Originally published on 5/25/2018 at Pharmaceutical Outsourcing
What are some of the current critical issues facing the industry regarding oral dosage manufacturing?
Certain well-known drug development challenges are impacting oral solid dose manufacturing. Notably, the ever more complex nature of new molecules coming out of discovery that feature one or more challenges in their bioavailability, formulation, scalability and manufacturability. This trend is coinciding with pressures on developers to reduce development timelines and costs. We are also seeing an increasing number of smaller innovators taking molecules further into the clinic, and even to market independently, and these companies are looking for outsourcing partners that have a broad range of services, and have expert teams to assist in areas where the innovator doesn’t have the resources ‘in house’.
Having the ability to match each customer's molecule with the right enabling technology is important, because finding the correct formulation solutions, which are faster to scale up and less likely to fail at a later stage of development may be critical to a product proceeding past a development milestone.
In the current competitive environment, payers require that new treatments show significant real world clinical outcomes if they are to be reimbursed, and the dose form is increasingly important in an environment where the link between patient acceptance of the dose form, regimen compliance, optimal outcomes, and total treatment cost is seen as important. This requires that the right dose design decisions are made at a suitably early phase of development, with a focus on patient acceptance, convenience, and suitability to the patient’s specific conditions (dose burden, swallowability, regimen complexity, etc.). Industry partners must be able to support their customers with the right input and advice to make such decisions earlier in the process, enable that decision with the most appropriate technologies, and provide flexible manufacturing solutions to deliver the treatment to help patients.
Jim Gregory, President and CEO for UPM Pharmaceuticals: Critical issues facing the industry today include rising cost pressures, the increasing expectations for patient-centric medicines and an ongoing need to reduce time-to-market. These issues drive demand for cheaper, more effective manufacturing solutions that provide safe and efficacious drugs while also providing value for investors.
Outsourcing of OSD manufacturing is an important strategy. Close collaboration between supply chain partners must be part of the solution; improving efficiencies and reducing costs cannot be achieved without dialogue and understanding between suppliers, manufacturers and pharmaceutical companies. In addition, the more integrated contract service providers can be, the more likely they’ll be strategic, long-range partners for pharmaceutical companies.
Another key issue is the increasing complexity of OSD formulations. Formulation is therefore a key aspect of the overall manufacturing process – particularly new ingredients and delivery technologies. Spending money and time early on to fully understand the API and consider multiple delivery forms generally leads to success.
Many changes, therefore, are happening in OSD manufacturing, with batches becoming smaller, different chemistries being used that require new approaches and the implementation of continuous processing.
Can you tell us about some new oral solid dosage manufacturing technologies and/or processes that are helping pharmaceutical companies bring new products to market or are reviving older products?
Gregory: Despite oral solid dosage drugs being the oldest most popular form, OSD development and manufacturing still present many challenges and opportunities. The need for specialized processing technologies is one of the main drivers for increased outsourcing of the production of oral solid forms. Responsive and flexible CDMOs with the abiltiy to address the challenges and leverage the opportunities will be successful going forward. Doing so will require the development and application of novel technologies and the establishment of collaborative partnerships across the supply chain.
High-throughput synthesis, solid-state technologies, spray drying, hot-melt extrusion, coprecipitation methods, nanomilling, targeted particle engineering for inhalation formulations, orally disintegrating formulations, direct-to-patient delivery for clinical trial materials, equipment sourcing, regulatory compliance, facility design, continuous manufacturing, track-and trace systems: all of these technologies and capabilites are now required to take an OSD drug from discovery through commercialization. A key driver for all of these efforts is the desire to develop oral solid dosage forms that increase patient adherence.
When a pharmaceutical company is choosing an oral solid dosage manufacturing/service provider, what questions should they ask? What qualities and expertise should an oral solid dosage manufacturer/service provider have to ensure that their clients get the best quality product?
Gregory: 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 from the laboratory to GMP clinical and ultimately commercial manufacturing.
These CDMOs eliminate the risk, time and cost associated with technology transfer and the need to manage multiple suppliers. 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.
Effective CDMOs also need to have a comprehensive understanding of the properties of a drug substance for OSD formulations – its solubility in solvents and buffer systems, compatibility with excipients, stability under different physiological conditions, solid-state characteristics, basic physicochemical properties, etc. This understanding 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.
What do you see as the future of oral solid dosage manufacturing?
Gregory: Providers of OSD development and manufacturing services are navigating an increasingly competitive landscape. Consolidation within the pharma industry has been on the rise and is reducing the customer base for contract manufacturers. In order to simplify supplier management activities, many pharma firms are consolidating the number of suppliers with which they partner. Various market analysts have predicted that as many as 30% of existing CDMOs will be forced to exit the market in the coming years.
To survive and prevail, contract service providers must be able to provide real value and continually anticipate the changing needs of their pharma customers. The drug development process is unpredictable and the unexpected should always be expected. CDMOs that have built in flexibility will be better positioned to address the challenges that arise.
In addition, CDMOs that have expertise in pre-formulation/formulation development and are also able to provide clinical trial supplies and achieve seamless scale-up and technology transfer for commercial manufacturing will have a distinct advantage. Those CDMOs with specialized capabilities, such as the production of highly potent compounds and controlled substances, the ability to overcome the challenges posed by poorly soluble APIs and the development of innovative dosage form technologies, will be further differentiated.