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The right processes used with the right excipient combinations address evolving formulation needs.
Coprocessed excipients are blends of different excipients subjected to physical processing that leads to modifications of their physical structures without causing any chemical changes. They possess unique functionality that cannot be achieved through simple blending and are increasingly important for addressing formulation issues posed by the highly complex APIs under development. Adoption of coprocessed excipients has been slow, however, because even when prepared using compendial excipients, they are considered “novel” by regulators. The lack of a separate excipient approval process means that drug developers must take on elevated risk when using such “novel” excipients in the formulation of drug candidates.
Oral solid dosage forms are traditionally formulated with combinations of individual excipients with differing functionalities (filler, binder, disintegrant, lubricant, flow-aid, solubilizer, etc.), says Ashish Joshi, pharma technical and business manager at BASF Pharma Solutions. The processes used to formulate these excipients into an oral dosage form are complicated as well as time-, energy-, and labor-intensive (e.g., granulation, spray-drying, roller compaction, etc.). In addition, the use of many individual excipients requires bracketing or optimization studies and has the risk of non-uniform distribution, which can adversely affect final product performance.
The ideal process for tablet formation is direct compression, as it eliminates the need for granulation or other prior processing steps, according to Joao Marcos Assis, global technical marketing manager, BASF Pharma Solutions. “Direct compression formulations, however, typically require multiple excipients to achieve good flowability, high bulk density, excellent compressibility, and fast disintegration (for immediate release formulations) because individual materials do not possess these multiple attributes,” he observes.
Coprocessed excipients can be used to overcome these formulation challenges through their enhancement of the resulting material’s performance and processability, Assis says.“By reducing manufacturing complexity and thus drug development time, coprocessed excipients can significantly expedite time-to-market,” he continues. Furthermore, API and coprocessed excipients normally fulfill the minimum functional requirements for tableting, consolidating quality-by-design efforts by simplifying the formulation. Analytical testing and material handling and warehousing needs and documentation requirements are also reduced.
The benefits of using coprocessed excipients are increased when multiple excipients can be coprocessed together. “Initially, most coprocessed materials were based on just two excipients, but increasingly coprocessed products being introduced to the market comprise multiple excipients,” notes Yeli Zhang, technical service manager at IFF Pharma Solutions.
The ability to combine many individual excipients and functionalities into a single high-functionality excipient enhances the ease of formulation and final performance as well as enables process simplification and cost-savings, Joshi adds. “Consequently, the major trend in developing coprocessed excipients is to reduce the number of individual excipients used in a formulation, with a focus on improving the flow-properties, compressibility, disintegration, and lubrication of oral solid dosage forms using a single coprocessed excipient,” he comments.
This trend is particularly true with coprocessed excipients intended for us in orally disintegrating tablets (ODTs). “Many companies are launching coprocessed excipients targeting this segment that combine a number of excipients because ODT formulations require a high number of excipients and are typically formed using direct compression,” adds Vinay Muley, research and development leader at IFF Pharma Solutions. Joshi agrees that single coprocessed excipients can provide not only good flow,
compressibility, and fast-disintegration, but also excellent taste and a pleasant, non-gritty mouthfeel.
Coprocessed excipients are also increasingly being used to convert more complicated, labor-intensive formulation processes such as wet granulation into quicker direct-compression processes without affecting the final product quality or performance, according to Joshi. He also notes that coprocessed excipients are being used to improve the efficiency of continuous manufacturing operations given that only a limited number of feeder ports are typically available and it is crucial to precisely control the flow-rate of excipients as they are added.
Developers of coprocessed excipients can theoretically use any material in their products, but most commonly, excipients that already have pharmacopeial monographs are selected because these excipients have a history of being used in pharmaceutical product formulations, according to Zhang. The key when selecting different ingredients to use in a particular coprocessed excipient is to choose those materials that will provide the functionality required to address customer needs, Zhang observes. Coprocessed excipients can improve drug processability and/or drug product performance. “Mainly excipient developers are looking to solve particular customer problems or provide particular benefits, and excipients are chosen that can maximize the needed functionality,” she says.
Ideally, adds Muley, the materials used to create coprocessed excipients will also have synergistic interactions that lead to enhancements in functionality, so that the coprocessed excipient will not only simplify formulation, but provide improved performance. Joshi adds that in addition to having complimentary and/or synergistic functionalities, the individual excipients chosen should be amenable to use in commonly available commercial processes (agglomeration, spray-drying, etc.) and behave reproducibly under the processing conditions. Ingredients used in coprocessed excipients also need to be nonreactive and inert so they do not undergo any chemical changes during production, according to Muley.
Typically, one or more fillers are coprocessed with binders, glidants, or disintegrants depending on the intended purpose of the product, according to Diogo Gomes Lopes, product development scientific team leader, Softgel and Oral Technologies at Catalent. “Coprocessed excipients that are intended to overcome any manufacturing limitations of the API, such as poor compressibility or poor flowability, are often composed of fillers, which are coprocessed with binders or glidants,” he explains. These types of coprocessed excipients also have the potential to increase drug loading in the drug product, allowing for production of a smaller dosage form that is more acceptable to the patient, Gomes says.
Some coprocessed excipients specifically aim to improve the performance of the drug product. Here again, Gomes points to coprocessed excipients for the manufacture of ODTs. “These coprocessed excipients allow for immediate disintegration of the tablet after administration while providing sufficient mechanical strength for packaging and transport,” he notes.
The materials chosen for coprocessing can include both small molecules, such as sugars and esters, and polymers such as polyvinyl acetate copolymers, microcrystalline cellulose (MCC), and starch. Coprocessing such varied materials together can lead to improved functionality, including greater processing properties as well as improved content uniformity, palatability, stability, and enhanced sustained-release performance.
Several methods are used to manufacture coprocessed excipients. The one feature they all have in common, according to Zhang, is that they involve physical processing of two or more excipients such that they interact with each other on a micro level, providing intimate mixing.
The most common methods include spray drying, flash drying, co-extrusion, granulation, high-shear granulation, fluid bed granulation, and roller compaction. “All of these processes are well known and are standard operations in pharmaceutical manufacturing,” Assis underscores. The key advantage is that under the mild conditions—moderate temperature and pH values, for example—chemical reactions between the ingredients can generally be excluded. It is important, he emphasizes, to determine the potential for incompatibilities between the different excipients used that could lead to chemical changes and avoid any combinations that might present reactivity concerns.
One exciting new method that could play a role in the production of coprocessed excipients, according to Muley, is 3D printing. Fused deposition modeling, he notes, is a good example of an additive manufacturing method very applicable to the production of coprocessed excipients. “The use of such methods is at the very preliminary stage, with exploration of the technology just beginning,” he says. Such approaches fit well with the push by FDA to adopt more efficient production technologies.
Although the development of coprocessed excipients does not involve combinatorial chemistry to impart many different chemical and molecular changes, there still are a large number of excipients to choose from. “Increasing functionality by modifying physical interactions only can present challenges, and pre-formulation studies using a design-of-experiment (DoE) strategy can be very helpful at the initial development stages,” Muley observes.
Computational methods can also be used to better support formulators during the development of drug products using coprocessed excipients, according to Silke Gebert, project engineer, BASF Pharma Solutions. For example, she points to ZoomLab, BASF’s Virtual Formulation Assistant for predicting and optimizing formulations using advanced algorithms and thereby expediting drug development. “Marketed coprocessed materials, new products, and prototypes can be characterized using the ZoomLab-logic to generate a chart that identifies each material’s favorable and less favorable properties, such as particle size distribution, compressibility index, and flowability,” she explains.
The need to accelerate drug development and also increase the efficiency and reduce the cost of drug manufacturing is driving excipient suppliers to seek more comprehensive coprocessed product solutions. “The most significant development in the coprocessed field relates to the growing focus on all-in-one coprocessed excipients,” Gebert contends.
All-in-one excipients, Gebert explains, are strategically designed multifunctional materials containing all the functionalities required to produce tablets: diluent/filler, disintegrant, binder, and lubricant at a minimum. “These materials are processed to achieve optimal bulk density, flowability, blend processability, drug uniformity, excellent compressibility, fast disintegration, and outstanding product performance,” she says. The drug manufacturing process then only requires blending the API and the all-in-one coprocessed excipient, then compressing the blend.
For these all-in-one products, Assis notes that common fillers include lactose, mannitol, and MCC; binders are often PVA-polyethylene glycol copolymers, PVP, or pre-gelatinized starch; disintegrants can be crospovidone, croscarmellose, or starch glycolate; and lubricant choices include sodium stearyl fumarate and magnesium stearate.
“Each ingredient in these compositions needs to be expertly selected with the end-use in mind,” Assis stresses. Furthermore, the excipient manufacturing process needs to be designed specifically to reduce chemical and physical instabilities.
Continuous tableting processes will benefit the most from the use of all-in-one coprocessed excipients, says Assis. “In order to reduce variability and dosage accuracy issues during the continuous manufacturing process, it is crucial to have a highly stable and controlled feed rate. With an all-in-one coprocessed excipient, rather than five feeders for the API, binder, filler, disintegrant, lubricant, only two are required for the API and the all-in-one coprocessed material, affording a more straightforward process,” he explains.
In addition, because coprocessed excipients reduce blend variability, they can contribute to reduced sampling and analytical errors for continuous processes monitored using inline/online/atline sensors, according to Assis. “Process analytical technology is increasingly being used during formulation development as well as in manufacturing. Coprocessed excipients have been shown to be less sensitive to shear, and due to their coprocessed multicomponent nature, the blend has lower intrinsic variability. In effect, this leads to more accurate and robust PAT [process analytical technology] models that do not require extensive model maintenance and updates,” he observes.
Beyond demonstrating that individual ingredients in coprocessed excipients have not undergone any chemical changes, there are a few other challenges to developing new coprocessed solutions. One, according to Zhang, is that coprocessed excipients have fixed ratios of the various ingredients and as a result they may not be as broadly applicable as simple blends of excipients. “The current solution for this challenge is to design the coprocessed excipient in a way so that it meets the majority of needs,” she says. They are also designed as fit-for-use.
Manufacturing coprocessed excipients that are truly highly functional is not easy either, Muley adds. “A deep understanding of the problem or issue that will be addressed by the coprocessed excipient and proper research and development efforts are both required to ensure that new coprocessed excipients are highly functional and produced using a robust manufacturing process,” he comments.
It is important, for instance, to understand and control the variability of the excipient’s material attributes, according to Dejan Lamešić, head of formulation and process development, Softgel and Oral Technologies with Catalent. “Doing so further supports pharmaceutical users in determining the potential impact of an excipient on a final drug product,” he says.
The higher cost of coprocessed excipients can be an issue as well, Lamešić notes. “Coprocessed excipients must demonstrate sufficient manufacturing process efficiency for customers,” he says. The uniqueness of coprocessed excipients, meanwhile, can be a concern for drug formulators from a security-of-supply perspective. “The excipients are usually only available from one supplier, which can increase supply risk and impact an innovator’s supply chain strategy,” Lamešić explains.
The biggest challenge to the adoption of coprocessed excipients, however, is a regulatory one. “Despite the significant positive feedback we have received about coprocessed excipients, there is a reluctance on the part of drug formulators to use these ‘novel’ excipients because of the higher risk they represent with respect to the regulatory approval process,” says Zhang.
The fact that many coprocessed excipients do not have an official monograph available is one of the major obstacles to their wider adoption in drug products, agrees Lamešić. “Although there have been developments in recent years, including the ongoing development of a general monograph on coprocessed excipients and guidance from the International Pharmaceutical Excipients Council on these products, there are still regulatory hurdles that need to be resolved,” he observes.
One of the fears surrounding the use of coprocessed excipients for formulators has been that regulatory agencies may request additional data to support the safety and efficacy of these materials, adds Joshi. He does note, however, that lately pharma companies have realized they cannot develop the drugs of tomorrow using traditional excipients that were developed decades ago.
In addition, Joshi points out that excipient manufacturers have put into place robust manufacturing and quality control mechanisms to ensure reproducible manufacture of high quality, coprocessed excipients. There is also significant regulatory support provided with Type IV drug master file (DMF) filings and well-documented analytical procedures. He also notes that FDA’s new pilot program to evaluate and approve new excipients before they are used in a drug filing is a significant positive step. “All these factors have significantly increased the acceptance and use of coprocessed excipients by the pharma industry, leading to their increasing use in FDA-approved formulations,” he concludes.
Despite these regulatory hurdles, the drive to reduce the time and cost for new drug development will continue to make coprocessed excipients attractive and lead to their growing use, according to Muley. The ability of these materials to help drug makers produce more robust oral solid dosage forms by overcoming manufacturing process challenges and reducing variabilities will also keep interest levels high, adds Assis. Growth will increase at an even greater rate if a regulatory pathway for coprocessed excipient approval is established, Zhang notes.
Cynthia A. Challener is contributing editor to Pharmaceutical Technology.
Vol. 46, No. 6
Pages: 24–26, 49
When referring to this article, please cite it as C. A. Challener, “Development of Coprocessed Excipients,” Pharmaceutical Technology 46 (6) (2022).