Dr. Klaus Pollinger and Dr. Martina Breuer, Aenova Group, explore the challenges of development and commercial manufacturing of oral solid dosage forms, from a CDMO perspective.
Two key trends can currently be identified in the pharmaceutical market: innovative drugs are strongly on the rise, and the oral solid dosage form will continue to be the preferred dosage form on the global market.
On the one hand, innovative active pharmaceutical ingredients are designed to be highly specific to their biomedical targets, which enables therapeutic breakthrough and lowered side effects. On the other hand, these substances have specific challenges, especially when formulation as oral solid dosage form is targeted. Such challenges are poor solubility and oral bioavailability, as well as the highly potent nature of active ingredients (up to OEB 5). Consequently, developers and manufacturers must leverage innovative technologies and offer solutions to handle highly potent APIs (HPAPIs).
Differentiated technologies for complex therapeutic systems and better bioavailability
Most of the drug substances in research and development belong to biopharmaceutical classification system (BCS) class II (low solubility / high permeability) and IV (low solubility / low permeability). To formulate these substances as solid dosage forms, three key technology solutions have been successfully applied:
- Amorphous solid dispersion
- Particle design
- Lipid-based formulations
The formation of amorphous solid dispersions has been gaining increasing attention in the last decade. Key technologies to generate amorphous solid dispersions are Hot Melt Extrusion, spray drying or co-precipitation. Particle design is often considered as micronisation of APIs, however, innovative technologies leading to nanocrystals have been successfully applied for several marketed medicines. With soft capsules as dosage form of choice, lipid-based formulations make use of the advantage to keep the API in a lipophilic environment.
In the field of complex solid dosage forms, intelligently encapsulated mini tablet systems (EMTS, see photo 1) or multi-unit pellet systems (MUPS) can control the release of the active ingredient(s). This can increase the bioavailability of the active ingredient, but it also enables the combination of different active ingredients to improve the therapeutic effect of different molecules. Additionally, the drug release can be designed in a way that is optimising therapeutic effects and therapy adherence.
Encapsulated mini tablet systems (EMTS) can control the release of the active ingredient(s) (Photo: Aenova)
Such innovations also include projects in the field of highly potent drugs, particularly in oncology, to offer patients a simplified and less burdensome form of therapy. This is especially relevant to overcome exhausting therapy cycles by applying oral solid dosage forms, which can improve patient acceptance level and consequently therapy success.
Every drug substance is unique in its physicochemical properties and its pharmacokinetics. Consequently, a CDMO must provide all of the above-named technologies paired with the respective formulation and process know-how. This is key to be in the position to select and apply the most suitable technology and formulation and deliver rapid and risk-mitigated development and launch.
Challenges in the development and production of HPAPIs
Oncology and hormone therapy have become increasingly important in the past decade, as innovation in drug research allowed to develop more and more target specific substances. These active substances exhibit an improved risk-benefit profile. Consequently, HPAPIs are on the rise and will play an important role in drug therapy in the future.
Market demands for cancer therapies is also growing rapidly. As a result, the targeted patient group is becoming smaller, as are the SKUs produced. However, the development and production of drugs with HPAPIs in the field of oncology is highly complex and often must be achieved under time pressure, as many of these new molecular entities (NMEs) are approved as "breakthrough therapy" in a fast-track process to quickly meet the high medical demand. This makes it all the more important to have a competent CDMO partner for a fast time to market, from development to commercial production.
Flexible commercial production of high potent APIs (Photo: Aenova)
Three pillars for safe and efficient handling of HPAPIs
Dealing with HPAPIs and the manufacturing of high potent medicinal products is challenging. The regulatory requirements to produce high potent drugs, which are laid down in various international guidelines, are consequently high and strict. This refers not only to the quality of the product, but also to the safety within production (see photo right).
In a risk assessment developed by Aenova, the potency of the active ingredient, the physio-chemical properties, the quantity, and the duration are set in relation to each other to achieve the best possible risk minimisation in development and production (see figure 1).
Figure 1: Risk assessment in the manufacturing of oral solid dosage form per process step (Graphic: Aenova)
To ensure safe and efficient handling of high potent products it is key to master a holistic production concept as a basis for the three pillars - production equipment, processes and people.
Production equipment, processes, people
It is important to provide a closed containment of the various equipment and production lines in combination with a clear flow of material. For example: starting with API dispensing in an isolator and all subsequent process steps, i.e. blending, granulation, sieving, tableting and tablet coating are executed in a closed containment environment. This equipment train ensures safe and efficient handling of HP products from powder handling to finished dosage form (see figure 2).
Figure 2: Closed containment concept for the manufacturing of high potent drug products (Graphic: Aenova)
In terms of optimal use of rooms and facilities, workflows and handling, there must be a deep understanding of efficiency and optimal use of all resources, e.g. implementation of lean and scalable processes, suitable room concepts, proper pressure concept, fitting supporting processes.
In addition to equipment and well-designed processes, there is a third, particularly important pillar: the highly qualified, experienced and well-trained employees with the appropriate awareness and the right mindset for handling highly potent active substances.
Outsourcing can speed up time to market
Contract manufacturers play a key role in the supply of medicines worldwide, and the trend towards outsourcing continues unabated. It is crucial for CDMOs to offer their pharma customers technology solutions, production concepts, regulatory support and know-how to serve the requirements of innovative and novel drug.
For the development and manufacture of highly potent products, pharmaceutical companies are turning to specialised service providers often. A CDMO specialised in a holistic HPAPI handling with decades of experience and readily available expert knowledge like the Aenova Group, offers its customers significant competitive advantages and enables them to bring innovative technologies and products to market quickly.