From products to formulation to scale-up Ashland offers a complete drug development portfolio
New product development is the life blood for pharmaceutical companies. As active pharmaceutical ingredients become more complex, they can present more changes and make pharmaceutical formulation and process development more source and time consuming.
Ashland is a global company that offers its expertise to many industries. For the pharmaceutical industry Ashland advances drug delivery with sophisticated science-based solutions. The company offers six technical centers positioned around the globe that contain the latest equipment, and their research scientists and formulators have the experience and technical capabilities to bring a product from concept to pilot scale manufacture.
Ashland’s Wilmington, DE location is their global headquarter, and center of excellence for pharmaceutical R&D. At this facility the company develops the advanced excipients needed to make today’s complex pharmaceuticals work better.
Speaking to the facility’s capabilities, Thomas Dürig, PhD, Ashland’s Global Head of R&D and Innovation, describes the broad range of services available at the Wilmington location, “We offer a wide range of advanced analytical services. We do contract development for customers here, and formulation development up to the proof-of-concept stage. We’re specifically focused on solid dosage form development and offer all the lab scale and pilot scale capabilities for all the usual formulation types and processes for all select dosage forms. We can do testing and development for solubilization, bioavailability enhancement, controlled release, pretty much any kind of tableting. The new area we’re investing in is more in the area of injectable drug delivery, and materials and excipients development for injectable drug delivery systems.”
Dürig goes on to explain that Ashland, as a full-service provider, helps its current clients and prospective clients in various ways. First, they develop advanced, highly functional excipients, which they offer to their clients, and can provide support. Other companies need full service, custom development capabilities, which the company can do entirely in their facility.
Looking at the company’s core competencies, Ashland’s Wilmington facility is designed to offer every capability to analyze, characterize and develop manufacturing processes for solid dosage formulations.
Dürig explains, “From making the tablets, or granulations or whatever you need, right through to testing, we have it here in our facility. For tableting, we have compaction simulators, high-speed compaction simulators, and we can do single layer, multiple layer tablets. We also have commercial-scale production presses, so we can really check feasibility of a batch before you go put it in the plant. We also have coating equipment that range in size to handle small batches; from approximately 100 grams through to 30 kilograms. We also offer fluid bed that range from very small through to pilot scale. Our spray drying capabilities can be scaled from one gram to the kilogram pilot scale.”
Dürig continues by adding that Ashland has just invested in a micro extruder to complement the larger 18 mm extruders they already have.
For assessment of dosage forms Ashland offers a complete range of dissolution testing capabilities; and for amorphous dispersions; to make sure they are making stable. In addition, the company offers X-ray diffraction, polarized microscopy, and all the different types of thermal analysis. “We have very advanced NMR analytical capabilities and various other spectroscopy techniques,” says Dürig. “We’re really good at characterizing drug delivery polymers.”
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Summing up Ashland’s capabilities, Vivian Bi, Ph.D., the company’s primary focus is on functional excipients. From formulated functional coating systems to products that assist with controlled release, solubilization, disintegration, and tablet binding, the company offers a variety of products to solve any solid dosage formulation challenge. “We have the broadest portfolio of functional excipients in the pharma arena,” says Bi.
Inside the Plant
Ashland’s Wilmington facility is structured so that each process or lab has its own suite. Below are some of the highlights from the facility.
Film Coating Lab
In the film coating lab, Ashland leverages the features of its Aquarius line of coating products to meet the needs of its clients. With the extensive polymer expertise, Ashland is able to back integrate their knowhow and knowledge on polymer to design unique coating systems that can effectively address the challenges that pharmaceutical companies are facing. For example, Ashland’s newly launched Aquariu Genesis film coating system can be used at high solid load that enables continuous coating and significantly reduce the operation time for batch coating process. Ashland also employs AI system in their color matching for pharmaceutical coating systems, which significantly increases the efficiency and improves turnaround time for color matching.
The film coating lab is also equipped with various analyzers to measure rheology, viscosity, surface roughness and gloss etc. All to enable clients to achieve the quality coatings they need.
Coating/Granulation/Drying Suites
As a customer’s project progresses through Ashland’s facility it is very important to see how the product perform at various scales of development. And as the product progress through larger and larger batch sizes, the product is analyzed and data collected to make sure specifications are being met. To achieve this, the company features several suites devoted to lab-scale and pilot-scale sizes of processing steps such as coating, granulation and drying.
As Bi notes, “In our research labs we have equipment that covers all pharmaceutical processes for oral solid dosage forms. We also have a full analytical capacity for the characterization of raw materials and formulated products. As the product moves through the facility, scale of the equipment grows to be more representative to the real production and scale.”
The labs/suites are also designed to be quite flexible making it easy to bring equipment in and out, depending on processes needed, or for routine cleaning.
“This is what makes us unique,” says Bi. “We can handle many different projects based on the customer’s needs.”
Compression Simulator
As data analysis become more important and supply of innovative APIs can be limited, running product simulations can provide a wealth of data and conserve limited, and frequently expensive, API. Ashland offers a compression simulator for scale-up studies of solid dosage products. The simulator is designed to mimic the compression behavior of high speed, rotary tablet presses.
Ashland labs are quipped with state-of-the-art compaction simulators. The simulators are designed to mimic the compression behavior of commerical high speed, rotary tablet presses.
“It’s really useful because at the early stage of pharmaceutical product development, you have a very limited amount of APIs,” notes Bi. “But on the other hand, you want to understand the risk associated with the manufacture of the product, so this machine becomes very valuable. We offer this as a special service to our customers and it’s also helpful for us for our own new product development. Because, like our customer, we might not have enough material at an early stage of new excipeint development but we want to understand the very fundamental properties. This simulator becomes a very useful tool. ”
In addition, as Bi mentions, it’s fairly rare for an excipient company to offer a compression simulator. ”There are not a lot of companies who have invested in this kind of technology, and we have two here on site.” says Bi.
Pilot Plant
Moving on to the larger scale equipment, Ashland’s pilot plant suites host a variety of pilot scale equipment. Two of the suites are specially designed for the handling of potent compounds. The equipment housed here provides Ashland with the ability to not only develop excipients but to offer expertise in process development and scaleup capacity. Putting all of the pieces together, Bi notes that Ashland’s expertise lies in its ability to gradually scale-up and really deliver some truly meaningful process technology to their customers. “So, it’s the polymer knowledge, formulation knowledge, and process knowledge that including scale-up; all these things combined together provide our clients with a complete service offering.”
“For each of our application areas we offer a very comprehensive service package; varying from polymers, formulation development to process development. We also offer expert systems that can help our customer to choose polymers and formulations for controlled-release and solid dispersion applications. Comparing with some of our competitors, our model is to offer better technical services to our customers, so we can engage them and help them in a very meaningful way.”
The pilot plant area also features the company’s fully-instrumented process development tablet press, tablet coater, high-shear granulator, fluid-bed granulator, spray dryer and twin-screw extruder etc. It is here that the company can develop unique solid dosage forms while collecting the data required to make downstream processing decisions.
Also, within this area of the facility, the company has the capability to handle high-potency APIs which are becoming increasingly common in the industry, as companies look to develop next generation treatments in important therapy areas such as oncology.
Industry Perspective
As the pharmaceutical industry continues to grow, new challenges to formulate products that are patient-centric are becoming critical issues. Companies that offer the technology and expertise to develop products from difficult to formulate APIs will see the demand for their product and services expand. Ashland has positioned itself to be that company.
“I think what our company specializes in is combining the know-how in the science of formulation - pharmaceutical formulation development, with the material science and materials engineering that’s very common in polymer chemical companies,” says Dürig. “So, we’re sort of right at that interface of; how would we modify an excipient to be more useful for drug delivery?”
Based on their line of functional excipients, and depth and breadth of technical expertise, Ashland has positioned itself as a leader in drug delivery and formulation and development science.
The Aquarius Functional Excipients Line
Aquarius™ Genesis Film Coating System
Ashland has a new, high-solids film-coating system for immediate-erelease applications. The Aquarius Genesis film coating is designed for application at up to 35% solids while producing films with outstanding strength, adhesion and smoothness.
The pharmaceutical industry is moving from traditional batch manufacturing to continuous manufacturing, which can save money by reducing waste, eliminating loss from failed batches and cutting inventory overhead costs. Aquarius Genesis film coating can significantly increase the throughput of continuous coaters.
This new film coating is also scalable across traditional batch coating equipment, providing shorter application times and therefore higher throughput. When purchase of a new coating line or expansion of an existing one is being considered, the use of Aquarius Genesis film coating system can substantially reduce the needed capital investment.
Aquarius™ Control Film Coating Systems
The Aquarius Control film coating systems consist of two types of coatings. Aquarius Control ENA film coating systems are delayed release (enteric) coatings that are designed to protect active pharmaceutical ingredients (APIs) that degrade in gastric fluid, or to prevent the release of APIs that may irritate the gastric mucosa.
Aquarius Control SRX film coating systems are sustained-release coatings for APIs that are most effective when released over time. These film coating systems have predictable and controllable release retardation; are custom-formulated based on drug solubility and desired release profile; do not require a coalescence step and have stable dissolution profiles over a wide pH range. Aquarius Control film coating systems are durable, coherent coatings, in which film formation occurs via solvent evaporation – not latex coalescence – and film robustness is related to the use of a high-molecular weight polymer.
Aquarius Control SRX film coating systems are solvent-dispersible ethylcellulose (EC) coatings for multiparticulates, potentially modified with hydroxypropylcellulose (HPC) as a pore former. They are available in several different porosities that can be matched to drug solubility and/or desired release profile. A key benefit of Aquarius Control SRX film coating systems is that they do not require curing after coating.
The release profiles of tablets enteric coated with Aquarius Control ENA film coating systems are remarkably stable over periods of up to 12 months, even under accelerated stability testing.
Aquarius™ Preferred Film Coating Systems
Aquarius Preferred film coating systems disperse easily in water. These film coatings are applicable to both pharmaceutical and nutraceutical solid dosage forms. Ashland formulators have access to an unrivaled range of cellulosic and other polymeric excipients, enabling Aquarius film coating systems to be tailored to meet exacting requirements.
To maximize the efficiency of the coating application process, high solids loadings are desirable. By reducing the coating time using high-solids formulations, productivity is increased and overall manufacturing costs are reduced. Aquarius Preferred film coating systems are state-of-the-art immediate-release coatings, which have been scientifically formulated with careful polymer selection. High-solids cellulosic or high-solids PVP/VA formulations improve film adhesion to all substrates, especially those that offer challenges in aqueous film coating. When compared to competitive offerings, Aquarius film coating systems have proven to offer smoother, more consistent coverage even at the highest solids levels.
Clear advantages in film coating process productivity are seen with high-solids suspensions. These formulations allow the solids content of the coating system to be increased significantly (typically up to 20 percent w/w solids for pigmented coatings, and in certain cases up to 25 percent) with viscosities in the range of 100 to 300 cP.
Aquarius™ Prime Film Coating Systems
Aquarius Prime film coating systems disperse easily in water and are applied to immediate-release dosage forms. Film coatings for immediate-release tablet-coating applications are typically comprised of a polymer, a plasticizer and optional pigment/opacifier. Aquarius Prime film coating systems are available in clear and white formulations off the shelf.
Aquarius Prime film coating systems can be matched to customers’ existing HPMC film coating systems. These products are useful in many applications where special coating functionality is not a major requirement. However, Ashland takes great care in formulating all film coatings in our portfolio. The selection of ingredients and ingredient levels for a formulation is a critical factor in obtaining the target appearance and performance on the tablet core and in minimizing processing problems. Optimizing a film coating formulation requires balancing critical properties, such as film strength, film adhesion, film flexibility and opacity.