By Ajay Pazhayattil, Marzena Ingram, Ramana Kumar, Sudhakara Rao, and Robin Meier
Continuous manufacturing (CM) is an integrated process that consists of a series of two or more unit operations. In such a process, the input materials are continuously fed into and transformed within the process, and the processed output materials are continuously removed from the system.1 Benefits for generic drug manufacturers of adopting a continuous manufacturing platform include the lower cost of goods sold (COGS), eliminating batch to batch variability, and gaining enough flexibility and agility in production to respond to market demands without compromising product quality.
Pharmaceutical organizations need to build the long-term capabilities and associations to benefit from cost-effective, reliable, and scalable operations. Continuous manufacturing, though well recognized by regulators and technology providers as a means to improve product quality, has seen a slow pace of adoption within the generic manufacturing sector. Generic manufacturers generate more than 90 percent of prescription volumes in the U.S. and, hence, adoption by the sector is key for the pharmaceutical industry as a whole.2 The FDA’s draft guidance for industry, Quality Considerations for Continuous Manufacturing, provides an initial framework for the industry.1 This article discusses the challenges and mitigation strategies for adoption of CM by generic drug product manufacturers.
The Promise Of Continuous Manufacturing
The FDA considers CM one of today’s most important tools for modernizing the pharmaceutical industry.3 Currently, there are a minimum of five approved products using CM and almost 20 additional firms working with the FDA to have their CM processes approved. The agency has budgeted $58 million for fiscal year 2019 to accelerate the development of regulatory and scientific pathways for technologies such as CM.4 The agency believes that generic manufacturers will hesitate to switch unless a clear pathway is established.
Today, approximately 27 percent of revenue is attributed to manufacturing costs, and it is estimated that CM can reduce those costs by up to 50 percent.5 The FDA’s consultation on a Center for Structured Organic Particulates (C-SOPs) document regarding current recommendations for implementing and developing continuous manufacturing of solid dose drug products in pharmaceutical manufacturing6 brought in some key points to address. Organizations believe that there is a need for harmonizing terminologies and aligning with ICH guidance requirements. It is also understood that while the three-stage current life cycle process validation approach7 fits validating a CM process, it needs some special considerations.
Generic manufacturers constantly need to take measures to keep drug prices low, and effective regulatory change management is part of a successful generic organization. The changes may be related to process optimization to improve operation efficiency, such as, for example, to improve on the initially validated tablet press speed. Using a continuous manufacturing process eliminates such efficiency optimization costs and hold time studies that are normal in traditional batch manufacturing. With closed-circuit operations, CM may lower energy and utility costs. Single changeovers and associated reductions in cleaning times are also advantages.
One of the challenges with implementing CM is that development efforts are estimated to be more expensive, with the need for more extensive trials than in traditional manufacturing. This is because the changes in materials and processes may impact the mean residence time, and the process model developed would need complete rework. However, with better specification controls and with enhanced characterization methods for materials, the impact of such changes on the process can be minimized. Further, with minimal variability and the continuous nature of the process, process efficiency and scaling related optimization work should be nonexistent for processes on continuous manufacturing technology. Newer post-approval change management regulations such as ICH Q128 are more applicable to CM processes, as the QbD development process well establishes the design space and process variables.
The lack of regulatory frameworks for adoption of continuous manufacturing is another challenge. Generic products are developed for multiple markets, and the regulatory requirements for submission vary across the globe. This makes it hard for pharmaceutical organizations to make any significant changes to an approved procedure, as any delay in the approval process will have adverse impacts on the market share in today’s highly competitive environment. The generic industry at this time is not confident about the acceptance of non-traditional methods in non-U.S. markets. Efforts such as those put forward by the FDA’s Emerging Technology Team accelerate the adoption, and more regulatory agencies are expected to follow suit.9
Along with trained regulatory reviewers for CM, policy changes are also needed. The requirements have been identified and agencies are moving toward supporting technology adoption, as it directly contributes to better patient safety and product quality.10 Organizations should use this as an opportunity to collaborate with regulators to build confidence in their CM development pipelines. Such a strategy can only have a positive long-term impact with respect to an organization’s regulatory reputation. Again, no matter the process technology, the target product quality profile and critical quality attributes remain the same for regulatory assessment, and CM as a platform manufacturing technology is capable of producing highly consistent results.
A generic drug product manufacturer developing a CM process with one of the few existing technology providers will have to continually invest with that provider for maintenance, replacement parts, etc., the cost of which can be artificially inflated due to the low likelihood of making changes. However, the percentage of such maintenance overhead is not significant to start with.11 The biggest piece is the equipment cost, as the technology incorporates process analytical technology (PAT), process modeling, and automation software. Depending on the equipment chosen, there will be process development restrictions. Some of the CM technologies are developed with twin-screw granulation technology, while others follow fluid bed granulation. It should be noted that some formulations may not be fit for the selected process technology. Feeder systems have differences and are restrictive in nature, which may necessitate a pre-blending step; additionally, continuous coating is still a challenge. PAT and multivariate analysis of data are key components for the technology. Hence, developing adequate processes to address decision making is important. The technology also provides an added advantage of eliminating potential segregation issues prone to traditional manufacturing since it involves unit operations and storage. There is also an opportunity to eliminate certain dispensing operations, where preblends are not used. Even though there may be some limitations, such as, for example, lack of specific spray pattern, vacuum drying, etc., process solutions can be still be devised with CM. The additional capital investment in the CM equipment may be offset by the savings from a smaller equipment footprint and minimal failure rate estimates.
The biggest challenge is the availability of industry expertise. Effective implementation of CM requires a specialized skillset that includes expertise in pharmaceutics, engineering, and statistics. The lack of training on new technology capabilities and innovations is expected to slow implementation of CM within generic manufacturing sites. Since new NDA solid dose products are focusing on such technologies, the available expertise is concentrated in the novel drug development side of the industry. However, the generic drug industry is currently in process of applying novel statistical tools and modeling techniques, and PAT is becoming more commonplace in the industry as well. With the CM-specific workshops offered by the equipment suppliers, the expertise and knowledge base will continue to grow exponentially, easing the shortage of skilled resources.
Brand Names Are Making The Switch
The prospect of minimal process variability with CM is a definitive reason for brand names to adopt the technology. There is a potential for a smaller number of generic versions post patent expiry due to technology adoption delays at major generic manufacturers, which will help expand the longevity of brand products. One of the impacts will be product monopolies and delays in patient access to affordable drugs. Many brand name firms already are planning to use CM platforms for their small molecule pipelines for these reasons.12, 13, 14 CM will be imperative for generics to match the low process variability displayed by the originator manufacturers. It is therefore not advisable to delay adoption in a generic R&D setting. As a continuous improvement strategy, generic firms should adopt CM for legacy products, further justifying the capital costs. Switching legacy products to CM while continuing with the traditional manufacturing process should limit the organizations’ exposure to any supply chain disruption risks. Use of CDMO sites may not be a long-term proposition if the focus is on delivering affordable drug products.
CM technology not only improves product quality, it improves manufacturing efficiency and reduces the cost of quality. Rather than adopting PAT per unit operation at a point in time, switching to CM will enable a complete overhaul in operational overheads. Higher initial development cost is compensated for by the elimination of any future scale-up costs. One benefit of CM is the flexibility in batch sizes and minimal scaling studies post implementation. Long-term efficiency/cost effectiveness is gained through CM, and the relevance of generics will be even more pronounced with CM technology adoption.
Another area of concern is the potential under utilization of existing capacity at major generic manufacturing sites. It has to be noted that capacity realignment is imperative for any generic manufacturer in any case, based on the fact that more and more recent generic molecules fall into the low-volume category. New ANDA submissions for existing generics require the reassessment of capacity.15 Increasing numbers of biologics and gene therapies also threaten the need for larger capacity facilities.16 Earlier adoption of CM will essentially enable organizations to be flexible, such that older technologies can be retired at a pace that ensures minimal impact on business processes. It will allow an organization to develop new infrastructure, capabilities, and procedures.
With the new guidance and higher volumes of submissions, the FDA is aiming to eliminate the time delays for manufacturers to switch to CM.17 Regulators are building capability, as evidenced by the strategic plan for mitigating drug shortages. The simple fact that the technology minimizes sources of variability makes it a good contender for a regulatory risk reduction strategy. In addition to having better control of the manufacturing process, adopting CM will condition generic manufacturers to be ready for the next generation of drug products from brand-name manufacturers. The long-term cost benefits from avoiding the need for scale-up studies, reduced cost of quality, minimal testing and inspection overheads, fewer compliance and integrity risks, minimal supply disruption, and gains in operational efficiency need to be factored into the decision-making process.