How Can You Get Two or Three API’s to Play Nice In One Capsule?

by | Jul 23, 2020 | Articles

Multiple-unit pellet system (MUPS) can offer a solution to complex dose control

Oral solid dose (OSD) delivery remains the most popular route for administering drugs. Market forces are prompting pharmaceutical companies to pursue a broad array of OSD development strategies to make their active pharmaceutical ingredients (APIs) and formulations therapeutically effective and patient friendly.

One choice that is growing in popularity to control dose frequency and side-effects are compressed, tablet form multiple-unit pellet systems (MUPS).  A versatile technology integrating proven pelletization and tablet delivery modalities. MUPS delivery offers new modified-release profiles and the dosing precision pharma needs

 for its advanced formulations and potent, combined APIs.  It’s a great way to get multiple APIs to “play nice” together. This technology is not new and has been used in the food and chemicals business for many years with many commercially available products, e.g. slow release fertilizers and flavorings.

Helping Complex Drugs Become Easier to Swallow

According to Nihad Al-Hashimi, et al, in the paper Oral Modified Release Multiple-Unit Particulate Systems: Compressed Pellets, Microparticles and Nanoparticles , no matter the particular nomenclature, “MUPS” offers process efficiencies and manufacturing economies and by design, patient-friendly attributes compared to capsules.[1]

Offering comprehensive value and utility, Multi-Unit Pellet System technologies can help manage API release control and modification more economically relative to formulation work.  This is because they can be made with higher processing throughput and therefore, are potentially less expensive to produce commercially compared to other oral solid dose form products.

Multi-Particle Formulations Require Particularly Solid Pellet and Tablet Capabilities

Although tablet manufacturing is generally well understood, it takes greater understanding and operational competency across a number of oral solids processing techniques to manufacture MUPS correctly.  It also requires well-organized operational and quality teams to meet the demanding requirements of formulators, developers, and regulators.

But fundamental to the success of any MUPS delivery strategy is the ability to formulate, process, and manufacture the pellets that are at the core of the finished dose form’s functionality.

Integrating Multiple Oral Solid Dose Technologies in a Single Dose

Playing a central role in the functional performance of the dosage form is complex pelletizing and particle processing techniques. The two most popular capabilities for this type of drug form are Extrusion-Spheronization and Polymeric Core Coating.Decades of technical advancement in OSD formulation and tablet processing capabilities provide the basis on which high-performance MUPS are built. The diagram shows how a MUPS dose combines multiple components including APIs, excipients, and multi-functional pellets in a single dose form.

Extrusion-Spheronization Provides Powerful Pellets for Today’s Multi-Unit Pellet System Delivery

Depending on the API compounds and delivery strategies, formulators and processors can leverage the attributes of the popular pellet technology to create precision release profiles for what are often referred to as the API “reservoirs” within a MUPS.

However, Al-Hashimi notes that the reservoir pellets have to have sufficient physical properties to withstand the pressures of MUPS tablet compression.  Similarly, the study explains pellets often require specialized polymeric coatings to control interactions between the tablet’s API/excipient formulation and the reservoir particles held in the oral solids matrix.

At the end of the day, specific attributes or limitations of the pellet technology relative to the interactions of materials, chemistry, and API payloads will ultimately determine the best particle process choice to meet drug product goals.

However, studies show extruded and spheronized API pellets have physical attributes that withstand tableting pressures better than particles made from coating inert cores.[1]

In the right hands with the right formulation, extrusion spheronization offers process reliability and broad utility and the flexibility to build the functionality developers want to achieve for their MUPS pellets.  Extrusion-spheronization is a well-understood process that, executed correctly, offers the quality, efficiency required to manufacture today’s complex (including potent) OSD therapeutics.

 

Advanced Technologies Unlock Extrusion-Spheronization’s Inherent Drug Delivery Potential

Continuous improvement over time has helped manufacturers optimize the technology and associated processes for commercial applications.

The equipment itself has also seen steady improvement (along with a host of incumbent tertiary systems) including the addition of more precise process analytical tools.  Consequently, some specialty manufacturers may be better prepared to manufacture complex encapsulated oral solid dose products with this technique than others.

Extrusion-Spheronization Provides an Optimal Processing Environment for MUPS

In the context of MUPS product and process quality, it is critical to offer CGMP tablet manufacturing integrated with optimized extrusion-spheronization capabilities.  Incorporating Quality-by-Design (QbD) chemistry, state-of-the-art mixing, extruding, and advanced spheronizing equipment within a continuous-flow process, specialty manufacturers have to commit operationally to do it well and meet all commercial, financial and regulatory expectations.

Extrusion-spheronization’s reputation as a versatile and economic manufacturing technique is well-earned.  It is viable for most of today’s sophisticated OSD development paths while proving effective as versatile formulation and manufacturing technology suitable for New Molecular Entities (NMEs), life-cycle management (LCM) patent extensions, and emerging OTC marketing strategies.

Increasingly pharmaceutical companies are relying on CDMOs to make their complex drugs because of their expertise and overall mastery of compliant, complex drug processing and manufacture.  For those seeking more effective outsourcing relationships, and more efficient and economic development routes, it’s become critically important to match drug strategy as closely as possible to the expertise and technical capabilities of your outsourcing partners.

At Bora, we understand solving complex drug delivery challenges with MUPS with an experienced project team will help you get your product to market faster.

Four Maintenance Tips to Extend the Life of Your Tablet Compression Tooling

Improving the quality of tooling, performing regular maintenance and repairs, and extending the service life of tooling are important considerations for enterprises to reduce costs and increase efficiency.  In this regard, many companies have also developed a tooling warranty management mechanism to ensure that the tooling is in an optimal production state.

Here are four easy tips we would like to share for extending the life of your tooling:

  1. Clean the upper and lower surfaces of the tooling before installing the tooling to ensure that the tooling mounting surface and the press table are not crushed and maintain the parallelism of the upper and lower mounting surfaces of the tooling in production.
  2. After the tooling is installed, open the tooling and clean all parts of the tooling, especially the guide mechanism. For the surface part tooling, the profile should be cleaned to ensure the quality of the part.
  3. Lubricate the sliding parts of the tooling, apply grease, and check the tooling for damage and safety of the parts.
  4. Professional tooling personnel should use a torque wrench to confirm tooling screw and use a GO/NO GO gauge to confirm tooling has no deformation. This is a vital step to ensure your compression tooling does not damage the tablet press turret which can accidentally introduce metal filings in compressed tablets.

Also, after production is completed, a comprehensive inspection, measurement, and recording of the tooling should be carried out, and the tooling should be thoroughly wiped to ensure the cleanliness and accuracy of the tooling.

By following these 4 simple steps including regular lubrication of the tooling during storage and managing the compression tooling parts to identify any undue wear in the tooling, you can reduce the need for having to replace worn tooling. Click here to watch a compression tooling polishing guide from Natoli Engineering.

Final Thoughts for Optimizing and Maintaining Tablet Compression Tooling

To improve the use of your compression tooling, your tablet manufacturer should follow Standard Operating Procedures (SOPs) based on the tooling storage management recommendations above.

Lubricate upper and lower punch bodies with a food-grade lubricant before installation (Fig. 6 and Fig. 7) and with trained professionals to complete the installation work tooling.

Implementing a cleaning procedure for tooling is an important but often overlooked first step to cost reduction. Dirty tools can cause tableting and product quality-related problems, including sticking and picking. Keeping tools clean can decrease premature tool wear and allow lubrication to be more effective as well as reduce the possibility of product cross-contamination.

 

Well-maintained tooling can shorten tooling assembly and adjustment time, reduce production failures, make the production run smoothly, ensure product quality, and reduce enterprise operating costs and fixed asset investment. When the next production cycle begins, the enterprise can successfully produce products of qualified quality.

For those of you that are working with a Contract Manufacturer, you should insist on seeing their SOP on Tooling Management.  Remember, tooling is a purchase that you have made and improper use and storage by your Contract Manufacturer costs you additional money!

In conclusion, for enterprises in the current fierce competitive manufacturing marketplace, effective introduction and use of a tooling management system to ensure tooling maintenance and performance can enhance producing good quality, consistent tablet products. This helps to reduce overall product costs and enhance market competitiveness.

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