsule technologies cover many different formulations, including liquids, semi solids, pellets, granules, powders, tablets and combinations thereof. The availability and use of new capsule technologies in conjunction with consumer data will drive the development of innovative and differentiated nutritional products. Within the nutritional market itself, many sectors exist where capsules continue to play a major role. For example, in the probiotics market, capsules represented nearly half of new product launches in 2015, according to Innova data.
A very important trend in this segment is linked to increased consumer demand for safe and clean label products. Some recent scandals in the food industry have reinforced a tendency of the consumer to "scrutinize" the product label to understand the composition and origin of the product they purchase. In this regard, vegetarian capsules are meeting many consumer expectations, and allow producers of nutritional products to reduce the number of unwanted excipients within a product. This market is also very dynamic and relies on suppliers who provide innovative products that respond to consumer trends and preferences.
So besides the dynamics in both of these markets, what are the special challenges in manufacturing capsule products?
Dynamics such as globalization, advanced drug delivery and manufacturing technologies, quality and traceability requirements, cost containment pressures and growth of domestic manufacturing continue to increase the challenges associated with manufacturing of any dosage form. Moreover, pharmaceutical or nutritional manufacturers increasingly recognize that patients require more than a white tablet as a dosage form.
With the introduction of QbD principles in development and Process Analytical Technology (PAT)-based manufacturing controls, companies are required to perform risk assessments of different drug delivery technologies and dosage forms. While there is no single dosage form or manufacturing technology that fits all drug products, there is growing evidence that unnecessary complexity in drug product development can be avoided by using the capsule dosage form. This is also supported by published data from capsule suppliers showing that the empty capsules are suitable for QbD-based drug product development based on the consistent performance. With the broader range of capsule types, companies are exploring additional dosage form options rather than assuming that one form fulfills all formulation needs.
What requirements do you have for production technologies? Based on which criteria do you decide?
For more than a decade, the pharmaceutical industry has undergone an intense transition - moving away from high-volume based blockbuster products that treat chronic diseases to low-volume orphan drugs. This has been made possible by advancements in genomic and molecular based technologies as well as an increased understanding of the phenotypic nature of diseases. Moreover, the simple model of efficacy, which shows proof of benefit against the targeted disease, is being expanded to effectiveness - evidence that the drug works in real patients beyond the clinical trial setting. Patient research as a way to provide patient-centric solutions is becoming an important component in the development of new drug products.
Further, innovative manufacturing technologies are being developed, like close loop continuous processing, as a way to substantially increase manufacturing efficiency. The pharmaceutical industry is investing in manufacturing platforms in both mature and emerging markets. Capsule filling technologies play an important role in such investments, especially for the delivery of patient-centric forms (e.g. pediatric formulation and fixed-dose combination products) in combination with new drug delivery technologies like spray dried particles or modified release pellets.
In the nutritional segment, creativity and innovation lies with suppliers and their related investments in manufacturing technologies. Suppliers with a substantial engineering, product development and patient research background have a significant advantage, as these are the key areas required to deliver innovative nutritional products.
The stringent requirments and demands in the production and the dynamics of the markets seem challenging to manufacture capsules. What are then the advantages that capsules provide to patients?
When talking about patients, we need to consider the different types of healthcare products and the respective patient populations. Patients attribute the same value in terms of quality and expected health outcomes to prescription medicines, OTC and nutritional products. However, the applications, outcomes and regulations of these products differ significantly.
The primary focus for prescription medicine has traditionally focused on efficacy of the drug for a clinically diagnosed disease. Only recently, substantial evidence has highlighted the importance of the drug product design on achieving this efficacy in real patients - outside of the clinical trial setting. Product design includes the delivery technology (e.g. immediate release, modified release) and the drug product design (e.g. product recognition, physical characteristics).
Further, with increasing polypharmacy, patient value is derived from reduced pill burden and complexity in how and when patients need to take medicines. This simplification significantly reduces the demand for managing the therapy and increases adherence, while preventing medication errors. This is the concept behind the fixed dose combination products and modified and dual release options realized through lipid multiparticulate or pellet technology in which the medications can be reduced to a single dose. For such products, capsules are typically the first choice as they allow high flexible dose ranging, efficient manufacturing and clear differentiation by color combinations and imprints. The lipid multiparticulate pellets can also be released from easy-to-open capsules (e.g. Capsugel's Coni-Snap® Sprinkle capsules) for patients with swallowing challenges such as older adults and children.
In contrast, OTC and nutritional products are purchased by consumers based on the perceived value of these products in addressing their health conditions or maintaining good health. In recent years, Capsugel's Press-Fit® capsule technology has been successfully used for several analgesic, anti-allergenic and cold OTC products in Europe and the U.S. The consumer perceives these products as higher quality and easier to swallow, while at the same time providing fast symptom relief.
Many nutritional products have technical challenges that make it difficult to deliver the active ingredient and dose in a single solid unit other than a capsule. For example, plant extracts or minerals can be hygroscopic or have a poor flowability and cannot be compressed. Other nutritional ingredients that are semi-solid or liquid can only be filled in capsules specially designed for these formulations. Another attribute often mentioned by consumers of nutritional products is the masking of unpleasant smells or tastes of some of these products, such as fish oil. And, importantly, capsules meet increasing consumer demand for clean label, vegetarian-based products.
In fact, data generated from our own patient research studies are an essential part of identifying patient needs and help provide direction in developing pharmaceutical products that meet the needs of the patients from the earliest phase onward. Thus, capsules provide many possible advantages as a dosage form that can be rationally explored and applied during the conceptual and development stage of pharmaceutical, OTC or nutritional products.
Mr. Stegemann, thank you very much for your answers.