What are some of the current critical issues facing the industry in regards to oral solid dosage manufacturing?
Dean Childers, Director, Operations, Manufacturing Science and Technology, Alcami: A critical obstacle for oral solid dosage manufacturing that can extend into other dosage forms is variations in excipients and active pharmaceutical ingredients (APIs). For oral solid dosage manufacturing, the variations have shown impact in processing parameters such as flow of the material into milling operations and/or final dosage operations (i.e. encapsulation, compression). There are some cases where the variations can impact testing parameters (i.e. disintegration, dissolution). In most cases, time and money is spent to characterize the process and materials by performing design of experiment studies using multiple lots of the material, but the studies are only testing a small sub-lot of these multi-ton processes. Sometimes the excipients are processed in large batch sizes making any variations difficult to detect during initial material testing. The same impact is found in APIs. In one particular case, it was not a surprise that the dissolution rate of an immediate release tablet was dependent on particle size, however, as part of an investigation, it was determined that the API supplier was completing a sublot milling process that blended different particle sizes to meet another testing parameter. The blending process was introducing random failures within the process. This example highlights the importance of open communication between the excipient and API suppliers.
James E. Gregory, President & CEO, UPM Pharmaceuticals: FDA's increased focus on quality, including not only metrics but also quality culture, is impacting all sectors of the pharmaceutical industry, including oral solid dose manufacturing. With the new Draft Quality Metrics Guidance published in late 2016 and the introduction of the New Inspection Protocol Project the same year, FDA is really looking at quality practices and the state of quality at pharmaceutical manufacturing sites. Quality has always been crucial to the industry and a deciding factor in the CDMO selection process, but with FDA now ranking and reporting publicly on quality performance, it is moving even more to the forefront. Pharma companies and contract service providers with excellent quality systems and quality cultures will be recognized and rewarded for their efforts.
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?
Childers: Two technologies that have seen an increase over the last three years are extended release beads in a capsule and sublingual tablets. With the early detection of many diseases, the extended release beads appear to be on the rise for both pediatric patients, as well as those with difficulty swallowing tablets. Another advantage is the release rate can be optimized, reducing the initial dose spike with immediate release tablets and target the therapeutic rate. The increased control is intended to reduce the side effects. A second technology is sublingual tablets which are capable of delivering medication quickly, bypassing the harsh environment of the digestive track. This technology is mainly used in pain management applications with APIs that have good absorption in the mouth. Considering nitro-based tablets have been around for decades, the sublingual tablet has opportunity to grow in the coming years.
Nuno Matos, Head of Continuous Manufacturing, R&D, Hovione: Amorphous solid dispersions (ASDs), commonly produced via spray drying (SD) or hot-melt extrusion (HME), provide drug formulations with higher apparent solubilities, faster dissolution rates and the stability required for safe and efficacious medicines. There are cases, however, where neither HME nor SD is ideal, particularly APIs with high melting points (>200°C) and limited solubilities in volatile organic solvents. For these increasingly prevalent compounds, either an alternative ASD method or a non-ASD approach, such as nanomilling or complexation with cyclodextrins, must be adopted. Co-precipitation of an API and a polymer is a scalable, attractive option for problematic APIs. Improvement of the co-precipitation process is needed, however, to make the technology more attractive for commercial drug formulation and manufacturing. Hovione is developing new techniques for co-precipitation that will allow its use as a robust and reliable third platform technology for ASD generation. Our approach involves the use of microfluidization, a solvent-controlled precipitation (SCP) process, in microreactors rather than the traditionally used stirred reactors. With this method, the particle size, size distribution and morphology and the level of nanoparticle aggregation can be finely controlled, enabling enhancement of the bioavailability of BCS Class II compounds with poor solubilities.
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 client gets the best quality product?
Childers: Choosing a solid dosage manufacturing service provider should focus on two questions, with the first being: “What is your most complex operation being completed?” Understanding that CMO’s cannot reveal client information, it is important for the provider to be able present the most complex operation in order to get a general understanding of the knowledge level of the workforce. A site manufacturing a simple formulation (i.e. direct compressed or granulated - compressed products) is not going to have the required knowledge base of a site manufacturing an extended release spheronized bead product that is encapsulated. The presentation of the process is important to gain an understanding of the expertise. The second question is: “What is the defect rate or deviation rate for the complex process over the last 6 to 12 months?” This question focuses on how the success of a process is being run. If the process has a high defect rate, the follow-up question would be: “What is the average time to close the issues?” We all understand that issues happen in manufacturing, however, the telling signs for the second question is how quickly do you resolve them and can the team get to the root cause.
Tim Tyson, Chairman, Chief Executive Officer, Avara: It is essential but not sufficient to be a highly flexible CDMO that provides excellent quality and on-time delivery. CDMOs must be fully integrated service providers in order to be able to serve as strategic, long-range partners for biotech and pharmaceutical companies. Drug manufacturers seeking outsourcing partners should look for a provider with a demonstrated track record of excellent performance across all activities - development, manufacturing and formulation capabilities, product and service quality, program management, technology transfer, problem solving and cost-effectiveness, to name a few.
For OSDs in particular, the CDMO should have extensive knowledge and expertise and advanced technical capabilities for overcoming solubility issues. A CDMO should also recognize the importance of speed to market and have systems designed to facilitate accelerated development, manufacturing and commercialization, even for complex and difficult OSD formulations, while still ensuring full regulatory compliance and maintenance of an effective quality culture. Ultimately, beyond the necessary expertise, technological capabilities and available capacities, pharma companies should be looking to partner with CDMOs that repeatedly delivery on their promises.
Gregory: Service providers must be able to provide real value and continually anticipate the changing needs of their pharmaceutical customers. To be one of the chosen, CDMOs must have the expertise to support fully integrated capabilities, be able to form truly collaborative relationships and provide highly customized solutions to meet aggressive development and commercialization timelines and project budgets. Flexibility, responsiveness and innovation are crucial. Consequently, CDMOs that have expertise in preformulation/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. 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.
How has the globalization of the pharmaceutical industry affected oral solid dosage manufacturing? How do you ensure that products manufactured meet individual country regulations?
Childers: The globalization of the pharmaceutical industry has not affected oral solid dosage manufacturing. With the continuing harmonization of the regulatory standards, the ability to supply multiple regulatory bodies is more simplified. The challenge centers around ensuring the products manufactured comply with the individual country regulatory filing. This can become difficult when different testing criteria are the limiting factor. Products should be produced and tested for the intended market. A method would be to align all specifications and manufacturing processes to the most stringent specification. This method removes the initial issue, but maintaining alignment of multiple individual filling can be problematic. Another method is to have individual process records and specifications for each country. This method requires maintenance of multiple documents and there is little flexibility for the supply chain with double the number of product presentations. The right approach would be a mixture of the two methods discussed. The mixture will depend on the number of individual countries and the complexity of the specifications.
Gwenaël Servant, Managing Director, Servier: When a drug innovator wishes to find the ultimate development partner, a CDMO that is embedded within a global pharmaceutical company brings certain advantages - as is the case with CDMOs that have ‘embedded expertise’ in process development, scale-up, analytical method development, and regulatory compliance. This is also true of CDMOs that possess a global network of manufacturing plants across the globe that provide optimized time-to-market with significant cost savings, while responding to the demand of authorities to produce locally. If API production can be done anywhere, OSD forms can be less global, with clients expressing a preference for local (or regional) manufacturing.
At Servier, the concept of embedded expertise also includes project management, quality and reliability. Without effective project management, quality systems and a culture of continuous improvement, it is not possible to be a fully optimized time-to-market organization. Servier has developed a global quality systems management (QSM) infrastructure that proactively assures the implementation of quality assurance/quality control best practices in each of its sites. With R&D, manufacturing, analytical and regulatory capabilities located within the same facility, we can take client projects from concept to approval and on to clinical trials. We also rapidly take developed processes to production, and handle transfers from one site to another with dedicated teams.
What do you see as the future of oral solid dosage manufacturing?
Childers: There will be a rise of biosimilars and biologics manufactured as solid oral dosage forms. Today, oral solid dosage forms are the highest priced medicines and the oral route has proven to be the most problematic route of delivery, but as new formulation technologies are developed that protect biomolecules from the upper GI tract and increase bioavailability there will be a rapid rise in approvals and usage in the market. These new technologies may also spur an increase in the number of reformulated BCS Class II and IV products for which the oral route was formerly abandoned due to poor bioavailability.
Dave DiProspero, Director of Pharmaceutical Process Technology, CRB: There are few sectors in pharma that do not have some stake in OSD innovation and development. From branded, generic and OTC producers – and throughout the supply chain’s contract service and equipment providers – few are expecting anything less than continued growth and investment in this key dosage form delivery category. The industry understands that reformulations, combination drugs, bioavailability technologies and complex layered formulations will continue to fuel OSD sector growth and manufacturing innovation for the next several years.
For companies seeking a future in OSD manufacturing, it’s clear they’re going to have to be more flexible and efficient than they are today. How to get there? By innovating - introducing new processing concepts such as continuous processing, integrated processing trains, process analytical technology – and pulling it together with a facility design that pays careful attention to modern and efficient flows, safety, ergonomics and output capacity flexibility.
As drug innovators and manufacturers navigate the pharma 3.0 landscape, they are increasingly tasking manufacturers to lower their costs via improved efficiencies. The OSD “Facility of the Future” must move beyond its age-old traditional inefficient batch operations roots. Pharma’s uptake of state-of-the-at processing, modern facility designs and technology is accelerating, and recent progress is already making an impact on pharma’s ability to fulfill its current commitment and future potential to varying and individualized patient drug needs worldwide.
Ed Godek, Manager, Process Technology, Glatt Air Techniques, Inc.: Pharmaceutical production in general is moving toward continuous manufacturing, and OSD manufacturing is no exception. Both sponsor firms and CDMOs are interested in continuous manufacturing because it is possible to reduce process times, waste and cost. For instance, the continuous process requires about 8% of the space of a batch process with powder feeding from a mezzanine into a high-shear granulator and then into the fluid bed and tablet press. Glatt has been working with universities and other entities to develop more science around continuous manufacturing. The company is also focusing on the application of process analytical technology (PAT) for continuous manufacturing. Realtime data about a process is needed to adjust the process conditions using feed-forward and feed backward controls in order to ensure continuous production of high-quality product. Examples include online determination of moisture content and particle size during granulation. Development times are compressed because the process is developed at the lab scale using design of experiments (DOE), with PAT methods developed simultaneously. In addition, scale-up involves running the process longer or with more identical setups in parallel, eliminating the need for tech transfer and reducing commercialization times.
Matos: We believe that continuous manufacturing will have a very important role in pharmaceutical manufacturing. There are a number of trends to reduce development time and costs, as well as a growing number of candidates with accelerated development designations (Fast Track, Breakthrough Therapy, Orphan Drug) that will shift the critical path to the CMC section, getting new therapies to market earlier. Continuous Manufacturing of Oral Dosage Forms, e.g. Continuous Tableting, offers the opportunity for much less effort in scaling-up as the same equipment can be used for development, clinical supply, and commercial manufacturing.
In addition to decreased development lead times, continuous manufacturing can also deliver on the promise of processes that are more efficient and with more consistent quality. The generation of high amounts of data during the several stages of the process lifecycle via process instrumentation and/or Process Analytical Technologies (PAT) enhances the ability to monitor or control the continuous operations. Furthermore, a data-rich environment better supports the adoption of Real Time Release testing (RTRt) for increased assurance of quality.
It's fair to say that the future is happening now. More and more companies have programs in place, or are about to start, in order to gain increased capability and install the capacity for continuous manufacturing. We have noticed a favorable combination of regulatory support, mature technology, better software and more advanced automation systems, all aligning to make continuous manufacturing a possibility and a success.
Gregory: Key industry trends, including rising cost pressures, increasing expectations for patient-centric medicines and the need to reduce time to market will continue to drive demand for cheaper, more effective manufacturing solutions that provide safe and efficacious drugs while also providing value for investors. However, consolidation within the CDMO industry may drive out smaller players and limit the availability of CDMOs, thereby driving higher costs for customers. Greater quality demands by clients and the FDA will drive CDMO overhead higher as well, adding to the barriers for entry into the outsourcing market for new players. Under these various conditions, close collaboration between supply chain partners will be an important part of the future of oral solid dose manufacturing. Improving efficiencies and reducing costs cannot be achieved without dialogue and understanding between all members of the pharma industry supply chain.