In this article, we’ll explore how extrusion-spheronization (E-S) is applied in manufacturing, the sophisticated dose forms the process helps create, and why it supports the controlled delivery of active pharmaceutical ingredients (APIs) and ultimately improves patient outcomes.

Manufacturing of oral solid dose (OSD) APIs leveraging E–S has gained favor because of the number of patient-centered benefits it provides formulators and drug developers. Because oral delivery is preferred, E-S is proving to be a versatile tool in finished drug product development, suitable for even the most complex OSD formulations and APIs, including new molecular entities (NMEs) and—life-cycle management extensions.

Formulations engineered using E-S offer a predictable vehicle to control the distribution and delivery of therapeutic agents around the body. The method is most often applied to create amorphous solid dispersions (ASDs) of particles containing API. This allows for great latitude in designing the treatment’s oral delivery profile including E fixed-dose combinations, combined, modified release tablets and capsule forms, and multi-unit particulate system tablet designs.

Pharma developers can take advantage of E-S to deliver high-throughput manufacturing, reduce waste during processing and improve yield. More importantly, because the methodology is so well understood, it provides the ability to control critical aspects of dosing complex APIs and formulations. The controlled, modified release E-S provides an effective, reliable means to manage API delivery effectively, managing treatment with less frequent individual doses over time.

Extrusion Spheronization Explained?

The E-S process is made up of four steps: wet granulation, extrusion, spheronization and drying/coating:

•  Wet granulation sees the combination of API, excipients and binders, in addition to sterile water, added in the desired ratios, to create a wet granulation batch ready for extrusion. The goal of this part of the process is to create a wet, homogenous mass that is able to retain its shape under pressure with enough gliding properties to keep extrusion flowing.
•  Extrusion is designed to produce extrudates suitable for spheronization. The process sees the forcing of the wet cake from a large diameter through to a small diameter. There are a number of specific technologies and equipment that manufacturers offer to achieve extrusion.
•  Spheronization is a rotating/milling process that tumbles the wet cake extrudates into uniform spherical shapes. A spheronizer uses a spinning friction plate that generate centrifugal force and friction to create micro-collisions, which shape the cylindrical extrudates into spheres.
•  Drying/coating sees the completion of the process, where the uniform spheres can be dried and/or subjected to a coating process to manage dose delivery goals, such as controlling API release or taste masking.

Taking Advantage of Advanced Knowledge

The spheronization stage was invented in 1964 by Norauo Nakahara and was subsequently commercialized under the trade name, “Marumerizer” – “maru” meaning round in Japanese. The innovation passed largely unnoticed until 1970 when articles on the process were published by employees of Eli Lilly.

Since this time, the ability to apply E-S to increase therapeutic performance or modify API release, without having an impact on the integrity of the compound or molecule, has been made possible through developments across pharmaceutical science. The industry’s knowledge regarding raw materials and ingredients, as well as the processes and controls behind the methodology, have all advanced to the present point, where a high level of control can be ensured over the dynamics of extrusion and spheronization.

By manipulating the blending of size and density during E-S, it is possible to control solubility and bioavailability—this, in turn, allows for the attainment of different release patterns over time. For manufacturers, this enables them to develop modified release dose forms, which can help to reduce or eliminate side effects common in other dosage forms, such as irritation of the gastrointestinal tract or to achieve release in the lower intestine.

Patient Centricity Driving Drug Design

There has been a shift across the industry in recent years to consider the patient first, which has led to “patient centricity” in drug development by placing the patient’s demands before all else. Increasingly the industry is emphasizing therapeutic value, adopting treatment approaches centered on improved patient health outcomes and a better overall patient experience.

Regulatory agencies worldwide have also been involved in this push for great attention to be paid to patient’s voices in drug R&D. Under the Prescription Drug User Fee Act (PDUFA V), the Food and Drug Administration (FDA) organized 24 disease-specific Patient-Focused Drug Development (PFDD) meetings to gather patients’ perspectives on their condition and on the therapies available to them. The report covering all 24 meetings was released at the end of 2019.¹ At the same time, in Europe, the European Medicines Agency (EMA) created its Patient Engagement Framework for guidance and thought leadership, with support from the European Patients’ Academy (EUPATI).²

It has become an established part of the industry that regulators and drug developers are actively searching for more effective ways to incorporate patient reported outcomes. In this way, a collective understanding of the value that new or redeveloped therapies can bring to a specific modality or treatment area is recognized. The conclusion that has been drawn by all entities in the industry is that the happier patients are with their treatments, the more likely they are to continue with them and therefore the more likely they are to be effective—benefiting everyone and, ultimately, potentially lowering overall healthcare costs by encouraging a healthier population.

Wider Than One Patient

It is clearly apparent that the pharmaceutical industry is listening and acting on individual patients’ voice. It has also learned how to apply these lessons more broadly, to more patient groups, regardless of size or disease category. It is now expected that the intellectual property holders behind a treatment will develop or adapt to precisely meet the needs of different groups of patients, such as tailoring dose forms to better suit a population’s special needs and treat the condition more effectively.

It is recognized that OSDs are the most popular for patients, as they are generally easier to swallow, require fewer doses to be effective over longer periods, and are able to reduce or avoid entirely unpleasant side effects.³

For drug designers looking to develop patient centric OSDs, the finished dose forms that E-S can deliver are offering new flexibility and utility. Modified release formulations can be effective for providing drug substances that need to be in an OSD to ensure adherence to the treatment regime, and it can also be necessary for substances that have a narrow therapeutic index.

Multi-particle, multi-sphere finished-dose forms are another way to provide patients with an effective treatment that can deliver complex patient-centric OSD drug strategies. Multi-particle systems are able to demonstrate higher levels of desired reproducible pharmacokinetics and pharmacodynamics, enabling improved therapeutic effects in patients.

Why Extrusion-Spheronization Offers Efficiency

E-S provides inherent efficiency, reliability and minimized variability. Due to the efficiencies related to drug loading and similar characteristics in formulation, the process generates economies on all fronts without diminishing quality.

By comparison, single APIs often require dispersion throughout a solid matrix to control release. As a result of these matrices, there can be a limit to the rate at which active ingredients are dispersed into the body.

The E-S process is also a reliable, flexible alternative to other spheronization or pellet agglomeration manufacturing techniques, such as coating or layering. Further, drug pelleting through E-S is known to be a much faster process than drug layering.

Practical Applications

In terms of what particular use cases E-S could prove to be invaluable, two examples serve to highlight the potential for drugmakers looking to improve the formulation of their treatments.

In the first case, one company was struggling with its first-in-class oncology treatment that had issues with solubility and bioavailability. If it were delivered in regular, single-fixed release forms then patients would be forced to take the treatment three times per day. From a dose-compliance and therapeutic value perspective, this was not an option for the company. Through the use of E-S, the company was able to modify and control the release of the API over a longer period, as part of a multiple-unit pellet system form. Instead of being required to take a three-a-day treatment, patients could take one capsule that provided a controlled release of active ingredients over 24 hours.

A second example saw a company facing the patent expiry of a key product and, as a result, they were looking to explore a 505(b)(2) life-cycle management strategy, involving integrating two proven but incompatible APIs into a single dose, controlled-release capsule. The aim was to provide a best-in-class therapy that improved patient outcomes and therapeutic performance against multiple doses of two medications. This was where E-S was able to provide a solution, by segregating and controlling previously incompatible APIs, alongside other functional ingredients in cohesive pellets, which could then be delivered within a single OSD form.

Continuing Innovation Ahead

Just because the technology has existed since the 1960s does not mean that development and refinement of the E-S process is not still taking place. At Bora, we have been working on continuous flow E-S manufacturing, with this process proving to be particularly well-suited to running continuously, offering considerable advantages at commercial scale. Although E-S manufacturing is already semi-continuous, a configuration as a completely continuous process has demonstrated that throughput can reach upwards of 200-300kg per hour.

However, working with a continuous process requires working with a partner of suitable experience, as technical and operational experience is a prerequisite. In addition, the process requires a team that has invested in the best quality process room infrastructure, as controlling temperature and relative humidity are critical to ensure the final product is to the required standard.

The demand for specialist expertise in this area continues to rise from drug developers, as they are increasingly seeking specialized outsourcing partners and solutions to manufacture and commercialize products. In the case of E-S, its ability to deliver safety, therapeutic efficacy and dose compliance across a range of therapeutic areas will likely see this only continue in the future. 

References
1.  https://www.fda.gov/industry/prescription-drug-user-fee-amendments/voice-patient-series-reports-fdas-patient-focused-drug-development-initiative
2.  https://www.eupati.eu/
3.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471246/