Designing Effective Drug Formulations: Keys to Successful Proof of Concept Services
Author: Ed Scholtz, Ph.D., UPM Pharmaceuticals
Oct 1, 2016 12:00:00 PM PAP-Q04-16-CL-004
Originally published in Pharma’s Almanac Q4 2016.
Increasing API complexity has created a need for innovative formulation solutions. To rapidly reach the formulation proof of concept stage, pharmaceutical companies frequently rely on outsourcing partners with extensive formulation development experience. Because the goal is commercialization, however, many sponsors prefer to work with contract development and manufacturing organizations (CDMOs) that can readily scale those proven formulations.
A comprehensive understanding of the properties of a drug substance — its solubility in solvents and buffer systems, compatibility with excipients, stability under different physiological conditions, solid-state characteristics, basic physicochemical properties, etc. — is necessary to select the most effective drug-delivery system and develop an optimal drug formulation, particularly for challenging and complex compounds that suffer from poor solubility or are highly potent. Preformulation studies offered as part of proof-of-concept services are designed to fully characterize the API and determine the dosage form and drug delivery system that will provide a safe, stable drug product with high efficacy.
Thorough preformulation studies can, however, be quite costly. Drug manufacturers are seeking service providers that can apply extensive experience with a broad array of compounds/chemistries to the design of comprehensive preformulation studies that include only relevant tests, as well as the selection of appropriate formulation technologies with the greatest potential for success.
Outsourcing to CDMOs that can take a project from the proof of concept stage all the way through to commercialization, thus eliminating the risk, time and cost associated with technology transfer and the need to manage multiple suppliers, is also increasing. Preferred service partners also continually invest in new equipment and facilities, provide dedicated project management support with personalized service, offer real manufacturing flexibility and focus on meeting customer milestones.
A strong development history
UPM Pharmaceuticals was founded as a formulation development company and has been providing development services for over 15 years. The company focuses on solid and semi-solid formulations and has extensive experience with many different types of APIs and solid/semi-solid dosage forms.
Once a project contract has been approved, UPM forms a dedicated project team that meets with the customer to understand the project goals and gather any available information on the API. These teams consist largely of scientists with Ph.D. or MS degrees that are extremely knowledgeable and focused on formulation science. They identify the analyses required to determine additional necessary information, and based on the obtained results, excipients and formulation/delivery technologies are suggested to the client.
Comparability studies using material prepared in minibatches (50- to 100-g scale) are then performed. Head-to-head comparisons of formulations that have different ingredients (except the API) help to quickly identify stable formulations. Throughout this process there is close cooperation between the analytical and development groups, which allows for the engineering of the optimum formulation that can be directly scaled to GMP clinical and commercial production.
Ongoing provision of innovative drug development and manufacturing solutions requires continual investment in advanced technologies, equipment and facilities.
Ongoing provision of innovative drug development and manufacturing solutions requires continual investment in advanced technologies, equipment and facilities. Recognizing the need of pharmaceutical customers for more rapid and cost-effective proof of concept services combined with GMP production capabilities, UPM moved from its original location in Baltimore, Maryland to a previous Pfizer manufacturing site in Bristol, Tennessee and invested over $12 million to expand production suites and modernize the facility, plus over $1 million to create a Solids Formulation R&D Facility.
The R&D facility includes a GLP laboratory with dedicated small-scale, state-of-the-art equipment identical to that used for GMP production of clinical and commercial material, allowing for easy scale-up. Capabilities include wet and dry granulation, particle size reduction, encapsulation, bi-layer tableting, granules and coating. HEPA filters, down-flow hoods, glove boxes, soft enclosures, advanced personnel protective equipment and a gowning room enable the handling of highly potent compounds. Three analytical laboratories for raw material, test method development, and in-process material and product testing provide support to the development lab. The facility also includes a dedicated R&D raw material warehouse and space for in-process material (with refrigerator/freezer capability and airflow, temperature and humidity controls) and equipment storage. Onsite maintenance support reduces the risk of equipment failure and project delays.
The new Solids Formulation R&D Facility offers UPM clients several advantages. First, very small batches using 50 to a few hundred grams can be processed in the mini-scale equipment, allowing a large number of runs to be performed without consuming large quantities of expensive API that may be in limited supply. Secondly, because the equipment is the same as that used for clinical and commercial manufacturing, scale-up is facilitated, leading to both time and cost savings.
UPM’s trademarked BREVI-BATCH® processing platform for solid dose mini-scale R&D formulation development targets batch sizes of 100 – 500 grams, a much smaller scale than typically found in R&D formulation development laboratories. In addition, the equipment is designed for easy setup, use and cleanup, and is small enough to allow processing of highly potent compounds under containment conditions.
During the formulation development process, approximately 10 mini-batches are run, with scalability and the availability and cost of raw materials considered from the initial formulation design stage. Notably, in some cases, batches can be run using as little as 25-50 grams of API. Use of the BREVI-BATCH® processing platform allows UPM customers to reduce the cost and time required to successfully complete the formulation development and proof of concept stages − increasing the likelihood of commercializing effective and innovative medicines and getting them to patients sooner.
UPM’s trademarked BREVI-BATCH® processing platform for solid dose mini-scale R&D formulation development targets batch sizes of 100 – 500 grams, a much smaller scale than typically found in R&D formulation development laboratories.
Dedicated project management
Effective project management is essential for achieving the smooth progression of a project through the proof of concept stage, onward through clinical material production, and ultimately into commercial manufacture. At UPM, project managers are selected not only for their technical knowledge and expertise, but also the ability to effectively communicate and collaborate. Managers adopt an ownership approach and, along with the entire project team, stay with a project from the kickoff meeting through formulation development, proof of concept and all the way to commercialization.
UPM recognizes that the drug development process is unpredictable and the unexpected should always be expected. Accordingly, we have built in flexibility for addressing the challenges that arise. With daily scheduling meetings, UPM is able to quickly respond to changing client and market needs. We also have the operational capability to respond to unexpected manufacturing issues.
Technical flexibility is also essential for developing effective, safe, robust formulation solutions for the challenging drug candidates moving through the pharmaceutical pipeline today. UPM has extensive experience in drug delivery technologies that are appropriate for solid and semi-solid dosage forms. For those clients that wish to run phase I studies using capsules containing neat API, we have substantial capability for meeting their needs with four specialized filling machines. In our R&D facility, we also have a small-scale packaging line for bottles and can perform manual packaging processes for the production of 10-20 bottles for various studies. Plans are in place to install a small-scale blister packaging line as well.
Along with manufacturing flexibility, personalized service is highly valued by pharmaceutical companies looking for innovative formulation solutions for their complex and challenging APIs. Although a smaller CDMO, UPM is closer to larger, integrated service providers, offering not only proof of concept services, but also clinical and commercial manufacturing support — but with the personalized, responsive service of a well-funded, family-owned organization that emphasizes customer service and satisfaction.
In fact, UPM customers are treated like family too, with project teams operating as extensions of their businesses. Both team leaders and team members take a high interest in projects. Face-to-face interactions are a key component of our relationships with our pharmaceutical partners. President and CEO James E. Gregory is accessible to clients and very engaged with the business and concerned about meeting customer needs for the rapid development of high-quality, cost-effective, innovative formulations and delivery solutions.
While clients recognize that formulation development and scale-up to clinical and commercial manufacturing rarely proceeds without some unexpected challenges, they still expect projects to be completed on time. The most successful CDMOs offering proof of concept services have a track record of consistently meeting client milestones on time and within budget. UPM is one such service provider. We focus on deliverables: meeting customer milestone timelines, such as for producing high-quality, on-spec clinical supply materials and completing regulatory filings. That means performing the work that needs to be done to move projects forward as rapidly and smoothly as possible.
UPM’s dedicated team of technical and manufacturing experts have nurtured projects starting from the proof of concept stage, clearly demonstrating our extensive expertise in early-stage formulation development and commercial production for solid and semi-solid oral dosage drugs, including immediate and controlled release products.