Extrusion processing is intended to continuously manufacture homogeneous and structured products. Due to its immense adaptability, extrusion has been widely utilized in diverse fields. It is being adopted more recently by the pharmaceutical industry at an unprecedented pace to address various drug product formulation and manufacturing needs. The twin screw extrusion process can be used to not only manufacture novel drug delivery systems but also replace batch granulation processes. During extrusion, powder blend(s) or a granular mix is compacted, forced through an orifice under controlled conditions and finally converted into a product with defined shape and density. Compared to a traditional batch process, this exciting yet complex technology offers many advantages including but not limited to excellent product uniformity and higher manufacturing efficiency.
Hot Melt Extrusion
HME has evolved into an enabling technology
As a continuous manufacturing process, extrusion was cemented in pharmaceutical manufacturing in 1980s with market launch of sustained-release Verapamil, which contains embedded crystalline active pharmaceutical ingredient (API) in polymers. Following the Verapamil launch, researchers have turned to hot melt extrusion (HME) as an effective enabling technology to manufacture amorphous solid dispersions (ASDs) for poorly soluble compounds. During HME, a powder blend consisting of crystalline API and polymer(s) is transformed into an extrudate, which contains molecularly dispersed API in a polymer matrix. The extrudate can be directly shaped or subsequently converted into granules or pellets for downstream processing. Rationally designed ASDs can achieve higher apparent solubility and improved bioavailability. AbbVie commercial products manufactured using HME include Kaletra®, Norvir®, Viekira Pak®, Mavyret® and Venclexta®.
As a continuous process, extrusion is an economical and efficient option for reducing production time. Furthermore, since HME is a mature technology, it also more scalable with tighter process control. In comparison to other techniques for manufacturing ADSs such as spray-drying, HME offers major advantages of smaller footprint and solvent-free process.
Successfully manufacturing ASD products using HME requires a thorough understanding of the formulation characteristics, proper selection of equipment, and comprehensive characterization of every stage of the extrusion process. Thus, it is sensible to partner with an experienced contract manufacturing organization (CMO) for delivery of a consistent, high-quality drug product for timely entry to market.
Thorough characterization is essential to effective HME
For HME to deliver its intended purpose for manufacturing ASD formulations, detailed characterization of each aspect of the ASD formulation is essential to ensure robust process and product quality. The physicochemical properties of API, including but not limited to solubility, melting temperature, solid states, lipophilicity and stability must be thoroughly characterized. Attention must also be given to the choice of polymer and their properties. An ideal polymer should demonstrate appropriate chemical and physical characteristics, such as flow properties, compressibility, and thermoplastic behavior including a suitable glass transition temperature (Tg), rheological properties, and good thermal stability. Often, a surfactant is also incorporated into an ASD formulation to increase the drug loading, further enhance the dissolution rate, and facilitate the extrusion process by reducing the process temperature. As phase separation could significantly impact the HME product quality, qualifying the miscibility among all components in the formulation and controlling impurity levels of all formulation components is extremely important.
Equipment selection and process design can also significantly impact the quality of an HME product. One of the most challenging aspects in developing an HME process for manufacturing an ASD is to achieve the balance between obtaining a uniform ASD by providing enough mixing and dispersing while minimizing degradation of the drug and/or polymer. A twin-screw extruder design is favorable for pharmaceutical applications due to its superior mixing capability and shorter material residence time. Extrusion is an integrated unit operation consisting of different functional zones (e.g. conveying, mixing, melting, degassing, shaping, etc.). The interplay between material properties and energy applied in different zones throughout the extruder is complicated and relevant controls need to be identified and implemented. Individual process parameters, including feed rate, screw speed, barrel temperature profile, and vacuum can be adjusted independently to meet product quality requirements.
Quality by Design (QbD) promotes a thorough understanding of the product and manufacturing process via a systematic approach. Fundamentally, HME product quality is determined directly by scale independent key system parameters including specific energy, residence time distribution, and pressure. Deployment of these scale-independent process parameters is an ideal way to bridge the gap between the quality attributes and process independent parameters. Developing the design space around the key system parameters ensure seamless process scale-up and manufacturing flexibility while maintaining critical quality attributes. In addition, extrusion simulation allows for cost efficient process scale-up with high confidence. Extrusion simulation is particularly useful when geometric similarity and classic scale-up strategies are not applicable. AbbVie has a demonstrated track record in implementing these tools and methodologies through many successful process development and scale -up programs for HME commercial products.
Granulation is a process of forming/producing granular materials from powdery solid substances. The granulation process is widely used in pharmaceutical industry to improve the flow, density, uniformity and compressibility of the material for downstream processing. Granulation methods can be categorized into wet granulation, dry granulation and melt granulation. The selection of an appropriate method is driven by the nature of the input materials. Melt granulation relies on amalgamation of a binding agent with the input materials upon heating. In contrast, wet granulation uses liquid and a binder to initiate aggregate formation. In dry granulation, the primary powder particles are typically aggregated through compaction and densification under high pressure. Granulation has traditionally been a batch process. However, continuous granulation has received increasing attention as it offers significant advantages in terms of improving efficiency and reduced cost related to development, scaleup and commercial production. AbbVie demonstrated that continuous granulation via extrusion is a viable option for manufacturing a variety of products. Extrusion granulation can eliminate the intra-granulate blending unit operation by directly feeding the individual ingredient to the extruder using loss weight feeders. With proper screw design and process setup, unimodal particle size distribution of granules may be achieved without a milling process, which can significantly streamline the process. Efficient mixing in an extruder also allows uniform product with less binder solution required for wet granulation, which subsequently reduces the drying time.
Extrusion offers many benefits
Widely recognized for its capacity to enhance the quality and processing characteristics of a drug product, extrusion is an established process for development of drug product and commercial manufacturing. Whether you wish to improve the bioavailability, enhance the solubility, mask an unpleasant taste, modulate drug release or to address drug stability issues, extrusion can be used to deliver on these objectives and more. To discuss extrusion applications or to learn more about how AbbVie CMO can help with your drug development efforts, contact us at 1-847-938-8524 or via www.abbviecontractmfg.com/lets-talk.html