The European Consortium on Continuous Pharmaceutical Manufacturing (ECCPM), looks at issues surrounding continuous processing
In the last years, the FDA has endorsed the transition towards continuous manufacturing (CM) as a way to shorten the supply chain, increase agility and flexibility of development and manufacturing and to improve product quality through real time process control. Significant resources and capital investment are required by industry, according to CDER director Janet Woodcock.
Several large pharmaceutical companies have been earlier adopters of CM. Vertex, J&J, GSK and Novartis are all working on continuous manufacturing facilities. Along with Pfizer, they already have secondary process equipment installed or under development. Novartis and GSK have been reported to be investing significant resources in continuous primary production and crystallization. On the academic side, several universities are researching continuous production technology, including the ERC on Structured Organic Materials led by Rutgers University, the MIT-Novartis Center for Continuous Manufacturing, and the Center for Continuous Manufacturing and Crystallisation at Strathclyde University and our multi-centre initiative the European Consortium of Continuous Pharmaceutical Manufacturing (ECCPM).
Several advantages are associated with CM – flexibility possibly being the most important one [1], [2]. For example, CM can contribute to the industry’s response capacity in case of changing market demands or emergencies by reducing the development and manufacturing time. Another advantage is speeding up the supply chain, which is critical being able to react to changing market demands. CM can reduce frequently occurring scale-up problems, since the development can be performed using the manufacturing equipment. Moreover, critical quality attributes (CQAs) are monitored in real time, improving the product quality. Since CM plants have a small footprint, they can be setup in flexible and portable environments, eg, containers allowing deployment around the world.
Several requirements are expected from a CM plant: Floor space should be small and the equipment should be easy to clean. Moreover, it should allow for rapid changeover for multiple-product manufacturing. CM systems must provide a reasonable range of throughputs, either to meet different product-volume requirements, or to enable coupling of other unit operations. Because continuous processing equipment is relatively small in the pharmaceutical industry (compared with the oil, food or plastics industries) it should be modular, portable, and transferrable, ie, skid-mounted to facilitate a ‘plug and play’ approach. CM plants should also be interchangeable with respect to coupling of different continuous processing unit operations for better process and formulation flexibility. In terms of process monitoring, the process should be adaptive and amenable to continuous quality verification of key process intermediates and the end product. Most importantly, the continuous process should afford a product with improved specific product quality.
Challenges of continuous processing
With so many perceived advantages, why has continuous processing not been adopted more quickly by the pharmaceutical industry?
For new products, the financial justification is clear in terms of significant API and resources saved in R&D. Equally significant are the savings in direct and indirect labour in commercial plants. However, financial justification for investment in continuous processing involves a well-planned and expansive transition from existing batch capacity. Here an important consideration is that batch capacity is probably in excess on an international level, given declining production volumes in the industry.
The regulatory framework means it can be expensive to switch existing products from batch to continuous production, requiring significant resources for post-approval changes. It requires development of a process design space, a control strategy, generation of stability data and possibly a bioequivalence study. For some products the business case might not be sufficiently strong. Geographical diversity can also be a factor. In some cases, pharmaceutical companies are required to produce in the country where the product is distributed or sold. CM plants may not be approvable by local authorities.
Technically there are some challenges. First is the issue of feeding and processing, as some APIs and excipients are difficult to handle due to their cohesive nature and low bulk density. Second are the numerous issues with process monitoring and control. To assure product quality, all of the Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) must be identified then measured and controlled within acceptable limits, preferably directly and not by surrogate means. Consider the projected lifecycle sales of a typical product (see Figure 1). The demand is not consistent, it rises then falls. A product dedicated line, sized to manufacture a peak demand of 250M tablets per annum, would operate well below full capacity for much of the product lifecycle.
Figure 1: Product lifecycle sales of a typical product
An alternative approach would be to deploy multiple continuous units to meet total demand across a portfolio of products. A key advantage of this approach is that the production scale is the same as the late phase development scale, eliminating technology transfer issues.
Other considerations
The product dose must be factored into calculations as seen in Table 1. It illustrates the number of weeks’ production required for different strength tablets, assuming 120 hours output per week. The two lower dose products could be manufactured in 50 weeks on one small machine if the product changeovers were efficient.
Table 1: Number of weeks required for different tablets
Issues needing attention are the financial environment, manufacturing strategies and various technical gaps, including PAT tools. Moreover, a change towards well-engineered API would enable simpler secondary process streams to be deployed.
The ECCPM
Though there are significant benefits of CM, implementation in the industry is just beginning. Beside technological issues, the regulatory perspective has to be considered, with the FDA encouraging continuous manufacturing submissions and the EMA beginning to embrace CM as well [3]. The ECCPM (www.eccpm.com) has been founded to facilitate the transfer of continuous manufacturing from R&D to production scale. This consortium focuses on the investigation, development and implementation of continuous manufacturing approaches for solid oral dosage forms. The need for better manufacturing brings together several companies and universities along the value chain to work on a collective vision on continuous manufacturing (see Figure 2).
Figure 2: ECCPM’s vision on continuous manufacturing
The objective and scope of the ECCPM are: i) focusing on the development and implementation of CM strategies for solid oral dosage forms, ii) several vertical (company specific) streams the so-called ‘use cases’, which represent the company-related work on a specific product sponsored by a pharmaceutical company partner, iii) one main horizontal (shared) stream, iv) two additional horizontal streams dealing with process simulation and process analytical technologies (see figure 3). Due to the open access strategy, additional partners with specific use cases can join at any time, if agreed by all the existing and already active partners.
Figure 3: Organisational structure of the ECCPM
The pre-competetive platform is the workshop series, in which all industrial and scientific partners are involved to an equal extent and share data, experience and information related to continuous manufacturing science. Topics of common interest for all project partners are addressed and discussed within biannual workshops.
In this context, the common platform works together on subsequent, exemplary mentioned topics:
- What is necessary and missing for RTRT and how can it be implemented in the virtual process supported by the recent developments in the field of PAT, process monitoring, and visualisation (see Figure 4).
- Developing of DEM Models for the simulation of particle related interactions (segregation, aggregation) within continuous processes (eg, mixing and transport) and units (eg, hopper, pipes).
- Pelletising of thermoplastic formulations with the target of narrow RSD micro pellets
Figure 4: Exemplary process line including material properties automatically and potentially monitored via PAT tools
The expected benefits for participating companies are: i) use of existing platform technologies ie, wet, dry granulation and HME) for the development of a continuous process for their specific drug products, ii) the economic evaluation in terms of costs (production, materials, footprint, etc.), efficiency and yield, iii) implementation of concepts for integrated quality control strategies, iv) access to consolidated scientific expertise (eg, simulation, material science, PAT), equipment and instrumentation suppliers without exposure to CAPEX and v) co-authorship of scientific publications and relevant conference presentation.
References
1. Implementing Continuous Manufacturing to Streamline and Accelerate Drug Development; Hurter, Thomas, Nadig, Emiabata-Smith and Paone; AAPS Newsmagazine, August 2013.
2. Rantanen J. and J.G. Khinast, The Future of Pharmaceutical Manufacturing Sciences, J. Pharm Sci. (2015) in press
3. Gretchen Allison, Yanxi Tan Cain, Charles Cooney, Tom Garcia, Tara Gooen, Oyvind Holt, Nirdosh Jagota, Bekki Komas, Evdokia Korakianiti, Dora Kourti, Rapti Madurawe, Elaine Morefield, Frank Montgomery, Moheb Nasr, William Randolph, Jean-Louis Robert, Dave Rudd, Diane Zezza, Regulatory and quality considerations for continuous manufacturing, ISCMP White paper 3 (2014)
Authors
Dave Doughty, Johannes Khinast, Massimo Bresciani, Stephan Laske, Research Center Pharmaceutical Engineering, Graz, Austria
Jarkko Ketolainen, University of Eastern Finland, School of Pharmacy
Thomas De Beer, University of Ghent, Laboratory of Pharmaceutical Process Analytical Technology