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The pharmaceutical industry is making efforts by internally assessing, developing, and implementing semi-continuous manufacturing processes to improve manufacturing efficiencies.
The continuous manufacturing concept originated from pig iron production using a blast furnace, where the process operates for multiple years without shutdown. The approach is followed in production processes for oil refining, chemicals, synthetic fibers, fertilizers, power generation, natural gas, and waste-water treatment. The application of continuous manufacturing in pharmaceutical and biopharmaceutical manufacturing has progressed in the past decade with adoption of the same approach as leading industries. So far, some pharmaceutical products are manufactured and marketed using this concept, notably by Janssen and Vertex (1).
The options of an in-line process analytical testing approach for process controls and automation in processing is providing some level of semi-continuous manufacturing, resulting in reduced waste and downtime with increased gross margin and profitability. The conversion of batch processes to continuous manufacturing is the future of the pharmaceutical industry, employing the continuous flow, end-to-end integration of manufacturing sub-processes with a significant level of control strategies. The benefits of continuous manufacturing over traditional batch processes are evident, but the implementation is still at snail speed (2). The pharmaceutical industry is acknowledging continuous manufacturing as an option to improve and sustain manufacturing operations. The pharmaceutical industry is making efforts by internally assessing, developing, and implementing semi-continuous manufacturing processes to improve manufacturing efficiencies.
For a successful integration of continuous manufacturing, an orchestrated coordination amongst several industry partners is essential. The three major components for successful implementation are equipment and process analytical tool manufacturers, API and excipient manufacturers with a focus on process controls in providing consistent supply, and the finished product manufacturing facility in developing strategies for integration of techniques for implementation. The integration of a segmented batch processing and testing to a single flow is a major task in achieving continuous operations. As such, processes have inbuilt significant lag-time between operations from start to end and delivering to patients, which can range from three to six months. The reconfiguration of equipment to control the quality of the API and excipient can improve the effective asset utilization (EAU) by having a dedicated production line for large-volume product manufacturing. To achieve such an objective, the organizational mindset, regulation, and technology balance is a challenge in the pharmaceutical industry. The success lies in achieving the concept of raw material input into the system at the beginning of the process and discharging all at once as finished product sometime afterwards. The key to this process is that the finished product has uniform characteristics throughout the processing and meets set quality standards (3).
The level of regulatory submission requirements and inconsistent requirements around the world makes it difficult for the pharmaceutical industry to make any significant changes to an approved process, as any delay results in loss of market share in a highly competitive environment. There are minimal regulations or industry guidance documents on continuous manufacturing, and nothing is prohibiting implementation (4). Regulatory agencies do recognize that continuous manufacturing is a modern manufacturing approach with the potential to improve the assurance of quality and consistency of drugs, enabling quality to be directly built into process following quality-by-design (QbD) efforts. Because a true continuous manufacturing process is not feasible, producing a finished product batch in a defined production time period based on variations due to different lots of API or excipient as input or equipment cycling capability utilizing a chain of unit operations in continuous mode is an acceptable approach. It will require a significant reconsideration of the control strategy and well-defined methods employed to assure uniform characteristics and quality within specified limits for finished products. These goals can be achieved by well-defined characterization of input materials, selection of appropriate in-process sampling frequency of testing, setting of appropriate acceptance criteria, and statistical process controls with a feedback mechanism.
Factors in processing, such as equipment, cycling capability, and interaction of unit operations, need to be controlled. FDA supports the implementation of continuous manufacturing using a science- and risk-based approach and recommends early and frequent discussion with the agency before implementation of manufacturing technology. FDA has developed a program to help industry through its new guidance on advancement of emerging technology applications to modernize pharmaceutical manufacturing base (5). The regulatory requirement for the quality of the product remains the same as in batch processing, but for continuous manufacturing, the sampling plan needs to be redefined, deviations need to be handled differently, variability should be controlled, manufacturing changes need proper management, and the rationale for testing of a continuous batch must be defined in comparison to the traditional model (6).
The current manufacturing process followed by most of the pharmaceutical industry has many unit operations performed in segregated locations to form a batch and has limitations in flexibility, as the process controls are not dynamic. Performing continuous manufacturing based on QbD principles with reorganized manufacturing equipment and testing instruments and improved technical skills of the professionals who run these processes is a challenging task. The process of switching from a traditional manufacturing process stream to continuous manufacturing requires a commitment for capital investment to upgrade manufacturing equipment and install appropriate process analytical tools to control the process and develop control strategies to ensure equivalency of the two processes (6). A decision to switch to continuous manufacturing is still a big question for users as risk of cross contamination, cleaning frequency, and equipment breakdown need to be addressed to a satisfactory level. The users are concerned that not all equipment can perform continuously. For instance, tablet compression tooling is constructed with stainless-steel of different grades that are not meant for continuous use because the force applied in the process generates stress on the stainless-steel, which results in wear and tear that can affect the product physical quality attributes. The product quality expectation remains the same for continuous manufacturing as for traditional batch manufacturing. The continuous manufacturing risk assessment requires a good understanding of the process dynamics, process conditions, and material attributes to manage the risk. The continuous manufacturing process requires use of model-based control, multivariate monitoring, and large database management for analysis in real time to support real-time release testing (RTRT). The communication of residual level of risk by acquiring effective control strategy to the risk assessment for product and process development, as well as product lifecycle management, requires linking of the system for effective feedback.
Continuous manufacturing requires an understanding of the process and dynamics impacted by interaction with process parameters and material attributes. The process dynamics require a level of controls including raw material controls, process monitoring, and detecting and handling deviation in real time to support a real-time release testing (7). The batch definition and control strategy verification should be defined up front. Process understanding of the continuous manufacturing should be established based on design space and design of experiment (DoE) at development stage. A predictive model should be built with simulation capability to define action limits and an approach to manage process deviation with adjustment of process parameters. The process dynamics controls characterized by residence time distribution help identify the failure mode or deviation and changes in set-point impacting the start-up and shut-down on material quality. For an effective control strategy to keep continuous manufacturing in a state of control, an appropriate approach for individual process and product as assessed by risk analysis is required. The control strategy should provide consistent assurance of process performance and quality and should be designed to mitigate product quality risk in response to deviation over the time of continuous manufacturing.
Any given process uses multiple raw material lots in a batch, which require a process to establish traceability in a finished product. For a smooth, continuous manufacturing process, particle size distribution and density of raw material should be controlled such that they do not affect the flow behavior, mixing of ingredients, and dosage uniformity. The monitoring process will require the appropriate use of process analytical tools and modeling capability. The decision to select a tool should consider interference generated in testing due to flow of powder, time of data acquisition with respect to flow, and locations and number of installed probes or sensors at key sampling points. There should be a backup plan for each sensor or probe in case of failure during the process, which can affect the process monitoring and data acquisition. The acquired data are critical as they support the real-time monitoring and multivariate analysis to keep the process in a controlled state.
The cost of replacing traditional batch manufacturing with continuous manufacturing could be a significant investment; however, it offers cost savings subsequently by reducing waste, loss of batches due to failure, cost of testing, and inventory overhead cost. It is a smart move if the pharmaceutical industry starts with a hybrid continuous manufacturing approach to keep the initial investment cost lower and start generating gains. These gains can offset the cost of equipment and instrumentation faster and provide more confidence in the newer technology. The manufacturing cost of products varies with the type of equipment used.Integrating the existing equipment on site with upgrades to achieve hybrid continuous manufacturing can be a cost-effective approach, rather than building a complete integrated system to replace existing systems. It is more appropriate to have a complete continuous manufacturing system to start in R&D environment, which gives more opportunity to master the continuous manufacturing technology to implement subsequently in a commercial environment with more success. Future manufacturing processes involving continuous manufacturing with increased processing speed and controlled and monitored quality parameters, which lowers the cost of manufacturing, gives a distinct advantage to generic-drug manufacturers.
1. R. Hernandez, BioPharm International, 28 (4) 20 – 27 (2015).
2. P. Poechlauer et al. Org. Process Res. Dev. 16 1586 – 1590 (2012).
3. S. L. Lee et al. Journal of Pharmaceutical Innovation, 10(3) 191 – 199 (2015).
4. S. Chatterjee, IFPAC Annual Meeting (Baltimore, MD, 2012).
5. FDA “Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base Guidance for Industry” Draft Guidance, December 2015.
6. G. Allison et al., International Symposium on Continuous Manufacturing of Pharmaceuticals: Implementation, Technology & Regulatory (Cambridge, MA, 2014).
7. G. Allison et al. J. Pharm. Sci. 104(3) 803 – 812 (2015).